APPENDIX - The prevention of non-steroidal anti

A comparison of the cost-effectiveness of five strategies for the prevention of non-steroidal anti-inflammatory drug-induced gastrointestinal toxicity: a systematic review with economic modelling

TJ Brown, L Hooper, RA Elliott, K Payne, R Webb, C Roberts, A Rostom and D Symmons

Health Technology Assessment 2006; Vol. 10: No. 38

HTAHealth Technology AssessmentNHS R&D HTA Programme

October 2006

Go to main textAppendices

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185

© Queen’s Printer and Controller of HMSO 2006. All rights reserved.

These are the corrected search strategies, whichnow collect the etodolac studies appropriately.

(a) Search strategy developed forEMBASE

On Ovid, run May 2002, period 1980 to date.

1. NSAID$.mp.2. ((nonsteroid$ or non-steroid$) adj3 (anti-

inflam$ or antiinflam$)).mp. 3. ("Cox 1" or Cox-1 or "cyclo-oxygenase 1" or

"cyclooxygenase 1" or clyclooxygenase-1 orcyclo-oxygenase-1).mp.

4. exp aceclofenac/ or exp acemetacin/ or expalminoprofen/ or exp amfenac/ or expampiroxicam/ or exp amtolmetin guacil/ orexp benorilate/ or exp butibufen/ or expclofezone/ or exp dexketoprofen/ or expdiclofenac/ or exp diflunisal/ or exp epirizole/or exp etodolac/ or exp etofenamate/ or expfenbufen/ or exp fenoprofen/ or exp fentiazac/or exp flunoxaprofen/ or exp flurbiprofen/ orexp furaprofen/ or exp glucametacin/ or expibuprofen/ or exp ibuproxam/ or expindometacin/ or exp isonixin/ or expkebuzone/ or exp ketoprofen/ or expketorolac/ or exp ketorolac trometamol/ or explonazolac/ or exp lonazolac calcium/ or explornoxicam/ or exp loxoprofen/ or expmeclofenamate sodium/ or exp meclofenamicacid/ or exp mefenamic acid/ or expmeloxicam/ or exp mofebutazone/ or expmofezolac/ or exp morazone/ or expmorniflumate/ or exp nabumetone/ or expnaproxen/ or exp niflumic acid/ or expoxametacin/ or exp phenylbutazone/ or exppiroxicam/ or exp pranoprofen/ or expproglumetacin/ or exp proquazone/ or expsulindac/ or exp tenoxicam/ or exp tiaprofenicacid/ or exp tiaramide/ or exp tolfenamic acid/or exp tolmetin/ or exp zaltoprofen/

5. (Aceclofenac$ or Preservex or Acemetacin$ orAcetmetacin$ or Emflex or Alminoprofen$ orAmfenac).mp.

6. (Ampiroxicam$ or Amtolmetin$ orAzapropazone$ or Rheumox or Benorylate$or benorilate$ or benoral or Butibufen$).mp.

7. (Cinmetacin$ or Clofezone$ orDexketoprofen$ or Keral or Diclofenac$ orVoltarol or Diclomax or Motifene).mp. [

8. (Difenpiramide$ or Diflunisal$ or Dolobid orEpirazole$ or Etodolac$ or Lodine).mp.

9. (Etofenamate$ or Fenbufen$ or Lederfen orFenoprofen$ or Fenopron or Fentiazac$ orFloctafenine$).mp.

10. (Flunoxaprofen$ or Flurbiprofen$ or Frobenor Furprofen$ or Glucametacin$ orIbuprofen$ or Arthrofen or Lidifen or Ebufacor Rimafen or Motrin or Nurofen orGalprofen or Orbifen or Brufen orFenbid).mp.

11. (Ibuproxam$ or Indomethacin$ orIndometacin$ or indomax or slo-indo).mp.

12. (Isonixin$ or Kebuzone$ or Ketoprofen$ orOrudis or oruvail or Ketorolac$ or toradol orLonazolac$ or Lornoxicam$ or Xefo orLoxoprofen$).mp.

13. (Meclofenamate$ or Mefenamic$ or Ponstanor Meloxicam$ or Mobic or Mofebutazone$ orMofezolac$ or Morazone$ or Morniflumate$or Nabumetone$ or Relifex or Naproxen$ orNaprosyn or Synflex).mp.

14. (Nifenazone$ or Niflumic$ or Oxametacin$ orPhenylbutazone$ or Butacote or Piroxicam$or Feldene or Brexidol).mp.

15. (Pranoprofen$ or Proglumetacin$ orProquazone$ or Ramifenazone$ or Sulindac$or Clinoril or Tenoxicam$ or Mobiflex orTiaprofenic$ or Surgam or Tiaramide$ orTolfenamic$ or Clotam or Tolmetin$ orZaltoprofen$).mp.

16. exp Misoprostol/ 17. exp Proton Pump Inhibitor/ 18. exp Histamine H2 Receptor Antagonist/ 19. (cytotec or misoprostil or "SC 29333" or "SC

30249").mp. 20. 59122-48-4.rn. 21. "hydrogen potassium adenosine

triphosphatase inhib$".mp. 22. "hydrogen potassium ATPase inhib$".mp. 23. (H2 adj3 (antagon$ or block$)).mp. 24. ("histamine 2" adj3 (block$ or antagon$)).mp. 25. (cimetidine$ or famotidine$ or nizatidine$ or

ranitidine$).mp. 26. (dyspamet or tagamet or algitec or pepcid or

axid or zantac or pylorid).mp.

Appendix 1

Search strategies

27. (omeprazole$ or lansoprazole$ orpantoprazole$ or rabeprazole$).mp.

28. (losec or zoton or protium or pariet).mp. 29. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10

or 11 or 12 or 13 or 14 or 15 30. 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23

or 24 or 25 or 26 or 27 or 2831. 29 and 30 32. (arthrotec or napratec).mp. or 31 33. (Cox-2 or Cox-II or "Cox 2" or "Cox II").mp. 34. (cyclooxygenase-2 or "cyclooxygenase 2" or

cyclooxygenase-II or "cyclooxygenase II").mp. 35. exp Cyclooxygenase 2 Inhibitor/ 36. celecoxib$.mp. 37. flosulide$.mp. 38. meloxicam$.mp. 39. nimesulide$.mp. 40. rofecoxib$.mp. 41. (cyclo-oxygenase-2 or "cyclo-oxygenase 2" or

cyclo-oxygenase-II or "cyclo-oxygenaseII").mp.

42. (celebrex or vioxx).mp. 43. etodolac$.mp 44. exp Etodolac/45. 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40

or 41 or 42 or 43 or 4446. 32 or 45 47. controlled study/ 48. randomized controlled trial/ 49. clinical trial/ 50. major clinical study/ 51. (trial$ or compar$ or control$).tw.52. study.tw. 53. "follow$ and up".tw. 54. (blind$ or clinic$ or placebo).tw. 55. placebo/ 56. clinical article/ 57. 47 or 48 or 49 or 50 or 52 or 53 or 54 or 55

or 5658. exp human/ 59. nonhuman/ 60. 59 not 58 61. 57 not 60 62. exp Longitudinal Study/ 63. exp Prospective Study/ 64. (cohort$ or quintile$ or quartile$ or tertile$

or quantile$).mp.65. (follow-up$ or followup$).mp,tw. 66. longitud$.mp. 67. ((prospectiv$ or observation$) adj5 (research$

or data$ or stud$)).mp. 68. 62 or 63 or 64 or 65 or 66 or 6769. 68 not 60 70. 69 or 61 71. 46 and 70 72. Child/ 73. Adult/

74. 72 and 73 75. 72 not 74 76. 71 not 75 77. exp In Vitro Study/ 78. exp In Vivo Study/ 79. 77 and 78 80. 77 not 79 81. 76 not 80

(b) Search strategy developed forMEDLINE

On Ovid, run May 2002, period 1966 to date:

1. NSAID$.mp. 2. ((nonsteroid$ or non-steroid$) adj3 (anti-

inflam$ or antiinflam$)).mp. 3. ("Cox 1" or Cox-1 or "cyclo-oxygenase 1" or




6. (Cinmetacin$ or Clofezone$ orDexketoprofen$ or Keral or Diclofenac$ orVoltarol or Diclomax or Motifene).mp.








14. (Pranoprofen$ or Proglumetacin$ orProquazone$ or Ramifenazone$ or Sulindac$

Appendix 1

186

or Clinoril or Tenoxicam$ or Mobiflex orTiaprofenic$ or Surgam or Tiaramide$ orTolfenamic$ or Clotam or Tolmetin$ orZaltoprofen$).mp.

15. exp diclofenac/ or exp diflunisal/ or expepirizole/ or exp etodolac/ or exp fenoprofen/or exp flufenamic acid/ or exp flurbiprofen/ orexp ibuprofen/ or exp indomethacin/ or expketoprofen/ or exp ketorolac/ or exp ketorolactromethamine/ or exp meclofenamic acid/ orexp mefenamic acid/ or exp naproxen/ or expniflumic acid/ or exp phenylbutazone/ or exppiroxicam/ or exp sulindac/ or exp tolmetin/

16. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10or 11 or 12 or 13 or 14 or 15

17. (cytotec or misoprostil or "SC 29333" or "SC30249").mp.

18. "hydrogen potassium adenosinetriphosphatase inhib$".mp.

19. "hydrogen potassium ATPase inhib$".mp. 20. (H2 adj3 (antagon$ or block$)).mp. 21. ("histamine 2" adj3 (block$ or antagon$)).mp. 22. (cimetidine$ or famotidine$ or nizatidine$ or

ranitidine$).mp. 23. (dyspamet or tagamet or algitec or pepcid or

axid or zantac or pylorid).mp. 24. (omeprazole$ or lansoprazole$ or

pantoprazole$ or rabeprazole$).mp. 25. (losec or zoton or protium or pariet).mp. 26. exp MISOPROSTOL/ 27. exp burimamide/ or exp cimetidine/ or exp

famotidine/ or exp metiamide/ or expMisoprostol/ or exp nizatidine/ or expomeprazole/ or exp ranitidine/

28. exp Histamine H2 Antagonists/ 29. 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24

or 25 or 26 or 27 or 28 30. 16 and 29 31. (arthrotec or napratec).mp. or 30 32. (Cox-2 or Cox-II or "Cox 2" or "Cox II").mp. 33. (cyclooxygenase-2 or "cyclooxygenase 2" or

cyclooxygenase-II or "cyclooxygenase II").mp. 34. (celecoxib$ or etodolac$).mp. 35. (flosulide$ or meloxicam$).mp. 36. exp Etodolac/ 37. nimesulide$.mp. 38. rofecoxib$.mp. 39. (cyclo-oxygenase-2 or "cyclo-oxygenase 2" or


40. (celebrex or vioxx).mp. 41. 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39

or 40 42. 31 or 41 43. randomized controlled trial.pt. 44. controlled clinical trial.pt. 45. Randomized controlled trials/

46. random allocation.sh. 47. double blind method.sh. 48. single-blind method.sh. 49. 43 or 44 or 45 or 46 or 47 or 48 50. (animal not human).sh. 51. 49 not 50 52. clinical trial.pt. 53. exp Clinical trials/ 54. (clin$ adj25 trial$).ti,ab. 55. ((singl$ or doubl$ or trebl$ or tripl$) adj

(blind$ or mask$)).ti,ab. 56. placebos.sh. 57. placebo$.ti,ab. 58. random$.ti,ab. 59. research design.sh. 60. comparative study.sh. 61. exp Evaluation studies/ 62. follow up studies.sh. 63. prospective studies.sh. 64. (control$ or prospectiv$ or volunteer$).ti,ab. 65. 52 or 53 or 54 or 55 or 56 or 57 or 58 or 59

or 60 or 61 or 62 or 63 or 64 66. 65 not 50 67. 51 or 66 68. exp Cohort Studies/ 69. (cohort$ or quintile$ or quartile$ or quantile$

or tertile$).mp. 70. (follow-up$ or followup$).mp,tw. 71. longitud$.mp. 72. ((prospectiv$ or observation$) adj5 (research$

or data$ or stud$)).mp. 73. 68 or 69 or 70 or 71 or 72 74. 73 not 50 75. 67 or 74 76. 42 and 75 77. Child/ 78. Adult/ 79. 77 and 78 80. 77 not 79 81. 76 not 80 82. exp in vitro/ 83. 81 not 82

(c) Search strategy developed forthe Cochrane Library

On CD rom, run on 2002, Issue 2.

1. NSAID*2. ((NONSTEROID* or NON-STEROID*) near

(ANTI-INFLAM* or ANTIINFLAM*))3. (COX1 or COX-1)4. COX5. (CYCLO-OXYGENASE* or

CYCLOOXYGENASE*)6. COX-1


187


7. COX8. ((((((ACECLOFENAC* or PRESERVEX) or

ACEMETACIN*) or ACETMETACIN*) orEMFLEX) or ALMINOPROFEN*) orAMFENAC)

9. (((((((AMPIROXICAM* or AMTOLMETIN*)or AZAPROPAZONE*) or RHEUMOX) orBENORYLATE*) or BENORILATE*) orBENORAL) or BUTIBUFEN*)

10. (((((((CINMETACIN* or CLOFEZONE*) orDEXKETOPROFEN*) or KERAL) orDICLOFENAC*) or VOLTAROL) orDICLOMAX) or MOTIFENE)

11. (((((DIFENPIRAMIDE* or DIFLUNISAL*) orDOLOBID) or EPIRAZOLE*) orETODOLAC*) or LODINE)

12. ((((((ETOFENAMATE* or FENBUFEN*) orLEDERFEN) or FENOPROFEN*) orFENOPRON) or FENTIAZAC*) orFLOCTAFENINE*)

13. (((((((((((((((FLUNOXAPROFEN* orFLURBIPROFEN*) or FROBEN) orFURPROFEN*) or GLUCAMETACIN*) orIBUPROFEN*) or ARTHROFEN) orLIDIFEN) or EBUFAC) or RIMAFEN) orMOTRIN) or NUROFEN) or GALPROFEN)or ORBIFEN) or BRUFEN) or FENBID)

14. ((((IBUPROXAM* or INDOMETHACIN*) orINDOMETACIN*) or INDOMAX) or SLO-INDO)

15. ((((((((((ISONIXIN* or KEBUZONE*) orKETOPROFEN*) or ORUDIS) or ORUVAIL)or KETOROLAC*) or TORADOL) orLONAZOLAC*) or LORNOXICAM*) orXEFO) or LOXOPROFEN*)

16. (((((((((((((MECLOFENAMATE* orMEFENAMIC*) or PONSTAN) orMELOXICAM*) or MOBIC) orMOFEBUTAZONE*) or MOFEZOLAC*) orMORAZONE*) or MORNIFLUMATE*) orNABUMETONE*) or RELIFEX) orNAPROXEN*) or NAPROSYN) or SYNFLEX)

17. (((((((NIFENAZONE* or NIFLUMIC*) orOXAMETACIN*) or PHENYLBUTAZONE*)or BUTACOTE) or PIROXICAM*) orFELDENE) or BREXIDOL)

18. ((((((((((((((PRANOPROFEN* orPROGLUMETACIN*) or PROQUAZONE*)or RAMIFENAZONE*) or SULINDAC*) orCLINORIL) or TENOXICAM*) orMOBIFLEX) or TIAPROFENIC*) orSURGAM) or TIARAMIDE*) orTOLFENAMIC*) or CLOTAM) orTOLMETIN*) or ZALTOPROFEN*)

19. DICLOFENAC*:ME20. DIFLUNISAL*:ME21. EPIRIZOLE*:ME

22. ETODOLAC*:ME23. FENOPROFEN*:ME24. IBUPROFEN*:ME25. FLUFENAMIC-ACID*:ME26. FLURBIPROFEN*:ME27. INDOMETHACIN*:ME28. KETOPROFEN*:ME29. MECLOFENAMIC-ACID*:ME30. MEFENAMIC-ACID*:ME31. NAPROXEN*:ME32. NIFLUMIC-ACID*:ME33. PHENYLBUTAZONE*:ME34. PIROXICAM*:ME35. SULINDAC*:ME36. TOLMETIN*:ME37. (((((((((((#1 or #2) or #3) or #4) or #5) or

#6) or #7) or #8) or #9) or #10) or #11) or#12)

38. (((((((((((#13 or #14) or #15) or #16) or #17)or #18) or #19) or #20) or #21) or #22) or#23) or #24)

39. (((((((((((#25 or #26) or #27) or #28) or #29)or #30) or #31) or #32) or #33) or #34) or#35) or #36)

40. ((#37 or #38) or #39)41. (CYTOTEC or MISOPROSTIL)42. (((CYTOTEC or MISOPROSTIL) or 29333)

or 30249)43. (HYDROGEN next (POTASSIUM next

(ADENOSINE next (TRIPHOSPHATASE nextINHIB*))))

44. (HYDROGEN next (POTASSIUM next(ATPASE next INHIB*)))

45. (HISTAMINE* near (BLOCK* orANTAGON*))

46. (((CIMETIDINE* or FAMOTIDINE*) orNIZATIDINE*) or RANITIDINE*)

47. ((((((DYSPAMET or TAGAMET) or ALGITEC)or PEPCID) or AXID) or ZANTAC) orPYLORID)

48. (((OMEPRAZOLE* or LANSOPRAZOLE*) orPANTOPRAZOLE*) or RABEPRAZOLE*)

49. (((LOSEC or ZOTON) or PROTIUM) orPARIET)

50. MISOPROSTOL*:ME51. BURIMAMIDE*:ME52. CIMETIDINE*:ME53. FAMOTIDINE*:ME54. METIAMIDE*:ME55. NIZATIDINE*:ME56. OMEPRAZOLE*:ME57. RANITIDINE*:ME58. HISTAMINE-H2-ANTAGONISTS*:ME59. ((((((((#42 or #43) or #44) or #45) or #46)

or #47) or #48) or #49) or #50)60. ((((((((#51 or #52) or #53) or #54) or #55)

or #56) or #57) or #58) or #59)

Appendix 1

188

61. (#60 and #40)62. (ARTHROTEC or NAPRATEC)63. (((COX-2 or COX-II) or

CYCLOOXYGENASE-2) or CYCLO-OXYGENASE-2)

64. (((((((CELECOXIB* or FLOSULIDE*) orMELOXICAM*) or NIMESULIDE*) orROFECOXIB*) or CELEBREX) or VIOXX)or ETODOLAC*)

65. ((#62 or #63) or #64)66. (#61 or #65)67. CHILD*:ME68. ADULT*:ME69. (#67 and #68)70. (#67 not #69)71. (#66 not #70)

(d) Search strategy developed forEMBASE to locate CCTs andcohort studies (similarstrategy used on MEDLINE)

On Ovid, run May 2002, period 1966 to date.

1. NSAID$.mp. 2. ((nonsteroid$ or non-steroid$) adj3 (anti-

inflam$ or antiinflam$)).mp. 3. ("cox 1" or cox-1 or "cyclo-oxygenase 1" or


4. exp aceclofenac/ or exp acemetacin/ or expalminoprofen/ or exp amfenac/ or expampiroxicam/ or exp amtolmetin guacil/ orexp benorilate/ or exp butibufen/ or expclofezone/ or exp dexketoprofen/ or expdiclofenac/ or exp diflunisal/ or exp epirizole/or exp etodolac/ or exp etofenamate/ or expfenbufen/ or exp fenoprofen/ or exp fentiazac/or exp flunoxaprofen/ or exp flurbiprofen/ orexp furaprofen/ or exp glucametacin/ or expibuprofen/ or exp ibuproxam/ or expindometacin/ or exp isonixin/ or expkebuzone/ or exp ketoprofen/ or expketorolac/ or exp ketorolac trometamol/ or explonazolac/ or exp lonazolac calcium/ or explornoxicam/ or exp loxoprofen/ or expmeclofenamate sodium/ or exp meclofenamicacid/ or exp mefenamic acid/ or expmeloxicam/ or exp mofebutazone/ or expmofezolac/ or exp morazone/ or expmorniflumate/ or exp nabumetone/ or expnaproxen/ or exp niflumic acid/ or expoxametacin/ or exp phenylbutazone/ or exppiroxicam/ or exp pranoprofen/ or expproglumetacin/ or exp proquazone/ or exp

sulindac/ or exp tenoxicam/ or exp tiaprofenicacid/ or exp tiaramide/ or exp tolfenamic acid/or exp tolmetin/ or exp zaltoprofen/



7. (Cinmetacin$ or Clofezone$ orDexketoprofen$ or Keral or Diclofenac$ orVoltarol or Diclomax or Motifene).mp.








15. (Pranoprofen$ or Proglumetacin$ orProquazone$ or Ramifenazone$ or Sulindac$or Clinoril or Tenoxicam$ or Mobiflex orTiaprofenic$ or Surgam or Tiaramide$ orTolfenamic$ or Clotam or Tolmetin$ orZaltoprofen$).mp.

16. exp Misoprostol/17. exp Proton Pump Inhibitor/18. exp Histamine H2 Receptor Antagonist/19. (cytotec or misoprostil or "SC 29333" or "SC

30249").mp. 20. 59122-48-4.rn.21. "hydrogen potassium adenosine

triphosphatase inhib$".mp. 22. "hydrogen potassium ATPase inhib$".mp. 23. (H2 adj3 (antagon$ or block$)).mp. 24. ("histamine 2" adj3 (block$ or

antagon$)).mp. 25. (cimetidine$ or famotidine$ or nizatidine$ or

ranitidine$).mp.


189


Appendix 1

190

26. (dyspamet or tagamet or algitec or pepcid oraxid or zantac or pylorid).mp.

27. (omeprazole$ or lansoprazole$ orpantoprazole$ or rabeprazole$).mp.

28. (losec or zoton or protium or pariet).mp. 29. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10

or 11 or 12 or 13 or 14 or 1530. 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23

or 24 or 25 or 26 or 27 or 2831. 29 and 3032. (arthrotec or napratec).mp. or 31 33. (cox-2 or cox-II or "cox 2" or "cox II").mp. 34. (cyclooxygenase-2 or "cyclooxygenase 2" or

cyclooxygenase-II or "cyclooxygenase II").mp. 35. exp Cyclooxygenase 2 Inhibitor/36. celecoxib$.mp.37. flosulide$.mp. 38. meloxicam$.mp. 39. nimesulide$.mp. 40. rofecoxib$.mp. 41. (cyclo-oxygenase-2 or "cyclo-oxygenase 2" or


42. (celebrex or vioxx).mp. [mp=title, abstract,subject headings, drug trade name, originaltitle, device manufacturer, drug manufacturername]

43. 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40or 41 or 42

44. 32 or 4345. controlled study/46. randomized controlled trial/47. clinical trial/48. major clinical study/

49. (trial$ or compar$ or control$).tw.50. study.tw.51. "follow$ and up".tw.52. (blind$ or clinic$ or placebo).tw.53. placebo/54. clinical article/55. 45 or 46 or 47 or 48 or 49 or 50 or 52 or 53

or 5456. exp human/57. nonhuman/58. 57 not 5659. 55 not 5860. exp Longitudinal Study/61. exp Prospective Study/62. (cohort$ or quintile$ or quartile$ or tertile$

or quantile$).mp.63. (follow-up$ or followup$).mp,tw.64. longitud$.mp.65. ((prospectiv$ or observation$) adj5 (research$

or data$ or stud$)).mp.66. 60 or 61 or 62 or 63 or 64 or 6567. 66 not 5868. 67 or 5969. 44 and 6870. Child/71. Adult/72. 70 and 7173. 70 not 7274. 69 not 7375. exp In Vitro Study/76. exp In Vivo Study/77. 75 and 7678. 75 not 7779. 74 not 78


191


(e) Letter sent to all contact authors of included studiesDear Professor X,

Re. Systematic review with economic modelling comparing the cost-effectiveness of four strategies for the prevention of NSAID-induced gastrointestinal toxicity (UK HTA review).

We would like to include details of your study (full reference of included study) in our meta-analysis. In order to represent your study adequately we need additional information and hope

you can help us. We would greatly appreciate if you could provide us with some information on the trial.

1. Would you be able to provide us with the number of events in each arm (and the total number ofpeople analysed)?

Please label each intervention arm.

CONTROL Group B Group C Group D

Total number analysed in this arm

Death (all-cause, with reasons for death)

Serious GI complications (pyloric obstruction, haemorrhage, haemorrhagic erosions, recurrent upper GI bleeds, perforation, inc death from any of these)

Symptomatic ulcers (gastric, duodenal, oesophageal, inc bleeding ulcers)

Serious cardiovascular or renal illness leading to contact with primary or secondary health care (inc. angina, MI, stroke, TIA, renal failure, or death from any of these)

Quality of life (details of measure/s used and results)

Appendix 1

192

2. We would also like information that would allow us to classify the study according to ourmethodological criteria and identify any missing data or studies:

Who was blinded in the trial (for example, patients, clinicians, outcome assessors)?

How was randomisation achieved: method(e.g. sealed envelopes, dice toss, central computer) and personnel involved(e.g. pharmacist, recruiting clinician or centralpersonnel)?

Please give details of any other publicationsthat report the results of this study (copies of these and of full trial reports would be gratefully received).

Do you know of any other studies (published, unpublished or ongoing) that meet our inclusion criteria? We attach a list of studies already included.

Thanking you in anticipation of your help. If you have any further questions regarding our requests,please feel free to contact me.

Yours sincerely,

Tamara Brown BA(Hons), MSc.


193


(a) NSAID proprietary names International List produced from Martindale: The Complete Drug Reference, 35th ed. Those NSAIDs in boldare not included in the review owing to toxicity or withdrawal (they are not realistic alternatives). ThoseNSAIDs in italics are currently available in the UK.

Appendix 2

NSAIDs and gastroprotective agents

Drug Brand names

Cox-I typeAceclofenac Preservex, Biofenac, Airtal, Falcol, Gerbin, Sanein, Barcan

Acemetacin Rheutrop, Altren, Peran, Rantudil, Acemix, Solart, Espledol, Oldan, Tilur

Acetmetacin Emflex

Aclofenac (withdrawn) Mervan

Alminoprofen Minalfene

Amfenac Fenazox

Amidopyrine (very toxic) Farmidone, Ftalazone, Fugantil, Malivan, Piroreumal, Rosetin, Termidon, Tiomidone

Ampiroxicam

Amtolmetin guacil Artromed, Eufans

Azapropazone Rheumox, Prolixan, Tolyprin, Prolixana

Benorylate, benorilate Benoral (salicylate)

Benoxaprofen (withdrawn) Opren

Bromfenac (withdrawn) Duract

Bumadizone calcium (very toxic) Rheumatol, Eumotol

Butibufen Mijal

Cinmetacin Cetanovo

Clofezone Perclusone

Dexketoprofen Keral

Diclofenac Voltarol, Diclomax, Motifene, Algefit, Delodor, Deflamat, Diclobene, Diclomelan,Diclosyl, Fenaren, Magulphen, Naclof, Tratul, Voltaren, Arthrotec, Diclohexal, Fenac,Cataflam, Polyflam, Novo-Difenac, Nu-Diclo, Flector, Voldal, Voltarene, Xenid,Allvoran, Arthrex, Arthrex Duo, Benfofen, Delphinac, Diclac, Diclo, Diclo-Puren,Diclo-Saar, Diclo-Spondyril, Diclo-Tablinen, Diclo-Wolff, Dicloberl, Diclofenbeta,Diclomerk, Diclophlogont, Diclorektal, Dignofenac, Diglo-Diclo, Dolobasan,DoloVisano Diclo, Duravolten, Effekton, Jenafenac, Lexobene, Monoflam, Myogit,Rewodina, Rheumasan D, Sigafenac, Silino, Toryxil, Diclomel, Difene, Vologen,Artrotec, Dealgic, Deflamat, Dicloftil, Dicloreum, Fenadol, Flogofenac, Forgenac,Misofenac, Novapirina, Ribex Flu, Naclof, Panamor, Pharmaflam, Sodiclo, Veltex, DiRetard, Dolotren, Liberalgium, Lause, Voltaren T, diclo-basan, Diclosifar, Ecofenac,Grofenac, Inflamac, Olfen, Primofenac, Rheufenac, Rhumalgan, Vifenac

Difenpiramide Difenax

Diflunisal Dolobid, Fluniget, Biartac, Diflusal, Dolobis, Adomal, Aflogos, Artrodol, Citidol,Difludol, Diflunil, Diflusan, Dolisal, Fluodonil, Flustar, Nalgisa, Noaldol, Reuflos,Dolocid, Diflonid, Donobid, Ilacen, Unisal

Droxicam (very toxic) Dobenam, Droxar, Drogelon, Ferpan, Ombolan, Pensatron

Epirizole Mebron

continued

Appendix 2

194

Drug Brand names

Etofenamate Rheumon, Traumon, Flexium, Algesalona E, Bayro, Afrolate, Deiron, Flogoprofen,Zenavan, Etofen, Traumalix

Felbinac (very toxic) Target, Flexfree, Dolinac, Traxam, Napageln, Dolinac

Fenbufen Lederfen, Cinopal, Cincopal

Fenoprofen calcium Fenopron, Nalfon, Fepron, Nalgesic, Progesic

Fentiazac Norvedan, Fentac, Domureuma, Flogene, O-Flam, Dermisone Fentiazaco, Donorest,Riscalon

Feprazone (very toxic) Zepelin, Brotazona, Cocresol, Rangozona, Represil, Reuflodol

Floctafenine Idarac, Idalon

Flufenamic acid (very toxic) Mobilisin, Rheugesal, Algesalona, Flexocutan, Flexilat, Assan, Assan-Thermo

Flunoxaprofen Priaxim

Flurbiprofen Froben, Ansaid, Novo-Flurprofen, Cebutid, Fenomel, Transact Lat, Antadys, NeoArtrol, Tulip

Furprofen Dolex

Glafenine (withdrawn) Glifan, Glifanan

Glucametacin Teoremac, Euminex

Ibuprofen Arthrofen, Lidifen, Ebufac, Rimafen, Motrin, Nurofen, Galprofen, Orbifen,Brufen, Fenbid, Avallone, Brufen, Dismenol neu, Dolgit, Dolibu, Dolofort, Doloren,Duafen, Ibudol, Ibupron, Iburem, Imbun, Kratalgin, Nurofen, Seractil, Tabcin, Urem,ACT-3, Actiprofen, Rafen, Tri-profen, Bufedon, Dolgit, Dolofin, Exidol, Ibu-Slow, Inabrin,Malafene, Motrin, Advil, Medipren, Novo-profen, Algifene, Analgyl, Ergix, Fenalgic,Gelufene, Nureflex, Oralfene, Tiburon, Aktren, Anco, Cesra, Contraneural, Dentigoa,Dignoflex, Dimidon, Dismenol, Dolgit, Dolo neos, Dolo-Dolgit, Dolo-Puren, Dolormin,dura-Ibu, duraibuprofen, Dysdolen, Esprenit, Exneural, Fibraflex, Gynofug, Ibol, Ibu, ibu-Attritin, Ibu-Vivimed, Ibubest, Ibubeta, Ibuflam, Ibufug, Ibuhexal, Ibumerck, Ibuphlogont,Ibuprof, Ibutad, Imbun, Jenaprofen, Kontagripp Mono, Logomed Schmerz, Mensoton,Mobilat, Novogent, Optalidon, Opturem, Parsal, Pfeil, Schmerz-Dolgit, Seclodin,stadasan, Tabalon, Tempil, Togal N, Trauma-dolgit, Trombufen, Urem, Bufigen, Cunil,Melfen, Proflex, Aciril, Arfen, Artene, Asepsal, Benflogin, Brufort, Dolocyl, Faspic,Flubenil, Focus, Gineflor, Ginenorm, Inabrin, Kos, Moment, Neo-Mindol, Prontalgin,Femapirin, Ibosure, Ibumetin, Nerofen, Zafen, Ibux, Abbifen, Adfen, Antiflam, Betagesic,Betaprofen, Brugesic, Clinofen, Dynofen, Ibopain, Ibufarm, Inza, Magnatex, Ranfen,Rofen, Solufen, Algiasidin, Algisan, Altior, Cusialgil, Dalsy, Doctril, Dolocyl, Dorival,Ediluna, Espidifen, Evasprin, Faspic, Femidol, Ibenon, Incefal, Isdol, Kalma, Leonal,Librofem, Liderfeme, Lisi-budol, Medipren, Neobrufen, Noalgil, Pocyl, Sadefen,Solufena, Spidifen, Todalgil, Duobrus, Algifor, Antalgit, Bufeno, Dismenol, Irfen, Neo-Helvagit, Panax N, Redufen, Serviprofen, Spedifen, Dynafed IB, Excedrin IB, Genpril,Haltran, Ibufon, Ibuprohm, Medipren, Menadol, Midol IB, Nuprin, Trendar

Ibuproxam Deflogon, Ibudros, Nialen

Indomethacin, indometacin (Only available in the UK as a generic; some generic names: Indomax 75, Slo-Indo), Flexidin, Gaurit, Indocid, Indocollyre, Indohexal, Indomellan, Indoptol,Liometacen, Luiflex, Ralicid, Arthrexin, Hicin, Indomed, Dolcidium, Indotec, Novo-methacin, Nu-indo, Rhodacine, Ainscrid, Chrono-Indocid, Amuno, Chibro-Amuno,Confortid, durametacin, Elmetacin, Indo-tablinen, Indocontin, Indomet-ratiopharm,Indomisal, Indorektal, Jenatacin, Mobilat, Rheubalmin Indo, Sigadoc, Vonum, Cidomel,Flexin Continus, Idomed, Imbrilon, Indomod, Boutycin, Cidalgon, Imet, Indocollirio,Indom Collirio, Indoxen, Liometacin, Metacen, Peralgon, Infree, Inteban, Dolazol,Dometin, Confortid, Acuflex, Aflamin, Arthrexin, Articulen, Betacin, Dynametcin,Famethacin, Flamaret, Flamecid, Indotal, Mediflex, Methabid, Methamax, Methocaps,Nisaid-25, Restameth-SR, Rumitard, Aliviosin, Artrinovo, Butidil, Flogoter, Inacid, IndoFraman, Indocaf, Indoftol, Indolgina, Indonilo, Mederreumol, Neo-Decabutin, Reumo,Reusin, Indomee, Bonidon, Helvecin, Indo-Mepha, Indophtal, Indoptic, Servimeta,Indochron

Isamfazone (withdrawn) Combiflexona, Frenespan

Isonixin Nixyn

continued


195


Drug Brand names

Kebuzone Ketazon, ChetopirKetoprofen Orudis, Oruvail, Actron, Keprodol, Profenid, Birofenid, Fastum, Rofenid, Toprek,

Apo-Keto, Novo-Keto, Orafen, Rhodis, Rhovail, Bi-Profenid, Ketum, Topfena, Toprec,Alrheumun, europan, Gabrilen, Spondylon, Alrheumat, Orugesic, Artrosilene, Dexal,Flexen, Iso-K, Kefenid, Ketalgin, Ketartrium, Keto, Ketodol, Ketofen, Meprofen, Oki,Profenil, Reuprofen, Salient, Sinketol, Zepelindue, Oscorel, Ketoflam, Myproflam,Orucote, Oruject, Arcental, Extraplus, Ketosolan, Reumoquin, Prodon, Profenid,Fenoket, Jomrthid, Ketil, Ketocid, Ketovail, Ketozip, Larafen, Actron

Ketorolac trometamol Toradol (only for postoperative pain), Aculare, Taradyl, Lixidol, Droal, Tonum, Lonazolac calcium Irritren, ArgunLornoxicam XefoLoxoprofen LoxoninMeclofenamate Meclomen, Lenidolor, Meclodol, Movens, MeclodiumMefenamic acid (only available in the UK as a generic, used to be Ponstan, Ponstan forte),

Parkemed, Mefic, Ponstan, Ponstyl, Ponalar, Mefac, Pinalgesic, Ponalgesic, Ponmel,Lysalgo, Clinstan, Fenamin, Mefalgic, Ponac, Ponstel, Coslan, Ecopan, Mefenacide,Ponstel

Mofebutazone Diadin M, MofesalMofezolac No brandsMorazone Rosimon-neuMorniflumate Nifluril, Flomax, Morniflu, Actol, NiflactolNaproxen Naprosyn, Synflex, Miranax, Naprobene, Nycopren, Proxen, Xenopan, Anaprox,

Inza, Naprogesic, Naxen, Synflex, Apranax, Diparene, Naprosyne, Nycopren, Apo-Napro-Na, Naxen, Novo-Naprox, Nu-Naprox, Dysmenalgit, Malexin, Napro-Dorsch,Genoxen, Gerinap, Napmel, Naprex, Alganil, Apredan, Artroxen, Axer, Floginax,Flogogin, Floxalin, Gibinap, Gibixen, Gynestrel, Laser, Leniartril, Naprium, Naprius,Naprodol, Naprorex, Natrioxen, Neo-Eblimon, Nitens, Numidan, Piproxen, Praxenol,Prexan, Primeral, Proxine, Synalgo, Ticoflex, Xenar, Aleve, Femex, Naprocoat,Naprovite, Alpoxen, Ledox, Acusprain, Clinosyn, Nafasol, Napflam, Naprel,Naproscript, Pranoxen, Traumox, Aliviomas, Antalgin, Denaxpren, Ilagagen, Lundiran,Naprokes, Naproval, Rofanten, Pronaxen, Naprolag, Servinaprox, Anaprox, Naprelan

Nifenazone Nicopyron, Algotrex, Neopiran, Reumatosil, Supermidone, ThylinNiflumic acid Actol, Nifluril, Flunir, NiflamOxametacin RestidOxaprozin (toxic) Deflam, DayproOxyphenbutazone (very toxic) Tanderil, Californit, Phlogont, Otone, DiflamilParsalmide (toxic) SinovialPhenylbutazone Butacote, Butazolidin, Novo-butazone, Butazolidine, Ambene, Demoplas, Butazina,

Butazolidina, Carudol, Kadol, Ticinil, Butrex, Inflazone, Scriptozone, Butadiona,Butadion, Cotylbutazone

Piroxicam Feldene, Brexidol, Brexen, Felden, Pirocam, Candyl, Fensaid, Mobilis, Pirox, Rosig,Brexine,Novo-Pirocam, Nu-Pirox, Brexin, Cycladol, Geldene, Inflaced, Olcam,Brexidol, durapirox, Fasax, Flexase, Jenapirox, Piro-Phlogont, Piro-Puren, Pirobeta,Piroflam, Rirorheum, Pirorheuma, Pirox, Pirox-Spondyril, Piroximerck, Pra-Brexidol,Rheumitin, Geroxicam, Pericam, Antiflog, Artroxicam, Brexin, Bruxicam, Cicladol,Ciclafast, Clevian, Dexicam, Flodol, Flogobene, Lampoflex, Nirox, Piroftal,Pivaloxicam, Polipirox, Reucam, Reudene, Reumagil, Riacen, Roxene, Roxenil, Roxiden,Roxim, Siartrol, Unicam, Zacam, Zelis, Zen, Zunden, Pirox, Tetram, Brexecam,Pixicam, Pyrocaps, Rheugesic, Roxicam, Xycam, Artragil, Brexinil, Dekamega,Doblexan, Improntal, Salcacam, Sasulen, Vitaxicam, Pirosol

Pranoprofen Pranox, Niflan, OftalarProglumetacin Protaxon, Tolindol, Afloxan, Proxil, Prodamox, ProtaxilProquazone BiarisonRamifenazone Delta-Tomanol

continued

Appendix 2

196

Drug Brand names

Sulindac Clinoril, Aclin, Clusinol, Saldac, Apo-Sulin, Novo-Sundac, Arthrocine, Aflodac,Algocetil, Citireuma, Clisundac, Lyndac, Reumyl, Sudac, Sulatrene, Sulen, Sulic, Sulinol,Sulreuma, R-Flex

Tenoxicam Mobiflex, Liman, Tilcotil, Dolmen, Rexalgan, Artriunic, Reutenox, Alganex

Tiaprofenic acid Surgam, Surgam LA, Artiflam, Albert Tiafen, Lindotab, Artroreuma, Suralgan,Surgamyl, Tiaprorex, Derilate, Surgamic

Tiaramide Solantal

Tolfenamic acid Clotam (not licensed for RA or OA), Rociclyn

Tolmetin Tolectin, Reutol, Artrocaptin

Zaltoprofen No brands

Cox-I type with added gastroprotectionDiclofenac with added misoprostol Arthrotec

Naproxen with added misoprostol Napratec

Cox-2 coxib typeCelecoxib Celebrex

Flosulide (?)

Rofecoxib Vioxx

Cox-2 preferential typeEtodolac

Meloxicam Mobic, Movalis, Mobec, MoviCox, MobiCox, Parocin, UtiCox

Nabumetone Relifex, Relafen, Arthaxan, Artaxan, Nabuser, Mebutan, Relifen, Relisan, Relitone,Dolsinal, Listran, Relif, Balmox

Nimesulide Mesulid, Aulin, Algolider, Eudolene, Fansidol, Flolid, Laidor, Ledoren, Nide, Nimedex,Nimesulene, Nims, Nisal, Remov, Resulin, Sulide, Teonim, Antifloxil, Guaxan, Nisulid

(B) Non-NSAID gastroprotective agents, proprietary names

Generic Brand

Gastroprotective agents

H2RAsCimetidine Cimetidine, Dyspamet, Tagamet

Famotidine Famotidine, Pepcid

Nizatidine Nizatidine, Axid

Ranitidine Ranitidine, Zantac

Ranitidine bismuth citrate Pylorid

Misoprosotol Cyctotec

With diclofenac (Arthrotec)

With naproxen (Napratec)

PPIs

Omeprazole Losec

Esomeprazole Nexium

Lansoprazole Zoton

Pantoprazole Protium

Rabeprazole sodium Pariet


197


Drug Daily oral dose: Comments Manufacturerrange in adults with rheumatic diseases (mg)

Older NSAIDsAceclofenac 100–200 UCB Pharma

Acetmetacin 120–180 Usual dose 120 mg daily Merck

Azapropazone 600–1800 Usual dose 1200 mg daily Goldshield

Dexketoprofen 50–75 Menarini

Diclofenac 75–150 Alpharma, Ashbourne, Berk,Dexcel Pharma, Eastern,Goldshield, IVAX, Kent,Lagap

Diflunisal 500–1500 MSD

Fenbufen 900 Cox, Generics, Genus,Hillcross, IVAX, Kent,Sterwin

Fenoprofen 900–3000 Typharm

Flurbiprofen 150–300 Usual dose 200 mg daily Abbott

Ibuprofen 600–2400 In divided doses, usually Alpharma, APS, Ashbourne, not more than 1800 mg daily Berk, CP, DDSA, IVAX, Kent,

Ranbaxy, Pharmacia,Sovereign, Sterwin

Indomethacin, indometacin 50–200 50 mg daily often sufficient Alpharma, Kent, MSD,Ranbaxy, Ashbourne,Generics, Hillcross, Lagap,Pharmacia

Ketoprofen 100–200 Hawgreen

Lornoxicam 12 CeNeS

Mefenamic acid 1500

Nabumetone 500–2000 Usually just 1000 mg at night Alpharma, APS, Generics,SmithKline Beecham

Naproxen 500–1250 Roche, Searle

Phenylbutazone 200–600 Not licensed for anything Novartisother than ankylosing spondylitis

Piroxicam 10–30 Pfizer

Sulindac 400 MSD

Tenoxicam 20 Roche

Tiaprofenic acid 600 Florizel

Tolfenamic acid

Cox-2 NSAIDs

Celecoxib 200–400 Pharmacia

Etodolac 600 Shire

Meloxicam 7.5–15 7.5 mg daily often sufficient Boehringer Ingelheim

Nimesulide 200 (Internet expert)

Rofecoxib 12.5–25 Can be increased to Merck50 mg daily in acute pain

continued

(c) BNF23 recommended doses

Appendix 2

198

Drug Daily oral dose: Comments Manufacturerrange in adults with rheumatic diseases (mg)

H2RAs

Cimetidine 400 Maintenance

Famotidine 20 Maintenance

Nizatidine 150 Maintenance

Ranitidine 150/300 150 for maintenance (following healing) 300 for prophylaxis

Ranitidine bismuth citrate Not recommended for maintenance

PA

Misoprosotol 40–800 µg Maintenance

With diclofenac (Arthrotec)

With naproxen (Napratec)

PPIs

Omeprazole 20 Prophylaxis

Esomeprazole 20 Maintenance

Lansoprazole 15–30 Prophylaxis

Pantoprazole Healing

Rabeprazole sodium Healing


199


Appendix 3

Inclusion and exclusion forms

(a) RCT inclusionNSAID inclusion/exclusion form

Ref ID:Coder name and date

RCT: Is the paper:

Yes No ?

A. An individually randomised controlled trial?

B. In adults (18 years plus, not healthy volunteers) who have taken NSAIDs for at least 3 weeks (21 days)?

C. Comparing1. Older NSAIDs plus H2RAs compared with older NSAIDs

(alone or with placebo gastroprotection)2. Older NSAIDs plus PPIs compared with older NSAIDs

(alone or with placebo gastroprotection)3. Older NSAIDs plus misoprostol compared with older NSAIDs

(alone or with placebo gastroprotection)4. Cox-2 inhibitors compared with older NSAIDs alone 5. Comparing any of the four gastroprotective strategies above

with any other active gastroprotective strategy

D. Assessing any of the following:Haemorrhage, perforation, pyloric obstruction, symptomatic ulcers, death, endoscopically proven ulcers, gastric symptoms, anaemia, occult bleeding, other adverse events, CV or renal events, drop-outs, quality of life

E. Are doses at least the minimum recommended daily prescribing dose as per BNF in at least 2 arms? (exclude less than minimum daily dose arms)

RCT for the SR

In / out

Appendix 3

200

(b) CCT or cohort inclusion/exclusionCCT or cohort: Is the paper:

Yes No ?

A parallel controlled trial or a cohort study?

In adults (18 years plus) who have taken NSAIDs for at least 3 weeks (21 days)?

Comparing 1. Older NSAIDs plus H2RAs compared with older NSAIDs

(alone or with placebo gastroprotection)2. Older NSAIDs plus PPIs compared with older NSAIDs (alone or

with placebo gastroprotection)3. Older NSAIDs plus misoprostol compared with older NSAIDs

(alone or with placebo gastroprotection)4. Cox-2 inhibitors compared with older NSAIDs alone 5. Comparing any of the four gastroprotective strategies above

with any other active gastroprotective strategy

If cohort, includes at least 500 participants at start of study (if not cohort, tick ‘yes’)

Assessing mortality

CCT or Cohort for the SRIn / out

Comments:

(c) Health economics papers to collectHealth economics: Is the paper:

Yes No ?

A parallel controlled trial or a cohort study?

Based on work performed at least partly in the UK?

In adults (18 years plus) who have taken NSAIDs for at least 3 weeks (21 days)?

Assessing at least one of the following1. Older NSAIDs plus H2RAs 2. Older NSAIDs (alone or with placebo gastroprotection)3. Older NSAIDs plus PPIs 4. Older NSAIDs plus misoprostol 5. Cox-2 inhibitors

Assessing any of the following:

Haemorrhage, perforation, pyloric obstruction, symptomatic ulcers, death, endoscopically proven ulcers, gastric symptoms, anaemia, occult bleeding, other adverse events, drop-outs, quality of life, satisfaction, preferences, chest pain, MI, other acute cardiac events, renal disease, resource use, unit costs, total costs of treatment (of drugs, of monitoring or follow-up, of management of adverse outcomes)

Economic assessmentIn / out

Comments:


201


Appendix 4

Quality assessment and data extraction

(a) Quality data assessment for RCTsSelection biasRandomisation procedure:

Allocation concealment❑ A. Adequate concealment ❑ B. Concealment unclear ❑ C. Inadequate concealment

Were groups comparable at baseline?❑ Yes❑ Unclear❑ No

Performance biasWere recipients aware of their assigned treatment?❑ Yes❑ Unclear❑ No

Were providers of care aware of the recipients assigned treatment?❑ Yes❑ Unclear❑ No

Detection biasWere outcome assessors aware of the recipients assigned treatment?❑ Yes❑ Unclear❑ No

Attrition biasDoes the study state how many fewer people were analysed than randomised?❑ Yes❑ Unclear❑ No

Was an a priori sample size conducted?❑ Yes❑ Unclear❑ No

Who funded the study (and which of the arms is their drug)?

Notes on allocation concealmentAdequate methods to ensure allocation concealment include:❑ centralised (e.g. allocation by a central office unaware of subject characteristics) or pharmacy-

controlled randomisation❑ pre-numbered or coded identical containers which are administered serially to participants

Appendix 4

202

❑ on-site computer system combined with allocations kept in a locked unreadable computer file that canbe accessed only after the characteristics of an enrolled participant have been entered

❑ sequentially numbered, sealed, opaque envelopes❑ similar approaches along with reassurance that the person who generated the allocation scheme did

not administer it.

Inadequate approaches to allocation concealment include: ❑ alternation❑ use of case record numbers ❑ dates of birth or day of the week ❑ any procedure that is entirely transparent before allocation, such as an open list of random numbers.

Unclear concealment approaches include:❑ stating that a list or table was used ❑ only specifying that sealed envelopes were used❑ reporting an apparently adequate concealment scheme in combination with other information that

leads the reviewer to be suspicious.

(b) Quality data assessment for non-RCTsType of study: ❑ Pseudo-randomised CT, ❑ Non-randomised parallel trial, ❑ Cohort study

Allocation concealment ❑ C. Inadequate concealment

Active arm Control arm

No. approached

No. agreed to participate

No. assessed

How were participants approached for inclusion?

How were participants chosen for inclusion?

Were participants blinded to the intervention? yes / no / unsure

Were assessors blinded to the intervention? yes / no / unsure

Were characteristics of the participants well described? yes / no / unsure

Potential differences between the two groups

Were characteristics of the drop-outs well described? yes / no / unsure

Were the participants in different intervention groups recruited from the same population? yes / no / unsure

Were the participants in different intervention yes / no / unsuregroups recruited at the same time?

Was there adequate adjustment for confounding in the analysis? yes / no / unsure

Were participants analysed in the groups to which yes / no / unsurethey were allocated?

Were deaths actively sought and recorded? yes / no / unsure


203


(c) Data extraction form for RCTs

Ref ID

Title

Author/Year

Dates of study

Location/setting

Method of recruitment

Participants general description (age, sex, baseline disease status, etc.)

Inclusion criteria Exclusion criteria

See Pages:

Remember to highlight relevant section(s) in paper

Appendix 4

204

DETAILS OF Group A Group B Group C Group DINTERVENTION CONTROL

Description of interventionInclude actual dose and frequency of NSAID and any gastroprotectors used if reported

Any other treatment received

Ratio, daily dose/min. to max. range in BNF i.e. 120 mg/90–150 mg

Details of any participant education regarding use of NSAID (type of advice given re potential side effects, how to respond if side-effects occur, and how such advice was provided)

Length of active treatment from randomisation

Maximum length of study from randomisation

Number and frequency of visits from randomisation

Aspirin allowed? YES/NO

Analgesic allowed? YES/NO

Washout period before randomisation? YES/NO details

BASELINE Group A Group B Group C Group DCHARACTERISTICS CONTROL

M/F

Age (mean, SD)

Smoking history

Alcohol history

H. pylori status + test details

History of aspirin use

Type + duration arthritis

History of 1a perforations

1b ulcers

1c bleeds

1d total

2 history of H2RA use


205


Concomitant use of 3a anti-coags

3b corticosteroids

3c antiplatelets

BASELINE Group A Group B Group C Group DCHARACTERISTICS CONTROL

4 Concurrent use >1 NSAID

Co-morbidities

5a % CVD

5b % diabetes (1 and 2)

5c % hypertensive

5d % renal/hepatic disease

5e total % co-morbidities

Total no. risk factors (1–5)

PARTICIPANT FLOW Group A Group B Group C Group D TOTALCONTROL

Number eligible

Number assigned to each group

Number assessed and timing of short-term assessment (3/52–8/52)

Number assessed and timing of medium-term assessment (>8/52–52/52)

Number assessed and timing of long-term assessment (>52/52)

Number assessed at end of study for total GI symptoms

Number completed

Total number of drop-outs at end of study

Number dead at end of study

What is the study’s main ITT as per protocol (only those receiving set regime) completer outcome and how were (all those finishing)participants analysed for this outcome?

Were participants excluded from analysis due to GI changes not including frank ulcers?

Appendix 4

206

OUTCOMES (Use a different page for each time of assessment, e.g. short,medium, long-term) Timing =

DON’T COUNT Group A Group B Group C Group DPT >ONCE IN CONTROLEACH CATEGORY)

Death (all-cause, GI, non-GI)Include age, sex

GIVE DENOMINATOR

Serious GI complications [including haemorrhage, (haemorrhagic erosions, recurrent upper GI bleeds), perforation, pyloric obstruction, melaena, incl. death from any of these]

GIVE DENOMINATOR

Symptomatic ulcers (gastric, duodenal, oesophageal, incl. bleeding ulcers)

GIVE DENOMINATOR

Serious cardiovascular or renal illness leading to contact with primary or secondary health care (incl. angina, MI, stroke, TIA, renal failure, or death from any of these)

GIVE DENOMINATOR

OUTCOMES (Use a different page for each time of assessment, e.g. short,medium, long-term) Timing =

Group A Group B Group C Group DCONTROL

Quality of life

GIVE DENOMINATOR

GI symptoms (nausea, dyspepsia, vomiting, abdo pain, diarrhoea, etc.). Give details

GIVE DENOMINATORAssume each GI symptom counted once for each participant unless otherwise stated

Endoscopic ulcers (≥3 mm diameter)

GIVE DENOMINATOR


207


Anaemia

GIVE DENOMINATOR

Occult bleeding

GIVE DENOMINATOR

Economic (YES/NO)

Participant satisfaction/preferences

Number of withdrawals due to GI adverse events

Pain assessment measures used, with scales (e.g. VAS 0 to 100)

How were adverse events assessed? (e.g. prespecified list checked at each visit or open question about ‘any side-effects’ or diary, etc.)

Compliance (how measured and results)

GIVE DENOMINATOR

Subgroup analyses? YES/NO with details

Any additional comments

CHECKLIST YES NO DATE COMPLETED

Data extraction 1

Data extraction 2

Checked and agreed (use as final copy)

Refs checked

Action required

INTER-RATER RELIABILITY

Ref. ID number: Agree?

YES NO

Number assessed at end of study

Total number of drop-outs at end of study

Total GI symptoms

Allocation concealment TB Y / N LH Y / N


209


Appendix 5

Subgrouping the meta-analyses by Cox-2 preferential or Cox-2 constitutional coxib

(a) Serious GI complications

Review: NSAID review (subgrouping by Cox-2 preferential)Comparison: 04 Cox-2 vs Cox-1Outcome: 12 Serious GI complications, subgrouped by Cox-2 or preferentials

01 Cox-2 preferentials Astorga Paulsen, 1991 Karbowski, 1991 Waterworth, 1992 Carrabba, 1995 Dore, 1995 Hosie, 1996 Linden, 1996 Wojtulewski, 1996 Hosie, 1997 Lightfoot, 1997 Rogind, 1997 Dequeker, 1998 Hawkey, 1998 Dougados, 1999 Huskison, 1999 Sharma, 1999 Yocum, 2000 Chang, 2001 Furst, 2001Subtotal (95% CI)Total events: 17 (Cox-2), 26 (Placebo)Test for heterogeneity: �2 = 5.02, df = 14 (p = 0.99), I2 = 0%Test for overall effect: z = 1.64 (p = 0.10)

02 Cox-2 constitutionals (coxibs) Bensen, 1999 Emery, 1999 Laine, 1999 Simon, 1999 Bombardier, 2000 CLASS, 2000 Cannon, 2000 Hawkey, 2000 Dougados, 2001 Goldstein, 2001 Kivitz, 2001 Truitt, 2001Subtotal (95% CI)Total events: 41 (Cox-2), 74 (Placebo)Test for heterogeneity: �2 = 6.17, df = 10 (p = 0.80), I2 = 0%Test for overall effect: z = 3.20 (p = 0.001)

Total (95% CI)Total events: 55 (Cox-2), 100 (Placebo)Test for heterogeneity: �2 = 11.29, df = 25 (p = 0.99), I2 = 0%Test for overall effect: z = 3.58 (p = 0.0003)

1/112 0/31 0/28 0/216 0/86 1/169 1/128 0/199 1/306 0/147 0/138 6/4320 3/4635 0/244 1/135 0/21 1/310 0/36 2/536

11797

0/399 0/326 1/381 0/693

18/4047 20/3897

0/516 0/369 0/80 2/269 0/420 0/174

11661

23458

0/106 1/33 1/29 0/109 1/82 1/167 2/127 0/180 0/149 1/139 2/133

11/4336 5/4688 1/108 0/144 0/28 0/153 0/36 0/181

10928

1/198 1/329 2/183 1/225

39/4029 24/3981

0/268 1/187 1/90 2/270 1/207

1/115 10082

21010

0.970.990.99

0.971.291.73

0.970.971.08

10.014.830.970.97

0.97

1.0828.79

0.970.971.720.97

31.8928.23

0.970.972.590.970.97

71.21

100.00

2.84 (0.12 to 68.97)0.35 (0.01 to 8.38)0.34 (0.01 to 0.12)Not estimable0.32 (0.01 to 7.70)0.99 (0.06 to 15.67)0.50 (0.05 to 5.40)Not estimable1.47 (0.06 to 35.77)0.32 (0.01 to 7.68)0.19 (0.01 to 3.98)0.55 (0.20 to 1.48)0.61 (0.15 to 2.54)0.15 (0.01 to 3.61)3.20 (0.13 to 77.85)Not estimable1.49 (0.06 to 36.25)Not estimable1.69 (0.08 to 35.13)0.61 (0.34 to 1.10)

0.17 (0.01 to 4.05)0.34 (0.01 to 8.23)0.24 (0.02 to 2.63)0.11 (0.00 to 2.66)0.46 (0.26 to 0.80)0.83 (0.46 to 1.50)Not estimable0.17 (0.01 to 4.14)0.37 (0.02 to 9.06)1.00 (0.14 to 7.07)0.16 (0.01 to 4.03)0.22 (0.01 to 5.38)0.54 (0.38 to 0.79)

0.56 (0.41 to 0.77)

Studyor subcategory

Cox-2n/N

Placebon/N

RR (random)95% CI

Weight%

RR (random)(95% CI)

0.1 0.2 0.5 1 2 5 10Favours placeboFavours Cox-2

Appendix 5

210

(b) Symptomatic ulcers

Review: NSAID review (subgrouping by Cox-2 preferentials)Comparison: 04 Cox-2 vs Cox-1Outcome: 13 Symptomatic ulcers, subgrouped by Cox-2 or preferentials

01 Cox-2 preferentials Karbowski, 1991 Perpignano, 1994 Linden, 1996 Wojtulewski, 1996 Goei The, 1997 Lightfoot, 1997 Rogind, 1997 Dequeker, 1998 Hawkey, 1998 Porto, 1998 Dougados, 1999 Roy, 1999 Sharma, 1999 Yocum, 2000 Chang, 2001 Furst, 2001Subtotal (95% CI)Total events: 23 (Cox-2), 59 (Placebo)Test for heterogeneity: �2 = 3.48, df = 13 (p = 1.00), I2 = 0%Test for overall effect: z = 3.84 (p = 0.0001)

02 Cox-2 constitutionals (coxibs) Bensen, 1999 Emery, 1999 Laine, 1999 Simon, 1999 Bombardier, 2000 CLASS, 2000 Cannon, 2000 Day, 2000 Dougados, 2001 Goldstein, 2001 Truitt, 2001 Kivitz, 2002Subtotal (95% CI)Total events: 97 (Cox-2), 184 (Placebo)Test for heterogeneity: �2 = 6.45, df = 10 (p = 0.78), I2 = 0%Test for overall effect: z = 5.78 (p < 0.00001)

Total (95% CI)Total events: 120 (Cox-2), 243 (Placebo)Test for heterogeneity: �2 = 10.37, df = 24 (p = 0.99), I2 = 0%Test for overall effect: z = 6.90 (p < 0.00001)

0/31 0/24 1/128 0/199 0/128 0/147 0/138 7/4320 5/4635 1/42 2/244 0/41 4/21 0/310 1/36 2/536

10980

0/399 0/326 1/381 0/693

55/4047 26/3987

4/516 0/477 0/80 5/269 0/174 6/547

11896

22876

1/33 1/29 3/127 2/180 1/130 3/139 1/133

17/4336 7/4688 3/41 4/108 0/49

12/28 0/153 4/36 0/181

10391

1/198 1/329 2/183 1/225

120/4029 41/3981

3/268 2/244 1/90 5/270 0/155 7/183

10115

20506

0.460.460.910.500.450.530.455.983.520.941.63

4.81

1.010.50

22.18

0.450.450.810.45

46.2619.31

2.080.500.463.07

3.9877.82

100.0

0.35 (0.01 to 8.38)0.40 (0.02 to 9.39)0.33 (0.03 to 3.14)0.18 (0.01 to 3.75)0.34 (0.01 to 8.23)0.14 (0.01 to 2.59)0.32 (0.01 to 7.82)0.41 (0.17 to 1.00)0.72 (0.23 to 2.27)0.33 (0.04 to 3.00)0.22 (0.04 to 1.19)Not estimable0.44 (0.17 to 1.18)Not estimable0.25 (0.03 to 2.13)1.69 (0.08 to 35.13)0.41 (0.26 to 0.65)

0.17 (0.01 to 4.05)0.34 (0.01 to 8.23)0.24 (0.02 to 2.63)0.11 (0.00 to 2.66)0.46 (0.33 to 0.63)0.63 (0.39 to 1.03)0.69 (0.16 to 3.07)0.10 (0.00 to 2.13)0.37 (0.02 to 9.06)1.00 (0.29 to 3.43)Not estimable0.29 (0.10 to 0.84)0.49 (0.38 to 0.62)

0.47 (0.38 to 0.58)

Studyor subcategory

Cox-2n/N

Placebon/N

RR (random)95% CI

Weight%

RR (random)(95% CI)



211


(c) Endoscopic ulcers

Review: NSAID review (subgrouping by Cox-2 preferentials)Comparison: 04 Cox-2 vs Cox-1Outcome: 14 Endoscopic ulcers, subgrouped by Cox-2 or preferentials

01 Cox-2 preferentials Taha, 1990 Perpignano, 1991 Perpignano, 1994 Porto, 1998 Chang, 2001Subtotal (95% CI)Total events: 5 (Cox-2), 10 (Placebo)Test for heterogeneity: �2 = 2.41, df = 4 (p = 0.06), I2 = 0%Test for overall effect: z = 1.01 (p = 0.31)

02 Cox-2 constitutionals (coxibs) Emery, 1999 Laine, 1999 Simon, 1999 Hawkey, 2000 Goldstein, 2001 Kivitz, 2002Subtotal (95% CI)Total events: 162 (Cox-2), 360 (Placebo)Test for heterogeneity: �2 = 3.25, df = 5 (p = 0.66), I2 = 0%Test for overall effect: z = 15.82 (p < 0.00001)

Total (95% CI)Total events: 167 (Cox-2), 370 (Placebo)Test for heterogeneity: �2 = 8.09, df = 10 (p = 0.62), I2 = 0%Test for overall effect: z = 15.82 (p < 0.00001)

0/15 1/10 2/24 1/42 1/36

127

8/212 44/364 23/423 42/369 24/269 21/547

2184

2311

1/15 0/8 2/29 3/41 4/36

129

33/218 76/167 36/137 88/187

109/267 18/183

1159

1288

0.290.300.810.590.632.61

5.1227.5312.1427.5717.23

7.8097.39

100.00

0.33 (0.01 to 7.58)2.45 (0.11 to 53.25)1.21 (0.18 to 7.95)0.33 (0.04 to 3.00)0.25 (0.03 to 2.13)0.58 (0.20 to 1.66)

0.25 (0.12 to 0.53)0.27 (0.19 to 0.37)0.21 (0.13 to 0.34)0.24 (0.18 to 0.33)0.22 (0.15 to 0.33)0.39 (0.21 to 0.72)0.25 (0.21 to 0.30)

0.25 (0.21 to 0.30)

Studyor subcategory

Cox-2n/N

Placebon/N

RR (random)95% CI

Weight%

RR (random)(95% CI)



213


Appendix 6

Full tables of characteristics of included studies

Appendix 6

214 (a)

H2R

A p

lus

NSA

ID v

ersu

s pl

aceb

o pl

us N

SAID

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Bian

chi P

orro

,19

8746

(boo

kch

apte

r)Lo

cati

on:o

nece

ntre

, Ita

ly

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

con

ceal

men

t:un

clea

r B

asel

ine

com

para

bilit

y:un

clea

r, no

det

ails

Part

icip

ant

blin

ding

:yes

Ass

esso

r bl

indi

ng:u

ncle

ar

Inte

ntio

n-to

-tre

at:N

oA

pri

ori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:end

osco

pype

rfor

med

and

exc

lude

d pa

rtic

ipan

tsw

ithou

t no

rmal

gas

tric

muc

osa

Bas

elin

e N

SAID

sta

tus:

all p

artic

ipan

tsta

king

one

or

mor

e N

SAID

sTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:rh

eum

atic

dise

ase,

no

furt

her

deta

ilsA

ge:n

ot s

tate

dSe

x:no

t st

ated

Incl

usio

n cr

iter

ia:p

atie

nts

with

rheu

mat

ic d

iseas

e, n

orm

al g

astr

ic m

ucos

aan

d tr

eate

d w

ith o

ne o

r m

ore

NSA

IDs

Excl

usio

n cr

iter

ia:n

o de

tails

Com

pari

son:

rani

tidin

e pl

us m

ixed

NSA

IDs

(b) v

s pl

aceb

o pl

us m

ixed

NSA

IDs

(a)

Dur

atio

n:4

wee

ksIn

terv

enti

ons:

b, r

aniti

dine

tab

lets

300

mg/

150–

300

mg

(150

mg

×2

daily

); a,

pla

cebo

N

SAID

s:pa

tient

s cu

rren

tlypr

escr

ibed

NSA

IDs,

no

furt

her

deta

ilsO

ther

med

icat

ion:

no d

etai

lsA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:not

sta

ted

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:not

sta

ted

Num

ber

and

freq

uenc

y of

vis

its:

not

stat

ed

Allo

cate

d:a

127,

b 1

19C

ompl

eted

:a 1

16,

b11

0D

rop-

out:

a 11

, b 9

Ass

esse

d:a

127,

b 1

19

Out

com

es r

epor

ted:

tota

l dro

p-ou

tH

ow w

ere

adve

rse

even

ts a

sses

sed:

not

stat

edH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:N

ode

tails

FU

ND

ING

Fund

ed b

y:no

det

ails

Affi

liati

on o

f con

tact

auth

or:L

. Sac

coH

ospi

tal,

Mila

n, It

aly

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:un

clea

r

Roth

198

747

Loca

tion

:one

cent

re, U

SA

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

con

ceal

men

t:un

clea

rB

asel

ine

com

para

bilit

y:un

clea

rPa

rtic

ipan

t bl

indi

ng:y

esA

sses

sor

blin

ding

:unc

lear

In

tent

ion

to t

reat

:no

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:end

osco

pype

rfor

med

and

exc

lude

d pa

rtic

ipan

ts w

ithul

cer

(had

to

have

impr

ovem

ent

from

grad

e II

or II

I fol

low

ing

8w

eeks

of

cim

etid

ine

or p

lace

bo)

Bas

elin

e N

SAID

sta

tus:

all p

artic

ipan

tsta

king

NSA

IDs

Type

and

dur

atio

n of

art

hrit

is (

year

s):

RA o

r re

late

d rh

eum

atic

diso

rder

s, O

A,

no fu

rthe

r de

tails

Age

:not

sta

ted

Sex:

not

stat

edIn

clus

ion

crit

eria

: 18

year

s or

old

er, R

Aor

rel

ated

rhe

umat

ic d

isord

ers

or O

A;

taki

ng N

SAID

s, o

ther

con

com

itant

arth

ritis

ther

apie

s su

ch a

s lo

w-d

ose

gluc

ocor

ticoi

ds (7

.5m

g of

pre

dniso

ne

Com

pari

son:

cim

etid

ine

plus

mix

ed N

SAID

s (b

) vs

plac

ebo

plus

mix

ed N

SAID

s (a

)D

urat

ion:

10 m

onth

sIn

terv

enti

ons:

b, c

imet

idin

eta

blet

s 40

0m

g/40

0m

g (2

00m

g×2

daily

); a,

mat

chin

g pl

aceb

ota

blet

s (×

2 da

ily)

Endo

scop

y:10

mon

ths

NSA

IDs:

adju

sted

thr

ough

out

stud

y w

ithou

t re

stric

tion:

indo

met

haci

n: a

1, b

2m

eclo

fem

anat

e so

dium

:a 1

, b 1

ib

upro

fin, a

2, b

1

napr

oxen

, a 3

, b 1

sa

lsala

te, a

2, b

1

aspi

rin, a

1, b

0

Allo

cate

d:36

in t

otal

Com

plet

ed:a

: 14,

b 1

2D

rop-

out:

10 in

tot

alA

sses

sed:

a: 1

4, b

12

Out

com

es r

epor

ted:

endo

scop

ic u

lcer

sH

ow w

ere

adve

rse

even

ts a

sses

sed:

not

stat

edH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:

All

part

icip

ants

had

rece

nt h

istor

y of

gra

deII

or II

I end

osco

pysc

ore

Con

com

itant

use

of

antic

oagu

lant

s(w

arfa

rin t

ype)

:a 0

, b

0 R

enal

/hep

atic

dise

ase:

a 0

b 0

FUN

DIN

GFu

nded

by:

Smith

Klin

e &

Fre

nch

Affi

liati

on o

f con

tact

auth

or:A

rthr

itis

Cen

ter,

Ariz

ona


215


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

daily

or

less

) wer

e al

low

ed, a

s w

ere

dise

ase-

mod

ifyin

g an

tirhe

umat

ic d

rugs

(met

hotr

exat

e so

dium

, pen

icill

amin

e,au

roth

iogl

ucos

e, h

ydro

xych

loro

quin

esu

lfate

) if s

tabi

lised

for

at le

ast

2m

onth

spr

ior

to s

tart

of s

tudy

and

dos

ages

not

incr

ease

d th

roug

hout

stu

dy; p

artic

ipan

tsha

d gr

ade

II (h

yper

emic

muc

osa,

fria

bilit

y;an

d gr

anul

arity

) and

gra

de II

I (er

osio

ns,

defin

ed a

s di

scon

tinua

tion

of e

pith

eliu

mw

ithou

t cr

ater

form

atio

n) a

nd c

ompl

eted

an 8

-wee

k RC

T, (

cim

etid

ine

300

mg

four

times

dai

ly v

s m

atch

ing

plac

ebo

four

tim

esda

ily),

part

icip

ants

with

an

impr

ovem

ent

in g

rade

at

endo

scop

y w

ere

then

elig

ible

for

this

stud

y Ex

clus

ion

crit

eria

:pre

gnan

t or

nur

sing

wom

en o

r th

ose

not

prac

tisin

g a

clin

ical

lyef

fect

ive

met

hod

of b

irth

cont

rol;

patie

nts

rece

ivin

g w

arfa

rin-t

ype

antic

oagu

lant

s,th

ose

who

had

prio

r ga

stric

sur

gery

or

ulce

rs, d

efin

ed a

s a

disc

ontin

uatio

n of

the

epith

eliu

m w

ith d

efin

ite u

lcer

cra

ter

pres

ent;

hist

ory

of e

vide

nce

of h

epat

ic,

rena

l or

othe

r di

seas

e th

at m

ight

inte

rfer

ew

ith e

ffica

cy o

r sa

fety

ana

lysis

othe

r:a

1, b

5

com

bina

tion:

a 3,

b 1

O

ther

med

icat

ion:

low

-dos

egl

ucoc

ortic

oids

and

DM

ARD

sal

low

ed, w

arfa

rin n

ot a

llow

ed,

som

e pa

rtic

ipan

ts t

akin

g sa

licyl

ates

,st

eroi

ds, g

old

salt,

pen

icill

amin

e,an

tineo

plas

tics

Asp

irin

allo

wed

:no

Ana

lges

ic a

llow

ed:n

ot s

tate

dPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:n

ot s

tate

dN

umbe

r an

d fr

eque

ncy

of v

isit

s:no

t st

ated

Inst

itute

s, P

hoen

ix,

AZ

, USA

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:un

clea

r

Appendix 6

216

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Ehsa

nulla

h, 1

98848

Loca

tion

:18

cent

res

in 5

coun

trie

s (F

ranc

e,Ir

elan

d, N

orw

ay,

Swed

en, U

K)

Met

hod

ofra

ndom

isat

ion:

‘dou

ble-

blin

d se

quen

tial b

asis’

acco

rdin

g to

apr

edet

erm

ined

rand

omisa

tion

code

bala

nced

in b

lock

s of

10

Allo

cati

on c

once

alm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

no, g

roup

b (r

aniti

dine

)yo

unge

r, ha

d ar

thrit

is lo

nger

Part

icip

ant

blin

ding

: yes

Ass

esso

r bl

indi

ng:u

ncle

arIn

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:yes

Sum

mar

y ri

sk o

f bia

s:H

igh

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd e

xclu

ded

part

icip

ants

with

out

zero

Lan

za s

core

B

asel

ine

NSA

ID s

tatu

s:a

46/1

26 a

nd

b 60

/137

had

no

prev

ious

use

of N

SAID

sTy

pe o

f art

hrit

is:O

A: a

96,

b 1

01RA

: a 2

8, b

34

Oth

er: a

2, b

2D

urat

ion

of a

rthr

itis

(ye

ars)

:a

6 (0

–45)

, b 8

(0–5

0)A

ge:a

60

(22–

87),

b 57

(25–

85)

Sex:

F/M

: 158

/105

Incl

usio

n cr

iter

ia:R

A o

r O

A, a

ged

over

18ye

ars,

req

uirin

g tr

eatm

ent

with

NSA

IDs,

zer

o La

nza

scor

e on

bas

elin

een

dosc

opy,

at

leas

t 1

wee

k w

ithou

t ta

king

NSA

IDs

prio

r to

stu

dy e

ntry

Excl

usio

n cr

iter

ia:p

atie

nts

taki

ng g

old,

peni

cilla

min

e az

athi

oprin

e or

chl

oroq

uine

;co

ncom

itant

use

of u

lcer

ogen

ic d

rugs

,tr

eatm

ent

for

pept

ic u

lcer

s du

ring

prec

edin

g 30

day

s (e

xcep

t fo

r lo

w-d

ose

anta

cids

), us

e of

cor

ticos

tero

ids,

preg

nanc

y or

lact

atio

n, G

I mal

igna

ncy,

dysp

hagi

a, R

A o

f the

cer

vica

l spi

ne,

impa

irmen

t of

live

r or

kid

ney

func

tion

Com

pari

son:

rani

tidin

e pl

us m

ixed

NSA

IDs

vs p

lace

bo p

lus

mix

edN

SAID

sD

urat

ion:

4–8

wee

ks (p

artic

ipan

tsco

ntin

ued

afte

r 4-

wee

k en

dosc

opy

only

if li

ttle

or

no g

astr

oduo

dena

lda

mag

e)In

terv

enti

ons:

b, r

aniti

dine

300

mg/

150–

300

mg

(150

mg

×2da

ily);

a, m

atch

ing

plac

ebo

(x2

daily

) En

dosc

opy:

4, 8

wee

ksN

SAID

s:na

prox

en ≥

750

mg/

day:

161

piro

xica

m ≥

20 m

g/da

y: 7

5di

clof

enac

≥10

0 m

g/da

y: 1

7in

dom

atha

cin

≥10

0 m

g/da

y: 1

0O

ther

med

icat

ion:

anta

cids

not

perm

itted

, gol

d, p

enic

illam

ine,

azat

hiop

rine,

chl

oroq

uine

,ul

cero

geni

c dr

ugs,

cor

ticos

tero

ids

excl

uded

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:y

es,

para

ceta

mol

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:yes

, 7 d

ays

Num

ber

and

freq

uenc

y of

vis

its:

3 (0

, 4 a

nd 8

wee

ks, a

lsopa

rtic

ipan

ts w

ith d

yspe

psia

‘dro

pped

in’)

Allo

cate

d: a

146

, b 1

51C

ompl

eted

:a 1

26,

b13

7D

rop-

out:

a: 2

0, b

14

Ass

esse

d: a

: 126

, b 1

37O

utco

mes

rep

orte

d:G

I sym

ptom

s,en

dosc

opic

ulc

ers,

serio

us c

ardi

ovas

cula

r or

rena

l illn

ess,

GI d

rop-

outs

How

wer

e ad

vers

eev

ents

ass

esse

d:pa

rtic

ipan

ts h

avin

gun

sche

dule

d vi

sit d

ue t

ody

spep

sia w

ere

enco

urag

ed t

o ha

veen

dosc

opy

How

was

com

plia

nce

asse

ssed

:tab

let

coun

tat

4 w

eeks

, 75%

part

icip

ants

too

k ov

er90

% o

f tre

atm

ent

med

icat

ion

Ris

k fa

ctor

s:hi

stor

yof

ulc

ers,

a 1

1, b

11

hist

ory

of H

2RA

use

: a21

, b20

Con

com

itan

t us

e of

cort

icos

tero

ids:

a 0,

b 0

Ren

al/h

epat

icdi

seas

e: a

0, b

0

FUN

DIN

GFu

nded

by:

uncl

ear

but

Gla

xo G

roup

Rese

arch

gen

erat

edth

e ra

ndom

isatio

nse

quen

ceA

ffilia

tion

of c

onta

ctau

thor

:Gla

xo G

roup

Rese

arch

, UK

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:3/

4O

ther

:par

ticip

ants

cont

inue

d af

ter

4-w

eek

endo

scop

yon

ly if

litt

le o

r no

gast

rodu

oden

alda

mag

e


217


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Robi

nson

, 198

949

Loca

tion

:10

cent

res

in t

he U

SA

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

assig

ned’

Allo

cati

on c

once

alm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

uncl

ear

Part

icip

ant

blin

ding

: yes

Ass

esso

r bl

indi

ng:u

ncle

arIn

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd p

artic

ipan

ts w

ithou

t ze

roen

dosc

opy

scor

e ex

clud

edTy

pe a

nd d

urat

ion

of a

rthr

itis

in(y

ears

):pr

imar

ily a

rthr

itis,

no

othe

rde

tails

Age

:F/M

: a 4

5.9/

43.1

, b 5

0.1/

47.0

Sex:

F/M

: 93/

51

Incl

usio

n cr

iter

ia:r

equi

ring

NSA

IDth

erap

y pr

imar

ily fo

r ar

thrit

isEx

clus

ion

crit

eria

:bas

elin

e st

omac

h or

duod

enum

end

osco

py s

core

of >

0,pr

evio

us g

astr

ic s

urge

ry, Z

ollin

ger–

Ellis

onsy

ndro

me

or o

ther

pat

holo

gica

l sec

reto

ryco

nditi

on, r

enal

impa

irmen

t (s

erum

crea

tinin

e 2

mg/

dl o

r m

ore)

, ele

vate

dSG

PT le

vel (

3×no

rmal

), hy

pers

ensit

ivity

to H

2an

tago

nist

s, u

se o

f NSA

IDs

with

in48

h pr

ior

to s

tart

of s

tudy

, con

sum

ptio

nof

ant

icho

liner

gics

, tric

lycl

ican

tidep

ress

ants

, pot

assiu

m s

uppl

emen

ts,

rese

rpin

e, s

ucra

lfate

or

ster

oids

dur

ing

the

wee

k pr

ior

to t

he s

tudy

, use

of

>10

mg

pred

niso

ne o

r eq

uiva

lent

per

day

,an

y un

stab

le m

edic

al p

robl

em, m

enta

lim

pairm

ent

or a

lcoh

olism

; pre

gnan

cy o

rla

ctat

ion

Com

pari

son:

rani

tidin

e pl

us m

ixed

NSA

IDs

vs p

lace

bo p

lus

mix

edN

SAID

sD

urat

ion:

8 w

eeks

Inte

rven

tion

s:b,

ran

itidi

ne30

0m

g/15

0–30

0m

g (1

50m

g×2

daily

); a,

pla

cebo

(×2

daily

)En

dosc

opy:

1, 4

and

8 w

eeks

NSA

IDs:

a +

b, c

hoic

e of

NSA

IDsp

ecifi

ed fo

r ea

ch p

artic

ipan

t by

refe

rrin

g ph

ysic

ian

or r

ando

mly

assig

ned

if ph

ysic

ian

had

nopr

efer

ence

ibup

rofe

n ≥

1600

mg/

day:

a 1

7, b

12

napr

oxen

≥75

0m

g/da

y: a

25,

b 2

7su

linda

c ≥

300

mg/

day:

a 1

7, b

19

indo

met

haci

n ≥

100

mg/

day:

a 8

, b 5

piro

xica

m ≥

20m

g/da

y: a

5, b

7

othe

r: a

0, b

2O

ther

med

icat

ion:

ant

acid

(Maa

lox)

per

mitt

ed,

antic

holin

ergi

cs, t

ricyc

lican

tidep

ress

ants

, pot

assiu

msu

pple

men

ts, r

eser

pine

, suc

ralfa

teor

ste

roid

s ex

clud

edA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:not

sta

ted

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:48

h fo

r N

SAID

s,1

wee

k fo

r an

ticho

liner

gics

, tric

yclic

antid

epre

ssan

ts, p

otas

sium

supp

lem

ents

, res

erpi

ne, H

2an

tago

nist

s, s

ucra

lfate

, ste

roid

sN

umbe

r an

d fr

eque

ncy

of v

isit

s:4

(0, 1

, 4 a

nd 8

wee

ks)

Allo

cate

d:a

72, b

72

Com

plet

ed: u

ncle

arD

rop-

out:

uncl

ear

Ass

esse

d:a

50, b

60

Out

com

es r

epor

ted:

endo

scop

ic u

lcer

s H

ow w

ere

adve

rse

even

ts a

sses

sed:

not

stat

edH

ow w

as c

ompl

ianc

eas

sess

ed:t

able

t co

unt,

resu

lt no

t re

port

ed

Ris

k fa

ctor

s:no

deta

ilsFU

ND

ING

Fu

nded

by:

Gla

xoA

ffilia

tion

of c

onta

ctau

thor

:Okl

ahom

aC

ity C

linic

, Okl

ahom

aC

ity, O

K, U

SAA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

1/7?

Oth

er: p

artic

ipan

tsw

ithdr

awn

if cl

inic

ally

signi

fican

t bl

eedi

ng o

nen

dosc

opy

Appendix 6

218

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Swift

, 198

9,50

Loca

tion

:U

nive

rsity

of

Wal

es,

rheu

mat

olog

ycl

inic

s at

Car

diff

and

Sing

leto

nH

ospi

tal,

UK

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

allo

cate

d by

pha

rmac

ist’

Allo

cati

on c

once

alm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

uncl

ear

Part

icip

ant

blin

ding

:yes

A

sses

sor

blin

ding

:unc

lear

In

tent

ion-

to-t

reat

:yes

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed: 4

par

ticip

ants

had

ulc

ers

(2ha

d oe

soph

agea

l ulc

ers,

1 h

adoe

soph

agea

l ulc

er a

nd d

uode

nal u

lcer

, 1

had

gast

ric u

lcer

), 19

had

ero

sions

of

othe

r ty

pes

and

1 ha

d no

rmal

end

osco

pyB

asel

ine

NSA

ID s

tatu

s:al

l par

ticip

ants

had

been

tak

ing

NSA

IDs

for

at le

ast

3m

onth

sTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:rh

eum

atoi

d di

seas

e n

=20

, OA

n=

3,ce

rvic

al s

pond

ylos

is n

=1,

no

othe

rde

tails

Age

:56.

5 (3

2–70

) Se

x: F

/M: 1

3/11

Incl

usio

n cr

iter

ia:p

atie

nts

atte

ndin

grh

eum

atol

ogy

clin

ics,

tak

ing

regu

lar

daily

dose

s of

an

NSA

ID fo

r 3

mon

ths

or m

ore

Excl

usio

n cr

iter

ia:n

o de

tails

Com

pari

son:

rani

tidin

e pl

us m

ixed

NSA

IDs

vs p

lace

bo p

lus

mix

edN

SAID

sD

urat

ion:

14 w

eeks

(2×

7w

eek

trea

tmen

t pe

riods

)In

terv

enti

ons:

c, r

aniti

dine

600

mg/

150–

300

(300

mg

×2 d

aily

)fo

r 7

wee

ks t

hen

300

mg/

150–

300

µg (1

50m

g×2

daily

) for

nex

t 7

wee

ks;

b, r

aniti

dine

300

mg/

150–

300

µg(1

50m

g ×2

dai

ly) f

or 7

wee

ks t

hen

600

mg/

150–

300

µg (3

00m

g ×2

daily

) for

nex

t 7

wee

ks;

a, p

lace

bo (n

umbe

r of

tab

lets

giv

enco

rres

pond

ed w

ith g

roup

s b

and

c)En

dosc

opy:

1, 8

and

15

wee

ksN

SAID

s: n

o de

tails

Oth

er m

edic

atio

n:ot

her

seco

nd-

line

ther

apy

allo

wed

to

cont

inue

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:n

ot s

tate

dPa

rtic

ipan

t ed

ucat

ion:

not

sta

ted

Was

hout

:yes

, 1 w

eek

Num

ber

and

freq

uenc

y of

vis

its:

4 (0

, 1, 8

and

15

wee

ks)

Allo

cate

d:a

8, b

8, c

8C

ompl

eted

: a 8

, b 8

, c

8D

rop-

out:

a 0,

b 0

, c 0

Ass

esse

d:a

8, b

8, c

8O

utco

mes

rep

orte

d:m

orta

lity,

end

osco

pic

ulce

rs, G

I dro

p-ou

ts,

tota

l dro

p-ou

tsH

ow w

ere

adve

rse

even

ts a

sses

sed:

daily

diar

y ca

rds

to r

ecor

dsy

mpt

oms

on s

cale

0–3

and

aver

age

daily

sco

res

for

each

7-w

eek

perio

dw

ere

calc

ulat

edH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:4

part

icip

ants

had

ulc

ers

(2 h

ad o

esop

hage

alul

cers

, 1 h

adoe

soph

agea

l ulc

er a

nddu

oden

al u

lcer

, 1

part

icip

ant

had

gast

ric u

lcer

)FU

ND

ING

Fu

nded

by:

uncl

ear,

but

Gla

xo p

rovi

ded

plac

ebo

Affi

liati

on o

f con

tact

auth

or:U

nive

rsity

Hos

pita

l of W

ales

, UK

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:0/

6O

ther

:2 p

lace

bogr

oups

ana

lyse

dto

geth

er; 2

par

ticip

ants

in g

roup

b a

nd 1

ingr

oup

c w

ere

taki

ngle

ss t

han

min

imum

reco

mm

ende

d do

se o

fN

SAID

s; p

artic

ipan

tsw

ith b

asel

ine

ulce

rex

clud

ed fr

om a

naly

ses

of e

ndos

copi

c da

ta;

part

icip

ants

with

base

line

ulce

r ca

nnot

be e

xclu

ded

from

othe

r ou

tcom

e da

ta b

yre

view

ers


219


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Sim

on,

1990

51,1

57,1

58

Loca

tion

:5

diffe

rent

cen

tres

incl

udin

gH

eide

lbur

g an

dH

ambu

rg,

Ger

man

y

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

con

ceal

men

t:un

clea

r B

asel

ine

com

para

bilit

y:ye

sPa

rtic

ipan

t bl

indi

ng:y

es

Ass

esso

r bl

indi

ng:u

ncle

ar

Inte

ntio

n-to

-tre

at:u

ncle

ar

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd e

xclu

ded

part

icip

ants

with

fran

k ul

cers

(but

not

hae

mor

rhag

es a

nd/o

rer

osio

ns)

Bas

elin

e N

SAID

sta

tus:

part

icip

ants

had

to h

ave

been

tak

ing

NSA

IDs

for

at le

ast

3m

onth

sTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:A

S, R

A, O

A, n

o ot

her

deta

ilsA

ge:a

52,

b 5

0Se

x:F/

M: 2

1/25

Incl

usio

n cr

iter

ia:A

S, R

A, O

A; m

ean

pre-

tria

l dur

atio

ns o

f NSA

ID (d

iclo

fena

c,in

dom

etha

cin,

piro

xica

m) u

se a

t le

ast

3m

onth

s, p

rese

nce

of e

piga

stric

dist

ress

,en

dosc

opic

ally

pro

ven

mor

phol

ogic

alch

ange

s in

gas

tric

and

duo

dena

l muc

osa

Excl

usio

n cr

iter

ia:h

istor

y of

gas

tric

ulce

rs a

nd/o

r ul

cer

com

plic

atio

ns;

preg

nanc

y, la

ctat

ion,

sev

ere

conc

omita

ntdi

seas

e, p

artic

ipan

ts t

akin

g co

rtic

oste

roid

sor

gol

d pr

epar

atio

ns

Com

pari

son:

rani

tidin

e pl

us m

ixed

NSA

IDs

vs p

lace

bo p

lus

mix

edN

SAID

sD

urat

ion:

4–8

wee

ks (t

reat

men

tco

ntin

ued

afte

r 4

wee

ks if

ero

sions

not

heal

ed)

Inte

rven

tion

s:b,

ran

itidi

ne30

0m

g/15

0–30

0 (1

50m

g ×2

dai

ly);

a, p

lace

bo (×

2 da

ily)

Endo

scop

y:4,

8 w

eeks

NSA

IDs:

a +

b: a

t pr

e-tr

ial d

osag

ele

vels

dicl

ofen

ac 1

00–3

00m

g/da

y: a

13,

b13

piro

xica

m 2

0–30

mg/

day:

a 5

, b 6

indo

met

haci

n 50

–300

mg/

day:

a 5

,b

4O

ther

med

icat

ion:

anta

cids

not

allo

wed

, cor

ticos

tero

ids

and

gold

prep

arat

ions

wer

e ex

clud

edA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:not

sta

ted

Part

icip

ant

educ

atio

n:no

t st

ated

W

asho

ut:n

ot s

tate

dN

umbe

r an

d fr

eque

ncy

of v

isit

s:3

(0, 4

and

8 w

eeks

)

Allo

cate

d:48

in t

otal

Com

plet

ed: u

ncle

arD

rop-

out:

uncl

ear

Ass

esse

d:a

23, b

23

Out

com

es r

epor

ted:

endo

scop

ic u

lcer

sH

ow w

ere

adve

rse

even

ts a

sses

sed:

diar

yca

rds,

45%

gro

up a

(pla

cebo

) vs

80%

gro

upb

(ran

itidi

ne) =

sym

ptom

free

but

mos

tpa

rtic

ipan

ts d

id n

otco

mpl

ete

diar

y ca

rds

How

was

com

plia

nce

asse

ssed

:tab

let

coun

t,re

sult

not

repo

rted

Ris

k fa

ctor

s:hi

stor

y of

PU

Bs:

a 0,

b 0

C

onco

mita

nt u

se o

fco

rtic

oste

roid

s:a

0,

b 0

FUN

DIN

GFu

nded

by:

not

stat

edA

ffilia

tion

of c

onta

ctau

thor

:Kra

nken

haus

Schw

etzi

ngen

,Sc

hwet

zing

enA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

0/4

Oth

er:t

reat

men

tco

ntin

ued

afte

r 4

wee

ks if

ero

sions

not

heal

ed

Appendix 6

220

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Yana

gaw

a, 1

99152

Loca

tion

:13

inst

itutio

ns in

Japa

n

Met

hod

ofra

ndom

isat

ion:

‘env

elop

em

etho

d’A

lloca

tion

con

ceal

men

t:un

clea

rB

asel

ine

com

para

bilit

y:ye

sPa

rtic

ipan

t bl

indi

ng:y

esA

sses

sor

blin

ding

:yes

In

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:U

ncle

arSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd e

xclu

ded

part

icip

ants

with

mor

e th

an e

rosio

n an

d ha

emor

rhag

e at

mor

e th

an 2

site

s an

d m

ore

than

one

are

aof

the

sto

mac

h; m

ore

than

ero

sion

and

haem

orrh

age

at 1

or

2 sit

es o

f the

duod

enum

Bas

elin

e N

SAID

sta

tus:

som

epa

rtic

ipan

ts w

ere

not

taki

ng N

SAID

s pr

ior

to s

tudy

, som

e w

ere,

num

bers

unc

lear

Type

and

dur

atio

n of

art

hrit

is (

year

s):

RA: a

11,

b 1

7Sp

ondy

losis

def

orm

ans,

a 2

, b 3

Lum

bago

, a 9

, b 6

Deg

ener

ativ

e go

narh

tros

is, a

1, b

3Sc

apul

ohum

eral

per

iart

hriti

s, a

2, b

1C

arvi

co-o

mo-

brac

hial

syn

drom

e, a

0, b

2O

ther

s, a

8, b

7N

o fu

rthe

r de

tails

A

ge:a

52.

9, b

53.

4Se

x:F/

M: 4

3/29

Incl

usio

n cr

iter

ia:p

artic

ipan

ts w

ithrh

eum

atic

dise

ase

or t

hose

with

lum

bago

and

cerv

ico-

omob

rach

ial s

yndr

ome

who

requ

ired

trea

tmen

t w

ith N

SAID

s, p

atie

nts

rece

ivin

g pr

evio

us t

reat

men

t w

ith N

SAID

sin

who

m a

1-w

eek

was

hout

per

iod

was

poss

ible

or

thos

e w

ho w

ere

not

unde

rtr

eatm

ent

with

NSA

IDs

at t

he s

tart

of t

hetr

ial,

patie

nts

who

had

did

not

hav

een

dosc

opic

ally

det

erm

ined

lesio

ns (L

anza

scor

e of

2 o

r m

ore)

in t

he s

tom

ach

ordu

oden

umEx

clus

ion

crit

eria

:pre

gnan

cy, n

ursin

gm

othe

rs, o

r pa

tient

s ju

dged

by

atte

ndin

gph

ysic

ian

as u

nsui

tabl

e

Com

pari

son:

rani

tidin

e pl

us m

ixed

NSA

IDs

vs p

lace

bo p

lus

mix

edN

SAID

sD

urat

ion:

8 w

eeks

Inte

rven

tion

s:b,

ran

itidi

ne30

0m

g/15

0–30

0 µg

(150

mg

×2da

ily);

a, p

lace

bo (×

2 da

ily)

plac

ebo

simila

r to

ran

itidi

ne in

appe

aran

ce, t

aste

and

odo

urEn

dosc

opy:

2, 4

and

8 w

eeks

(adj

uste

d w

ith a

ppea

ranc

e of

subj

ectiv

e or

obj

ectiv

e sy

mpt

oms)

NSA

IDs:

a +

b:

indo

met

haci

n: a

1, b

3

dicl

ofen

ac: a

12,

b 1

6 m

efan

amic

aci

d: a

4, b

6

piro

xica

m: a

12,

b 1

0 ot

hers

: a 4

, b 4

Oth

er m

edic

atio

n:co

ncom

itant

use

of d

rugs

for

gast

ritis,

ant

iulc

erdr

ugs,

ant

icho

liner

gics

and

ant

acid

sw

as p

rohi

bite

dA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:not

sta

ted

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:yes

, 1 w

eek

Num

ber

and

freq

uenc

y of

vis

its:

4 (0

, 2, 4

and

8 w

eeks

)

Allo

cate

d:a

37, b

43

Com

plet

ed:a

7, b

7D

rop-

out:

a 30

, b 3

6A

sses

sed:

a 7,

b 7

Out

com

es r

epor

ted:

GI s

ympt

oms,

endo

scop

ic u

lcer

s, t

otal

drop

-out

How

wer

e ad

vers

eev

ents

ass

esse

d:su

bjec

tive

and

obje

ctiv

esy

mpt

oms

wer

eas

sess

ed o

n sc

ale

of 1

–4(s

ever

e, m

oder

ate,

sligh

t, no

ne),

seve

rity,

dura

tion,

ext

ratr

eatm

ent

requ

ired

and

clin

ical

cou

rse

reco

rded

and

rela

tion

to N

SAID

inve

stig

ated

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:C

VD (i

nclu

ding

hype

rten

sion)

: a 1

0,

b 12

Hep

atic

dise

ase:

a 4

, b

6hi

stor

y of

gast

rodu

oden

aldi

seas

e: a

5, b

7FU

ND

ING

Fund

ed b

y:no

t st

ated

Affi

liati

on o

f con

tact

auth

or:S

t M

aria

nna

Uni

vers

ity S

choo

l of

Med

icin

e, Ja

pan

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:0/

5O

ther

:par

ticip

ants

with

less

er le

sions

wer

e re

mov

ed fr

omtr

ial w

hen

lesio

ns w

ere

seen

on

endo

scop

y


221


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Levi

ne, 1

99345

Loca

tion

:mul

tiple

sites

in U

SA

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

con

ceal

men

t:un

clea

rB

asel

ine

com

para

bilit

y:ye

sPa

rtic

ipan

t bl

indi

ng:y

esA

sses

sor

blin

ding

:unc

lear

Inte

ntio

n-to

-tre

at:y

es(p

artic

ipan

ts n

ot r

etur

ning

are

clas

sed

as t

reat

men

tfa

ilure

s)A

pri

ori

sam

ple

size

:yes

Sum

mar

y ri

sk o

f bia

s:m

oder

ate

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd e

xclu

ded

part

icip

ants

with

acut

e ul

cer

Bas

elin

e us

e of

NSA

IDs:

all o

n da

ilyN

SAID

sTy

pe a

nd d

urat

ion

of a

rthr

itis

:OA

, no

othe

r de

tails

Age

:a 5

7.5

b 56

.9

Sex:

F/M

: 325

/171

Incl

usio

n cr

iter

ia:O

A, d

aily

the

rapy

expe

cted

to

cont

inue

with

an

NSA

ID(p

iroxi

cam

, ibu

prof

en, n

apro

xen,

dicl

ofen

ac s

odiu

m) a

nd c

ompl

aint

s of

NSA

ID a

ssoc

iate

d sy

mpt

oms

Excl

usio

n cr

iter

ia:e

ndos

copy

disc

losin

gac

tive

pept

ic u

lcer

atio

n 3m

m o

r la

rger

;tr

eatm

ent

with

ano

ther

aci

d-lo

wer

ing

agen

t; hi

stor

y of

a d

efin

itive

aci

d-lo

wer

ing

oper

atio

n; p

revi

ous

esop

hage

al o

r ga

stric

surg

ery;

pyl

oric

ste

nosis

; con

curr

ent

serio

us s

yste

mic

diso

rder

s; a

ny c

ondi

tion

asso

ciat

ed w

ith p

oor

patie

nt c

ompl

ianc

e;ad

miss

ion

labo

rato

ry v

alue

s ou

tsid

e th

eno

rmal

ran

ge; w

omen

of c

hild

bear

ing

pote

ntia

l not

usin

g an

app

rove

d m

etho

dof

con

trac

eptio

n, p

regn

ant

or la

ctat

ing

wom

en

Com

pari

son:

niza

tidin

e pl

us m

ixed

NSA

IDs

vs p

lace

bo p

lus

mix

edN

SAID

sD

urat

ion:

3 m

onth

sIn

terv

enti

ons:

b, n

izat

idin

e30

0m

g/15

0µg

(150

mg

×2 d

aily

); a,

pla

cebo

(×2

daily

)En

dosc

opy:

1, 2

and

3 m

onth

sN

SAID

s:a

+ b

piro

xica

m,

ibup

rofe

n, n

apro

xen,

dic

lofe

nac,

all

with

in la

bel m

edic

atio

n do

se fo

rO

A

Oth

er m

edic

atio

n:liq

uid

anta

cid

pres

crib

ed fo

r m

oder

ate

to s

ever

eab

dom

inal

pai

n, o

ther

aci

d-lo

wer

ing

drug

s, p

roki

netic

age

nts

and

miso

pros

tol n

ot a

llow

edA

spir

in a

llow

ed:y

es, n

o m

ore

than

5g

daily

for

card

iac

prop

hyla

xis

Ana

lges

ic a

llow

ed:y

esac

etam

inop

hen,

cod

eine

,pr

opax

yphe

ne fo

r no

n-G

I pai

n re

lief

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:not

sta

ted

Num

ber

and

freq

uenc

y of

vis

its:

4 (0

, 1, 2

and

3 m

onth

s)

Allo

cate

d:a

248,

b 2

48C

ompl

eted

:a 1

71,

b18

5D

rop-

out:

a 77

, b 6

3(b

ut in

clud

es p

artic

ipan

tsw

ith u

lcer

s at

last

visi

ten

dosc

opy)

Ass

esse

d:a

248,

b 2

48O

utco

mes

rep

orte

d:m

orta

lity,

ser

ious

GI

com

plic

atio

ns, s

erio

usca

rdio

vasc

ular

or

rena

lill

ness

, GI s

ympt

oms,

endo

scop

ic u

lcer

s,an

aem

ia, G

I dro

p-ou

ts,

tota

l dro

p-ou

tsH

ow w

ere

adve

rse

even

ts a

sses

sed:

solic

ited

repo

rts

ofad

vers

e ev

ents

at

each

visit

How

was

com

plia

nce

asse

ssed

:cro

ss-

chec

king

pat

ient

dai

lylo

gs w

ith n

umbe

r of

pill

sre

mai

ning

for

stud

y dr

ugan

d N

SAID

s

Ris

k fa

ctor

s:hi

stor

y of

ulc

ers,

a 4

5,b

43FU

ND

ING

R

isk

fact

ors:

node

tails

Fund

ed b

y:El

i Lill

yA

ffilia

tion

of c

onta

ctau

thor

:Lill

y Re

sear

chLa

bora

torie

s, E

li Li

lly,

USA

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:3/

3

Appendix 6

222

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Rugs

tad,

199

453

Loca

tion

:Nor

way

,m

ultic

entr

e

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

con

ceal

men

t:un

clea

r B

asel

ine

com

para

bilit

y:un

clea

r, im

bala

nce

atba

selin

e re

gard

ing

prev

ious

GI

disc

omfo

rt:a

19%

,b

23%

Part

icip

ant

blin

ding

:yes

A

sses

sor

blin

ding

:unc

lear

In

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:yes

Sum

mar

y ri

sk o

f bia

s:m

oder

ate

Bas

elin

e G

I st

atus

:no

endo

scop

ype

rfor

med

, som

e pa

rtic

ipan

ts h

ad G

Isy

mpt

oms

Bas

elin

e N

SAID

sta

tus:

73/2

59 (g

roup

a) a

nd 7

1/25

3 (g

roup

b)

had

not

prev

ious

ly t

aken

NSA

IDs

Type

of a

rthr

itis

(ye

ars)

:OA

(new

lydi

agno

sed)

: a 7

3, b

71

Age

:M/F

: ove

r 70

yea

rs: a

90/

29, b

89/

22Se

x:F/

M: 3

57/1

55In

clus

ion

crit

eria

:pat

ient

s 18

yea

rs o

rol

der

with

OA

kne

e an

d/or

hip

, con

firm

edw

ith X

-ray

and

with

sym

ptom

s of

ade

gree

tha

t re

quire

d an

NSA

ID

Excl

usio

n cr

iter

ia:p

regn

ant

orbr

east

feed

ing

fem

ales

, hist

ory

of G

Ibl

eedi

ng o

r bl

eedi

ng d

isord

ers;

pep

ticul

cer

or s

erio

us d

yspe

ptic

sym

ptom

sdu

ring

the

last

12

mon

ths;

kno

wn

idio

sync

rasy

to

NSA

ID, a

spiri

n or

cim

etid

ine;

hist

ory

of a

sthm

a,co

ncom

itant

tre

atm

ent

with

ora

lan

ticoa

gula

nts,

phe

nyto

ine,

the

ophy

lline

,gl

ucoc

ortic

oids

and

ant

acid

s

Com

pari

son:

cim

etid

ine

plus

mix

ed N

SAID

s vs

pla

cebo

plu

sm

ixed

NSA

IDs

Dur

atio

n:4

wee

ksIn

terv

enti

ons:

b, c

imet

idin

e80

0m

g/40

0m

g (4

00m

g ×2

dai

ly);

a, m

atch

ing

plac

ebo

(tw

ice

daily

)N

SAID

s:a

+ b

: eith

er s

tart

ed o

rco

ntin

ued

NSA

ID, c

hoic

e an

d do

sele

ft to

phy

sicia

n re

spon

sible

Oth

er m

edic

atio

n:co

ncom

itant

trea

tmen

t w

ith o

ral a

ntic

oagu

lant

s,ph

enyt

oin,

the

ophy

lline

,gl

ucoc

ortic

oids

and

ant

acid

sex

clud

edA

spir

in a

llow

ed:y

esA

nalg

esic

allo

wed

:yes

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:not

sta

ted

Num

ber

and

freq

uenc

y of

vis

its:

3 (0

, 2 a

nd 4

wee

ks)

Allo

cate

d:a

285,

b 2

85C

ompl

eted

: not

sta

ted

Dro

p-ou

t:no

t st

ated

A

sses

sed:

a 25

9, b

253

Out

com

es r

epor

ted:

GI s

ympt

oms

How

wer

e ad

vers

eev

ents

ass

esse

d:“H

ave

you

expe

rienc

ed a

nysid

e-ef

fect

s?”

if ye

s“H

ave

you

expe

rienc

edan

y G

I sid

e-ef

fect

s?”

ifye

s as

ked

rega

rdin

gab

dom

inal

pai

n,ep

igas

tria

l pai

n,he

artb

urn,

bel

chin

g,na

usea

, vom

iting

,di

arrh

oea

How

was

com

plia

nce

asse

ssed

:tab

let

coun

t,92

% t

ook

70%

or

mor

em

edic

atio

n in

gro

up a

(pla

cebo

) and

94%

too

k70

% o

r m

ore

med

icat

ion

in g

roup

b(c

imet

idin

e), b

utpa

rtic

ipan

ts w

ith m

issin

gva

lues

wer

e as

sum

edco

mpl

iant

Ris

k fa

ctor

s:hi

stor

yof

ulc

er (p

revi

ous

12/1

2): a

0, b

0

His

tory

of b

leed

s:a

0b

0 C

onco

mit

ant

use

ofan

tico

agul

ants

:a 0

,b

0 C

ardi

ovas

cula

r dr

ugus

e: a

165

, b 1

53FU

ND

ING

Fu

nded

by:

not

sta

ted

Affi

liati

on o

f con

tact

auth

or:D

epar

tmen

tof

Clin

ical

Phar

mac

olog

y,Ri

ksho

spita

let,

Oslo

,N

orw

ayA

ffilia

tion

of

stat

isti

cian

:Life

Insu

ranc

e C

ompa

nies

Inst

itute

of M

edic

alSt

atist

ics,

Oslo

,N

orw

ayA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:0/

4


223


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Sim

on, 1

99454

(abs

trac

t)Lo

cati

on:

mul

ticen

tre,

USA

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

con

ceal

men

t:un

clea

r B

asel

ine

com

para

bilit

y:un

clea

rPa

rtic

ipan

t bl

indi

ng: y

esA

sses

sor

blin

ding

: unc

lear

In

tent

ion-

to-t

reat

:yes

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd e

xclu

ded

part

icip

ants

with

ulce

rsTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A, n

o fu

rthe

r de

tails

Age

: 59.

4 (2

3–86

) in

tota

lSe

x:F/

M: n

o de

tails

Incl

usio

n cr

iter

ia:p

atie

nts

who

req

uire

dN

SAID

s to

tre

at O

A, a

bsen

ce o

f gas

tric

ulce

ratio

nEx

clus

ion

crit

eria

:gas

tric

ulc

erat

ion

onen

dosc

opy

(muc

osal

bre

ak o

f 3m

m o

rm

ore)

Com

pari

son:

fam

otid

ine

plus

NSA

IDs

vs p

lace

bo p

lus

NSA

IDs

Dur

atio

n:12

wee

ksIn

terv

enti

ons:

c, fa

mot

idin

e80

mg/

20m

g (4

0m

g ×2

dai

ly);

b,fa

mot

idin

e 40

mg/

20m

g (2

0m

g×2

dai

ly);

a, m

atch

ing

plac

ebo

(×2

daily

)En

dosc

opy:

4, 8

and

12

wee

ksN

SAID

s:a

+ b

: NSA

IDs,

no

furt

her

deta

ilsO

ther

med

icat

ion:

no d

etai

lsA

spir

in a

llow

ed:y

esA

nalg

esic

allo

wed

:yes

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:not

sta

ted

Num

ber

and

freq

uenc

y of

vis

its:

3(0

, 2 a

nd 4

wee

ks)

Allo

cate

d:a

102,

b

100,

c 1

03C

ompl

eted

:not

sta

ted

Dro

p-ou

t:no

t st

ated

A

sses

sed:

a 10

2, b

100,

c 10

3O

utco

mes

rep

orte

d:Se

rious

GI

com

plic

atio

ns,

endo

scop

ic u

lcer

sH

ow w

ere

adve

rse

even

ts a

sses

sed:

not

stat

edH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:no

deta

ilsFU

ND

ING

Fund

ed b

y:no

t st

ated

Affi

liati

on o

f con

tact

auth

or:M

erck

Rese

arch

Lab

orat

orie

sA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

?/5

Appendix 6

224

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Taha

, 199

655,1

59

Loca

tion

:Gla

sgow

and

Not

tingh

am,

UK

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

assig

ned

with

the

use

of a

com

pute

r-ge

nera

ted

sche

dule

’, st

ratif

ied

by t

ype

of a

rthr

itis

Allo

cati

on c

once

alm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:yes

Ass

esso

r bl

indi

ng:u

ncle

ar

Inte

ntio

n-to

-tre

at:y

esA

pri

ori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd e

xclu

ded

part

icip

ants

with

ulce

rB

asel

ine

use

of N

SAID

s:al

l par

ticip

ants

taki

ng N

SAID

s fo

r at

leas

t 1

mon

thTy

pe o

f art

hrit

is:R

A/O

A; a

76/

17,

b80

/15

Dur

atio

n of

art

hrit

is (

year

s):

a 9.

6 (0

–50)

, b 1

2.2

(0–4

4), c

10.

1 (0

–47)

Age

:a 5

3.4

(22–

78),

b 57

.2 (1

8–88

),c

55(2

2–83

)Se

x:F/

M: 2

08/7

7In

clus

ion

crit

eria

:18

year

s or

mor

e,RA

or O

A, s

tand

ard

dose

s of

NSA

ID fo

rat

leas

t 1

mon

th a

nd li

kely

to

cont

inue

for

next

6 m

onth

sEx

clus

ion

crit

eria

:tak

ing

antiu

lcer

dru

gsot

her

than

ant

acid

s w

ithin

7 d

ays

befo

reen

rolm

ent,

7.5

mg/

day

or m

ore

ofpr

edni

solo

ne (o

r th

e eq

uiva

lent

with

anot

her

cort

icos

tero

ids)

, met

hotr

exat

e or

antin

eopl

astic

; lac

tatio

n, c

hild

bear

ing

pote

ntia

l in

abse

nce

of c

ontr

acep

tion,

rena

l fai

lure

, ins

ulin

-dep

ende

nt d

iabe

tes

mel

litus

, clin

ical

ly im

port

ant

abno

rmal

labo

rato

ry t

ests

, ulc

ers

on b

asel

ine

endo

scop

y

Com

pari

son:

fam

otid

ine

plus

mix

ed N

SAID

s vs

pla

cebo

plu

sm

ixed

NSA

IDs

Dur

atio

n:24

wee

ksIn

terv

enti

ons:

c, f

amot

idin

e80

mg/

20µg

(40

mg

×2da

ily);

b, fa

mot

idin

e 40

mg/

20m

g (2

0m

gx2

dai

ly);

a pl

aceb

o (×

2 da

ily)

Endo

scop

y:4,

12

and

24 w

eeks

NSA

IDs:

a +

b:

dicl

ofen

ac, a

24,

b 2

6, c

22

indo

met

haci

n, a

19,

b 1

5, c

19

napr

oxen

, a 1

9, b

13,

c 1

8 ib

upro

fen,

a 9

, b 1

0, c

11

keto

prof

en, a

5, b

5, c

5

fenb

rufe

n, a

4, b

6, c

6

othe

r, a

14, b

23,

c 2

0O

ther

med

icat

ion:

anta

cid

(Maa

lox)

pre

scrib

ed fo

r re

lief o

fdy

spep

sia, D

MA

RDs

allo

wed

incl

udin

g su

lfasa

lazi

ne, g

old,

peni

cilla

min

e, p

redn

isolo

ne,

hydr

oxyc

hlor

oqui

neA

spir

in a

llow

ed:y

es, n

ot fu

ll do

seA

nalg

esic

allo

wed

: not

sta

ted

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:not

sta

ted

Num

ber

and

freq

uenc

y of

vis

its:

4 (0

, 4, 1

2 an

d 24

wee

ks)

Allo

cate

d:a

93, b

95,

c97

Com

plet

ed: a

80,

b 8

1,c

81D

rop-

out:

a: 1

3, b

14,

c16 A

sses

sed:

a 93

, b 9

5,

c 97

O

utco

mes

rep

orte

d:sy

mpt

omat

ic u

lcer

,se

rious

car

diov

ascu

lar

orre

nal i

llnes

s, G

Isy

mpt

oms,

end

osco

pic

ulce

rs, G

I dro

p-ou

ts,

tota

l dro

p-ou

tsH

ow w

ere

adve

rse

even

ts a

sses

sed:

part

icip

ants

ask

ed t

ore

cord

abd

omin

alsy

mpt

oms

on d

iary

card

s, a

bdom

inal

pai

nas

sess

ed o

n a

3-po

int

scal

e (1

=m

ild,

2=

mod

erat

e,3

=se

vere

), pa

rtic

ipan

tsqu

estio

ned

abou

tad

vers

e ev

ents

at

each

visit

H

ow w

as c

ompl

ianc

eas

sess

ed:r

ecor

ded

tabl

et c

ount

a 1

2, b

11,

c 14

had

poo

rco

mpl

ianc

e w

ith s

tudy

drug

s or

NSA

IDs

Ris

k fa

ctor

s:hi

stor

y of

ulc

ers:

9,

b 15

, c 1

3 FU

ND

ING

Fu

nded

by:

Mer

ckA

ffilia

tion

of c

onta

ctau

thor

:Gla

sgow

Roya

l Inf

irmar

y, U

KA

ffilia

tion

of

stat

isti

cian

:App

lied

Stat

istic

sA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r: 3

/10


225


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Ten

Wol

de, 1

99656

Loca

tion

:rh

eum

atol

ogy

outp

atie

nts,

The

Net

herla

nds

Met

hod

ofra

ndom

isat

ion:

‘con

secu

tive

patie

nts

rand

omly

ass

igne

d’,

pred

eter

min

edra

ndom

isatio

n lis

t ba

lanc

edin

blo

cks

of 1

0A

lloca

tion

con

ceal

men

t:in

adeq

uate

Bas

elin

e co

mpa

rabi

lity:

no Part

icip

ant

blin

ding

:yes

Ass

esso

r bl

indi

ng:u

ncle

arIn

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

high

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd e

xclu

ded

part

icip

ants

with

activ

e ul

cer

(or

incl

uded

afte

r ul

cer

heal

ing

with

ran

itidi

ne 3

00m

g ×2

dai

ly fo

r4

wee

ks)

Bas

elin

e us

e of

NSA

IDs:

all o

n N

SAID

sTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:RA

, a 1

3, b

22

Age

:a 5

8, b

67

Sex:

F/M

: 10/

10In

clus

ion

crit

eria

:RA

who

nee

ded

chro

nic

NSA

ID m

edic

atio

n (4

day

s pe

rw

eek

or m

ore)

had

a h

istor

y of

PU

D a

ses

tabl

ished

by

endo

scop

y or

bar

ium

mea

lra

diog

raph

y, b

ut h

ad n

o ac

tive

ulce

r as

esta

blish

ed b

y en

dosc

opy

at e

ntry

to

stud

y (if

PU

D fo

und

at b

asel

ine

then

patie

nt w

as t

reat

ed w

ith r

aniti

dine

300

mg

twic

e da

ily fo

r 4

wee

ks a

nd o

nly

afte

r ul

cer

heal

ing

was

est

ablis

hed

byen

dosc

opy

was

the

pat

ient

con

sider

edel

igib

le fo

r th

e st

udy)

Excl

usio

n cr

iter

ia:s

ever

e co

ncom

itant

dise

ase

or a

rec

ent

GI h

aem

orrh

age

Com

pari

son:

rani

tidin

e pl

us m

ixed

NSA

IDs

vs p

lace

bo p

lus

mix

edN

SAID

sD

urat

ion:

12 m

onth

sIn

terv

enti

ons:

b, r

aniti

dine

,60

0m

g/15

0–30

0m

g (3

00m

g×2

daily

); a,

plac

ebo

(×2

daily

)En

dosc

opy:

6 an

d 12

mon

ths

Oth

er m

edic

atio

n:Pa

rtic

ipan

tsta

king

DM

ARD

s an

d pr

edni

sone

allo

wed

to

cont

inue

NSA

IDs:

a +

b: p

artic

ipan

tsen

cour

aged

to

use

NSA

IDs

in d

aily

dose

s as

sta

ble

as p

ossib

leA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:not

sta

ted

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:not

sta

ted

Num

ber

and

freq

uenc

y of

vis

its:

6 (0

, 3, 6

, 9 a

nd 1

2 m

onth

s)

Allo

cate

d:a

15, b

15

Com

plet

ed:u

ncle

arD

rop-

out:

uncl

ear

Ass

esse

d:a

10, b

10

Out

com

es r

epor

ted:

mor

talit

y, e

ndos

copi

cul

cers

, GI d

rop-

out

How

wer

e ad

vers

eev

ents

ass

esse

d:pa

rtic

ipan

ts a

sked

abo

utga

stric

sym

ptom

s ev

ery

3 m

onth

sH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:hi

stor

y of

ulc

ers:

all

part

icip

ants

FUN

DIN

GFu

nded

by:

Gla

xo, a

llm

edic

atio

ns p

acke

dan

d pr

ovid

ed b

y G

laxo

Affi

liati

on o

f con

tact

auth

or:U

nive

rsity

Hos

pita

l Lei

den,

the

Net

herla

nds

Affi

liati

on o

fst

atis

tici

an:

Uni

vers

ity H

ospi

tal

Leid

en, T

heN

ethe

rland

sA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:0/

3

Appendix 6

226

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Van

Gro

enen

dael

,19

9657

Loca

tion

:rh

eum

atol

ogy

clin

ics,

Rot

terd

am,

The

Net

herla

nds

Met

hod

ofra

ndom

isat

ion:

‘pre

dete

rmin

edra

ndom

isatio

n lis

t ba

lanc

edin

blo

cks

of 6

’A

lloca

tion

con

ceal

men

t:un

clea

rB

asel

ine

com

para

bilit

y:ye

sPa

rtic

ipan

t bl

indi

ng:y

esA

sses

sor

blin

ding

:unc

lear

In

tent

ion-

to-t

reat

:yes

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd p

artic

ipan

ts e

xclu

ded

ifm

ore

than

zer

o La

nza

scor

e (n

on-e

rosiv

e)in

Stu

dy 1

and

if n

ot 1

–3 L

anza

sco

re(e

rosiv

e bu

t w

ithou

t pe

ptic

ulc

er d

iseas

e)in

Stu

dy 2

; all

part

icip

ants

had

to

pres

ent

with

dys

pept

ic c

ompl

aint

s B

asel

ine

use

of N

SAID

s:al

l par

ticip

ants

taki

ng N

SAID

s pr

ior

to s

tudy

Type

of a

rthr

itis

:OA

/RA

Stud

y 1:

a 18

/11,

b 1

9/10

Stud

y 2:

a 12

/5, b

7/1

0D

urat

ion

of a

rthr

itis

(ye

ars)

: St

udy

1: a

6 (2

–30)

, b 5

(0.5

–18)

Stud

y 2:

a 5

(1–3

1), b

6 (2

–33)

Age

:St

udy

1: a

52,

b 5

3 St

udy

2: a

60,

b 6

2Se

x:St

udy

1: F

/M: 4

5/13

Stud

y 2:

F/M

: 26/

9In

clus

ion

crit

eria

:RA

or

OA

, with

naus

ea, h

eart

burn

, epi

gast

ric p

ain,

eruc

tatio

n an

d/or

vom

iting

Excl

usio

n cr

iter

ia:t

akin

g an

tipep

ticm

edic

atio

n in

the

4 w

eeks

pre

cedi

ng t

hest

udy,

dys

pept

ic c

ompl

aint

s no

t re

late

d to

NSA

ID u

se a

ccor

ding

to

the

inve

stig

ator

,hi

stor

y of

pep

tic u

lcer

dise

ase

docu

men

ted

with

X-r

ay a

nd/o

ren

dosc

opy

Com

pari

son:

rani

tidin

e pl

us m

ixed

NSA

IDs

vs p

lace

bo p

lus

mix

edN

SAID

sD

urat

ion:

4 w

eeks

Inte

rven

tion

s:b,

ran

itidi

ne30

0m

g/15

0–30

0m

g (1

50m

g×2

daily

); a,

pla

cebo

(×2

daily

)N

SAID

s:St

udy

1 an

d 2:

a +

b:

daily

sta

ble

dose

s of

NSA

IDs

(ket

opro

fen

200,

indo

met

haci

n 15

0,na

prox

en 1

000,

piro

xica

m 2

0,sa

licyl

ates

360

0m

g/da

y)En

dosc

opy:

at 4

wee

ks

Oth

er m

edic

atio

n:an

taci

dsob

tain

ed fr

om h

ospi

tal p

harm

acy,

DM

ARD

use

allo

wed

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:n

ot s

tate

dPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:n

ot s

tate

dN

umbe

r an

d fr

eque

ncy

of v

isit

s:tw

ice

(0 a

nd 4

wee

ks)

Allo

cate

d:St

udy

1: a

29,

b 2

9St

udy

2: a

18,

b 1

8C

ompl

eted

: St

udy

1: a

29,

b 2

9St

udy

2: a

18,

b 1

7D

rop-

out:

St

udy

1: a

0, b

0St

udy

2: a

0, b

1A

sses

sed:

Stud

y 1:

a 2

9, b

29

Stud

y 2:

a 1

8, b

17

Out

com

es r

epor

ted:

Stud

y 1:

mor

talit

y,se

rious

GI

com

plic

atio

ns,

sym

ptom

atic

ulc

ers,

GI

sym

ptom

s, G

I dro

p-ou

ts, t

otal

dro

p-ou

tsSt

udy

2: m

orta

lity,

serio

us G

Ico

mpl

icat

ions

, GI

sym

ptom

s, e

ndos

copi

cul

cers

, GI d

rop-

outs

,to

tal d

rop-

outs

How

wer

e ad

vers

eev

ents

ass

esse

d:no

tst

ated

How

was

com

plia

nce

asse

ssed

:tab

let

coun

t,re

sults

not

rep

orte

d

Ris

k fa

ctor

s:hi

stor

yof

ulc

ers:

a 0

, b 0

FU

ND

ING

Fund

ed b

y:G

laxo

Affi

liati

on o

f con

tact

auth

or:D

r D

anie

l den

Hoe

d K

linie

k, T

heN

ethe

rland

sA

ffilia

tion

of

stat

isti

cian

:Era

smus

Uni

vers

ity o

fRo

tter

dam

, The

Net

herla

nds

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

0/4

Oth

er:s

alic

ylat

es u

sed

as N

SAID

tre

atm

ent

by 1

0 pa

rtic

ipan

ts in

tota

l (St

udie

s 1

and

2co

mbi

ned

= 1

0/94

)


227


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

Hud

son,

199

758

Loca

tion

:N

ottin

gham

and

Gla

sgow

, UK

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’

Allo

catio

n co

ncea

lmen

t:un

clea

r B

asel

ine

com

para

bilit

y:ye

sPa

rtic

ipan

t bl

indi

ng:y

esA

sses

sor

blin

ding

:unc

lear

Inte

ntio

n-to

-tre

at:y

esA

pri

ori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd p

artic

ipan

ts o

nly

incl

uded

with

hea

led

ulce

rs fo

llow

ing

heal

ing

stud

yor

in t

he 4

wee

ks fo

llow

ing,

(pat

ient

sw

ithou

t ul

cera

tion

prio

r to

the

hea

ling

stud

y en

tere

d a

prop

hyla

xis

stud

y, s

eeTa

ha e

t al

.55)

Bas

elin

e us

e of

NSA

IDs:

all p

artic

ipan

tsha

d be

en t

akin

g N

SAID

s fo

r at

leas

t1

mon

th, b

ut N

SAID

s w

ithdr

awn

to h

eal

ulce

rs o

ver

the

prev

ious

4–1

2 w

eeks

Type

and

dur

atio

n of

art

hrit

is:

RA: a

33,

b 3

4; O

A: a

6, b

5; n

o ot

her

deta

ilsA

ge: m

edia

n: a

55

(35–

89),

b 58

(32–

79)

Sex:

F/M

: 52/

26In

clus

ion

crit

eria

:18

year

s or

mor

e, R

Aor

OA

, had

bee

n re

ceiv

ing

an N

SAID

with

in t

he r

ange

of s

tand

ard

reco

mm

ende

d do

sage

for

at le

ast

1m

onth

bef

ore

endo

scop

y, h

eale

d ul

cers

durin

g he

alin

g st

udy

or fo

llow

ing

4 w

eeks

and

wish

ed t

o co

ntin

ue N

SAID

the

rapy

Excl

usio

n cr

iter

ia:t

akin

g an

tiulc

er d

rugs

othe

r th

an a

ntac

ids

for

less

tha

n 7

days

befo

re s

tudy

ent

ry o

r w

ere

taki

ng s

tero

ids

at a

dos

age

equi

vale

nt t

o 7.

5 m

gpr

edni

solo

ne d

aily

or

mor

e, m

etho

trex

ate

or a

ntin

eopl

astic

dru

gs, l

acta

tion,

chi

ld-

bear

ing

pote

ntia

l, re

nal f

ailu

re, d

iabe

tes

orcl

inic

ally

sig

nific

ant

pre-

stud

y la

bora

tory

abno

rmal

ities

Com

pari

son:

fam

otid

ine

plus

mix

ed N

SAID

s vs

pla

cebo

plu

sm

ixed

NSA

IDs

Dur

atio

n:24

wee

ksIn

terv

enti

ons:

b, fa

mot

idin

e80

mg/

20m

g (4

0m

g ×2

dai

ly);

a, p

lace

bo (×

2 da

ily)

Endo

scop

y:4,

12

and

24 w

eeks

NSA

IDs:

a +

b:

napr

oxen

: a 1

1, b

14

indo

mat

haci

n: a

9, b

3

dicl

ofen

ac: a

4, b

6

othe

r: a

15,

b 1

6O

ther

med

icat

ion:

antiu

lcer

dru

gsot

her

than

ant

acid

s, s

tero

ids

at a

dosa

ge e

quiv

alen

t to

7.5

mg

pred

niso

lone

dai

ly o

r m

ore,

met

hotr

exat

e or

ant

ineo

plas

ticdr

ugs

wer

e ex

clud

edA

spir

in a

llow

ed:y

esA

nalg

esic

allo

wed

:not

sta

ted

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

: no

Num

ber

and

freq

uenc

y of

vis

its:

4 (0

, 4, 1

2, 2

4 w

eeks

)

Allo

cate

d:a:

39,

b 3

9C

ompl

eted

:unc

lear

Dro

p-ou

t:un

clea

rA

sses

sed:

a: 3

9, b

38

for

endo

scop

y O

utco

mes

rep

orte

d:de

aths

, end

osco

pic

ulce

rsH

ow w

ere

adve

rse

even

ts a

sses

sed:

abdo

min

al s

ympt

oms

reco

rded

dai

ly o

nsp

ecifi

c di

ary

card

s,op

en q

uest

ioni

ng a

t ea

chvi

sitH

ow w

as c

ompl

ianc

eas

sess

ed:t

able

t co

unt,

resu

lt no

t re

port

ed

Ris

k fa

ctor

s:hi

stor

y of

ulc

ers:

all

part

icip

ants

Dia

bete

s:a:

0, b

0

FUN

DIN

G

Fund

ed b

y:M

erck

A

ffilia

tion

of c

onta

ctau

thor

:Uni

vers

ityH

ospi

tal o

fN

ottin

gham

, UK

Affi

liati

on o

fst

atis

tici

an:A

pplie

dSt

atist

ics

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

3/9

Oth

er:‘

data

for

24-w

eek

endo

scop

yco

nfou

nded

by

sele

ctiv

e dr

op-o

ut o

ful

cer

patie

nts’

Appendix 6

228 (b)

PP

I pl

us N

SAID

ver

sus

plac

ebo

plus

NSA

ID

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Ekst

rom

, 199

659

Loca

tion

:18

hosp

itals

in F

inla

nd,

Nor

way

and

Swed

en

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

con

ceal

men

t:un

clea

r B

asel

ine

com

para

bilit

y:no

, mor

e pa

rtic

ipan

ts w

ithRA

in o

mep

razo

le a

rm (b

)Pa

rtic

ipan

t bl

indi

ng:y

esA

sses

sor

blin

ding

:unc

lear

In

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:yes

Sum

mar

y ri

sk o

f bia

s:hi

gh

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

y pe

rfor

med

but

exc

lude

dpa

rtic

ipan

ts w

ithou

t hi

stor

y of

pre

viou

sdy

spep

sia o

r un

com

plic

ated

pep

tic u

lcer

dise

ase

Bas

elin

e N

SAID

sta

tus:

rece

ivin

gco

ntin

uous

NSA

ID t

reat

men

tTy

pe o

f art

hrit

is:O

A: a

54,

b 4

9;

RA: a

8, b

14;

oth

er: a

28.

b 2

2. N

o ot

her

deta

ilsA

ge:a

59

(30-

78),

b 58

(25–

80)

Sex:

M/F

: a 2

3/67

, b 3

1/54

Incl

usio

n cr

iter

ia:2

5–78

yea

rs, r

equi

ring

cont

inuo

us N

SAID

tre

atm

ent

for

at le

ast

3 m

onth

s be

caus

e of

OA

, RA

,sp

ondy

lart

hriti

s, A

S or

any

oth

erco

nditi

on r

equi

ring

cont

inuo

us N

SAID

ther

apy

and

with

a h

istor

y of

dys

peps

ia o

run

com

plic

ated

pep

tic u

lcer

dise

ase

Excl

usio

n cr

iter

ia:p

atie

nts

who

had

take

n m

ore

than

hal

f the

rec

omm

ende

dm

inim

um d

ose

of N

SAID

s du

ring

the

4w

eeks

prio

r to

ran

dom

isatio

n, h

adre

cent

ulc

er b

leed

ing

or p

revi

ous

maj

orbl

eedi

ng o

r pe

rfor

atio

n, m

ore

than

mild

dysp

eptic

sym

ptom

s at

incl

usio

n, h

istor

yof

gas

tric

sur

gery

, or

verif

ied

gast

ro-

oeso

phag

eal r

eflu

x di

seas

e, w

ere

preg

nant

or b

reas

t-fe

edin

g, n

eede

d sy

stem

icm

edic

atio

n w

ith p

redn

isolo

ne in

dos

es o

fm

ore

than

10

mg

daily

or

equi

vale

ntdo

ses

of o

ther

ste

roid

s w

ere

cont

rain

dica

ted

for

stud

y dr

ugs

or h

adcl

inic

ally

sig

nific

ant

abno

rmal

ities

inba

selin

e la

bora

tory

scr

een

Com

pari

son:

omep

razo

le p

lus

mix

ed N

SAID

s (b

) vs

plac

ebo

plus

mix

ed N

SAID

s (a

)D

urat

ion:

3 m

onth

sIn

terv

enti

ons:

b, o

mep

razo

le20

mg/

20m

g (2

0m

g on

ce d

aily

); a,

iden

tical

pla

cebo

(onc

e da

ily)

NSA

IDs:

open

NSA

ID t

reat

men

tat

leas

t m

inim

um r

ecom

men

ded

dose

, com

bina

tions

and

cha

nges

inty

pe a

nd d

ose

wer

e pe

rmitt

ed,

incl

uded

(des

cend

ing

orde

r w

ithm

ost

com

mon

firs

t) n

apro

xen,

dicl

ofen

ac, t

enox

icam

, ibu

prof

en,

keto

prof

en, s

ulin

da a

nd o

ther

sEn

dosc

opy:

1 an

d 3

mon

ths

Oth

er m

edic

atio

n: n

o de

tails

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:n

ot s

tate

dPa

rtic

ipan

t ed

ucat

ion:

not

sta

ted

Was

hout

:not

sta

ted

Num

ber

and

freq

uenc

y of

vis

its:

3 (0

, 1 a

nd 3

mon

ths)

Allo

cate

d:a

91, b

86

Com

plet

ed:u

ncle

arD

rop-

out:

uncl

ear

Ass

esse

d:a

90, b

85

Out

com

es r

epor

ted:

serio

us G

Ico

mpl

icat

ions

,sy

mpt

omat

ic u

lcer

s, G

Isy

mpt

oms,

end

osco

pic

ulce

rs, G

I dro

p-ou

tsH

ow w

ere

adve

rse

even

ts a

sses

sed:

not

stat

edH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:hi

stor

yof

ulc

ers,

a 2

1, b

23

FUN

DIN

GFu

nded

by:

Ast

ra,

Swed

enA

ffilia

tion

of c

onta

ctau

thor

:San

dvik

ens

Hos

pita

l, Sw

eden

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:un

clea

rO

ther

:par

ticip

ants

wer

e w

ithdr

awn

if≥

10 e

rosio

ns, o

r m

ore

than

mild

dys

pept

icsy

mpt

oms


229


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Bian

chi P

orro

,19

9860

Loca

tion

:rh

eum

atol

ogy

unit,

L. S

acco

Uni

vers

ityH

ospi

tal,

Mila

n,Ita

ly

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’

Allo

cati

on c

once

alm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:yes

Ass

esso

r bl

indi

ng:u

ncle

ar

Inte

ntio

n-to

-tre

at:n

oA

pri

ori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd e

xclu

ded

part

icip

ants

with

out

norm

al U

GI e

ndos

copy

Ty

pe o

f art

hrit

is:

OA

: a 5

3, b

50;

no

othe

r de

tails

Age

:a 5

1.6

b 53

.1Se

x:M

/F: a

11/

42, b

5/4

5In

clus

ion

crit

eria

:OA

req

uirin

g at

leas

t3

wee

ks o

f NSA

ID t

reat

men

t, no

rmal

UG

I end

osco

py o

n sc

reen

ing,

wom

en o

fch

ild-b

earin

g po

tent

ial h

ad a

dequ

ate

cont

race

ptio

nEx

clus

ion

crit

eria

:car

diov

ascu

lar,

GI,

rena

l, m

etab

olic

, neu

rolo

gica

l and

haem

atol

ogic

al d

iseas

e, p

sych

iatr

icdi

sord

ers,

pre

viou

s G

I sur

gery

, alc

ohol

ismor

dru

g de

pend

ency

Com

pari

son:

Om

epra

zole

plu

sm

ixed

NSA

IDs

(b) v

s pl

aceb

o pl

usm

ixed

NSA

IDs

(a)

Dur

atio

n:3

wee

ksIn

terv

enti

ons:

b, o

mep

razo

le20

mg/

20m

g (2

0m

g on

ce d

aily

); a,

iden

tical

pla

cebo

(onc

e da

ily)

NSA

IDs:

open

tre

atm

ent

with

:in

dom

etha

cin

100

mg

daily

: a 2

0,b

16ke

topr

ofen

150

mg

daily

: a 1

4, b

17

dicl

ofen

ac 1

50m

g da

ily: a

19, b

17

Endo

scop

y:3

wee

ksO

ther

med

icat

ion:

none

wer

ere

ceiv

ing

antis

ecre

tory

dru

gs o

r an

ym

ucos

al p

rote

ctiv

e dr

ug a

t tim

e of

stud

yA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:not

sta

ted

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

: at

leas

t 7

days

for

prev

ious

NSA

IDs

Num

ber

and

freq

uenc

y of

vis

its:

2 (0

and

3 w

eeks

)

Allo

cate

d:a

57, b

57

Com

plet

ed: a

53,

b 5

0D

rop-

out:

a 4,

b 7

Ass

esse

d: a

53,

b 5

0 O

utco

mes

rep

orte

d:se

rious

GI

com

plic

atio

ns, G

Isy

mpt

oms,

end

osco

pic

ulce

rs, t

otal

dro

p-ou

tH

ow w

ere

adve

rse

even

ts a

sses

sed:

not

stat

edH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:C

VD: a

0, b

0

FUN

DIN

GFu

nded

by:

not

stat

ed

Affi

liati

on o

f con

tact

auth

or:S

acco

Uni

vers

ity H

ospi

tal,

Italy

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:un

clea

r

Appendix 6

230

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Cul

len,

199

861

Loca

tion

:19

cent

res

in Ir

elan

d,H

unga

ry, F

ranc

e,U

K, U

SA

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

con

ceal

men

t:un

clea

r B

asel

ine

com

para

bilit

y:ye

sPa

rtic

ipan

t bl

indi

ng:y

esA

sses

sor

blin

ding

:unc

lear

In

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:yes

Sum

mar

y ri

sk o

f bia

s:m

oder

ate

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd e

xclu

ded

part

icip

ants

who

wer

e no

t fr

ee o

f ulc

ers

and

with

10

orfe

wer

gas

tric

ero

sions

and

10

or fe

wer

duod

enal

ero

sions

Type

of a

rthr

itis

:OA

: a 4

1, b

38;

RA

: a 3

1, b

33;

no

othe

r de

tails

Age

:a 5

6, b

55

Sex:

M/F

: a 3

0/55

, b 2

6/57

Incl

usio

n cr

iter

ia:p

atie

nts

18–8

5 ye

ars

who

wer

e al

read

y ta

king

and

nee

ded

toco

ntin

ue N

SAID

s (w

ith m

ore

than

am

inim

um d

aily

dos

e) a

nd w

ho h

ad n

om

ore

than

mild

dys

pept

ic s

ympt

oms

(epi

gast

ric o

r ab

dom

inal

pai

n or

em

pty

feel

ing,

hea

rtbu

rn, n

ause

a or

blo

atin

g),

free

of u

lcer

s an

d w

ith 1

0 or

few

er g

astr

icer

osio

ns a

nd 1

0 or

few

er d

uode

nal

eros

ions

on

base

line

endo

scop

yEx

clus

ion

crit

eria

: use

of a

nti-u

lcer

med

icat

ion

or s

tero

ids

in e

xces

s of

apr

edni

solo

ne d

osag

e eq

uiva

lent

to

10m

gda

ily, e

rosiv

e ga

stro

-oes

opha

geal

ref

lux

dise

ase,

clin

ical

ly im

port

ant

blee

ding

or

pylo

ric s

teno

sis, h

istor

y of

ulc

erpe

rfor

atio

n or

sur

gery

, sev

ere

conc

urre

ntdi

seas

e or

nec

k in

stab

ility

ren

derin

gen

dosc

opy

dang

erou

s

Com

pari

son:

omep

razo

le p

lus

mix

ed N

SAID

s (b

) vs

plac

ebo

plus

mix

ed N

SAID

s (a

)D

urat

ion:

6 w

eeks

Inte

rven

tion

s:b,

om

epra

zole

20m

g/20

mg

(20

mg

once

dai

ly);

a, p

lace

bo (o

nce

daily

)En

dosc

opy:

at

0, 1

, 3 a

nd6

mon

ths

NSA

IDs:

with

min

imum

dai

ly d

ose

stat

ed:

dicl

ofen

ac 5

0m

g: a

22,

b 3

1na

prox

en 5

00m

g: a

17,

b 1

7in

dom

etha

cin

50m

g: a

10,

b 8

nabu

met

one

500

mg:

a 7

, b 8

piro

xica

m 1

0m

g: a

8, b

6ot

her:

a 2

1, b

13

Oth

er m

edic

atio

n: n

o ot

her

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:n

ot s

tate

dPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:n

ot s

tate

dN

umbe

r an

d fr

eque

ncy

of v

isit

s:4

(0, 1

, 3 a

nd 6

mon

ths)

Allo

cate

d:a

86, b

83

Com

plet

ed:u

ncle

arD

rop-

out:

uncl

ear

Ass

esse

d:a

85, b

83

Out

com

es r

epor

ted:

sym

ptom

atic

ulc

ers,

GI

sym

ptom

s, e

ndos

copi

cul

cers

How

wer

e ad

vers

eev

ents

ass

esse

d:

not

stat

edH

ow w

as c

ompl

ianc

eas

sess

ed:t

able

t co

unt,

97.4

–99.

4% o

fpa

rtic

ipan

ts t

ook

at le

ast

75%

of m

edic

atio

n

Ris

k fa

ctor

s:hi

stor

y of

ulc

ers:

a 2

1,b

27FU

ND

ING

Fund

ed b

y:A

stra

Phar

mac

eutic

als

Affi

liati

on o

f con

tact

auth

or:N

ottin

gham

GI T

rials

Serv

ice

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:2

of 7

wor

ked

for

Ast

ra

Oth

er:M

inim

umal

low

ed d

aily

dos

e of

dicl

ofen

ac b

elow

reco

mm

ende

dm

inim

um d

aily

dos

e in

BNF


231


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Haw

key,

1998

62,6

5,20

9–21

3

OM

NIU

MLo

cati

on:9

3ce

ntre

s in

14

coun

trie

s in

clud

ing

UK

and

USA

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

assig

ned’

, ran

dom

isatio

nph

ase

not

form

ally

bal

ance

dac

cord

ing

to t

reat

men

tas

signm

ent

in t

he h

ealin

gph

ase

Allo

cati

on c

once

alm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:yes

Ass

esso

r bl

indi

ng:u

ncle

ar

Inte

ntio

n-to

-tre

at:n

oA

pri

ori

sam

ple

size

:yes

Sum

mar

y ri

sk o

f bia

s:m

oder

ate

Bas

elin

e G

I st

atus

:end

osco

pype

rfor

med

and

exc

lude

d pa

rtic

ipan

tsw

ithou

t tr

eatm

ent

succ

ess

follo

win

g4–

8w

eeks

hea

ling

phas

e (o

mep

razo

le20

mg/

day

vs o

mep

razo

le 4

0m

g/da

y vs

miso

pros

tol 2

00 µ

g/da

y); t

reat

men

tsu

cces

s de

fined

as

abse

nce

of u

lcer

s in

the

stom

ach

or d

uode

num

and

the

pre

senc

eof

few

er t

han

five

gast

ric e

rosio

ns, f

ewer

than

five

duo

dena

l ero

sions

, and

not

mor

eth

an m

ild s

ympt

oms

of d

yspe

psia

(cor

resp

onde

d to

a 2

-poi

nt r

educ

tion

inLa

nza

scal

e fr

om g

rade

4 t

o gr

ade

2)

Type

of a

rthr

itis

:OA

: a 7

0, b

129

,c

142;

RA

: a 5

6, b

107

, c 1

18ot

her:

a 2

5, b

33,

c: 3

0co

mbi

natio

n:a

5, b

5, c

6A

ge:a

57

(20–

80),

b 58

(23–

79),

c 58

(23–

85)

Sex:

M/F

: a 4

8/10

7, b

101

/173

, c 1

18/1

78In

clus

ion

crit

eria

:18–

85 y

ears

of a

gean

d w

ho h

ad a

ny c

ondi

tion

requ

iring

cont

inuo

us t

reat

men

t w

ith o

ral o

r re

ctal

NSA

IDs

abov

e a

pred

eter

min

ed m

inim

aldo

se (n

o m

axim

al d

ose)

; tre

atm

ent

succ

ess

defin

ed a

s ab

senc

e of

ulc

ers

in t

hest

omac

h or

duo

denu

m a

nd t

he p

rese

nce

of fe

wer

tha

n fiv

e ga

stric

ero

sions

, few

erth

an fi

ve d

uode

nal e

rosio

ns a

nd n

ot m

ore

than

mild

sym

ptom

s of

dys

peps

ia(c

orre

spon

ded

to a

2-p

oint

red

uctio

n in

Lanz

a sc

ale

from

gra

de 4

to

grad

e 2)

Excl

usio

n cr

iter

ia:c

oncu

rren

t re

flux

oeso

phag

itis

at s

tage

3 o

r 4

acco

rdin

g to

the

Sava

ry–M

iller

cla

ssifi

catio

n, c

linic

ally

impo

rtan

t G

I ble

edin

g, p

ylor

ic s

teno

sis,

hist

ory

of g

astr

ic s

urge

ry, o

r G

I diso

rder

sth

at m

ight

impa

ir th

e ab

sorp

tion

of t

hest

udy

drug

s

Com

pari

son:

miso

pros

tol p

lus

mix

ed N

SAID

s (c

) vs

omep

razo

lepl

us m

ixed

NSA

IDs

(b) v

s pl

aceb

opl

us m

ixed

NSA

IDs

(a)

Dur

atio

n:6

mon

ths

Inte

rven

tion

s:c,

miso

pros

tol

400

µg /4

00–8

00 µ

g/da

y, (2

00 µ

g×2

dai

ly; b

, om

epra

zole

20m

g/20

mg

(20

mg

×1 d

aily

); a,

iden

tical

pla

cebo

En

dosc

opy:

1, 3

and

6 m

onth

sN

SAID

s:(m

inim

um a

nd m

ean

dose

)di

clof

enac

(50

mg,

129

mg/

day)

23%

tot

al p

artic

ipan

tske

topr

ofen

(100

mg,

137

mg)

16%

tota

l par

ticip

ants

napr

oxen

(500

mg,

844

mg)

22%

tota

l par

ticip

ants

Oth

er m

edic

atio

n:pa

tient

s co

uld

ente

r th

e st

udy

if th

ey w

ere

taki

nggl

ucoc

ortic

oids

at

a do

se ≤

10m

g of

pred

niso

lone

(or

its e

quiv

alen

t)A

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:not

sta

ted

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:not

sta

ted

Num

ber

and

freq

uenc

y of

vis

its:

4 (0

, 1, 3

and

6 m

onth

s)

Allo

cate

d:a

155,

b

274,

c 2

96 (7

part

icip

ants

una

ccou

nted

for)

Com

plet

ed: a

139

,b

242,

c 2

47D

rop-

out:

a 16

, b 3

3,

c 50

Ass

esse

d:a

155,

b 2

75,

c 29

7 O

utco

mes

rep

orte

d:se

rious

GI

com

plic

atio

ns, q

ualit

y of

life,

end

osco

pic

ulce

rs,

tota

l dro

p-ou

tH

ow w

ere

adve

rse

even

ts a

sses

sed:

part

icip

ants

ask

ed if

had

spec

ific

dysp

eptic

sym

ptom

s du

ring

the

last

7 d

ays

and

tode

scrib

e an

y U

GI

sym

ptom

s on

tha

t da

y,sy

mpt

oms

grad

ed, a

lsosy

mpt

om d

iary

car

dus

ed d

urin

g in

itial

4w

eeks

How

was

com

plia

nce

asse

ssed

:tab

let

coun

t,re

sult

not

repo

rted

Ris

k fa

ctor

s:63

–64%

of p

artic

ipan

ts in

eac

hgr

oup

had

rece

nthi

stor

y of

ulc

ers

(rem

aini

ng p

artic

ipan

tsha

d re

cent

hist

ory

ofm

ore

than

10

gast

ricor

duo

dena

l ero

sions

FU

ND

ING

Fund

ed b

y:A

stra

Has

sle, S

wed

enA

ffilia

tion

of c

onta

ctau

thor

:Not

tingh

amG

astr

oint

estin

al T

rials

Serv

ice,

Uni

vers

ityH

ospi

tal N

ottin

gham

,U

KA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

One

aut

hor

serv

es a

s a

cons

ulta

ntfo

r Se

arle

, Aus

tral

iaO

ther

:par

ticip

ants

wer

e di

scon

tinue

d an

dex

clud

ed fr

om a

naly

sisif

deve

lope

d m

ore

than

10

eros

ions

or

mor

e th

an m

oder

ate

dysp

epsia

or

adve

rse

even

ts

Appendix 6

232

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Bian

chi P

orro

,20

0063

Loca

tion

:O

utpa

tient

s,

L. S

acco

Uni

vers

ityH

ospi

tal,

Mila

n,Ita

ly

Met

hod

ofra

ndom

isat

ion:

‘com

pute

r-ge

nera

ted

rand

omisa

tion

list’

Allo

cati

on c

once

alm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

no, 4

3% p

anto

praz

ole

arm

(b) h

ad d

yspe

ptic

sym

ptom

svs

18%

pla

cebo

arm

(a)

Part

icip

ant

blin

ding

:yes

Ass

esso

r bl

indi

ng:u

ncle

ar

Inte

ntio

n-to

-tre

at:n

oA

pri

ori

sam

ple

size

:yes

Sum

mar

y ri

sk o

f bia

s:hi

gh

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd e

xclu

ded

part

icip

ants

with

out

lesio

ns g

rade

0, 1

or

2Ty

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A: a

15,

b 2

4; R

A: a

19,

b 4

6;a

5.1

year

s, b

4.4

yea

rs

Age

:a 5

9, b

58

Sex:

M/F

: a 6

/28,

b 1

2/58

Incl

usio

n cr

iter

ia: o

utpa

tient

s ov

er18

year

s of

age

and

affe

cted

by

RA o

r O

A,

trea

ted

with

effe

ctiv

e an

d co

nsta

nt d

oses

of N

SAID

s (d

iclo

fena

c, k

etop

rofe

n or

indo

met

haci

n) fo

r at

leas

t 8

wee

ks p

rior

to t

he s

tart

of t

he s

tudy

, Lan

za g

rade

0, 1

or 2

on

endo

scop

y, fe

mal

es w

ho w

ere

post

-men

opau

sal,

surg

ical

ly s

teril

ised

orus

ing

adeq

uate

con

trac

eptio

nEx

clus

ion

crit

eria

:gas

tric

sur

gery

,re

cent

upp

er G

I ble

edin

g, G

I mal

igna

ncy,

infla

mm

ator

y bo

wel

dise

ase,

chr

onic

or

acut

e re

nal o

r he

patic

diso

rder

s,en

dosc

opic

evi

denc

e of

oes

opha

gitis

grad

e 2,

3 o

r 4

(Sav

ary–

Mill

ercl

assif

icat

ion)

, pyl

oric

or

duod

enal

sten

osis,

hist

ory

of Z

ollin

ger–

Ellis

onsy

ndro

me,

reg

ular

inta

ke o

f dru

gs w

ithpH

-dep

ende

nt a

bsor

ptio

n (s

uch

aske

toco

nazo

le) o

r se

vere

car

diac

or

pulm

onar

y im

pairm

ent,

patie

nts

need

ing

antis

ecre

tory

, cyt

opro

tect

ive

orco

rtic

oste

roid

dru

gs, p

regn

ant

or la

ctat

ing

fem

ales

Com

pari

son:

pant

opra

zole

plu

sm

ixed

NSA

IDs

(b) v

s pl

aceb

o pl

usm

ixed

NSA

IDs

(a)

Dur

atio

n:12

wee

ksIn

terv

enti

ons:

b, p

anto

praz

ole

40m

g/20

mg

(40

mg

×1da

ily);

a, id

entic

al p

lace

bo (x

1 da

ily)

Endo

scop

y: 0

, 4 a

nd 1

2 w

eeks

,un

sche

dule

d en

dosc

opy

if dy

spep

ticsy

mpt

oms

for

at le

ast

48 h

NSA

IDs:

dicl

ofen

ac: a

13,

b 2

4ke

topr

ofen

: a 9

, b 2

6in

dom

etha

cin:

a 1

2, b

24

Oth

er m

edic

atio

n:an

taci

dsal

low

ed, m

axim

um 3

tab

lets

per

day

for

no m

ore

than

48

cons

ecut

ive

hour

s, a

ny a

dditi

onal

med

icat

ion

for

GI n

ot p

erm

itted

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:n

ot s

tate

dPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:n

ot s

tate

dN

umbe

r an

d fr

eque

ncy

of v

isit

s:3

(0, 4

and

12

wee

ks)

Allo

cate

d:a

34, b

70

Com

plet

ed:u

ncle

arD

rop-

out:

uncl

ear

Ass

esse

d:a

30, b

65

Out

com

es r

epor

ted:

serio

us G

Ico

mpl

icat

ions

,en

dosc

opic

ulc

ers,

GI

drop

-out

sH

ow w

ere

adve

rse

even

ts a

sses

sed:

not

stat

edH

ow w

as c

ompl

ianc

eas

sess

ed:t

able

t co

unt,

part

icip

ants

req

uire

d to

take

at

leas

t 70

%N

SAID

s an

d st

udy

med

icat

ion,

4pa

rtic

ipan

ts in

eac

hgr

oup

wer

e ce

nsor

ed b

yw

eek

4 fo

r no

n-co

mpl

ianc

e

Ris

k fa

ctor

s:co

ncom

itant

use

of

cort

icos

tero

ids:

a 0,

b

0 re

nal/h

epat

ic d

iseas

e:a

0, b

0FU

ND

ING

Fund

ed b

y:no

t st

ated

Affi

liati

on o

f con

tact

auth

or:S

acco

Uni

vers

ity H

ospi

tal,

Italy

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:1

of 5

wor

ked

for

Byk

Gul

den

Italia

, Mila

n,Ita

ly


233


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

Gra

ham

, 200

264,2

14

Loca

tion

:63

cent

res

in N

orth

Am

eric

a

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

assig

ned

in b

lock

s of

4’,

‘rand

omisa

tion

sche

dule

was

gene

rate

d by

a s

tatis

tical

spec

ialis

t w

ho w

as n

otin

volv

ed in

the

tria

l des

ign,

the

rand

omisa

tion

was

code

d an

d st

ored

in s

eale

den

velo

pes’

Allo

cati

on c

once

alm

ent:

adeq

uate

Bas

elin

e co

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:yes

A

sses

sor

blin

ding

:yes

(the

stat

istic

ian)

, end

osco

pist

also

blin

ded

Inte

ntio

n-to

-tre

at:n

oA

pri

ori

sam

ple

size

:yes

Sum

mar

y ri

sk o

f bia

s:lo

w

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed, p

atie

nts

had

to b

e w

ithou

tH

.pyl

ori,

have

hist

ory

of e

ndos

copi

cally

docu

men

ted

gast

ric u

lcer

with

or

with

out

co-e

xist

ing

duod

enal

ulc

er o

r G

I ble

edin

g(2

/3 p

artic

ipan

ts h

ad p

revi

ously

com

plet

ed p

artic

ipat

ion

in a

hea

ling

tria

lfo

r N

SAID

-ass

ocia

ted

gast

ric u

lcer

);ex

clud

ed p

atie

nts

with

gas

tric

or

duod

enal

ulce

r cr

ater

at

leas

t 5

mm

in d

iam

eter

or

mor

e th

an 2

5 er

osio

ns o

r er

osiv

e re

flux

oeso

phag

itis

Bas

elin

e N

SAID

sta

tus:

trea

tmen

t w

ithst

able

full

ther

apeu

tic d

oses

of a

n N

SAID

for

at le

ast

the

prev

ious

mon

th (e

xcep

tna

bum

eton

e or

asp

irin

at 1

300

mg/

day

orm

ore)

Type

and

dur

atio

n of

art

hrit

is (

year

s):

no d

etai

lsA

ge:a

60.

5, b

59.

4, c

61.

6, d

60.

2Se

x:M

/F: a

46/

87, b

43/

91, c

50/

86,

d48

/84

Incl

usio

n cr

iter

ia: 1

8 ye

ars

or o

lder

,hi

stor

y of

end

osco

pica

lly d

ocum

ente

dga

stric

ulc

er w

ith o

r w

ithou

t du

oden

alul

cer

or g

astr

oint

estin

al b

leed

ing,

trea

tmen

t w

ith s

tabl

e fu

ll th

erap

eutic

dose

s of

an

NSA

ID (w

ith t

he e

xcep

tion

ofna

bum

eton

e or

asp

irin

at 1

300

mg/

day

orm

ore;

low

-dos

e as

pirin

for

card

iova

scul

arpr

otec

tion

was

per

mitt

ed) f

or a

t le

ast

the

prev

ious

mon

thEx

clus

ion

crit

eria

:pos

itive

for

H. P

ylor

i,ga

stric

or

duod

enal

ulc

er c

rate

r of

5m

mor

mor

e or

sev

ere

eros

ions

def

ined

as

mor

e th

an 2

5 er

osio

ns, e

rosiv

e re

flux

oeso

phag

itis,

use

of P

PI, m

isopr

osto

l or

H2R

As

with

in 2

4 h

of s

tart

of s

tudy

Com

pari

son:

lans

opra

zole

(c, d

)pl

us m

ixed

NSA

IDs

vs m

isopr

osto

l(b

) plu

s m

ixed

NSA

IDs

vs m

ixed

NSA

IDs

(a)

Dur

atio

n:12

wee

ksIn

terv

enti

ons:

d, la

nsop

razo

le30

mg/

15–3

0m

g (3

0m

g ×1

dai

ly);

c, la

nsop

razo

le 1

5m

g/15

–30

mg

(15

mg

×1 d

aily

); b,

miso

pros

tol

800

µg /4

00–8

00 µ

g (2

00 µ

g ×4

dai

ly);

a, p

lace

boN

SAID

use

: ib

upro

fen:

40%

napr

oxen

: 35%

dicl

ofen

ac: 3

2%as

pirin

or

aspi

rin c

ombi

natio

ns:

22%

piro

xica

m: 1

7%O

ther

NSA

IDs:

34%

Patie

nts

coul

d ha

ve t

aken

mor

eth

an o

ne N

SAID

Endo

scop

y:1,

2 a

nd 3

mon

ths

Oth

er m

edic

atio

n: a

ntac

idpr

ovid

ed fo

r us

e as

nee

ded

for

sym

ptom

rel

ief,

inst

ruct

ed t

o av

oid

antiu

lcer

med

icat

ion

othe

r th

anst

udy

med

icat

ion,

ulc

erog

enic

med

icat

ion

and

agen

ts t

hat

alte

rha

emos

tasis

Asp

irin

allo

wed

:yes

Ana

lges

ic a

llow

ed:n

ot s

tate

dPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:n

ot s

tate

dN

umbe

r an

d fr

eque

ncy

of v

isit

s:?4

(0, 4

, 8 a

nd 1

2 w

eeks

)

Allo

cate

d:a

134,

b13

4, c

136

, d 1

33C

ompl

eted

:a 1

11,

b11

1, c

122

, d 1

14D

rop-

out:

a 23

, b 2

3,c

14, d

19

Ass

esse

d:a

133,

b 1

34,

c 13

6, d

132

Out

com

es r

epor

ted:

mor

talit

y, s

erio

us G

Ico

mpl

icat

ions

, ser

ious

card

iova

scul

ar o

r re

nal

illne

ss (e

xtra

dat

a)en

dosc

opic

ulc

ers,

tot

aldr

op-o

uts

How

wer

e ad

vers

eev

ents

ass

esse

d:pa

rtic

ipan

ts k

ept

diar

y of

daily

sym

ptom

s an

das

ked

dire

ct q

uest

ions

at

each

visi

tH

ow w

as c

ompl

ianc

eas

sess

ed: t

able

t co

unt,

90%

in g

roup

s a,

c a

ndd

wer

e co

mpl

iant

com

pare

d w

ith 7

3% in

grou

p b

(miso

pros

tol)

Ris

k fa

ctor

s:hi

stor

yof

ulc

ers:

all

part

icip

ants

FUN

DIN

GFu

nded

by:

TAP

Phar

mac

eutic

alPr

oduc

tsA

ffilia

tion

of c

onta

ctau

thor

:Vet

eran

sA

ffairs

Med

ical

Cen

tre,

Texa

s, U

SAA

ffilia

tion

of

stat

isti

cian

:Abb

ott

Labo

rato

ries;

stat

istic

ian

was

also

the

outc

ome

asse

ssor

Affi

liati

on o

f stu

dyad

min

istr

ator

:TA

PPh

arm

aceu

tical

Prod

ucts

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:2

of 7

Appendix 6

234 (c)

Mis

opro

stol

plu

s N

SAID

ver

sus

plac

ebo

plus

NSA

ID

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Gra

ham

,19

8866

,214

,215

Loca

tion

: mul

ti-ce

ntre

d, U

SA

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

con

ceal

men

t:un

clea

r B

asel

ine

com

para

bilit

y:un

clea

rPa

rtic

ipan

t bl

indi

ng:y

esA

sses

sor

blin

ding

:unc

lear

Inte

ntio

n-to

-tre

at:n

oA

pri

ori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd e

xclu

ded

patie

nts

with

endo

scop

ic u

lcer

s (o

r jo

ined

afte

r4–

8w

eeks

of t

reat

men

t w

ith m

isopr

osto

lor

pla

cebo

with

a h

eale

d ul

cer)

;pa

rtic

ipan

ts h

ad a

bdom

inal

pai

n th

ough

tre

late

d to

NSA

IDS

Bas

elin

e N

SAID

sta

tus:

all u

sed

NSA

IDs

for

1 ye

arTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A =

all,

mea

n 8

year

sA

ge:t

otal

: 58.

9 (2

2–90

)Se

x:M

/F t

otal

: 147

/274

Incl

usio

n cr

iter

ia:O

A a

nd c

urre

ntly

rece

ivin

g ib

upro

fen,

piro

xica

m o

rna

prox

en fo

r th

eir

arth

ritic

diso

rder

,es

timat

ed t

o re

quire

at

leas

t 3

mon

ths

cont

inue

d N

SAID

tre

atm

ent,

had

abdo

min

al p

ain,

at

or a

bove

min

imum

age

of c

onse

nt, o

nly

wom

en w

ithou

tch

ildbe

arin

g po

tent

ial (

post

men

opau

sal,

surg

ical

ly s

teril

ised,

or

prac

tisin

g an

acce

ptab

le m

etho

d of

birt

h co

ntro

l) Ex

clus

ion

crit

eria

:hist

ory

or p

rese

nce

of p

rove

n re

curr

ent

gast

ric u

lcer

dise

ase,

activ

e bl

eedi

ng u

lcer

, mal

igna

nt d

isord

eror

met

asta

sis t

o th

e U

GI t

ract

, pyl

oric

or

duod

enal

obs

truc

tion,

acu

te h

epat

itis,

panc

reat

itis,

infla

mm

ator

y bo

wel

dise

ase,

blee

ding

dia

thes

is or

sev

ere

rena

lim

pairm

ent,

patie

nts

taki

ng a

ntin

eopl

astic

drug

s, a

ntic

oagu

lant

s or

ant

i-ulc

er d

rugs

(oth

er t

han

anta

cids

)

Com

pari

son:

miso

pros

tol p

lus

mix

ed N

SAID

s (b

, c) v

s pl

aceb

opl

us m

ixed

NSA

IDs

(a)

Dur

atio

n:12

wee

ksIn

terv

enti

ons:

c, m

isopr

osto

l80

0µg

/400

–800

µg

(4×

200

µgda

ily);

b, m

isopr

osto

l40

0µg

/400

–800

µg

(4×

100

µgda

ily);

a,m

atch

ing

plac

ebo

(4×

daily

) (m

edic

atio

n ta

ken

with

mea

ls an

d at

bed

time)

NSA

IDs:

ibup

rofe

n: 3

6% t

otal

piro

xica

m: 2

8% t

otal

napr

oxen

: 36%

tot

alen

dosc

opy:

0, 4

, 8 a

nd 1

2 w

eeks

Oth

er m

edic

atio

n: a

ntac

id(a

mph

ojel

) no

mor

e th

an 4

per

day

for

initi

al w

eek

for

pain

rel

ief,

antin

eopl

astic

dru

gs, a

ntic

oagu

lant

sor

ant

i-ulc

er d

rugs

exc

lude

d A

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:not

sta

ted

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:Not

sta

ted

Num

ber

and

freq

uenc

y of

vis

its:

4 (0

, 4, 8

and

12

wee

ks)

Allo

cate

d:a

138,

b

143,

c 1

40C

ompl

eted

:a 9

6, b

98,

c 99

Dro

p-ou

t:a

42, b

45,

c41

Ass

esse

d fo

r G

Isy

mpt

oms:

a 1

38,

b14

3, c

140

Out

com

es r

epor

ted:

mor

talit

y, s

erio

usca

rdio

vasc

ular

or

rena

lill

ness

, GI s

ympt

oms,

endo

scop

ic u

lcer

s, t

otal

drop

-out

sH

ow w

ere

adve

rse

even

ts a

sses

sed:

not

stat

edH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:hi

stor

y of

ulc

ers:

55/4

21,

22/4

21 (j

ust

rece

ived

heal

ing

trea

tmen

t fo

rul

cers

)FU

ND

ING

Fund

ed b

y:G

D S

earle

Affi

liati

on o

f con

tact

auth

or:V

eter

an’s

Affa

irs M

edic

al C

ente

r,H

oust

on, T

X, U

SAA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

uncl

ear


235


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Bolte

n, 1

98967

Loca

tion

:9ce

ntre

s in

Ger

man

y

Met

hod

ofra

ndom

isat

ion:

‘rand

omisi

eeru

ngsli

ste’

Allo

cati

on c

once

alm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

uncl

ear

Part

icip

ant

blin

ding

:yes

Ass

esso

r bl

indi

ng:u

ncle

ar

Inte

ntio

n-to

-tre

at:u

ncle

arA

pri

ori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd p

atie

nts

excl

uded

with

pept

ic u

lcer

but

incl

uded

pat

ient

s w

ithle

sion

and

uppe

r ab

dom

inal

com

plai

nts

Type

and

dur

atio

n of

art

hrit

is (

year

s):

RA: a

ll pa

rtic

ipan

ts, n

o fu

rthe

r de

tails

Age

:no

deta

ilsSe

x:M

/F: 3

2/35

in t

otal

Incl

usio

n cr

iter

ia:1

8–83

yea

rs,

ambu

lato

ry w

ith c

hron

ic p

olya

rthr

itis

and

bein

g tr

eate

d w

ith N

SAID

s fo

r up

per

abdo

min

al c

ompl

aint

sEx

clus

ion

crit

eria

:pre

gnan

cy, n

on-

NSA

ID-r

elat

ed g

astr

ic o

r du

oden

al il

lnes

san

d pe

ptic

ulc

ers

Com

pari

son:

miso

pros

tol p

lus

mix

ed N

SAID

s (b

) vs

plac

ebo

plus

mix

ed N

SAID

s (a

) D

urat

ion:

4 w

eeks

Inte

rven

tion

s:b,

miso

pros

tol

800

µg/4

00-8

00µg

(400

µg×2

daily

); a,

pla

cebo

En

dosc

opy:

2 a

nd 4

wee

ksN

SAID

s:di

clof

enac

: 33%

keto

prof

en: 1

6%pi

roxi

cam

: 4.5

%in

dom

etha

cin:

22.

5%ib

upro

fen:

12%

othe

r: 1

2%O

ther

med

icat

ion:

no d

etai

lsA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:not

sta

ted

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

: not

sta

ted

Num

ber

and

freq

uenc

y of

vis

its:

3 (0

, 2 a

nd 4

wee

ks)

Allo

cate

d:a

36, b

31

Com

plet

ed:u

ncle

arD

rop-

out:

uncl

ear

Ass

esse

d fo

r G

Isy

mpt

oms:

a 3

6, b

31

Out

com

es r

epor

ted:

serio

us G

Ico

mpl

icat

ions

, GI

sym

ptom

s, G

I dro

p-ou

tsH

ow w

ere

adve

rse

even

ts a

sses

sed:

node

tails

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:no

tst

ated

FUN

DIN

G

Fund

ed b

y:no

t st

ated

Affi

liati

on o

f con

tact

auth

or:R

heum

aklin

ikBa

d Ra

ppen

au,

Ger

man

yA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

0/1

Appendix 6

236

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Cha

ndra

seka

ran,

1991

68

Loca

tion

:Ind

ia

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

allo

tted

’A

lloca

tion

con

ceal

men

t:un

clea

rB

asel

ine

com

para

bilit

y:ye

sPa

rtic

ipan

t bl

indi

ng: y

esA

sses

sor

blin

ding

:unc

lear

In

tent

ion-

to-t

reat

:yes

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:nor

mal

end

osco

py

Type

and

dur

atio

n of

art

hrit

is (

year

s):

OA

: a 1

5, b

15;

RA

: a 1

5, b

15;

sero

nega

tive

spon

dart

hrop

athy

: a 1

5, b

15(n

o ot

her

deta

ils)

Age

:a 3

8.2

b 39

.9Se

x:M

/F: a

24/

21, b

21/

24In

clus

ion

crit

eria

:OA

, RA

or

sero

nega

tive

spon

dart

hrop

athy

, pat

ient

sab

ove

18 y

ears

of a

ge, f

ree

of U

GI

sym

ptom

s, n

orm

al p

re-t

rial U

GI

endo

scop

y, n

ot t

akin

g N

SAID

s in

prec

edin

g m

onth

Excl

usio

n cr

iter

ia:p

regn

ancy

, ren

al,

hepa

tic o

r ca

rdio

vasc

ular

dise

ase,

infla

mm

ator

y bo

wel

dise

ase,

mal

igna

ncy

of a

ny t

ype,

hist

ory

of p

revi

ous

surg

ery

onth

e st

omac

h or

duo

denu

m, h

istor

y of

alco

holis

m a

nd k

now

n se

nsiti

vity

to

pros

tagl

andi

ns

Com

pari

son:

miso

pros

tol p

lus

mix

ed N

SAID

s (b

) vs

plac

ebo

plus

mix

ed N

SAID

s (a

) D

urat

ion:

4 w

eeks

Inte

rven

tion

s:b,

miso

pros

tol

600

µg/4

00–8

00µg

(3×

200

µgda

ily);

a, m

atch

ing

plac

ebo

(3×

daily

)En

dosc

opy:

base

line

then

at

4w

eeks

NSA

IDs:

dicl

ofen

ac s

odiu

m15

0m

g/75

–150

mg

(to

15 O

Apa

rtic

ipan

ts in

eac

h gr

oup

daily

)in

dom

etha

cin

75m

g/50

–200

mg

(to

15 s

eron

egat

ive

spon

dart

hrop

athy

part

icip

ants

in e

ach

grou

p da

ily)

ibup

rofe

n 12

00m

g/60

0–24

00m

g(t

o 20

RA

par

ticip

ants

dai

ly, n

oot

her

deta

ils)

aspi

rin 2

700

mg/

?? (t

o 10

RA

part

icip

ants

dai

ly, n

o ot

her

deta

ils)

(giv

en 3

×da

ily in

equ

al d

ivid

eddo

ses

with

mea

ls)O

ther

med

icat

ion:

no a

ntac

ids

adm

inist

ered

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:n

ot s

tate

dPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:n

ot s

tate

dN

umbe

r an

d fr

eque

ncy

of v

isit

s:5

(0, 1

, 2, 3

, 4 a

nd 5

wee

ks)

Allo

cate

d:a

45, b

45

Com

plet

ed:a

45,

b 4

5D

rop-

out:

a 0,

b 0

Ass

esse

d fo

r G

Isy

mpt

oms:

a 4

5, b

45

Out

com

es r

epor

ted:

serio

us G

Ico

mpl

icat

ions

, GI

sym

ptom

s, e

ndos

copi

cul

cers

, GI d

rop-

outs

How

wer

e ad

vers

eev

ents

ass

esse

d:as

sess

ed b

y ph

ysic

ian

wee

kly

for

sym

ptom

s of

naus

ea, h

eart

burn

,ep

igas

tric

pai

n/di

stre

ss,

impr

ovem

ent

of a

rthr

itic

sym

ptom

s an

d sid

e-ef

fect

s if

any

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:no

CVD

: a 0

, b 0

rena

l/hep

atic

dise

ase:

a 0,

b 0

FU

ND

ING

Fund

ed b

y:un

clea

rA

ffilia

tion

of c

onta

ctau

thor

:unc

lear

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:1

of 7

auth

ors

is D

irect

or o

fM

edic

al A

ffairs

for

Sear

le In

dia

Oth

er:u

ncle

ar h

owm

any

part

icip

ants

inea

ch g

roup

had

asp

irin


237


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Gei

s, 1

99169

Loca

tion

:14

coun

trie

s (n

ofu

rthe

r de

tails

)

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

con

ceal

men

t:un

clea

r B

asel

ine

com

para

bilit

y:un

clea

rPa

rtic

ipan

t bl

indi

ng:y

esA

sses

sor

blin

ding

:unc

lear

Inte

ntio

n-to

-tre

at:y

esA

pri

ori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

mor

e th

an3

eros

ions

and

/or

10 p

etec

hial

haem

orrh

ages

at

base

line

endo

scop

y(s

ome

had

>10

ero

sions

, ooz

ing

or in

tra-

lum

inal

blo

od o

r ul

cera

tion

orig

inal

ly b

utha

d un

derg

one

trea

tmen

t w

ithm

isopr

osto

l to

impr

ove

GI s

tatu

s)Ty

pe a

nd d

urat

ion

of a

rthr

itis

:RA

or

OA

, no

furt

her

deta

ilsA

ge:n

ot s

tate

d Se

x:no

t st

ated

Incl

usio

n cr

iter

ia:O

A o

r RA

and

had

used

NSA

IDs

cont

inuo

usly

for

6 m

onth

s,re

quire

d ch

roni

c N

SAID

tre

atm

ent

but

coul

d no

t to

lera

te c

ontin

uous

use

ow

ing

to G

I dist

urba

nce

or h

ad r

ecei

ved

NSA

IDs

for

at le

ast

1 m

onth

and

pre

sent

ed w

ithsig

nific

ant

lesio

ns. O

n en

dosc

opy

thos

ew

ith >

10 e

rosio

ns, o

ozin

g or

intr

a-lu

min

al b

lood

or

ulce

ratio

n w

ere

give

n6

wee

ks o

f miso

pros

tol a

nd r

e-en

dosc

oped

. Tho

se w

ith n

o m

ore

than

3er

osio

ns a

nd/o

r 10

pet

echi

alha

emor

rhag

es a

t in

itial

or

follo

w-u

pen

dosc

opy

wer

e el

igib

le fo

r th

is st

udy

Excl

usio

n cr

iter

ia:n

one

men

tione

d

Com

pari

son:

miso

pros

tol p

lus

dicl

ofen

ac (b

) vs

plac

ebo

plus

dicl

ofen

ac (a

) D

urat

ion:

52 w

eeks

Inte

rven

tion

s:b,

miso

pros

tol

400–

600

µg/4

00–8

00 µ

g (2

–3 x

200

µg) d

aily

; a, m

atch

ing

plac

ebo

(2–3

×da

ily) (

miso

pros

tol o

rpl

aceb

o ta

ken

with

eac

h do

se o

fdi

clof

enac

)N

SAID

s:a

and

b: d

iclo

fena

c10

0–15

0m

g/75

–150

mg:

(2

–3 ×

50m

g da

ily)

Endo

scop

y:(0

, 12,

24,

52

wee

ks)

Oth

er m

edic

atio

n:no

det

ails

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:n

ot s

tate

dPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:n

ot s

tate

dN

umbe

r an

d fr

eque

ncy

of v

isit

s:7

(0, 6

, 12,

18,

24,

36,

52

wee

ks)

Allo

cate

d:a

99, b

96

Com

plet

ed:n

ot s

tate

d(d

ata

only

sup

plie

d to

24w

eeks

: a 6

0, b

54)

D

rop-

out:

for

24w

eeks

: a 3

9, b

42

Ass

esse

d fo

r G

Isy

mpt

oms:

not

stat

edO

utco

mes

rep

orte

d:en

dosc

opic

ulc

ers

How

wer

e ad

vers

eev

ents

ass

esse

d:no

tst

ated

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:no

deta

ils (s

ome

part

icip

ants

had

hist

ory

of u

lcer

atio

n)FU

ND

ING

Fu

nded

by:

Sear

leA

ffilia

tion

of c

onta

ctau

thor

:Sea

rleRe

sear

ch a

ndD

evel

opm

ent

Affi

liati

on o

fst

atis

tici

an:S

earle

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

4/4

empl

oyed

by

Sear

le

Appendix 6

238

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Sagg

ioro

, 199

170

Loca

tion

:Ita

lyM

etho

d of

rand

omis

atio

n:‘ra

ndom

ised’

Allo

cati

on c

once

alm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:yes

Ass

esso

r bl

indi

ng:u

ncle

arIn

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

mor

e th

an 3

eros

ions

or

pete

chai

e at

bas

elin

een

dosc

opy,

no

GI s

ympt

oms

Type

and

dur

atio

n of

art

hrit

is:

RA: a

14.

b 1

0; O

A: a

70,

b 7

2;

a 4.

7 ye

ars,

b 4

.9 y

ears

Age

:a 5

4.9,

b 5

6.1

Sex:

M/F

: a 3

4/50

, b 3

4/48

Incl

usio

n cr

iter

ia:O

A o

r RA

, ove

r18

year

s of

age

, fem

ale

patie

nts

ofch

ildbe

arin

g ag

e w

ho w

ere

neith

erpr

egna

nt o

r la

ctat

ing

and

wer

e em

ploy

ing

suita

ble

cont

race

ptio

n, w

ere

estim

ated

to

requ

ire a

t le

ast

1 m

onth

of c

ontin

ued

NSA

ID t

hera

py, w

ere

free

of u

pper

GI

sym

ptom

s, w

ere

to b

e fr

ee o

f sig

nific

ant

gast

rodu

oden

al le

sions

(end

osco

pic

scor

eof

1 o

r le

ss)

Excl

usio

n cr

iter

ia:h

istor

y of

sur

gery

on

stom

ach

and

duod

enum

or

had

asig

nific

ant

GI d

iseas

e, c

ardi

ovas

cula

r or

rena

l dys

func

tion

or r

equi

red

anti-

arth

ritic

ther

apy

with

ste

roid

s, g

old

orm

etho

trex

ate,

pat

ient

s w

ho h

ad r

ecei

ved

NSA

IDs

in la

st 3

0 da

ys b

efor

e st

udy

adm

issio

n

Com

pari

son:

miso

pros

tol p

lus

mix

ed N

SAID

s (b

) vs

plac

ebo

plus

mix

ed N

SAID

s (a

)D

urat

ion:

4 w

eeks

(±4

days

)In

terv

enti

ons:

b, m

isopr

osto

l80

0µg

/400

–800

µg

(4×

200

µgda

ily);

a, m

atch

ing

plac

ebo

(4×

daily

)N

SAID

s:(m

ean

daily

dos

es)

piro

xica

m (2

0m

g/10

–30

mg)

a 2

8,b

30di

clof

enac

(150

mg/

75–1

50m

g):

a30

, b 2

2na

prox

en (7

50m

g/50

0–12

50m

g):

a 19

, b 2

4ib

upro

fen

(100

0m

g/60

0–24

00m

g):

a 7,

b 6

Endo

scop

y:(0

, 4 w

eeks

)O

ther

med

icat

ion:

ster

oids

, gol

dor

met

hotr

exat

e ex

clud

edA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:not

sta

ted

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

: pat

ient

s w

ho h

adre

ceiv

ed N

SAID

s in

last

30

days

befo

re s

tudy

adm

issio

n w

ere

excl

uded

Num

ber

and

freq

uenc

y of

vis

its:

2 (0

, 4 w

eeks

)

Allo

cate

d:a

84, b

82

Com

plet

ed:a

80,

b 7

3D

rop-

out:

a 4,

b 9

Ass

esse

d fo

r G

Isy

mpt

oms:

a 8

0, b

78

Out

com

es r

epor

ted:

GI s

ympt

oms,

endo

scop

y, G

I dro

p-ou

ts

How

wer

e ad

vers

eev

ents

ass

esse

d:no

tst

ated

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:co

ncom

itant

ant

i-co

agul

ants

a 0

, b 0

FU

ND

ING

Fund

ed b

y:no

t st

ated

Affi

liati

on o

f con

tact

auth

or:a

ddre

ss is

Sear

le, I

taly

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:0/

6


239


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Bolte

n, 1

99271

Loca

tion

:A

ustr

alia

, Bel

gium

,C

anad

a, F

ranc

e,G

erm

any,

Gre

ece,

Luxe

mbo

urg,

Mex

ico,

Por

tuga

l,U

K, V

enez

uela

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

assig

ned’

Allo

cati

on c

once

alm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:yes

Ass

esso

r bl

indi

ng:u

ncle

ar

Inte

ntio

n-to

-tre

at:n

oA

pri

ori

sam

ple

size

:yes

Sum

mar

y ri

sk o

f bia

s:m

oder

ate

Bas

elin

e G

I st

atus

:no

mor

e th

an 1

0er

osio

ns o

n ba

selin

e en

dosc

opy

Type

and

dur

atio

n of

art

hrit

is (

year

s):

OA

: <1y

ear:

a 1

1, b

7; 1

–10

year

s: a

109

,b

119;

>10

yea

rs: a

63,

b 5

2A

ge:a

61.

3 (3

7–87

), b

59.2

(31–

91)

Sex:

M/F

: a 5

4/12

9, b

43/

125

Incl

usio

n cr

iter

ia:p

atie

nts

of b

oth

sexe

sof

the

lega

l age

of c

onse

nt, c

onfir

med

diag

nosis

of O

A h

ip a

nd/o

r kn

ee o

f at

leas

t 3

mon

ths

dura

tion,

req

uirin

gco

ntin

uous

NSA

ID t

hera

py fo

r du

ratio

n of

the

stud

y an

d to

hav

e a

func

tiona

l cap

acity

clas

sific

atio

n I–

III, f

emal

es r

equi

red

toha

ve n

egat

ive

preg

nanc

y te

st a

nd t

o us

ead

equa

te c

ontr

acep

tion

Excl

usio

n cr

iter

ia:a

rthr

itis

othe

r th

anO

A, a

ny o

ther

rhe

umat

ic d

iseas

e,ps

oria

sis, a

cute

join

t tr

aum

a at

the

OA

site,

any

mus

culo

skel

etal

diso

rder

of t

helu

mbs

acra

l are

a, s

yphi

litic

neu

ropa

thy,

ochr

onos

is or

met

abol

ic b

one

dise

ase,

mor

e th

an 1

0 er

osio

ns in

the

sto

mac

h or

duod

enum

, oes

opha

geal

, gas

tric

, pyl

oric

chan

nel o

r du

oden

al u

lcer

, any

act

ive

GI

dise

ase,

ren

al o

r he

patic

diso

rder

s, o

rm

alig

nanc

y, u

se o

f DM

ARD

s,co

rtic

oste

roid

s in

pre

cedi

ng 3

0da

ys, u

seof

ana

lges

ics

or N

SAID

s (in

clud

ing

aspi

rin)

in a

chr

onic

way

Com

pari

son:

dicl

ofen

ac–m

isopr

osto

l fix

edco

mbi

natio

n (b

) vs

dicl

ofen

ac–p

lace

bo fi

xed

com

bina

tion

(a)

Dur

atio

n:4

wee

ksIn

terv

enti

ons:

b, m

isopr

osto

l40

0–60

0 µg

/400

–800

µg

(2–3

×20

0µg

dai

ly) p

lus

dicl

ofen

ac10

0–15

0m

g/75

–150

mg

(2–3

×50

mg

daily

) fix

ed c

ombi

natio

n:

a pl

aceb

o (2

–3×

daily

) plu

sdi

clof

enac

100

–150

mg/

75–1

50m

g(2

–3×

50m

g da

ily) f

ixed

com

bina

tion

Endo

scop

y:at

0 a

nd 4

wee

ks

Oth

er m

edic

atio

n:D

MA

RDs

and

cort

icos

tero

ids

excl

uded

A

spir

in a

llow

ed:n

oA

nalg

esic

allo

wed

:no

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:no

Num

ber

and

freq

uenc

y of

vis

its:

3 (0

, 2 a

nd 4

wee

ks)

Allo

cate

d:a

183,

b 1

78C

ompl

eted

:a 1

66,

b15

9D

rop-

out:

a 17

, b 1

9A

sses

sed

for

GI

sym

ptom

s: a

183

,b

178

Out

com

es r

epor

ted:

GI s

ympt

oms,

endo

scop

ic u

lcer

s, G

Idr

op-o

uts

How

wer

e ad

vers

eev

ents

ass

esse

d:no

tst

ated

How

was

com

plia

nce

asse

ssed

:met

hod

not

repo

rted

, but

‘mea

nco

mpl

ianc

e w

as in

exce

ss o

f 90%

rega

rdle

ss o

f gro

up o

rdo

sage

’

Ris

k fa

ctor

s:co

ncom

itant

ant

i-co

agul

ants

: a 0

, b 0

>1

NSA

ID: a

0, b

0re

nal/h

epat

ic d

iseas

e:a

0, b

0

FUN

DIN

GFu

nded

by:

not

stat

edA

ffilia

tion

of c

onta

ctau

thor

:GD

Sea

rleA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

2/4

wor

ked

for

GD

Sea

rleO

ther

:2 p

artic

ipan

tsw

ith g

astr

oduo

dena

lul

cers

at

base

line

wer

ein

corr

ectly

enr

olle

d in

grou

p b,

bot

h he

aled

at e

nd-p

oint

endo

scop

y an

dex

clud

ed fr

om a

naly

sisby

rev

iew

ers

Appendix 6

240

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Doh

erty

, 199

272

Loca

tion

:43

phys

icia

ns in

9co

untr

ies

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

con

ceal

men

t:un

clea

r B

asel

ine

com

para

bilit

y:ye

s Pa

rtic

ipan

t bl

indi

ng:y

esA

sses

sor

blin

ding

:unc

lear

Inte

ntio

n-to

-tre

at:u

ncle

arA

pri

ori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:tho

se w

ith a

ctiv

e G

Idi

seas

e w

ere

excl

uded

(no

base

line

endo

scop

y)Ty

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A: a

ll <

0.5

year

s: a

7, b

95.

0–9.

9 ye

ars:

a 4

6, b

52

15 y

ears

or

mor

e: a

22,

b 2

1A

ge:a

62.

2 (2

0–85

), b

62.3

(20–

86)

Sex:

M/F

: a 8

7/14

0, b

81/

147

Incl

usio

n cr

iter

ia:d

iagn

osis

of p

rimar

yO

A o

f the

hip

, kne

e or

bot

h (3

hist

oric

alcr

iteria

and

1 r

adio

grap

hic

findi

ngre

quire

d fo

r di

agno

sis) f

or a

t le

ast

3m

onth

s be

fore

the

stu

dy a

nd a

Stei

nbro

cker

func

tiona

l cap

acity

of C

lass

I,II

or II

IEx

clus

ion

crit

eria

:the

pre

senc

e of

any

othe

r ty

pe o

f art

hriti

c co

nditi

on, a

nyac

tive

GI d

iseas

e, o

r a

sche

dule

dho

spita

lisat

ion

for

bed

rest

or

join

tre

plac

emen

t su

rger

y be

caus

e of

art

hriti

s,pr

egna

ncy

or b

reas

t-fe

edin

g. A

lsoin

elig

ible

if a

ny o

f the

follo

win

g ha

d be

enus

ed in

the

30

days

bef

ore

the

stud

y –

antin

eopl

astic

age

nts,

cor

ticos

tero

ids

(incl

udin

g in

tra-

artic

ular

inje

ctio

ns),

gold

salts

, pen

icill

amin

e, c

olch

icin

es, c

hron

ican

alge

sic a

gent

s, o

r co

ntin

uous

NSA

IDs

(incl

udin

g as

pirin

)

Com

pari

son:

Art

hrot

ec (b

) vs

dicl

ofen

ac (a

) D

urat

ion:

4 w

eeks

Inte

rven

tion

s:(id

entic

al t

able

tsgi

ven

at m

ealti

mes

)b,

miso

pros

tol 4

00–6

00 µ

g/40

0–80

0 µg

(2–3

×20

0 µg

dai

ly)

plus

dic

lofe

nac

100–

150

mg/

75–1

50m

g (2

–3×

50m

g da

ily)

Art

hrot

ec, f

ixed

com

bina

tion;

a,

pla

cebo

(2–3

×da

ily) p

lus

dicl

ofen

ac 1

00–1

50m

g/75

–150

mg

(203

×50

mg

daily

) fix

edco

mbi

natio

n2×

daily

: a 1

51, b

157

3×da

ily: a

76,

b 7

3(1

6% c

hang

ed d

ose

durin

g st

udy)

Endo

scop

y:no

neO

ther

med

icat

ion:

antin

eopl

astic

agen

ts, c

ortic

oste

roid

s (in

clud

ing

intr

a-ar

ticul

ar in

ject

ions

), go

ld s

alts

,pe

nici

llam

ine

and

colc

hici

nes

wer

eex

clud

edA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:not

sta

ted

but

chro

nic

anal

gesic

use

in p

revi

ous

30da

ys w

as a

n ex

clus

ion

crite

rion

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:Not

sta

ted

but

patie

nts

on c

ontin

uous

NSA

IDs

wer

eex

clud

edN

umbe

r an

d fr

eque

ncy

of v

isit

s:3

(0, 2

, 4 w

eeks

)

Allo

cate

d:a

227,

b 2

28C

ompl

eted

:unc

lear

Dro

p-ou

t:un

clea

rA

sses

sed

for

GI

sym

ptom

s:no

tas

sess

edO

utco

mes

rep

orte

d:se

rious

adv

erse

eve

nts,

effic

acy

How

wer

e ad

vers

eev

ents

ass

esse

d:no

tst

ated

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:no

deta

ilsFU

ND

ING

Fund

ed b

y:no

t st

ated

Affi

liati

on o

f con

tact

auth

or:C

ity H

ospi

tal,

Not

tingh

am, U

KA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

uncl

ear


241


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Mel

o G

omes

,19

9273

Loca

tion

:mul

ti-ce

ntre

, Por

tuga

l

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

eco

mpa

rabi

lity:

yes

reRA

Stu

dy 1

, no

re O

ASt

udy

2Pa

rtic

ipan

t bl

indi

ng:

yes

Ass

esso

r bl

indi

ng:

uncl

ear

Inte

ntio

n-to

-tre

at:n

oA

pri

ori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

Stud

y 1

mod

erat

e,

Stud

y 2

high

Bas

elin

e G

I st

atus

:no

mor

e th

an10

eros

ions

or

any

ulce

rs a

t ba

selin

een

dosc

opy,

61%

dic

lofe

nac

grou

p an

d 62

%of

art

hrot

ec g

roup

in S

tudy

1 (R

A) h

adno

rmal

muc

osa

on b

asel

ine,

57%

dic

lofe

nac

and

65%

art

hrot

ec g

roup

in S

tudy

2 (O

A)

had

norm

al m

ucos

aTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:St

udy

1: R

A: a

ll; <

0.5

year

s: a

4, b

3;

5.0–

9.9

year

s: a

48,

b 4

5; ≥

15 y

ears

: a 3

1,

b 26

Stud

y 2:

OA

: all;

<0.

5 ye

ars:

a 4

, b 0

; 5.

0–9.

9 ye

ars:

a 4

2, b

51;

≥15

yea

rs: a

27,

b

22A

ge:

Stud

y 1:

a 5

3.4

(19–

86),

b 53

.2 (2

2–83

)St

udy

2: a

61.

3 (3

7–87

), b

59.2

(31–

91)

Sex:

M/F

Stud

y 1:

a 3

8/13

7, b

41/

123

Stud

y 2:

a 5

4/12

9, b

43/

135

Incl

usio

n cr

iter

ia:f

ree

of s

igni

fican

t U

GI

dam

age

and

requ

iring

con

tinuo

us N

SAID

ther

apy

for

dura

tion

of t

he s

tudy

St

udy

1: R

A, c

ortic

oste

roid

s, g

old

salts

,pe

nici

llam

ine,

met

hotr

exat

e, c

olch

icin

e or

antim

alar

ials

wer

e pe

rmitt

ed if

sta

rted

mor

eth

an 3

0da

ys b

efor

e st

art

of t

he s

tudy

and

no c

hang

e in

dos

e du

ring

thos

e 30

days

Stud

y 2:

pat

ient

s w

ith O

A w

ere

requ

ired

toha

ve in

volv

emen

t of

the

hip

and

/or

knee

for

at le

ast

3 m

onth

s an

d a

func

tiona

l cap

acity

clas

sific

atio

n of

I–III

Excl

usio

n cr

iter

ia:a

ny s

igni

fican

t U

GI

muc

osal

dam

age,

act

ive

GI d

iseas

e, o

ther

serio

us il

lnes

ses

Stud

y 2:

if a

ny a

ntin

eopl

astic

s, a

ntim

alar

ials,

chro

nic

anal

gesic

s, c

olch

icin

e,co

rtic

oste

roid

s, c

ontin

uous

NSA

IDs,

gol

dsa

lts o

r pe

nici

llam

ine

wer

e us

ed w

ithin

30da

ys o

f the

sta

rt o

f the

stu

dy

Com

pari

son:

Art

hrot

ec (b

) vs

dicl

ofen

ac (a

) D

urat

ion:

Stud

y 1

= 1

2 w

eeks

Stud

y 2

= 4

wee

ksIn

terv

enti

ons:

(iden

tical

tab

lets

give

n at

mea

ltim

es)

b: m

isopr

osto

l 400

–600

µg/

400–

800

µg (2

–3 ×

200

µg d

aily

)pl

us d

iclo

fena

c 10

0–15

0m

g/75

–150

mg

(2–3

×50

mg

daily

)A

rthr

otec

, fix

ed c

ombi

natio

na:

pla

cebo

(2–3

×da

ily) p

lus

dicl

ofen

ac 1

00–1

50m

g/75

–150

mg

daily

) fix

ed c

ombi

natio

n2×

daily

Stud

y 1:

a 7

5, b

81

Stud

y 2:

a 1

32, b

129

3×da

ily:

Stud

y 1:

a 1

00, b

83

Stud

y 2:

a 5

1, b

49

Endo

scop

y:St

udy

1: 0

and

12

wee

ksSt

udy

2: 0

and

4 w

eeks

Oth

er m

edic

atio

n:St

udy

1: c

ortic

oste

roid

s, g

old

salts

,pe

nici

llam

ine,

met

hotr

exat

e,co

lchi

cine

or

antim

alar

ials

wer

epe

rmitt

ed if

sta

rted

mor

e th

an30

days

bef

ore

star

t of

the

stu

dyan

d no

cha

nge

in d

ose

durin

g th

ose

30da

ysA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:no

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:No

Num

ber

and

freq

uenc

y of

vis

its:

Stud

y 1:

4×

(0, 4

, 8 a

nd 1

2 w

eeks

)St

udy

2: 3

×(0

, 2 a

nd 4

wee

ks)

Allo

cate

d:St

udy

1: a

175

, b 1

64St

udy

2: a

183

, b 1

78C

ompl

eted

:unc

lear

Dro

p-ou

t:un

clea

rA

sses

sed

for

GI

sym

ptom

s:

Stud

y 1:

a 1

53, b

137

Stud

y 2:

a 1

67, b

162

Out

com

es r

epor

ted:

endo

scop

ic u

lcer

sH

ow w

ere

adve

rse

even

ts a

sses

sed:

not

stat

edH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:no

deta

ilsFU

ND

ING

Fund

ed b

y:no

t st

ated

Affi

liati

on o

f con

tact

auth

or:u

ncle

arA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

uncl

ear

Oth

er: 2

par

ticip

ants

in A

rthr

otec

gro

up o

fst

udy

2 (O

A) h

adul

cers

at

base

line

whi

ch w

ere

heal

ed a

t4-

wee

k en

dosc

opy

–ex

clud

ed fr

om a

naly

ses

by r

evie

wer

Appendix 6

242

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Verd

ickt

, 199

274

Loca

tion

: Bel

gium

,U

K, G

erm

any,

Mex

ico

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d’A

lloca

tion

conc

ealm

ent:

unc

lear

B

asel

ine

com

para

bilit

y: y

esPa

rtic

ipan

t bl

indi

ng:

yes

Ass

esso

r bl

indi

ng:

uncl

ear

Inte

ntio

n-to

-tre

at:

uncl

ear

A p

riori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

mor

e th

an 1

0er

osio

ns in

sto

mac

h an

d/or

10

eros

ions

indu

oden

um, o

esop

hage

al, g

astr

ic, p

ylor

icch

anne

l, no

duo

dena

l ulc

er a

t ba

selin

een

dosc

opy

Nor

mal

muc

osa:

a 1

07, b

101

No

mor

e th

an 1

0 er

osio

ns: a

68,

b 6

3Ty

pe a

nd d

urat

ion

of a

rthr

itis

:RA

: all

part

icip

ants

<1.

0 ye

ars:

a 1

0, b

8; 5

.0–9

.9ye

ars:

a 4

8;

b 45

; ≥10

yea

rs: a

65,

b 7

1A

ge:a

53.

4 (1

9–86

), b

53.2

(22–

83)

Sex:

M/F

: a 3

8/13

7, b

41/

123

Incl

usio

n cr

iter

ia:l

egal

age

of c

onse

nt,

conf

irmed

dia

gnos

is of

RA

, req

uire

dco

ntin

uous

NSA

ID t

hera

py fo

r du

ratio

n of

stud

y, w

omen

of c

hild

bear

ing

pote

ntia

l wer

ere

quire

d to

use

ade

quat

e co

ntra

cept

ion

and

to h

ave

a ne

gativ

e pr

egna

ncy

test

with

in72

h of

rec

eivi

ng fi

rst

dose

of s

tudy

med

icat

ion

Excl

usio

n cr

iter

ia:t

he p

rese

nce

of a

rthr

itis

othe

r th

an a

dult

RAs,

any

oth

er r

heum

atic

dise

ase

or p

soria

sis; c

hron

ic o

r ac

ute

rena

lor

hep

atic

diso

rder

s, m

alig

nanc

y of

any

typ

e,th

e pr

esen

ce o

f sig

nific

ant

UG

Imuc

osal

dam

age

(>10

eros

ions

in t

he s

tom

ach,

>10

eros

ions

in t

he d

uode

num

,oe

soph

agea

l, ga

stric

, pyl

oric

cha

nnel

or

duod

enal

ulc

er a

t ba

selin

e en

dosc

opy)

, any

activ

e G

I dise

ase,

hist

ory

of s

ubst

ance

abus

e, u

se o

f ant

ineo

plas

tics

(oth

er t

han

met

hotr

exta

e as

ant

iart

hriti

c th

erap

y) d

urin

gth

e 30

day

s pr

eced

ing

the

stud

y, in

itiat

ion

ordo

se a

ltera

tion

of a

ny D

MA

RD d

urin

g th

e30

days

pre

cedi

ng t

he s

tudy

, cor

ticos

tero

iddo

ses

grea

ter

than

the

equ

ival

ent

of 1

0m

gpr

edni

sone

per

day

, pat

ient

s w

ho h

ad u

sed

Com

pari

son:

miso

pros

tol/d

iclo

fena

c fix

edco

mbi

natio

n (b

) vs

plac

ebo/

dicl

ofen

ac fi

xed

com

bina

tion

(a)

Dur

atio

n:12

wee

ksIn

terv

enti

ons:

b, m

isopr

osto

l40

0–60

0 µg

/400

–800

µg

(2–3

×20

0µg

dai

ly))

plu

s di

clof

enac

100–

150

mg/

75–1

50m

g (2

–3×

50m

gdai

ly);

a, p

lace

bo (2

–3×

daily

)pl

us d

iclo

fena

c 10

0–15

0m

g/75

–150

mg

(2–3

×50

mg

daily

)En

dosc

opy:

0 an

d at

12

wee

ksO

ther

med

icat

ion:

othe

r N

SAID

san

d an

tiulc

er d

rugs

pro

hibi

ted,

antin

eopl

astic

s (o

ther

tha

nm

etho

trex

tae

as a

ntia

rthr

itic

ther

apy)

dur

ing

the

30 d

ays

prec

edin

g th

e st

udy,

initi

atio

n or

dose

alte

ratio

n of

any

DM

ARD

durin

g th

e 30

day

s pr

eced

ing

the

stud

y, c

ortic

oste

roid

dos

es g

reat

erth

an t

he e

quiv

alen

t of

10

mg

pred

niso

ne p

er d

ay w

ere

excl

usio

ncr

iteria

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed: n

oPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:n

ot s

tate

dN

umbe

r an

d fr

eque

ncy

of v

isit

s:4

(0, 4

, 8 a

nd 1

2 w

eeks

)

Allo

cate

d: a

175

, b 1

64

Com

plet

ed:a

144

,b

132

Dro

p-ou

t:a

31, b

32

Ass

esse

d fo

r G

Isy

mpt

oms:

a 1

75, b

164

O

utco

mes

rep

orte

d:G

I sym

ptom

s,en

dosc

opy

How

wer

e ad

vers

eev

ents

ass

esse

d:no

tst

ated

How

was

com

plia

nce

asse

ssed

:not

sta

ted,

>90

% c

ompl

ianc

e fo

rbo

th g

roup

s

Ris

k fa

ctor

s:re

nal/h

epat

ic d

iseas

e:

a 0,

b 0

>

1 N

SAID

a 0

, b 0

FU

ND

ING

Fund

ed b

y:no

t st

ated

Affi

liati

on o

f con

tact

auth

or:a

ddre

ss is

Sear

le, S

koki

e, IL

, USA

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:2/

6em

ploy

ed b

y Se

arle

Rese

arch

&D

evel

opm

ent


243


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

an in

vest

igat

ive

drug

dur

ing

the

30 d

ays

prio

r to

stu

dy e

nrol

men

t, kn

own

hype

rsen

sitiv

ity t

o di

clof

enac

sod

ium

or

othe

r N

SAID

s, o

r m

isopr

osto

l or

othe

rpr

osta

glan

dins

Gra

ham

, 199

375

Loca

tion

:Priv

ate

Vete

rans

Affa

irs,

heal

th m

aint

enan

cean

d ac

adem

icpr

actic

es in

USA

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d an

dba

lanc

ed w

ithin

eac

hce

ntre

’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

eco

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:yes

In

tent

ion-

to-t

reat

:yes

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

ulce

r or

ero

sions

of

3m

m o

r m

ore

at b

asel

ine

endo

scop

yTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A: 7

5% o

f tot

alA

ge (

med

ian)

:a 6

1, b

59

Sex:

:M/F

: a 1

63/1

60, b

169

/151

Incl

usio

n cr

iter

ia:R

A, O

A, p

soria

ticar

thrit

is, A

S or

the

Rei

ter

synd

rom

e,ex

pect

ed t

o re

quire

at

leas

t 3

addi

tiona

lm

onth

s of

dai

ly N

SAID

tre

atm

ent

with

eith

er ib

upro

fen,

piro

xica

m, n

apro

xen,

sulin

dac,

tol

met

in, i

ndom

etha

cin

ordi

clof

enac

, wom

en w

ere

requ

ired

to b

epo

stm

enop

ausa

l, su

rgic

ally

ste

rilise

d or

prac

tisin

g ad

equa

te c

ontr

acep

tion

Excl

usio

n cr

iter

ia:h

istor

y of

pep

tic u

lcer

dise

ase

requ

iring

tre

atm

ent

in t

he 3

0da

ysim

med

iate

ly b

efor

e en

try,

UG

I mal

igna

ncy,

pylo

ric o

bstr

uctio

n, a

cute

hep

atiti

s,pa

ncre

atiti

s, b

leed

ing

diat

hesis

, UG

I sur

gery

with

in 3

0 da

ys o

r se

vere

ren

al im

pairm

ent,

part

icip

ants

tak

ing

antin

eopl

astic

s,an

ticoa

gula

nts,

ant

i-ulc

er d

rugs

oth

er t

han

the

stud

y dr

ug, o

r pr

edni

sone

at

dose

s of

mor

e th

an 7

.5m

g/da

y

Com

pari

son:

miso

pros

tol p

lus

mix

ed N

SAID

s (b

) vs

plac

ebo

plus

mix

ed N

SAID

s (a

)D

urat

ion:

12 w

eeks

Inte

rven

tion

s:b,

miso

pros

tol

800

µg /4

00–8

00 µ

g (4

×20

0 µg

daily

with

mea

ls an

d at

bed

time

with

food

); a,

mat

chin

g pl

aceb

o (4

×da

ily w

ith m

eals

and

at b

edtim

ew

ith fo

od)

Endo

scop

y: b

asel

ine

then

at

4, 8

and

12 w

eeks

NSA

IDs:

(at

sam

e do

sage

as

prio

rto

sta

rt o

f stu

dy) i

bupr

ofen

,pi

roxi

cam

, nap

roxe

n, s

ulin

dac,

tolm

etin

, ind

omet

haci

n or

dicl

ofen

acO

ther

med

icat

ion:

ant

acid

(am

phog

el 6

00m

g) 3

tab

lets

or

less

per

day

for

first

2w

eeks

for

relie

fof

UG

I pai

n, a

ntin

eopl

astic

s,an

tioco

agul

ants

, ant

i-ulc

er d

rugs

othe

r th

an t

he s

tudy

dru

g, o

rpr

edni

sone

at

dose

s of

mor

e th

an7.

5m

g/da

y w

ere

not

allo

wed

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed: n

ot s

tate

dPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:N

ot s

tate

dN

umbe

r an

d fr

eque

ncy

of v

isit

s:4

(0, 4

, 8 a

nd 1

2 w

eeks

)

Allo

cate

d:a

323,

b 3

20

Com

plet

ed:a

240

,b

215

Dro

p-ou

t: a

83,

b 1

05A

sses

sed

for

GI

sym

ptom

s: a

319

,b

319

Out

com

es r

epor

ted:

Mor

talit

y, G

I sym

ptom

s,en

dosc

opic

ulc

ers

How

wer

e ad

vers

eev

ents

ass

esse

d:no

tst

ated

How

was

com

plia

nce

asse

ssed

:non

-co

mpl

ianc

e de

fined

as

failu

re t

o ta

ke a

t le

ast

60%

pre

scrib

edm

edic

atio

n, d

eter

min

edby

pill

cou

nt a

t 4,

8 a

nd12

wee

ks: a

14%

,b

24%

= n

on-c

ompl

iant

Ris

k fa

ctor

s:hi

stor

yof

ulc

ers:

a 8

4, b

80

antic

oagu

lant

s: a

0, b

0>

1 N

SAID

: a 0

b 0

FUN

DIN

GFu

nded

by:

GD

Sea

rleA

ffilia

tion

of c

onta

ctau

thor

:Vet

eran

’sA

ffairs

Med

ical

Cen

ter,

Hou

ston

, TX

, USA

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:1/

10 fo

rLe

derle

Lab

orat

orie

s

Appendix 6

244

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Hen

rikss

on, 1

99376

Loca

tion

:Ka

rolin

ska

Hos

pita

l,St

ockh

olm

, Sw

eden

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

allo

cate

d’A

lloca

tion

conc

ealm

ent:

unc

lear

B

asel

ine

com

para

bilit

y:un

clea

rPa

rtic

ipan

t bl

indi

ng:

yes

Ass

esso

r bl

indi

ng:

uncl

ear

Inte

ntio

n-to

-tre

at:n

oA

pri

ori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd e

xclu

ded

patie

nts

with

sym

ptom

atic

ulc

er o

r tr

eatm

ent

for

pept

icul

cer

in la

st 3

0 da

ys (1

of 2

0 in

pla

cebo

grou

p ha

d fr

ank

asym

ptom

atic

ulc

er a

nd 5

of 2

0 in

pla

cebo

gro

up h

ad e

rosio

ns, 5

of 1

9in

miso

pros

tol g

roup

had

ero

sions

, 15

of 3

9ha

d ha

emor

rhag

ic le

sions

and

13

of 3

9 ha

dno

rmal

muc

osa)

Type

and

dur

atio

n of

art

hrit

is (

mon

ths)

: RA

: a 3

8, b

36

Age

:a 5

4 (4

7–64

), b

60 (5

2–66

)Se

x:M

/F: a

7/1

3, b

3/1

6 In

clus

ion

crit

eria

:RA

and

con

tinuo

usly

trea

ted

with

NSA

IDs

Excl

usio

n cr

iter

ia:t

akin

g D

MA

RDs

in la

st3

mon

ths,

fem

ale

patie

nts

of c

hild

bear

ing

age

with

out

cont

race

ptio

n, p

atie

nts

with

clin

ical

or

bioc

hem

ical

evi

denc

e of

sev

ere

card

iac,

hep

atic

or

rena

l dise

ase,

pat

ient

str

eate

d fo

r ul

cers

in p

rece

ding

30

days

or

with

sym

ptom

atic

ulc

ers

Com

pari

son:

miso

pros

tol p

lus

mix

ed N

SAID

s (b

) vs

plac

ebo

plus

mix

ed N

SAID

s (a

) D

urat

ion:

4 w

eeks

Inte

rven

tion

s: b

, miso

pros

tol

800

µg/4

00–8

00 µ

g (3

×20

0 µg

daily

imm

edia

tely

afte

r fo

od);

a, m

atch

ing

plac

ebo

(3×

daily

imm

edia

tely

afte

r fo

od)

Endo

scop

y:ba

selin

e an

d at

4w

eeks

NSA

IDs:

(med

ian

daily

dos

e w

hen

used

as

singl

e dr

ug):

keto

prof

en (2

00m

g/10

0–20

0m

g)di

clof

enac

(150

mg/

75–1

50m

g)na

prox

en (1

000

mg/

500–

1250

mg)

ibup

rofe

n (1

200

mg/

600–

2400

mg)

piro

xica

m (2

0m

g/10

–30

mg)

indo

met

haci

n (1

50m

g/50

–200

mg)

ASA

(300

0m

g/?)

sodi

um s

alic

ylat

e (4

000m

g/ ?)

Oth

er m

edic

atio

n:D

MA

RDs

not

allo

wed

A

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:yes

,pa

race

tam

ol a

d lib

itum

and

inse

vere

cas

es in

trar

ticul

ar s

tero

ids

(1 in

eac

h gr

oup

at d

ay 1

0)Pa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:n

ot s

tate

dN

umbe

r an

d fr

eque

ncy

of v

isit

s:2

(0 a

nd 4

wee

ks)

Allo

cate

d:a:

20,

b 2

0 C

ompl

eted

:a 2

0, b

19

Dro

p-ou

t:a

0, b

1A

sses

sed

for

GI

sym

ptom

s: a

20,

b 1

9 O

utco

mes

rep

orte

d:G

I sym

ptom

s,en

dosc

opic

ulc

ers

How

wer

e ad

vers

eev

ents

ass

esse

d:no

tst

ated

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:C

VD,

a0,

b 0

R

enal

/hep

atic

dise

ase:

a 0,

b 0

FU

ND

ING

Fund

ed b

y:Sw

edish

Soci

ety

Aga

inst

Rheu

mat

ism, K

ing

Gus

tav

V 80

-yea

rsFo

unda

tion,

U a

nd G

af U

ggla

s Fo

unda

tion,

San

d R

Sund

sFo

unda

tion,

Nan

naSv

artz

and

Rut

h an

dRi

char

d Ju

linFo

unda

tions

, Sw

edish

Soci

ety

of M

edic

ine,

Swed

ish M

edic

alRe

sear

ch C

ounc

il an

dSe

arle

Affi

liati

on o

f con

tact

auth

or:K

arol

insk

aH

ospi

tal,

Stoc

khol

m,

Swed

enA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

0/4


245


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Mel

o G

omes

,19

9377

,217

Loca

tion

:13

coun

trie

s

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

eco

mpa

rabi

lity:

no,

stat

istic

ally

sig

nific

ant

diffe

renc

e in

OA

sev

erity

betw

een

grou

psPa

rtic

ipan

t bl

indi

ng:

yes

Ass

esso

r bl

indi

ng:

uncl

ear

Inte

ntio

n-to

-tre

at:N

oA

pri

ori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

high

Bas

elin

e G

I st

atus

:no

mor

e th

an 1

0er

osio

ns in

the

sto

mac

h or

10

eros

ions

inth

e du

oden

um, o

r oe

soph

agea

l, ga

stric

,py

loric

cha

nnel

, no

duod

enal

ulc

er a

tba

selin

e en

dosc

opy

Type

and

dur

atio

n of

art

hrit

is (

year

s):

OA

: all

<0.

5 ye

ars:

a 1

, b 6

, c 4

; 5.0

–9.9

year

s:

a 59

, b 4

4, c

69;

≥15

yea

rs: a

32,

b 3

0, c

23

Age

:a: 5

9.5

(33–

85),

b 58

.7 (2

6–89

) c

60.7

(30–

84)

Sex:

M/F

: a 4

8/16

2, b

55/

162,

c 5

2/16

4In

clus

ion

crit

eria

:leg

al a

ge o

f con

sent

,do

cum

ente

d ra

diog

raph

ic e

vide

nce

and

sym

ptom

atic

evi

denc

e of

OA

of t

he h

ipan

d/or

kne

e of

at

leas

t 3

mon

ths

dura

tion,

func

tiona

l cap

acity

cla

ssifi

catio

n of

I–III

, had

phys

icia

n an

d pa

tient

glo

bal a

sses

smen

ts o

far

thrit

is th

at w

ere

rate

d no

bet

ter

than

‘fair

’, w

ere

expe

rienc

ing

join

t pa

in, a

ndre

quire

d co

ntin

uous

NSA

ID t

hera

py fo

rdu

ratio

n of

stu

dyEx

clus

ion

crit

eria

:any

acu

te jo

int

trau

ma

at t

he s

ite o

f OA

, chr

onic

or

acut

e re

nal o

rhe

patic

diso

rder

s, s

igni

fican

t U

GI d

amag

e,an

y ac

tive

GI d

iseas

e, u

se o

f any

NSA

IDdu

ring

the

10 d

ays

or a

ny a

nalg

esic

(oth

erth

an p

arac

etam

ol) d

urin

g th

e 2

days

bef

ore

the

base

line

arth

ritis

asse

ssm

ents

, kno

wn

hype

rsen

sitiv

ity t

o an

y N

SAID

s or

any

pros

tagl

andi

n

Com

pari

son:

dicl

ofen

acso

dium

/miso

pros

tol (

c) v

spi

roxi

cam

(b) v

s na

prox

en (a

) D

urat

ion:

4 w

eeks

Inte

rven

tion

s:c,

miso

pros

tol

400

µg/4

00–8

00 µ

g (2

×20

0 µg

daily

) plu

s di

clof

enac

sod

ium

100

mg

(2×

50m

g da

ily) f

ixed

com

bina

tion;

b, p

iroxi

cam

20m

g/10

–30

mg

(2×

10m

g da

ily);

a na

prox

en 7

5m

g/50

0–12

50m

g(2

×37

5m

g da

ily) (

iden

tical

mat

chin

g pl

aceb

o, a

ll pa

rtic

ipan

tsto

ok 1

tab

let

and

1 ca

psul

e w

ithm

orni

ng m

eal a

nd a

gain

with

even

ing

mea

l)En

dosc

opy:

base

line

and

4 w

eeks

Oth

er m

edic

atio

n:no

t st

ated

A

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:yes

,pa

race

tam

olPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

es, 1

0 da

ys fo

r N

SAID

s,2

days

for

anal

gesic

sN

umbe

r an

d fr

eque

ncy

of v

isit

s:3

(0, 2

and

4 w

eeks

)

Allo

cate

d:a

210,

b21

7, c

216

Com

plet

ed:a

185

,b

200,

c 1

93D

rop-

out:

a 25

, b 1

7,c

23A

sses

sed

for

GI

sym

ptom

s: a

210

,b

217,

c 2

16O

utco

mes

repo

rted

:ser

ious

GI

com

plic

atio

ns, G

Isy

mpt

oms,

end

osco

pic

ulce

rs, G

I dro

p-ou

tsH

ow w

ere

adve

rse

even

ts a

sses

sed:

not

stat

edH

ow w

as c

ompl

ianc

eas

sess

ed:t

able

t co

unt,

part

icip

ants

ask

ed if

miss

ed m

edic

atio

n on

2or

mor

e co

nsec

utiv

eda

ys, a

t le

ast

95%

in a

ll3

grou

ps w

ere

com

plia

nt a

t 4

wee

ks

Ris

k fa

ctor

s:re

nal/h

epat

ic d

iseas

e:

a 0,

b 0

FU

ND

ING

Fund

ed b

y: n

ot s

tate

dA

ffilia

tion

of c

onta

ctau

thor

:GD

Sea

rleA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

6/6

auth

ors

empl

oyed

by

GD

Sear

le

Appendix 6

246

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Roth

, 199

378

Loca

tion

:6ce

ntre

s in

the

USA

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’, p

artic

ipan

tsas

signe

d a

trea

tmen

tnu

mbe

r th

atco

rres

pond

ed w

ithtr

eatm

ent

med

icat

ion

Allo

cati

onco

ncea

lmen

t:un

clea

r B

asel

ine

com

para

bilit

y:N

o,m

isopr

osto

l gro

upco

ntai

ned

youn

ger

part

icip

ants

and

mor

ew

ith n

orm

al e

ndos

copi

esPa

rtic

ipan

t bl

indi

ng:

uncl

ear

Ass

esso

r bl

indi

ng:y

esIn

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

high

Bas

elin

e G

I st

atus

:no

mor

e th

an3

eros

ions

at

base

line

endo

scop

y no

rmal

end

osco

py: a

17,

b 1

8, c

27

hype

rem

ia: a

24,

b 2

0, c

17

eros

ions

: a 1

7, b

15,

c 1

3Ty

pe a

nd d

urat

ion

of a

rthr

itis

:O

A: a

ll pa

rtic

ipan

ts, n

o ot

her

deta

ilsA

ge:6

0–64

: a 1

5, b

17,

c 2

2; 6

5–74

: a 3

4,b

32, c

35;

≥75

: a 9

, b, 4

c 3

Sex:

F/M

: a 1

9/39

, b 1

2/41

, c 1

1/49

Incl

usio

n cr

iter

ia:O

A a

ged

60 y

ears

or

olde

r, A

CR

func

tiona

l cla

ss II

or

III, u

sed

anN

SAID

for

at le

ast

3 m

onth

s be

fore

enro

lmen

t an

d ex

pect

ed t

o co

ntin

ue t

he u

seof

thi

s cl

ass

of m

edic

atio

n fo

r at

leas

t3

mon

ths

Excl

usio

n cr

iter

ia:h

istor

y of

hype

rsen

sitiv

ity r

eact

ion

to a

ny o

f the

stu

dydr

ugs,

inef

ficac

y or

into

lera

nce

to ib

upro

fen,

hist

ory

of M

I with

in la

st 6

mon

ths,

cong

estiv

e he

art

failu

re, m

edic

ally

unco

ntro

lled

hype

rten

sion

or a

rrhy

thm

ias,

hist

ory

of a

n ul

cer

or G

I tra

ct b

leed

ing

with

in 1

yea

r of

stu

dy e

ntry

, hist

ory

ofga

stro

duod

enal

or

eoso

phag

eal s

urge

ry,

signi

fican

t lo

wer

bow

el d

iseas

e (in

clud

ing

regi

onal

ent

eriti

s, u

lcer

ativ

e co

litis,

inte

stin

alby

pass

sur

gery

, fre

quen

tly b

leed

ing

haem

orrh

oids

), O

A w

hich

req

uire

dtr

eatm

ent

with

mul

tiple

NSA

IDs

with

in3

mon

ths

of e

nrol

men

t, pa

tient

s co

nsid

ered

to b

e ca

ndid

ates

for

join

t re

plac

emen

tdu

ring

time

of t

he s

tudy

, pat

ient

s w

ho h

adre

ceiv

ed in

tra-

artic

ular

ste

roid

inje

ctio

ns o

ror

al s

tero

ids

with

in 1

mon

th o

f enr

olm

ent

Com

pari

son:

miso

pros

tol p

lus

ibup

rofe

n (c

) vs

ibup

rofe

n (b

) vs

nabu

met

one

(a)

Dur

atio

n:12

wee

ksIn

terv

enti

ons:

c, m

isopr

osto

l80

0µg

/400

–800

µg

(4×

200

µgda

ily)

NSA

IDs:

c, ib

upro

fen

2400

mg/

600–

2400

mg

(4×

600

mg

daily

,ad

min

ister

ed c

oncu

rren

tly w

ithm

isopr

osto

l); b

, ibu

prof

en 2

400

mg/

600–

2400

mg

(4×

600

mg

daily

);a,

nabu

met

one

1000

mg/

500–

2000

mg

daily

(no

othe

rde

tails

)En

dosc

opy:

0, 2

, 6, 1

2 w

eeks

and

at e

arly

with

draw

alO

ther

med

icat

ion:

conc

omita

ntm

edic

atio

n w

as a

llow

ed w

ith t

heex

cept

ion

of a

ntic

oagu

lant

s, o

ther

anti-

infla

mm

ator

ies,

cor

ticos

tero

ids,

imm

unos

uppr

essa

nt t

hera

py, u

lcer

ther

apy

(H2R

As,

suc

ralfa

te, l

ong-

term

ant

acid

the

rapy

)A

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:par

acet

amol

max

12×

325

mg

tabl

ets

in 2

4 ho

urs

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:yes

, 3–1

0 da

ys d

urin

gw

hich

adm

inist

ered

pla

cebo

3×

daily

Num

ber

and

freq

uenc

y of

vis

its:

7 (0

, 2, 4

, 6, 8

, 10

and

12 w

eeks

)

Allo

cate

d:a,

58,

b 5

3,c

60

Com

plet

ed:a

46,

b 2

5,c

45D

rop-

out:

a 12

, b 2

8,c

15A

sses

sed

for

GI

sym

ptom

s: a

58,

b 5

3,c

60O

utco

mes

rep

orte

d:G

I sym

ptom

s,en

dosc

opic

ulc

ers,

anae

mia

, GI d

rop-

outs

H

ow w

ere

adve

rse

even

ts a

sses

sed:

part

icip

ants

ask

ed if

ther

e ha

d be

en a

nypr

oble

ms

since

last

visi

tH

ow w

as c

ompl

ianc

eas

sess

ed:t

able

t co

unt

Ris

k fa

ctor

s:hi

stor

yof

ulc

ers

(1 y

ear

orm

ore

ago)

a 10

, b 1

4, c

14;

all

part

icip

ants

age

d60

year

s or

mor

e C

VDa

0, b

0FU

ND

ING

Fund

ed b

y:Sm

ithK

line

Beec

ham

Phar

mac

eutic

als

Affi

liati

on o

f con

tact

auth

or:A

rthr

itis

Cen

ter,

Phoe

nix,

AZ

,U

SAA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

uncl

ear


247


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Del

mas

, 199

479,2

18

Loca

tion

: Fra

nce,

mul

ticen

tre

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

eco

mpa

rabi

lity:

uncl

ear

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:un

clea

r In

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:0–3

ero

sions

at

base

line

endo

scop

yTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A: t

otal

77,

infla

mm

ator

y jo

int

dise

ase,

tota

l 123

, oth

er t

otal

56

Age

:who

le g

roup

: 54

Sex:

M/F

: who

le g

roup

: 151

/105

In

clus

ion

crit

eria

:pat

ient

s w

ith r

heum

atic

dise

ase

(deg

ener

ativ

e O

A, i

nfla

mm

ator

yjo

int

dise

ase,

oth

er),

requ

iring

con

tinuo

usN

SAID

tre

atm

ent

for

at le

ast

28 d

ays

and

ifth

ey h

ad n

o pa

tent

gas

trod

uode

nal m

ucos

alle

sions

(0–3

ero

sions

or

sube

pith

elia

lha

emor

rhag

es) u

pon

endo

scop

yEx

clus

ion

crit

eria

:pre

gnan

t or

lact

atin

gw

omen

and

wom

en o

f chi

ldbe

arin

g ag

e no

tus

ing

effe

ctiv

e co

ntra

cept

ion,

act

ive

pept

icul

cer

dise

ase,

gas

tric

hyp

erse

cret

ion,

use

of

NSA

IDs

with

in 1

0da

ys b

efor

e in

clus

ion,

cont

rain

dica

tions

to

NSA

IDs

(acu

tehe

patit

is, in

flam

mat

ory

bow

el d

iseas

e,se

vere

ren

al d

ysfu

nctio

n)

Com

pari

son:

miso

pros

tol p

lus

mix

ed N

SAID

s (b

, c) v

s pl

aceb

opl

us m

ixed

NSA

IDs

(a)

Dur

atio

n:4

wee

ksIn

terv

enti

ons:

b, m

isopr

osto

l40

0µg

/400

–800

µg

(2×

200

µgda

ily a

fter

mea

ls) c

, miso

pros

tol

800

µg/4

00–8

00 µ

g (2

x 40

0µg

dai

lyaf

ter

mea

ls); a

, ide

ntic

al p

lace

bo(2

×da

ily)

Endo

scop

y: b

asel

ine

then

at

day

28N

SAID

s:(m

inim

um d

aily

dos

e)

dicl

ofen

ac (1

00m

g/75

–150

mg)

napr

oxen

(500

mg/

500

–125

0m

g)pi

roxi

cam

(20

mg/

10–3

0m

g)ib

upro

fen

(100

0 m

g/60

0–24

00m

g)in

dom

etha

cin

(100

mg/

50–

200

mg)

keto

prof

en (1

50 m

g/10

0–20

0m

g)tia

prof

enic

aci

d (3

00 m

g/60

0m

g)

Oth

er m

edic

atio

n:no

t st

ated

Asp

irin

allo

wed

: not

sta

ted

Ana

lges

ic a

llow

ed: y

es,

para

ceta

mol

for

addi

tiona

l pai

nre

lief

Part

icip

ant

educ

atio

n: n

ot s

tate

dW

asho

ut:1

0 da

ys fo

r N

SAID

s N

umbe

r an

d fr

eque

ncy

of v

isit

s:2

(0 a

nd d

ay 2

8)

Allo

cate

d: a

103

, b 7

3,c

80C

ompl

eted

:a 8

7, b

59,

c 49

Dro

p-ou

t: a

16,

b 1

4,c

31A

sses

sed

for

GI

sym

ptom

s: a

103

, b 7

3,c

80O

utco

mes

rep

orte

d:m

orta

lity,

ser

ious

GI

com

plic

atio

ns, G

Isy

mpt

oms,

end

osco

pic

ulce

rs,

How

wer

e ad

vers

eev

ents

ass

esse

d:no

tst

ated

How

was

com

plia

nce

asse

ssed

: not

sta

ted

Ris

k fa

ctor

s:hi

stor

y of

ulc

ers

in 4

%of

par

ticip

ants

rena

l/hep

atic

dise

ase:

a

0, b

0

FUN

DIN

GFu

nded

by:

uncl

ear

Affi

liati

on o

f con

tact

auth

or:H

ôpita

lEd

ouar

d-H

errio

t,Ly

on, F

ranc

eA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

1/3

(Sea

rleLa

bora

torie

s, F

ranc

e)D

osag

e:tia

prof

enic

acid

less

tha

n m

inim

umre

com

men

ded

dose

inBN

F

Appendix 6

248

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Ellio

tt, 1

99480

Loca

tion

: Art

hriti

scl

inic

s of

2 h

ospi

tals

in M

elbo

urne

,A

ustr

alia

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’,

stra

tific

atio

n ac

cord

ing

topr

esen

ce o

r ab

senc

e of

ulce

r at

scr

eeni

ngen

dosc

opy

and

whe

ther

smok

er o

r no

n-sm

oker

Allo

cati

onco

ncea

lmen

t:un

clea

r B

asel

ine

com

para

bilit

y:no

,ba

selin

e en

dosc

opy

wor

se in

pla

cebo

gro

up,

mor

e w

ith R

A, o

n go

ld,

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

high

Bas

elin

e G

I st

atus

:bas

elin

e ul

cer

did

not

show

fran

k ul

cer

or, i

f ulc

er p

rese

nt t

reat

edw

ith 3

mon

ths

rani

tidin

e an

d no

ulc

erpr

esen

t on

rep

eat

endo

scop

y (in

tot

al 1

2ha

d he

aled

ulc

ers)

Type

and

dur

atio

n of

art

hrit

is (

year

s):

OA

: a 1

4, b

22;

RA

: a 2

2. b

15

othe

r: a

7, b

3A

ge:a

66,

b 6

5Se

x:M

/F: a

21/

22, b

25/

15

Incl

usio

n cr

iter

ia:p

atie

nts

over

18

year

s of

age,

on

stab

le o

ral N

SAID

the

rapy

, who

wer

e at

tend

ing

arth

ritis

clin

ics

in t

he 2

stu

dyho

spita

ls, c

hron

ic r

heum

atic

diso

rder

s an

dha

d be

en o

n N

SAID

the

rapy

(inc

ludi

ngas

pirin

and

its

ente

ric-c

oate

d pr

epar

atio

ns,

but

excl

udin

g en

teric

-coa

ted

prep

arat

ions

of

any

othe

r N

SAID

s) fo

r at

leas

t 3

mon

ths,

fem

ales

wer

e re

quire

d to

hav

e a

nega

tive

preg

nanc

y te

st a

t en

try

and

at e

ach

follo

w-

up v

isit

Excl

usio

n cr

iter

ia:o

vert

UG

I hae

mor

rhag

ew

ithin

1m

onth

prio

r to

ent

ry, p

revi

ous

gast

ric s

urge

ry fo

r pe

ptic

ulc

er,

infla

mm

ator

y bo

wel

dise

ase

or c

hron

icdi

arrh

oea,

mal

igna

ncy

of a

ny t

ype,

adm

inist

ratio

n of

oth

er a

nti-u

lcer

dru

gs

Com

pari

son:

miso

pros

tol p

lus

mix

ed N

SAID

s (b

) vs

plac

ebo

plus

mix

ed N

SAID

s (a

) D

urat

ion:

12 m

onth

sIn

terv

enti

ons:

b, m

isopr

osto

l60

0–80

0 µg

/400

–800

µg

(3–4

x20

0µg

dai

ly) 2

8 pa

rtic

ipan

ts t

ook

600

µg/d

aily

and

4 p

artic

ipan

ts80

0µg

dai

ly; a

, pla

cebo

(3–4

×da

ily)

(dos

age

regi

me

tailo

red

tofr

eque

ncy

of N

SAID

dos

ing,

NSA

IDs

cont

inue

d at

dos

ede

term

ined

by

patie

nts

rheu

mat

olog

ist)

Endo

scop

y:ba

selin

e th

en a

t 3,

6an

d 12

mon

ths

NSA

IDs:

piro

xica

m: a

7, b

5su

linda

c: a

10,

b 1

1na

prox

en: a

9, b

6in

dom

etha

cin:

a 6

, b 5

ibup

rofe

n: a

3, b

0di

fluni

sal:

a 5,

b 3

aspi

rin: a

1, b

6ke

topr

ofen

: a 0

, b 2

doxi

prin

: a 2

, b 2

O

ther

med

icat

ion:

anta

cid

(myl

anta

) pro

vide

d an

d al

low

ed u

pto

3 t

able

ts p

er d

ay, D

MA

RDs

allo

wed

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:n

ot s

tate

dPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:n

ot s

tate

dN

umbe

r an

d fr

eque

ncy

of v

isit

s:6

(0, 1

, 3, 6

, 9 a

nd 1

2 m

onth

s)

Allo

cate

d:a:

43,

b 4

0 C

ompl

eted

:unc

lear

Dro

p-ou

t:un

clea

rA

sses

sed

for

GI

sym

ptom

s: a

43,

b 4

0 O

utco

mes

rep

orte

d:se

rious

GI

com

plic

atio

ns,

sym

ptom

atic

ulc

ers,

GIs

ympt

oms,

endo

scop

ic u

lcer

s, G

Idr

op-o

uts

How

wer

e ad

vers

eev

ents

ass

esse

d:as

sess

ed d

iary

car

d in

whi

ch s

ympt

oms

wer

ere

cord

edH

ow w

as c

ompl

ianc

eas

sess

ed:t

able

t co

unt,

asse

ssed

dia

ry c

ard

inw

hich

all

med

icat

ions

take

n w

ere

reco

rded

Ris

k fa

ctor

s:pa

rtic

ipan

ts w

ho h

adju

st c

ompl

eted

trea

tmen

t fo

r ul

cer

heal

ing:

a 6

, b 6

hist

ory

of u

lcer

s: a

12,

b 11

C

onco

mita

nt u

se o

fst

eroi

ds: a

9, b

7FU

ND

ING

Fund

ed b

y:G

D S

earle

Affi

liati

on o

f con

tact

auth

or:U

nive

rsity

of

Mel

bour

neA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

uncl

ear

Oth

er:7

/83

part

icip

ants

too

kas

pirin

as

NSA

ID


249


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Vian

a de

Que

iroz,

1994

81

Loca

tion

:8co

untr

ies

incl

udin

gPo

rtug

al, C

anad

a,G

erm

any,

USA

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

eco

mpa

rabi

lity:

unc

lear

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:yes

A p

riori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:exc

lude

d pa

rtic

ipan

tsw

ith a

ctiv

e G

I dise

ase

(incl

udin

g pe

ptic

ulce

r), b

ut n

o ba

selin

e en

dosc

opy

Type

and

dur

atio

n of

art

hrit

is:

RA: a

ll pa

rtic

ipan

ts, n

o ot

her

deta

ilsA

ge:a

56.

0, b

56.

8 Se

x:M

/F: a

42/

127,

b 4

8/12

9In

clus

ion

crit

eria

:leg

al a

ge R

A fo

r at

leas

t6

mon

ths,

act

ive

RA a

nd a

func

tiona

lca

paci

ty c

lass

ifica

tion

of I–

III a

t tim

e of

enro

lmen

t, ha

d th

eir

dise

ase

adeq

uate

lyco

ntro

lled

by a

sta

ble

regi

men

of d

iclo

fena

cso

dium

50

mg

2–3

times

dai

ly fo

r at

leas

t30

days

prio

r to

ent

erin

g st

udy,

fem

ales

of

child

bear

ing

pote

ntia

l wer

e re

quire

d to

use

adeq

uate

con

trac

eptio

n an

d ha

ve a

neg

ativ

epr

egna

ncy

test

with

in 7

2 h

prio

r to

rec

eivi

ngfir

st d

ose

of s

tudy

med

icat

ion

Excl

usio

n cr

iter

ia:a

rthr

itis

othe

r th

an R

A,

any

othe

r rh

eum

atic

dise

ase,

pso

riasis

,ac

tive

GI d

iseas

e (e

.g. p

eptic

ulc

er o

rin

flam

mat

ory

bow

el d

iseas

e) c

hron

ic o

rac

ute

rena

l or

hepa

tic d

isord

ers,

or

mal

igna

ncie

s of

any

typ

e, u

sed

any

drug

sw

hich

wou

ld c

onfo

und

the

unde

rsta

ndin

g of

the

stud

y (a

ntin

eopl

astic

s an

d D

MA

RDs)

Com

pari

son:

miso

pros

tol/d

iclo

fena

c fix

edco

mbi

natio

n (b

) vs

plac

ebo/

dicl

ofen

ac fi

xed

com

bina

tion

(a)

Dur

atio

n:12

wee

ksIn

terv

enti

ons:

b, m

isopr

osto

l40

0–60

0 µg

/400

–800

µg

(2–3

×20

0µg

dai

ly) p

lus

dicl

ofen

ac10

0–15

0m

g/75

–150

mg

(2–3

×50

mg

daily

) fix

ed c

ombi

natio

n;a,

plac

ebo

plus

dic

lofe

nac

100–

150

mg/

75–1

50m

g (2

–3×

50m

g da

ily) f

ixed

com

bina

tion

(with

mea

ls, n

ot c

hew

ed o

rsw

allo

wed

who

le??

?)En

dosc

opy:

not

perf

orm

edO

ther

med

icat

ion:

not

stat

edA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:no

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:not

sta

ted

Num

ber

and

freq

uenc

y of

vis

its:

4 (0

, 4, 8

and

12

wee

ks)

Allo

cate

d:a

169?

,b

177?

C

ompl

eted

:a 1

33,

b 13

9 D

rop-

out:

a 36

, b 3

8 A

sses

sed

for

GI

sym

ptom

s:a

169,

b17

7 O

utco

mes

rep

orte

d:G

I sym

ptom

sH

ow w

ere

adve

rse

even

ts a

sses

sed:

diar

yca

rds

How

was

com

plia

nce

asse

ssed

:tab

let

coun

t,m

ean

com

plia

nce

91–9

9% in

bot

h gr

oups

Ris

k fa

ctor

s:re

nal/h

epat

ic d

iseas

e:a

0, b

0

FUN

DIN

GFu

nded

by:

not

stat

edA

ffilia

tion

of c

onta

ctau

thor

:no

cont

act

auth

or s

tate

dA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

3/6

empl

oyed

by

Sear

leRe

sear

ch &

Dev

elop

men

t

Appendix 6

250

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Agr

awal

, 199

582

Loca

tion

:ho

spita

ls,un

iver

sitie

s an

dpr

ivat

e in

stitu

tions

in U

SA a

nd B

elgi

um

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

eco

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:un

clea

rA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:<3

eros

ions

follo

win

gop

en la

bel t

reat

men

t w

ith m

isopr

osto

l (fo

r>

10 e

rosio

ns o

r ul

cer

or v

isibl

e ve

ssel

or

oozi

ng o

r in

tral

umin

al b

lood

) Ty

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A: a

92

(9.0

yea

rs),

b 99

(10.

3 ye

ars)

; RA

: a 9

9 (1

2.1

year

s), b

93

(10.

0 ye

ars)

; one

part

icip

ant

had

neith

er O

A n

or R

A

Age

:a 5

7.5,

b 5

7.3

Sex:

M/F

: a 5

8/13

3, b

65/

128

Incl

usio

n cr

iter

ia:l

egal

age

of c

onse

nt,

with

RA

and

/or

OA

req

uirin

g ch

roni

cN

SAID

tre

atm

ent,

fem

ales

of c

hild

bear

ing

pote

ntia

l had

to

have

had

a n

egat

ive

preg

nanc

y te

st 7

2h

prio

r to

firs

t do

se o

fst

udy

med

icat

ion,

req

uire

d to

hav

eco

mpl

eted

the

scr

eeni

ng a

nd t

reat

men

tph

ases

and

hav

e an

end

osco

py s

core

of 3

or

less

on

endo

scop

y af

ter

trea

tmen

t Ex

clus

ion

crite

ria: c

hang

es in

dos

es o

fse

cond

-line

ant

iart

hriti

c th

erap

ies

(e.g

. gol

d,m

etho

trex

ate

or p

enic

illam

ine)

dur

ing

the

3m

onth

s pr

ior

to e

nter

ing

the

stud

y,es

opha

geal

var

ices

or

ulce

ratio

n,ga

strin

oma,

Zol

linge

r–El

lison

syn

drom

e,ul

cera

ted

hiat

us h

erni

a, a

hist

ory

of g

astr

icor

duo

dena

l sur

gery

, inf

lam

mat

ory

bow

eldi

seas

e, m

alig

nanc

y, h

epat

ic o

r re

nal

dysf

unct

ion,

alc

ohol

ism

Com

pari

son:

miso

pros

tol p

lus

dicl

ofen

ac (b

) vs

plac

ebo

plus

dicl

ofen

ac (a

)D

urat

ion:

52 w

eeks

Inte

rven

tion

s:b,

miso

pros

tol

400–

600

µg/4

00–8

00 µ

g (2

–3×

200

µg d

aily

a: p

lace

bo (2

–3×

daily

)N

SAID

s:a

+ b

: dic

lofe

nac

100–

150

mg/

75–1

50m

g (2

–3×

50m

g da

ily)

Miso

pros

tol a

nd d

iclo

fena

c w

ere

co-a

dmin

ister

ed, d

iclo

fena

c do

sein

crea

sed

or d

ecre

ased

as

nece

ssar

yO

ther

med

icat

ion:

Maa

lox

tabl

ets

prov

ided

to

use

if ne

cess

ary

for

dysp

epsia

Asp

irin

allo

wed

: not

sta

ted

Ana

lges

ic a

llow

ed:n

ot s

tate

dPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut: n

ot s

tate

dN

umbe

r an

d fr

eque

ncy

of v

isit

s:7

(0, 6

, 12,

18,

24,

36

and

52w

eeks

)En

dosc

opy:

0, 1

2, 2

4 an

d52

wee

ks

Allo

cate

d:a

191,

b 1

93C

ompl

eted

: unc

lear

Dro

p-ou

t:un

clea

rA

sses

sed

for

GI

sym

ptom

s: a

191

,b

193

Out

com

es r

epor

ted:

GI s

ympt

oms,

endo

scop

ic u

lcer

s, G

Idr

op-o

uts

How

wer

e ad

vers

eev

ents

ass

esse

d:pa

rtic

ipan

ts p

rovi

ded

asse

ssm

ents

of s

peci

ficG

I sym

ptom

s(a

bdom

inal

pai

n,he

artb

urn,

nau

sea,

vom

iting

, eru

ctat

ion,

cons

tipat

ion,

dia

rrho

ea)

How

was

com

plia

nce

asse

ssed

:tab

let

coun

t,le

ss t

han

60%

of t

he 2

tabl

et d

aily

reg

imen

wer

e no

t ev

alua

ted

Ris

k fa

ctor

s:

hist

ory

of g

astr

icul

cers

: a 8

2, b

84hi

stor

y of

duo

dena

lul

cers

: a73

, b 6

4hi

stor

y of

ble

eds:

a 1

8,b

25FU

ND

ING

Fund

ed b

y:G

D S

earle

Affi

liati

on o

f con

tact

auth

or:G

D S

earle

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:1

or 2

/4O

ther

:par

ticip

ants

wer

e w

ithdr

awn

ifsc

ored

≥10

ero

sions

,oo

zing

or

intr

alum

inal

bloo

d on

end

osco

py


251


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Rask

in, 1

99543

Loca

tion

:135

cent

res

in t

he U

SA

Met

hod

ofra

ndom

isat

ion:

cent

ralis

ed c

ompu

ter-

gene

rate

d ra

ndom

isatio

nsc

hedu

le, e

ach

cent

rew

as a

ssig

ned

to 1

or

mor

e ra

ndom

isatio

nbl

ocks

of 7

in s

eale

den

velo

pes,

pat

ient

s th

enas

signe

d se

quen

tially

to

trea

tmen

tA

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

eco

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:no

Inte

ntio

n-to

-tre

at:n

oA

pri

ori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd e

xclu

ded

patie

nts

with

out

UG

I sym

ptom

s (b

ut e

xclu

ded

endo

scop

icev

iden

ce o

f gas

tric

or

duod

enal

ulc

ers,

any

oeso

phag

eal e

rosio

ns,a

muc

osal

def

ect

ofan

y siz

e w

ith p

erce

ptib

le d

epth

, a g

astr

ic o

rdu

oden

al m

ucos

al d

efec

t 0.

3cm

or

mor

e)Ty

pe a

nd d

urat

ion

of a

rthr

itis

: O

A: a

341

, b 3

47, c

356

, d 1

80

RA: a

73,

b 6

9, c

71,

d 2

5O

ther

: a 3

2, b

42, c

43,

d 2

1A

ge:m

edia

n: a

58

(21–

83),

b 58

(18–

89)

c 58

(23–

85),

d 58

(28–

81)

Sex:

F/M

: a 1

86/2

68, b

203

/259

c 19

0/28

4, d

91/

137

Incl

usio

n cr

iter

ia:c

linic

al d

iagn

osis

of O

A,

RA, p

soria

tic a

rthr

itis,

ank

ylos

ing

spon

dylit

isor

Rei

ter

synd

rom

e an

d w

ere

rece

ivin

gN

SAID

the

rapy

tha

t w

as e

xpec

ted

toco

ntin

ue u

nint

erru

pted

for

at le

ast

3ad

ditio

nal m

onth

s at

a fi

xed

dose

, pat

ient

sha

d to

be

havi

ng U

GI s

ympt

oms

such

as

cram

p, p

ain,

blo

atin

g or

hea

rtbu

rnEx

clus

ion

crit

eria

:pat

ient

s w

ith a

gas

tric

or d

uode

nal m

ucos

al d

efec

t of

0.3

cm o

rm

ore,

a m

ucos

al d

efec

t of

any

siz

e w

ithpe

rcep

tible

dep

th, a

ny o

esop

hage

al e

rosio

nsor

ulc

ers,

UG

I sur

gery

with

in 3

0da

ys o

fan

ticip

ated

ent

ry in

to t

he s

tudy

, UG

Im

alig

nanc

y, p

ylor

ic o

bstr

uctio

n, a

cute

hepa

titis,

pan

crea

titis,

infla

mm

ator

y bo

wel

dise

ase

or a

ble

edin

g di

athe

sis

Com

pari

son:

miso

pros

tol p

lus

mix

ed N

SAID

s (b

, c, d

) vs

plac

ebo

plus

mix

ed N

SAID

s (a

)D

urat

ion:

12 w

eeks

Inte

rven

tion

s:b,

miso

pros

tol

400

µg /4

00–8

00 µ

g (2

×20

0 µg

daily

) plu

s id

entic

al p

lace

bo(2

×da

ily);

c, m

isopr

osto

l 600

µg/

400–

800

µg (3

× 20

0 µg

dai

ly) p

lus

iden

tical

pla

cebo

(1×

daily

); d,

miso

pros

tol 8

00 µ

g/40

0–80

0 µg

(4×

200

µg d

aily

); a,

iden

tical

plac

ebo

(4×

daily

) (do

ses

take

n at

brea

kfas

t, lu

nch,

din

ner

and

bedt

ime,

for

the

initi

al 3

day

s al

lpa

rtic

ipan

ts t

ook

half

of 1

tab

let

4×da

ily)

NSA

IDs

(min

imum

dai

ly d

oses

)(%

):na

prox

en 7

50m

g/50

0–12

50m

g:

a 21

, b 2

4, c

25,

d 2

2ib

upro

fen

1200

mg/

600–

2400

mg:

a

26, b

24,

c 2

4, d

29

piro

xica

m 2

0m

g/10

–30

mg:

a 1

7,b

16, c

19,

d 1

7su

linda

c 20

0m

g/40

0m

g: a

7, b

7,

c 6,

d 5

othe

r: a

29

b 29

, c 2

6, d

27

Oth

er m

edic

atio

n:an

taci

d ta

blet

spr

ovid

ed, 4

tab

lets

per

day

or

less

for

uppe

r ab

dom

inal

sym

ptom

s in

the

initi

al 3

wee

ks o

nly

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:n

ot s

tate

dPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:n

ot s

tate

dN

umbe

r an

d fr

eque

ncy

of v

isit

s:4

(0, 4

, 8 a

nd 1

2 w

eeks

)

Allo

cate

d:un

clea

rC

ompl

eted

:unc

lear

Dro

p-ou

t:a:

95,

b 9

0,

c 11

0, d

62

Ass

esse

d fo

r G

Isy

mpt

oms:

a 45

4,b

462,

c 4

74, d

228

O

utco

mes

rep

orte

d:m

orta

lity,

GI s

ympt

oms,

endo

scop

ic u

lcer

s,G

Idro

p-ou

tsH

ow w

ere

adve

rse

even

ts a

sses

sed:

not

stat

edH

ow w

as c

ompl

ianc

eas

sess

ed:t

able

t co

unt

to e

nsur

e 60

%co

mpl

ianc

eN

on-c

ompl

ianc

e:

a 12

/454

, b 5

/462

,c

9/47

4, d

5/2

28W

ere

part

icip

ants

excl

uded

from

anal

yses

pre

-ulc

er?

uncl

ear

Ris

k fa

ctor

s:hi

stor

y of

GI d

iseas

e:

a 2,

b 2

FU

ND

ING

Fu

nded

by:

GD

Sea

rleA

ffilia

tion

of c

onta

ctau

thor

:Vet

eran

sA

ffairs

Med

ical

Cen

ter,

Mia

mi,

FR, U

SAA

ffilia

tion

of

stat

isti

cian

:W

Arc

hanb

ault,

G

D S

earle

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

uncl

ear,

JGFo

rt h

elpe

d pr

epar

eth

e m

anus

crip

t(?

med

ical

dire

ctor

at

Sear

le)

Oth

er:1

par

ticip

ant

inm

isopr

osto

l gro

up c

had

pept

ic u

lcer

at

base

line;

the

sepa

rtic

ipan

ts w

ere

excl

uded

from

ana

lyse

s%

dat

a fo

r ty

pe o

far

thrit

is do

es n

ot a

ddup

to

tota

l num

ber

ofpa

rtic

ipan

ts in

eac

har

m, n

umbe

r of

dro

p-ou

ts d

oes

not

add

up

Appendix 6

252

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Silv

erst

ein,

199

56

MU

CO

SALo

cati

on:6

61pr

actic

es in

USA

, 3

in C

anad

a

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d in

bloc

ks o

f fou

r’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

eco

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:yes

Inte

ntio

n-to

-tre

at:

uncl

ear

A p

riori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:with

out

activ

e pe

ptic

ulce

r di

seas

e in

last

30

days

(no

base

line

endo

scop

y)Ty

pe a

nd d

urat

ion

of a

rthr

itis

:RA

: all

part

icip

ants

a 1

2.7

year

s (1

–73)

, b

13.1

yea

rs (1

–70)

Age

:a 6

7.6,

b 6

7.6

Sex:

M/F

: a 1

299/

3136

, b 1

271/

3130

Incl

usio

n cr

iter

ia:a

mbu

lato

ry p

atie

nts

atle

ast

52 y

ears

of a

ge w

ho h

ad c

hron

ic R

Aan

d w

ere

expe

cted

to

be t

akin

g 1

of 1

0sp

ecifi

ed N

SAID

s at

pre

defin

ed m

inim

umdo

ses

for

6m

onth

sEx

clus

ion

crit

eria

:act

ive

pept

ic u

lcer

dise

ase

with

in 3

0 da

ys o

f stu

dy e

nrol

men

t,w

ere

taki

ng o

r ex

pect

ed t

o ne

ed a

nti-u

lcer

med

icat

ion

(HH

2RA

, suc

rafa

te, o

mep

razo

le),

or a

ny e

xper

imen

tal m

edic

atio

n du

ring

the

stud

y, Z

ollin

ger–

Ellis

on s

yndr

ome,

pyl

oric

or

duod

enal

obs

truc

tion,

pre

viou

s ga

stric

rese

ctio

n or

vag

otom

y, g

astr

oeso

phag

eal

reflu

x di

seas

e, v

aric

es o

r ci

rrho

sis, h

istor

y of

infla

mm

ator

y bo

wel

dise

ase,

UG

I tra

ctm

alig

nanc

ies,

hep

atiti

s, a

lcoh

olism

or

blee

ding

dia

thes

is, w

ere

estim

ated

to

have

alif

e ex

pect

ancy

of l

ess

than

8m

onth

s or

had

do-n

ot-r

esus

cita

te s

tatu

s, w

omen

of

child

bear

ing

pote

ntia

l, co

uld

not

tole

rate

miso

pros

tol o

r an

y pr

osta

glan

din

Com

pari

son:

miso

pros

tol p

lus

mix

ed N

SAID

s (b

) vs

plac

ebo

plus

mix

ed N

SAID

s (a

)D

urat

ion:

6m

onth

sIn

terv

enti

ons:

b, m

isopr

osto

l40

0–80

0 µg

/400

–800

µg

(2–4

×20

0µg

dai

ly);

a pl

aceb

o (2

–4x

daily

); (w

ith m

eals

and

at b

edtim

e)[s

tart

ed t

akin

g ha

lf ta

blet

(100

µg

orpl

aceb

o) 4

×da

ily fo

r 10

day

s th

en if

tole

rate

d in

crea

sed

up t

o fu

ll ta

blet

(200

µg

or p

lace

bo) 4

µda

ily]

Full

dose

, 800

µg

(or

plac

ebo)

dai

ly:

a 35

24, b

297

4H

alf d

ose,

400

µg

(or

plac

ebo)

daily

: a: 6

90, b

123

0N

ot s

tate

d: a

207

, b 2

00N

SAID

s:(m

inim

um d

aily

dos

es)

aspi

rin (2

000m

g/?)

a 2

97, b

335

dicl

ofen

ac 1

00m

g/75

–150

mg:

a

894,

b 8

34flu

rbip

rofe

n 20

0m

g/15

0–30

0 m

g:a

385,

b 3

67ib

upro

fen

1200

mg/

600–

2400

mg:

a

514,

b 5

04in

dom

etha

cin

65m

g/50

–200

mg:

a

115,

b 1

16ke

topr

ofen

150

mg/

100–

200

mg:

a 13

1, b

146

napr

oxen

750

mg/

500–

1250

mg:

a

1014

, b 9

88pi

roxi

cam

20

mg/

10–3

0m

g: a

464

,b

473

sulin

dac

200

mg/

400

mg:

a 3

11,

b 30

9to

lmet

in 1

200m

g/?:

a 10

9, b

112

low

er d

ose:

a 55

b 5

2no

ne o

f the

abo

ve N

SAID

s: a

46,

b45

Allo

cate

d:

a 44

39, b

440

4 C

ompl

eted

:a 2

822,

b

2553

D

rop-

out:

a 16

17,

b 18

51A

sses

sed

for

GI

sym

ptom

s: a

443

9b

4404

O

utco

mes

rep

orte

d:m

orta

lity,

ser

ious

GI

com

plic

atio

ns,

sym

ptom

atic

ulc

ers,

GI

sym

ptom

s, G

I dro

p-ou

ts

How

wer

e ad

vers

eev

ents

ass

esse

d:ph

ysic

ians

inst

ruct

ed t

ow

atch

clo

sely

for

clin

ical

signs

of G

I ble

edin

g or

othe

r G

I com

plic

atio

ns,

to in

quire

abo

utsy

mpt

oms

and

toin

vest

igat

e su

spic

ious

episo

des

by a

ppro

pria

tecl

inic

al p

roce

dure

sH

ow w

as c

ompl

ianc

eas

sess

ed:t

able

t co

unt

Ris

k fa

ctor

s:

hist

ory

of u

lcer

s:

a 63

8,

b 64

3 hi

stor

y of

ble

eds:

a

281,

b

292

conc

omita

nt u

se o

fco

rtic

oste

roid

s: a

1871

, b 1

887

>1

NSA

ID: a

60,

b 7

5FU

ND

ING

Fu

nded

by:

G D

Sea

rleA

ffilia

tion

of c

onta

ctau

thor

:G D

Sea

rleA

ffilia

tion

of

stat

isti

cian

:Qui

ntile

sTr

ansn

atio

nal

Affi

liati

on o

f tri

alad

min

istr

ator

:dat

aco

llect

ion

done

by

Qui

ntile

s Tr

ansn

atio

nal

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:un

clea

r bu

tat

leas

t 1

of 7

wor

ked

for

Sear

le

Oth

er: s

ome

part

icip

ants

not

tak

ing

NSA

IDs

a 40

, b 4

0.Su

linda

c le

ss t

han

min

imum

reco

mm

ende

d do

se in

BNF


253


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Endo

scop

y:no

neO

ther

med

icat

ion:

coul

d co

ntin

uew

ith D

MA

RDs

such

as

gold

and

cort

icos

tero

ids

and

take

ant

acid

s(n

ot c

onta

inin

g m

agne

sium

), w

ere

allo

wed

to

rece

ive

mor

e th

an1

NSA

ID

Asp

irin

allo

wed

:yes

Ana

lges

ic a

llow

ed:n

ot s

tate

dPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:n

ot s

tate

dN

umbe

r an

d fr

eque

ncy

of v

isit

s:7

(bas

elin

e 1,

2, 3

, 4, 5

, 6 m

onth

s)

Appendix 6

254

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Boca

negr

a, 1

99883

Loca

tion

: 56

sites

in U

SA

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

allo

cate

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

eco

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:un

clea

r In

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:fre

e of

ulc

ers

and

with

10 o

r fe

wer

ero

sions

in s

tom

ach

ordu

oden

um o

n ba

selin

e en

dosc

opy

Type

and

dur

atio

n of

art

hrit

is (

year

s):

OA

: a 1

1.9

year

s, b

10.

3 ye

ars,

c 1

1.9

year

sA

ge:a

62.

9, b

62.

8, c

62.

3Se

x:M

/F: a

44/

110,

b 5

8/11

7, c

49/

103

Incl

usio

n cr

iter

ia:a

dult

patie

nts

with

sym

ptom

atic

OA

of t

he k

nee

and/

or h

ip, a

func

tiona

l cap

acity

cla

ssifi

catio

n I–

III a

nd a

docu

men

ted

hist

ory

but

not

curr

ent

pres

ence

of s

igni

fican

t U

GI m

ucos

al d

amag

e,fe

mal

es w

ith a

dequ

ate

cont

race

ptio

n an

dno

t la

ctat

ing

and

mus

t ha

ve h

ad a

neg

ativ

epr

egna

ncy

test

72

h be

fore

rec

eivi

ng fi

rst

dose

of s

tudy

med

icat

ion,

wor

seni

ng o

f OA

sym

ptom

s co

mpa

red

to s

cree

ning

eva

luat

ion

and

afte

r w

asho

ut

Excl

usio

n cr

iter

ia:a

rthr

itis

othe

r th

an O

A,

mal

igna

ncy

of a

ny t

ype,

ren

al, h

epat

ic o

rco

agul

atio

n di

sord

er t

hat

in t

he o

pini

on o

fth

e in

vest

igat

or m

ay p

ose

a sa

fety

risk

for

the

patie

nt, p

rese

nce

of g

astr

ic o

r du

oden

alul

cer

or m

ore

than

10

eros

ions

at

the

base

line

UG

I end

osco

py, a

ny a

ctiv

e G

Idi

seas

e, a

hist

ory

of a

ny g

astr

ic o

r du

oden

alsu

rger

y ot

her

than

a s

impl

e ov

erse

w, r

ecen

tus

e of

cor

ticos

tero

ids

(incl

udin

g in

tra-

artic

ular

inje

ctio

ns, o

r an

ticoa

gula

nts

or u

seof

any

NSA

ID e

xcep

t as

pirin

no

mor

e th

an32

5m

g/da

y, o

r an

alge

sic w

ithin

3da

ys p

rior

to t

he b

asel

ine

asse

ssm

ents

Com

pari

son:

arth

rote

c 50

(b) v

sar

thro

tec

75 (c

) vs

dicl

ofen

ac (a

)D

urat

ion:

6 w

eeks

Inte

rven

tion

s:c,

miso

pros

tol

600

µg /4

00–8

00 µ

g (3

×2 0

0 µg

daily

) plu

s di

clof

enac

150

mg/

75–1

50m

g (3

×50

mg

daily

)(e

nter

ic c

oate

d di

clof

enac

sod

ium

50m

g su

rrou

nded

by

a m

antle

of

200

µg m

isopr

osto

l, (3

×da

ily);

b, m

isopr

osto

l 400

µg/

400–

800

µg(2

× 20

0 µg

dai

ly) p

lus

dicl

ofen

ac15

0m

g/75

–150

mg

(2×

75m

g da

ily)

(ent

eric

coa

ted

dicl

ofen

ac s

odiu

m75

mg

surr

ound

ed b

y a

man

tle o

f20

0 µg

miso

pros

tol,

(2×

daily

); a,

dic

lofe

nac

sodi

um,

150

mg/

75–1

50m

g (2

×75

mg

daily

)En

dosc

opy:

at 0

and

6 w

eeks

Oth

er m

edic

atio

n:no

t st

ated

Asp

irin

allo

wed

:yes

, no

mor

eth

an 3

25m

g da

ilyA

nalg

esic

allo

wed

:not

sta

ted

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:3–1

4 da

ys fo

r N

SAID

sN

umbe

r an

d fr

eque

ncy

of v

isit

s:3

(0, 2

and

6 w

eeks

)

Allo

cate

d:a

154,

b17

5, c

152

Com

plet

ed:a

126

,b

142,

c 1

31

Dro

p-ou

t:a

28, b

33,

c

21A

sses

sed

for

GI

sym

ptom

s: a

154

,b

175,

c 1

52

Out

com

es r

epor

ted:

GI s

ympt

oms,

endo

scop

ic u

lcer

sH

ow w

ere

adve

rse

even

ts a

sses

sed:

diar

ies

to r

ecor

d an

yne

w s

ympt

oms,

info

rmat

ion

colle

cted

and

tran

scrib

ed t

o st

udy

case

rep

ort

form

s at

each

visi

tH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:a

docu

men

ted

hist

ory

but

not

curr

ent

pres

ence

of s

igni

fican

tU

GI m

ucos

al d

amag

e,no

ren

al o

r he

patic

dise

ase

at b

asel

ine

FUN

DIN

GFu

nded

by:

GD

Sea

rleA

ffilia

tion

of c

onta

ctau

thor

:GD

Sea

rleA

ffilia

tion

of

stat

isti

cian

:GD

Sear

leA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:5

of 8

wor

ked

for

GD

Sea

rleO

ther

:with

draw

als

due

to G

I adv

erse

even

ts d

o no

t ad

d up

,pl

aceb

o gr

oup

pres

ent

but

not

repo

rted

her

e


255


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Haw

key

1998

b62,6

5,20

9,21

0

OM

NIU

MLo

cati

on: 9

3ce

ntre

s in

14

coun

trie

s in

clud

ing

UK

and

USA

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d’,

rand

omisa

tion

phas

e no

tfo

rmal

ly b

alan

ced

acco

rdin

g to

tre

atm

ent

assig

nmen

t in

the

hea

ling

phas

eA

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

eco

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:un

clea

r In

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:end

osco

py p

erfo

rmed

and

excl

uded

par

ticip

ants

with

out

trea

tmen

tsu

cces

s fo

llow

ing

4–8

wee

ks h

ealin

g ph

ase

(om

epra

zole

20

mg/

day

vs o

mep

razo

le40

mg/

day

vs m

isopr

osto

l 200

µg/

day)

;tr

eatm

ent

succ

ess

defin

ed a

s ab

senc

e of

ulce

rs in

the

sto

mac

h or

duo

denu

m a

nd t

hepr

esen

ce o

f few

er t

han

five

gast

ric e

rosio

ns,

few

er t

han

five

duod

enal

ero

sions

and

not

mor

e th

an m

ild s

ympt

oms

of d

yspe

psia

(cor

resp

onde

d to

a 2

-poi

nt r

educ

tion

inLa

nza

scal

e fr

om g

rade

4 t

o gr

ade

2)

Type

of a

rthr

itis

:OA

: a 7

0, b

129

, c 1

42;

RA: a

56,

b 1

07, c

118

; Oth

er: a

25,

b 3

3,c

30C

ombi

nati

on:a

5, b

5, c

6A

ge:a

57

(20–

80),

b 58

(23–

79),

c 58

(23–

85)

Sex:

M/F

: a 4

8/10

7, b

101

/173

, c 1

18/1

78In

clus

ion

crit

eria

:18–

85 y

ears

of a

ge a

ndw

ho h

ad a

ny c

ondi

tion

requ

iring

con

tinuo

ustr

eatm

ent

with

ora

l or

rect

al N

SAID

s ab

ove

a pr

edet

erm

ined

min

imal

dos

e (n

o m

axim

aldo

se);

trea

tmen

t su

cces

s de

fined

as

abse

nce

of u

lcer

s in

the

sto

mac

h or

duo

denu

m a

ndth

e pr

esen

ce o

f few

er t

han

five

gast

ricer

osio

ns, f

ewer

tha

n fiv

e du

oden

al e

rosio

ns,

and

not

mor

e th

an m

ild s

ympt

oms

ofdy

spep

sia (c

orre

spon

ded

to a

2-p

oint

redu

ctio

n in

Lan

za s

cale

from

gra

de 4

to

grad

e 2)

Excl

usio

n cr

iter

ia:c

oncu

rren

t re

flux

oeso

phag

itis

at s

tage

3 o

r 4

acco

rdin

g to

the

Sava

ry–M

iller

cla

ssifi

catio

n, c

linic

ally

impo

rtan

t G

I ble

edin

g, p

ylor

ic s

teno

sis,

hist

ory

of g

astr

ic s

urge

ry, o

r G

I diso

rder

sth

at m

ight

impa

ir th

e ab

sorp

tion

of t

hest

udy

drug

s

Com

pari

son:

miso

pros

tol p

lus

mix

ed N

SAID

s (c

) vs

omep

razo

lepl

us m

ixed

NSA

IDs

(b) v

s pl

aceb

opl

us m

ixed

NSA

IDs

(a)

Dur

atio

n:6

mon

ths

Inte

rven

tion

s:c,

miso

pros

tol

400

µg/4

00–8

00 µ

g /d

ay (2

00 µ

g×2

daily

; b, o

mep

razo

le20

mg/

20m

g (2

0m

g ×1

dai

ly);

a, id

entic

al p

lace

bo

Endo

scop

y:1,

3 a

nd 6

mon

ths

NSA

IDs:

(min

imum

and

mea

ndo

se)

dicl

ofen

ac (5

0m

g, 1

29m

g/da

y):

23%

tot

al p

artic

ipan

tske

topr

ofen

(100

mg,

137

mg)

: 16%

tota

l par

ticip

ants

napr

oxen

(500

mg,

844

mg)

: 22%

tota

l par

ticip

ants

Oth

er m

edic

atio

n: p

atie

nts

coul

den

ter

the

stud

y if

they

wer

e ta

king

gluc

ocor

ticoi

ds a

t a

dose

less

than

/equ

al t

o 10

mg

ofpr

edni

solo

ne (o

r its

equ

ival

ent)

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:n

ot s

tate

dPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:n

ot s

tate

dN

umbe

r an

d fr

eque

ncy

of v

isit

s:4

(0, 1

, 3 a

nd 6

mon

ths)

Allo

cate

d:a

155,

b27

4, c

296

(7pa

rtic

ipan

tsun

acco

unte

d fo

r)C

ompl

eted

:a 1

39,

b24

2, c

247

Dro

p-ou

t:a

16, b

33,

c50

Ass

esse

d:a

155,

b 2

75,

c 29

7O

utco

mes

rep

orte

d:se

rious

GI

com

plic

atio

ns, Q

oL,

endo

scop

ic u

lcer

s, t

otal

drop

-out

How

wer

e ad

vers

eev

ents

ass

esse

d:pa

rtic

ipan

ts a

sked

if h

adsp

ecifi

c dy

spep

ticsy

mpt

oms

durin

g th

ela

st 7

day

s an

d to

desc

ribe

any

uppe

r G

Isy

mpt

oms

on t

hat

day,

sym

ptom

s gr

aded

, also

sym

ptom

dia

ry c

ard

used

dur

ing

initi

al4

wee

ksH

ow w

as c

ompl

ianc

eas

sess

ed:t

able

t co

unt,

resu

lt no

t re

port

ed

Ris

k fa

ctor

s:63

–64%

of p

artic

ipan

ts in

eac

hgr

oup

had

rece

nthi

stor

y of

ulc

ers

(rem

aini

ng p

artic

ipan

tsha

d re

cent

hist

ory

ofm

ore

than

10

gast

ricor

duo

dena

l ero

sions

FU

ND

ING

Fund

ed b

y:A

stra

Has

sle, S

wed

enA

ffilia

tion

of c

onta

ctau

thor

:Not

tingh

amG

astr

oint

estin

al T

rials

Serv

ice,

Uni

vers

ityH

ospi

tal N

ottin

gham

,U

KA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

One

aut

hor

serv

es a

s a

cons

ulta

ntfo

r Se

arle

, Aus

tral

iaO

ther

:par

ticip

ants

wer

e di

scon

tinue

d an

dex

clud

ed fr

om a

naly

sisif

deve

lope

d m

ore

than

10

eros

ions

or

mor

e th

an m

oder

ate

dysp

epsia

or

adve

rse

even

ts

Appendix 6

256

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

Gra

ham

, 200

264,2

14

Loca

tion

:63

cent

res

in N

orth

Am

eric

a

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d in

bloc

ks o

f 4’,

‘rand

omisa

tion

sche

dule

was

gen

erat

ed b

y a

stat

istic

al s

peci

alist

who

was

not

invo

lved

in t

hetr

ial d

esig

n, t

hera

ndom

isatio

n w

as c

oded

and

stor

ed in

sea

led

enve

lope

s’A

lloca

tion

conc

ealm

ent:

adeq

uate

Bas

elin

eco

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:no

Ass

esso

r bl

indi

ng: y

es(s

tatis

ticia

n), e

ndos

copi

stal

so b

linde

dIn

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

low

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed, p

atie

nts

had

to b

e w

ithou

tH

.pyl

ori,

have

hist

ory

of e

ndos

copi

cally

docu

men

ted

gast

ric u

lcer

with

or

with

out

coex

istin

g du

oden

al u

lcer

or

GI b

leed

ing

(2/3

par

ticip

ants

had

pre

viou

sly c

ompl

eted

part

icip

atio

n in

a h

ealin

g tr

ial f

or N

SAID

-as

soci

ated

gas

tric

ulc

er);

excl

uded

pat

ient

sw

ith g

astr

ic o

r du

oden

al u

lcer

cra

ter

at le

ast

5m

m in

dia

met

er o

r m

ore

than

25

eros

ions

or e

rosiv

e re

flux

oeso

phag

itis

Bas

elin

e N

SAID

sta

tus:

trea

tmen

t w

ithst

able

full

ther

apeu

tic d

oses

of a

n N

SAID

for

at le

ast

the

prev

ious

mon

th (e

xcep

tna

bum

eton

e or

asp

irin

at 1

300

mg/

day

orm

ore)

Type

and

dur

atio

n of

art

hrit

is (

year

s):

no d

etai

lsA

ge:a

60.

5, b

59.

4, c

61.

6, d

60.

2Se

x:M

/F: a

46/

87, b

43/

91, c

50/

86, d

48/

84In

clus

ion

crit

eria

:18

year

s or

old

er,

hist

ory

of e

ndos

copi

cally

doc

umen

ted

gast

ric u

lcer

with

or

with

out

duod

enal

ulc

eror

GI b

leed

ing,

tre

atm

ent

with

sta

ble

full

ther

apeu

tic d

oses

of a

n N

SAID

(with

the

exce

ptio

n of

nab

umet

one

or a

spiri

n at

1300

mg/

day

or m

ore;

low

-dos

e as

pirin

for

card

iova

scul

ar p

rote

ctio

n w

as p

erm

itted

)fo

r at

leas

t th

e pr

evio

us m

onth

Excl

usio

n cr

iter

ia:p

ositi

ve fo

r H

. pyl

ori,

gast

ric o

r du

oden

al u

lcer

cra

ter

of 5

mm

or

mor

e or

sev

ere

eros

ions

def

ined

as

mor

eth

an 2

5 er

osio

ns, e

rosiv

e re

flux

oeso

phag

itis,

use

of P

PI, m

isopr

osto

l or

H2R

As

with

in 2

4 h

of s

tart

of s

tudy

Com

pari

son:

lans

opra

zole

(c, d

)pl

us m

ixed

NSA

IDs

vs m

isopr

osto

l(b

) plu

s m

ixed

NSA

IDs

vs m

ixed

NSA

IDs

(a)

Dur

atio

n:12

wee

ksIn

terv

enti

ons:

d, la

nsop

razo

le30

mg/

15–3

0m

g (3

0m

g ×1

dai

ly);

c la

nsop

razo

le, 1

5m

g/15

–30

mg

(15

mg

×1 d

aily

); b,

miso

pros

tol

800

µg/4

00–8

00 µ

g (2

00 µ

g×4

daily

); a,

pla

cebo

NSA

ID u

se:

ibup

rofe

n: 4

0%na

prox

en: 3

5%di

clof

enac

: 32%

aspi

rin o

r as

pirin

com

bina

tions

:22

%pi

roxi

cam

:17%

othe

r N

SAID

s: 3

4%En

dosc

opy:

1, 2

and

3m

onth

sO

ther

med

icat

ion:

ant

acid

prov

ided

for

use

as n

eede

d fo

rsy

mpt

om r

elie

f, in

stru

cted

to

avoi

dan

tiulc

er m

edic

atio

n ot

her

than

stud

y m

edic

atio

n, u

lcer

ogen

icm

edic

atio

n an

d ag

ents

tha

t al

ter

hem

osta

sisA

spir

in a

llow

ed:y

esA

nalg

esic

allo

wed

:not

sta

ted

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:not

sta

ted

Num

ber

and

freq

uenc

y of

vis

its:

?4 (0

, 4, 8

and

12

wee

ks)

Allo

cate

d:a

134,

b13

4, c

136

, d 1

33C

ompl

eted

:a 1

11,

b11

1, c

122

, d 1

14D

rop-

out:

a 23

, b 2

3,c

14 d

19

Ass

esse

d:a

133,

b 1

34,

c 13

6, d

132

Out

com

es r

epor

ted:

mor

talit

y, s

erio

us G

Ico

mpl

icat

ions

, ser

ious

card

iova

scul

ar o

r re

nal

illne

ss (e

xtra

dat

a)en

dosc

opic

ulc

ers,

tot

aldr

op-o

uts

How

wer

e ad

vers

eev

ents

ass

esse

d:pa

rtic

ipan

ts k

ept

diar

y of

daily

sym

ptom

s an

das

ked

dire

ct q

uest

ions

at

each

visi

tH

ow w

as c

ompl

ianc

eas

sess

ed: t

able

t co

unt,

90%

in g

roup

s a,

c a

ndd

wer

e co

mpl

iant

com

pare

d w

ith 7

3% in

grou

p b

(miso

pros

tol)

Ris

k fa

ctor

s:hi

stor

yof

ulc

ers:

all

part

icip

ants

FUN

DIN

GFu

nded

by:

TAP

Phar

mac

eutic

alPr

oduc

tsA

ffilia

tion

of c

onta

ctau

thor

:Vet

eran

sA

ffairs

Med

ical

Cen

ter,

Hou

ston

, TX

, USA

Affi

liati

on o

fst

atis

tici

an:A

bbot

tLa

bora

torie

sA

ffilia

tion

of s

tudy

adm

inis

trat

or:T

AP

Phar

mac

eutic

alPr

oduc

ts

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:2

of 7


257


(d)

Cox

-2 N

SAID

ver

sus

Cox

-1 N

SAID

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Bens

en,

1999

84,2

20,2

21

Loca

tion

: 71

clin

ical

site

s in

USA

and

Can

ada

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

assig

ned’

, str

atifi

ed b

yce

ntre

usin

g bl

ock

size

of 1

0A

lloca

tion

con

ceal

men

t:un

clea

r B

asel

ine

com

para

bilit

y:ye

sPa

rtic

ipan

t bl

indi

ng:y

esA

sses

sor

blin

ding

:unc

lear

In

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:yes

Sum

mar

y ri

sk o

f bia

s:m

oder

ate

Bas

elin

e G

I st

atus

:end

osco

py n

otpe

rfor

med

but

exc

lude

d pa

rtic

ipan

ts w

ithoe

soph

agea

l or

gast

rodu

oden

al u

lcer

atio

nw

ithin

30

days

prio

r to

sta

rt o

f stu

dy

Type

and

dur

atio

n of

art

hrit

is (

year

s):

OA

: a 1

0, b

10,

c 9

A

ge: a

: 62

(33–

86),

b 62

(32–

84),

c 63

(25–

87)

Sex:

M/F

: a 5

7/14

1, b

53/

144,

c 5

7/14

5In

clus

ion

crit

eria

:out

patie

nts

18 y

ears

or m

ore,

prim

ary

OA

(kne

e, A

CR

crite

ria)

and

func

tiona

l cla

ss I,

II o

r III

,sy

mpt

omat

ic O

A [d

efin

ed w

orse

ning

of

signs

and

sym

ptom

s fo

llow

ing

disc

ontin

uatio

n N

SAID

s or

oth

eran

alge

sics,

or

if no

t re

ceiv

ing

NSA

IDs

oran

alge

sics

with

unc

ontr

olle

d O

A p

atie

ntas

sess

men

t of

art

hriti

s pa

in 4

0m

m o

rm

ore

on V

AS,

OA

Sev

erity

Inde

x Sc

ore

of7

or m

ore,

pat

ient

glo

bal a

sses

smen

tgr

ade

poor

or

very

poo

r, ph

ysic

ian

glob

alas

sess

men

t gr

ade

poor

or

very

poo

r (3

of

thes

e 4

crite

ria n

eed

to b

e m

et)]

, no

cort

icos

tero

ids

with

in 4

wee

ks o

f sta

rt o

fst

udy

Excl

usio

n cr

iter

ia:a

ctiv

e co

ncom

itant

GI

trac

t, re

nal,

hepa

tic o

r co

agul

atio

ndi

sord

ers,

mal

igna

ncy

(unl

ess

rem

oved

surg

ical

ly w

ith n

o re

curr

ence

with

in5

year

s), o

r oe

soph

agea

l or

gast

rodu

oden

al u

lcer

atio

n w

ithin

30

days

prio

r to

rec

eivi

ng s

tudy

dru

g, a

nyin

flam

mat

ory

arth

ritis,

gou

t or

acu

tetr

aum

a of

the

kne

e, k

now

nhy

pers

ensit

ivity

to

NSA

IDs

orsu

lfona

mid

es

Com

pari

son:

cel

ecox

ib (b

, c) v

sna

prox

en (a

) D

urat

ion:

12 w

eeks

Inte

rven

tion

s:b,

cel

ecox

ib20

0m

g/20

0–40

0m

g (1

00m

g ×2

dai

ly);

c, c

elec

oxib

400

mg/

200–

400

mg

(200

mg

×2 d

aily

); a,

nap

roxe

n,10

00m

g/50

0–12

50m

g (5

00m

g ×2

dai

ly)

Oth

er m

edic

atio

n:ot

her

NSA

IDs,

cort

icos

tero

ids

and

antic

oagu

lant

sw

ere

proh

ibite

dA

spir

in a

llow

ed: y

es, i

n st

able

dose

s 32

5m

g/da

y or

less

and

for

3co

nsec

utiv

e da

ys o

r le

ss (n

ot in

48h

prio

r to

ass

essm

ents

)A

nalg

esic

allo

wed

:yes

,pa

race

tam

ol 2

g/da

y or

less

and

for

3 co

nsec

utiv

e da

ys o

r le

ss (n

ot in

48 h

prio

r to

ass

essm

ents

)Pa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut: 2

–7 d

ays

Num

ber

and

freq

uenc

y of

vis

its:

4 (0

, 1, 2

, 6 a

nd 1

2 w

eeks

)

Allo

cate

d:a

198,

b19

7, c

202

Com

plet

ed:u

ncle

ar(5

69 in

tot

al, i

nclu

ding

plac

ebo

arm

and

cele

coxi

b 10

0m

g da

ilyar

m)

Dro

p-ou

t: u

ncle

ar (4

34in

tot

al)

Ass

esse

d: a

198

, b 1

97,

c 20

2 O

utco

mes

rep

orte

d:se

rious

GI

com

plic

atio

ns,

sym

ptom

atic

ulc

ers,

GI

sym

ptom

s, G

I dro

p-ou

tsH

ow w

ere

adve

rse

even

ts a

sses

sed:

not

stat

ed

How

was

com

plia

nce

asse

ssed

:not

sta

ted,

but

33/1

003

patie

nts

wer

e di

scon

tinue

d du

eto

non

-com

plia

nce

Ris

k fa

ctor

s:co

ncom

itant

use

of

antic

oagu

lant

s: a

0,

b 0,

co

rtic

oste

roid

s:

a 0,

b: 0

>1

NSA

IDs:

a 0

, b 0

rena

l/hep

atic

dise

ase:

a0,

b 0

FUN

DIN

GFu

nded

by:

in p

art

byG

D S

earle

Affi

liati

on o

f con

tact

auth

or:2

6 C

harlt

onA

venu

e, S

uite

203

,H

amilt

on, O

N, C

anad

aA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

7 of

10

auth

ors

wor

ked

for

Sear

le R

esea

rch

and

Dev

elop

men

t, Sk

okie

,IL

, USA

Oth

er:p

lace

bo a

rman

d ce

leco

xib

100

mg

daily

arm

exc

lude

dfr

om a

naly

sis

Appendix 6

258

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Emer

y, 1

99985

,222

Loca

tion

:132

cent

res

in E

urop

e,Is

rael

, Sou

th A

fric

a,A

ustr

alia

, New

Zea

land

Met

hod

ofra

ndom

isat

ion:

‘com

pute

r-ge

nera

ted

rand

omisa

tion

num

bers

’ A

lloca

tion

con

ceal

men

t:un

clea

rB

asel

ine

com

para

bilit

y:no Pa

rtic

ipan

t bl

indi

ng:y

esA

sses

sor

blin

ding

:yes

,pe

rfor

atio

n, b

leed

ing

orob

stru

ctio

ns w

ere

asse

ssed

by a

com

mitt

ee o

fin

depe

nden

tga

stro

ente

rolo

gist

s un

awar

eof

tre

atm

ent

stat

usIn

tent

ion-

to-t

reat

:yes

A p

riori

sam

ple

size

:yes

Sum

mar

y ri

sk o

f bia

s:hi

gh

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

y bu

t ex

clud

ed p

artic

ipan

ts w

ithac

tive

or s

uspe

cted

pep

tic u

lcer

atio

n or

GI b

leed

ing

Type

and

dur

atio

n of

art

hrit

is:

RA: a

9.9

, b 1

1.0

Age

:a 5

4.5,

b 5

5.9

Sex:

F/M

: a 9

5/23

4, b

79/

247

Incl

usio

n cr

iter

ia:d

iagn

osis

of a

dult-

onse

t RA

of 6

mon

ths

or lo

nger

dur

atio

n(A

RA c

riter

ia),

func

tiona

l cap

acity

clas

sific

atio

n of

III o

r le

ss, a

ntic

ipat

ed t

ore

quire

con

tinuo

us t

reat

men

t w

ith N

SAID

for

dura

tion

of t

rial

Excl

usio

n cr

iter

ia:d

iagn

osis

of a

nyco

ncom

itant

rhe

umat

ic c

ondi

tion,

act

ive

or s

uspe

cted

pep

tic u

lcer

atio

n or

GI

blee

ding

, im

port

ant

coag

ulat

ion

defe

ct o

ran

y di

sord

er t

hat

mig

ht p

recl

ude

NSA

IDus

e, m

alig

nant

dise

ase,

ren

al o

r he

patic

diso

rder

, inf

lam

mat

ory

bow

el d

iseas

e,di

clof

enac

into

lera

nce,

or

hype

rsen

sitiv

ityto

Cox

-2 in

hibi

tors

, sul

fona

mid

es o

rN

SAID

s, c

linic

ally

abn

orm

al v

alue

s on

pret

reat

men

t la

bora

tory

tes

ts, p

regn

ant

or la

ctat

ing,

rec

eive

d an

y D

MA

RD o

r or

alco

rtic

oste

roid

sta

rted

less

tha

n12

wee

ksbe

fore

sta

rt o

f stu

dy, i

njec

ted

cort

icos

tero

id g

iven

with

in 4

wee

ks o

ran

y ot

her

stud

y m

edic

atio

n w

ithin

30

days

of t

he fi

rst

dose

of t

he s

tudy

dru

g

Com

pari

son:

cele

coxi

b (b

) vs

dicl

ofen

ac S

R (a

)D

urat

ion:

24 w

eeks

Inte

rven

tion

s:b,

cel

ecox

ib40

0m

g/20

0–40

0m

g (2

00m

g ×2

dai

ly);

a, d

iclo

fena

c SR

150

mg/

75–1

50m

g (7

5m

g x2

dai

ly);

doub

le d

umm

ies

used

Oth

er m

edic

atio

n:us

e of

antic

oagu

lant

s, N

SAID

s ot

her

than

stud

y dr

ug o

r an

ti-ul

cer

drug

spr

ohib

ited

Asp

irin

allo

wed

:no

Ana

lges

ic a

llow

ed:y

es, b

utch

roni

c us

e pr

ohib

ited

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:no

Num

ber

and

freq

uenc

y of

vis

its:

7 (0

, 4, 8

, 12,

16,

20

and

24w

eeks

)

Allo

cate

d:a

329,

b 3

26

Com

plet

ed:a

235

,b

258

Dro

p-ou

t:a

94, b

68

Ass

esse

d:a

329,

b 3

26

Out

com

es r

epor

ted:

serio

us G

Ico

mpl

icat

ions

,sy

mpt

omat

ic u

lcer

, GI

sym

ptom

s, e

ndos

copi

cul

cers

, ana

emia

, GI

drop

-out

sH

ow w

ere

adve

rse

even

ts a

sses

sed:

not

stat

edH

ow w

as c

ompl

ianc

eas

sess

ed:t

able

t co

unt

Ris

k fa

ctor

s:hi

stor

y of

ulc

ers:

a 2

7,b

28

hist

ory

of b

leed

s: a

1,

b 4

conc

omita

nt u

se o

fan

ticoa

gula

nts:

a 0,

b0

cort

icos

tero

ids:

a

157,

b 1

24;

rena

l/hep

atic

dise

ase:

a

0, b

0

FUN

DIN

G

Fund

ed b

y:G

DSe

arle

, Sko

kie,

IL, U

SAA

ffilia

tion

of c

onta

ctau

thor

:Sea

rleRe

sear

ch &

Dev

elop

men

t, Sk

okie

,IL

, USA

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:6

or 1

0au

thor

s em

ploy

ed b

ySe

arle


259


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Lain

e, 1

99941

,223

Loca

tion

:34

sites

in U

SA

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

assig

ned’

and

str

atifi

edre

gard

ing

pres

ence

or

abse

nce

of h

istor

y of

GI

even

ts (P

UBs

) in

bloc

ks o

f 4fr

om a

com

pute

r-ge

nera

ted

list,

each

cen

tre

prov

ided

with

indi

vidu

ally

sea

led

enve

lope

sA

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:yes

Ass

esso

r bl

indi

ng:y

esIn

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:yes

Sum

mar

y ri

sk o

f bia

s:m

oder

ate

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd e

xclu

ded

part

icip

ants

with

activ

e du

oden

al, g

astr

ic o

r oe

soph

agea

lul

cers

, pyl

oric

obs

truc

tion

or e

rosiv

eoe

soph

agiti

s Ty

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A n

o ot

her

deta

ilsA

ge:a

62

(49–

87),

b 62

(49–

83),

c 62

(49–

86)

Sex:

M/F

: a 6

2/12

1, b

60/

135,

c 5

8/12

8In

clus

ion

crit

eria

:50

year

s or

mor

e,O

A, r

equi

ring

NSA

ID t

reat

men

t fo

r 6

mon

ths

or lo

nger

Excl

usio

n cr

iter

ia:h

istor

y of

UG

Isu

rger

y, in

flam

mat

ory

bow

el d

iseas

e,se

rum

cre

atin

ine

of m

ore

than

2m

g/dl

,cr

eatin

ine

clea

ranc

e of

30

ml/m

in o

r le

ss,

faec

al o

ccul

t bl

ood,

uns

tabl

e m

edic

aldi

seas

e, h

istor

y of

mal

igna

ncy

in p

ast

5ye

ars,

cer

ebro

vasc

ular

eve

nts

in p

ast

2ye

ars,

ble

edin

g di

asth

esis,

req

uire

men

tfo

r an

ticoa

gula

nt t

hera

py, c

ortic

oste

roid

s,tic

lopi

dine

or

aspi

rin

Com

pari

son:

rofe

coxi

b (b

, c) v

sib

upro

fen

(a)

Dur

atio

n:24

wee

ksIn

terv

enti

ons:

b, r

ofec

oxib

25m

g/12

.5–2

5m

g (o

nce

daily

); c,

rof

ecox

ib 5

0m

g/12

.5–2

5m

g(o

nce

daily

); a,

ibup

rofe

n 24

00m

g/60

0–24

00m

g (8

00m

g ×3

dai

ly);

doub

le d

umm

y de

sign

Oth

er m

edic

atio

n: a

ntac

idpe

rmitt

ed a

s ne

eded

(Gel

usil)

.N

on-s

tudy

NSA

IDs,

cor

ticos

tero

ids,

antic

oagu

lant

s, t

iclo

pidi

ne, H

2RA

s,su

cral

fate

, PPI

s, m

isopr

osto

l or

anta

cids

oth

er t

han

Gel

usil

not

perm

itted

Asp

irin

allo

wed

:no

Ana

lges

ic a

llow

ed:

acet

amin

ophe

n (m

ax. 2

600

mg

daily

) sup

plie

d, a

llow

ed n

on-N

SAID

pain

med

icat

ion

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:yes

, 2 w

eeks

for

prev

ious

NSA

IDs,

ant

i-sec

reto

rym

edic

atio

ns, c

ytop

rote

ctiv

e dr

ugs

and

antib

iotic

sN

umbe

r an

d fr

eque

ncy

of v

isit

s:4

(0, 6

, 12

and

24 w

eeks

)

Allo

cate

d:a

183,

b19

5, c

186

Com

plet

ed:a

72,

b13

6, c

122

Dro

p-ou

t:a

112,

b 5

9,c

64A

sses

sed:

a 16

7, b

186

,c

178

Out

com

es r

epor

ted:

serio

us G

Ico

mpl

icat

ions

,sy

mpt

omat

ic u

lcer

s, G

Isy

mpt

oms,

end

osco

pic

ulce

rs

How

wer

e ad

vers

eev

ents

ass

esse

d:no

deta

ilsH

ow w

as c

ompl

ianc

eas

sess

ed:a

sses

sed

atea

ch v

isit,

met

hod

not

stat

ed, w

as m

ore

than

95%

in a

ll gr

oups

Ris

k fa

ctor

s:hi

stor

y of

PU

Bs: a

35,

b 43

, c 3

3co

ncom

itant

use

of

antic

oagu

lant

s: a

0, b

0co

rtic

oste

roid

s: a

0,

b 0

>1

NSA

IDs:

a 0

, b 0

FU

ND

ING

Fund

ed b

y:H

elsin

nH

ealth

care

,Sw

itzer

land

Affi

liati

on o

f con

tact

auth

or:H

elsin

nH

ealth

care

Affi

liati

on o

fst

atis

tici

an:I

DV

Dat

enan

alse

und

Vers

uchs

plan

ung,

Ger

man

yA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear,

Hel

sinn

Hea

lthca

re c

ontr

ibut

edto

dev

elop

men

t of

stud

yN

o. o

f aut

hors

empl

oyed

by

spon

sor:

1 of

8

Appendix 6

260

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Sim

on, 1

99986

,219

Loca

tion

:79

clin

ical

site

s in

USA

and

Can

ada

Met

hod

ofra

ndom

isat

ion:

‘com

pute

r-ge

nera

ted

rand

omisa

tion

sche

dule

str

atifi

ed b

y ce

ntre

in b

lock

s of

10’

Allo

cati

on c

once

alm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:yes

Ass

esso

r bl

indi

ng:y

esIn

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:yes

Sum

mar

y ri

sk o

f bia

s:m

oder

ate

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd e

xclu

ded

patie

nts

with

oeso

phag

eal,

gast

ric o

r du

oden

al u

lcer

or

mor

e th

an 1

0 er

osio

ns

Type

and

dur

atio

n of

art

hrit

is (

year

s):

RA: a

10,

b 1

1, c

11,

d 1

0A

ge:a

55

(28–

81),

b 54

(22–

85),

c 55

(20–

90),

d 54

(22–

85)

Sex:

M/F

: a 6

3/16

2, b

62/

178,

c 6

3/17

2,d

61/1

57In

clus

ion

crit

eria

: out

patie

nts

18 y

ears

or m

ore,

AC

R cr

iteria

for

diag

nosis

of R

A(e

vide

nt fo

r at

leas

t 3

mon

ths)

and

infu

nctio

nal c

lass

I, II

or

III. D

oses

of a

nygl

ucoc

ortic

oids

, DM

ARD

s or

met

hotr

exat

e ha

d be

en s

tabl

e an

d w

ere

expe

cted

to

rem

ain

cons

tant

thr

ough

out

the

stud

y, s

ympt

omat

ic R

A fl

are

follo

win

gw

asho

ut o

f NSA

IDs

or a

ny a

nalg

esic

sco

nfirm

ed a

t ba

selin

e by

phy

sicia

ns a

ndpa

tient

s Ex

clus

ion

crit

eria

:act

ive

GI t

ract

, ren

al,

hepa

tic o

r co

agul

atio

n di

sord

ers,

hist

ory

of m

alig

nanc

y (u

nles

s re

mov

ed s

urgi

cally

with

no

recu

rren

ce w

ithin

5ye

ars)

,oe

soph

agea

l or

gast

rodu

oden

al u

lcer

atio

nw

ithin

the

pre

viou

s 30

days

, hist

ory

ofga

stric

or

duod

enal

sur

gery

oth

er t

han

over

sew

, oes

opha

geal

, gas

tric

or

duod

enal

ulce

r or

10

eros

ions

or

mor

e at

bas

elin

een

dosc

opy

Com

pari

son:

cele

coxi

b (b

, c, d

) vs

napr

oxen

Dur

atio

n:12

wee

ksIn

terv

enti

ons:

b, c

elec

oxib

200

mg/

200–

400

mg

(100

mg

×2 d

aily

); c,

cel

ecox

ib40

0m

g/20

0–40

0m

g (2

00m

g ×2

dai

ly);

d, c

elec

oxib

800

mg/

200–

400

mg

(400

mg

×2 d

aily

); a,

nap

roxe

n10

00m

g/50

0–12

50m

g (5

00m

g ×2

dai

ly)

Oth

er m

edic

atio

n: o

ther

NSA

IDS,

inje

ctab

le c

ortic

oste

roid

s,an

ticoa

gula

nts

and

anti-

ulce

r dr

ugs

proh

ibite

d, s

tabl

e do

ses

of o

ral

gluc

ocor

ticoi

ds, D

MA

RDs

allo

wed

Asp

irin

allo

wed

:yes

, sta

ble

dose

sof

325

mg/

day

or le

ss

Ana

lges

ic a

llow

ed:y

es,

acet

amin

ophe

n 2

g da

ily o

r le

ss fo

r3

cons

ecut

ive

days

or

less

(exc

ept

with

in 4

8 h

of a

rthr

itis

asse

ssm

ent)

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:yes

, 2–7

day

s fo

rpr

evio

us N

SAID

s or

any

ana

lges

icm

edic

atio

nN

umbe

r an

d fr

eque

ncy

of v

isit

s:4

(0, 2

, 6, 1

2 w

eeks

)

Allo

cate

d:a

225,

b 2

40c

235,

d 2

18C

ompl

eted

:a 1

38,

b 15

4, c

158

, d 1

37D

rop-

out:

a 87

, b 8

6,c

77, d

81

Ass

esse

d:a

225,

b 2

40,

c 23

5, d

218

Out

com

es r

epor

ted:

serio

us G

Ico

mpl

icat

ions

,sy

mpt

omat

ic u

lcer

s,se

rious

car

diac

or

rena

lill

ness

, QoL

, GI

sym

ptom

s, e

ndos

copi

cul

cers

, GI d

rop-

outs

How

wer

e ad

vers

eev

ents

ass

esse

d:no

tst

ated

How

was

com

plia

nce

asse

ssed

:tab

let

coun

t,pl

asm

a le

vels

at d

ay 2

1

Ris

k fa

ctor

s:co

ncom

itant

use

of

cort

icos

tero

ids:

a 31

, b

42, c

37,

d 3

4>

1 N

SAID

: a 0

, b 0

FUN

DIN

GFu

nded

by:

GD

Sea

rleA

ffilia

tion

of c

onta

ctau

thor

:Bet

h Is

rael

Dea

cone

ss M

edic

alC

ente

r, M

A, U

SAA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f stu

dyad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

6 of

11

auth

ors

empl

oyed

by

Sear

le


261


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Bom

bard

ier,

2000

87

Loca

tion

:301

cent

res

in 2

2co

untr

ies

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

assig

ned’

, str

atifi

edac

cord

ing

to p

rese

nce

orab

senc

e of

hist

ory

ofga

stro

duod

enal

ulc

er, u

pper

GI b

leed

ing,

gas

trod

uode

nal

perf

orat

ions

A

lloca

tion

con

ceal

men

t:un

clea

r B

asel

ine

com

para

bilit

y:ye

sPa

rtic

ipan

t bl

indi

ng:y

esA

sses

sor

blin

ding

:yes

,in

depe

nden

t bl

inde

d en

d-po

int

com

mitt

eeIn

tent

ion-

to-t

reat

:yes

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:end

osco

py n

otpe

rfor

med

but

exc

lude

d if

had

posit

ive

test

for

faec

al o

ccul

t bl

ood

at b

asel

ine

Type

and

dur

atio

n of

art

hrit

is:

RA fo

r le

ss t

han

2 ye

ars:

a 4

55, b

430

2–10

year

s: a

199

6, b

199

1>

10 y

ears

: a 1

571,

b 1

623

Age

:a 5

8, b

58

Sex:

M/F

: a 8

14/3

215,

b 8

24/3

223

Incl

usio

n cr

iter

ia:R

A, 5

0 ye

ars

or m

ore

(or

40 y

ears

or

mor

e an

d re

ceiv

ing

long

-te

rm g

luco

cort

icoi

d th

erap

y) a

ndex

pect

ed t

o re

quire

NSA

IDs

for

at le

ast

1ye

arEx

clus

ion

crit

eria

:hist

ory

of a

ny o

ther

type

of i

nfla

mm

ator

y ar

thrit

is, U

GI

surg

ery,

or

infla

mm

ator

y bo

wel

dise

ase,

estim

ated

cre

atin

ine

clea

ranc

e30

ml/m

inut

e or

less

, a p

ositi

ve t

est

for

faec

al o

ccul

t bl

ood,

an

unst

able

med

ical

cond

ition

, hist

ory

of c

ance

r or

alc

ohol

or

drug

abu

se in

pas

t 5

year

s, a

hist

ory

ofce

rebr

ovas

cula

r ev

ents

in p

ast

2ye

ars,

hist

ory

of M

I or

coro

nary

byp

ass

in p

ast

year

, mor

bid

obes

ity, r

equi

red

trea

tmen

tw

ith a

spiri

n, t

iclo

pidi

ne, a

ntic

oagu

lant

s,cy

clos

porin

e, m

isopr

osto

l, su

cral

fate

, PPI

sor

H2R

As

in p

resc

riptio

n-st

reng

th d

oses

Com

pari

son:

rof

ecox

ib (b

) vs

napr

oxen

(a)

Dur

atio

n:m

edia

n 9

mon

ths

Inte

rven

tion

s:b,

rof

ecox

ib 5

0m

g/12

.5–2

5m

g (o

nce

daily

); a,

nap

roxe

n 10

00m

g/50

0–12

50m

g(5

00m

g ×2

dai

ly)

Oth

er m

edic

atio

n:D

MA

RDs,

anta

cids

and

H2R

As

allo

wed

(up

to15

0m

g da

ily r

aniti

dine

or

niza

tidin

e, 2

0m

g da

ily fa

mot

idin

e,40

0m

g da

ily c

imet

idin

e);

ticlo

pidi

ne, a

ntic

oagu

lant

s,cy

clos

porin

e, m

isopr

osto

l,su

cral

fate

, PPI

s or

H2R

As

inpr

escr

iptio

n-st

reng

th d

oses

wer

eex

clud

edA

spir

in a

llow

ed:n

oA

nalg

esic

allo

wed

:yes

,ac

etam

inop

hen

and

non-

NSA

IDan

alge

sics

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:yes

, 3–1

4 da

ysN

umbe

r an

d fr

eque

ncy

of v

isit

s:0,

6 w

eeks

, 4 m

onth

s, 8

mon

ths

and

then

eve

ry 4

mon

ths

(tel

epho

ne c

onta

ct a

t w

eek

10 a

ndth

en e

very

4 m

onth

s)

Allo

cate

d: a

402

9,b

4047

C

ompl

eted

:a 2

881,

b28

61

Dro

p-ou

t:a

1148

,b

1186

A

sses

sed:

uncl

ear

Out

com

es r

epor

ted:

mor

talit

y, s

erio

us G

Ico

mpl

icat

ions

,sy

mpt

omat

ic u

lcer

s,se

rious

car

diov

ascu

lar

orre

nal e

vent

s, G

Isy

mpt

oms,

end

osco

py,

GI d

rop-

outs

H

ow w

ere

adve

rse

even

ts a

sses

sed:

not

stat

edH

ow w

as c

ompl

ianc

eas

sess

ed:t

able

t co

unt

and

ques

tioni

ng d

urin

gte

leph

one

calls

, 99%

of

part

icip

ants

in b

oth

grou

ps t

ook

thei

rm

edic

atio

n on

at

leas

t75

% o

f stu

dy d

ays

Ris

k fa

ctor

s:hi

stor

y of

clin

ical

GI

even

ts:

a 31

6, b

314

conc

omita

nt H

2RA

s:

a 33

5, b

365

>1

NSA

ID: a

0, b

0C

VD: a

0, b

0

FUN

DIN

G

Fund

ed b

y:M

erck

Affi

liati

on o

f con

tact

auth

or:I

nstit

ute

for

Wor

k an

d H

ealth

,To

ront

o, C

anad

aA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

11 o

f 13

prin

cipa

l aut

hors

hav

eha

d fin

anci

alas

soci

atio

ns w

ithM

erck

and

in m

ost

case

s w

ith m

any

othe

rco

mpa

nies

, 2 p

rinci

pal

auth

ors

wer

eem

ploy

ees

of M

erck

D

oses

:rof

ecox

ibpr

escr

ibed

abo

vem

axim

umre

com

men

ded

dose

Appendix 6

262

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Can

non,

200

088

Loca

tion

:m

ultic

entr

e, U

SA

Met

hod

ofra

ndom

isat

ion:

‘rand

omisa

tion

occu

rred

follo

win

g an

elig

ibili

tyvi

sit b

y a

com

pute

r-ge

nera

ted

rand

omisa

tion

sche

dule

’ A

lloca

tion

conc

ealm

ent:

adeq

uate

B

asel

ine

com

para

bilit

y:ye

sPa

rtic

ipan

t bl

indi

ng:

yes

Ass

esso

r bl

indi

ng:

uncl

ear

Inte

ntio

n-to

-tre

at:y

esA

pri

ori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

low

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ype

rfor

med

, GI s

tatu

s no

t as

sess

ed, p

eopl

ew

ith h

istor

y of

gas

trod

uode

nal u

lcer

or

GI

blee

ding

wer

e al

low

ed t

o pa

rtic

ipat

eTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A: a

11.

4, b

11.

1, c

11.

5A

ge:a

62.

5, b

62.

8, c

62.

8Se

x:M

/F: a

83/

185,

b 9

0/16

9, c

82/

175

Incl

usio

n cr

iter

ia:4

0 ye

ars

or m

ore,

clin

ical

and

radi

ogra

phic

evi

denc

e of

OA

(kne

e, jo

int

spac

e na

rrow

ing

and

the

pres

ence

of

oste

ophy

tes,

or

hip,

join

t spa

ce n

arro

win

g)w

ith s

tudy

join

t prim

ary

sour

ce o

f pai

n or

disa

bilit

y, fu

nctio

nal c

lass

I, II

or

III(S

tein

broc

ker

crite

ria),

thos

e on

NSA

IDs

had

to h

ave

at le

ast m

oder

ate

pain

whe

n w

alki

ng(4

0m

m o

r m

ore

on V

AS)

and

an

incr

ease

inpa

in w

hen

wal

king

(15

mm

or

mor

e on

VA

Sco

mpa

red

with

scr

eeni

ng le

vel)

afte

rw

asho

ut, a

lso p

hysic

ian’

s as

sess

men

t of

dise

ase

stat

e w

orse

than

at s

cree

ning

, tho

seon

ace

tam

inop

hen

had

at le

ast m

oder

ate

pain

whe

n w

alki

ng a

fter

12h

with

out

acet

amin

ophe

n (4

0m

m o

r m

ore

on V

AS)

,pa

tient

’s a

nd p

hysic

ian’

s as

sess

men

t of

dise

ase

stat

us h

ad to

be

fair,

poo

r or

ver

ypo

or, w

omen

pos

t-m

enop

ausa

l or

non-

grav

idEx

clus

ion

crit

eria

:sig

nific

ant

rena

lim

pairm

ent,

clin

ical

ly s

igni

fican

t abn

orm

aliti

eson

phy

sical

or

labo

rato

ry e

xam

inat

ions

,po

sitiv

e fa

ecal

occ

ult

bloo

d, c

lass

III/I

Van

gina

, unc

ontr

olle

d co

nges

tive

hear

t fa

ilure

,un

cont

rolle

d hy

pert

ensio

n, s

trok

e or

tran

sient

isch

aem

ic a

ttac

k w

ithin

2 y

ears

of

stud

y, a

ctiv

e he

patic

dise

ase,

hist

ory

ofre

cent

neo

plas

tic d

iseas

e, a

llerg

y to

acet

amin

ophe

n or

NSA

IDs,

req

uirin

g as

pirin

(any

dos

e), c

ortic

oste

roid

s, w

arfa

rin o

rtic

lopi

dine

Com

pari

son:

rof

ecox

ib (b

, c) v

sdi

clof

enac

(a)

Dur

atio

n:52

wee

ksIn

terv

enti

ons:

b, r

ofec

oxib

12.5

mg/

12.5

–25

mg

(onc

e da

ily);

c, r

ofec

oxib

25

mg/

12.5

–25

mg

(onc

e da

ily);

a, d

iclo

fena

c 15

0m

g/75

–150

mg

(50

mg

×3 d

aily

); do

uble

dum

mie

s us

ed

Oth

er m

edic

atio

n:no

det

ails

Asp

irin

allo

wed

:no

Ana

lges

ic a

llow

ed:y

es,

acet

amin

ophe

n (m

ax. 2

.6g/

day)

Pa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

esN

umbe

r an

d fr

eque

ncy

ofvi

sits

:11

(0, 2

, 4, 8

, 12,

19,

26,

33,

39, 4

5, 5

2 w

eeks

)

Allo

cate

d:a

268,

b25

9, c

257

Com

plet

ed:a

145

,b

161,

c 1

42D

rop-

out:

a 12

3, b

98,

c 11

5A

sses

sed:

a 26

8, b

259

;c

257

Out

com

es r

epor

ted:

serio

us G

Ico

mpl

icat

ions

,sy

mpt

omat

ic u

lcer

s,se

rious

car

diov

ascu

lar

orre

nal i

llnes

s, G

Isy

mpt

oms,

GI d

rop-

outs

How

wer

e ad

vers

eev

ents

ass

esse

d:sp

onta

neou

sly r

epor

ted

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:co

ncom

itant

use

of

cort

icos

tero

ids:

a 0

,b

0 C

VD: a

0, b

0

rena

l/hep

atic

dise

ase:

a

0, b

0FU

ND

ING

Fund

ed b

y:M

erck

Rese

arch

Lab

orat

orie

sA

ffilia

tion

of c

onta

ctau

thor

:Mer

ckA

ffilia

tion

of

stat

isti

cian

: Mer

ckA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:5

out

of9

auth

ors

wor

ked

for

Mer

ck


263


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Cla

ss, 2

00089

Loca

tion

:USA

and

Can

ada

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d’,

stra

tifie

d by

OA

/RA

stat

us, r

emot

e in

tera

ctiv

evo

ice-

activ

ated

res

pons

esy

stem

use

d to

rand

omise

afte

r ba

selin

evi

sitA

lloca

tion

conc

ealm

ent:

adeq

uate

Bas

elin

e co

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:yes

(GEC

com

mitt

ee b

linde

dan

d st

udy

pers

onne

lbl

inde

d)In

tent

ion-

to-t

reat

:yes

A p

riori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

low

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd p

atie

nts

excl

uded

if h

adoe

soph

agea

l, ga

stric

, pyl

oric

cha

nnel

or

duod

enal

ulc

erTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A/R

A: a

10.

9/9.

9, b

10.

5/10

.4, c

11.

2/10

.3A

ge:a

59.

5, b

60.

1, c

60.

6Se

x:M

/F: a

580

/140

5, b

650

/134

6,c

1255

/273

2In

clus

ion

crit

eria

:leg

al a

ge o

f con

sent

or

olde

r, fo

r w

omen

of c

hild

bear

ing

pote

ntia

l,ha

d be

en u

sing

adeq

uate

con

trac

eptio

nsin

ce la

st m

ense

s an

d ag

reed

to

cont

inue

to

use

adeq

uate

con

trac

eptio

n du

ring

the

stud

y, n

ot b

een

lact

atin

g an

d ha

d a

nega

tive

seru

m p

regn

ancy

tes

t w

ithin

7da

ys b

efor

ere

ceiv

ing

the

first

dos

e of

stu

dy m

edic

atio

n;ha

d a

docu

men

ted

clin

ical

dia

gnos

is of

OA

or R

A o

f at

leas

t 3

mon

ths

dura

tion;

requ

ired

chro

nic

NSA

ID t

hera

py in

the

inve

stig

ator

’s o

pini

on; e

xpec

ted

topa

rtic

ipat

e fo

r th

e fu

ll du

ratio

n of

the

stu

dyEx

clus

ion

crit

eria

: act

ive

mal

igna

ncy

of a

nyty

pe o

r a

hist

ory

of m

alig

nanc

y (e

xcep

thi

stor

y of

bas

al c

ell c

arci

nom

a th

at h

ad b

een

trea

ted

and

hist

ory

of o

ther

mal

igna

ncie

sth

at h

ad b

een

surg

ical

ly r

emov

ed a

nd w

hoha

d no

evi

denc

e of

rec

urre

nce

for

at le

ast

5ye

ars

befo

re s

tart

of t

he s

tudy

); di

agno

sed

as h

avin

g or

had

rec

eive

d tr

eatm

ent

for

oeso

phag

eal,

gast

ric, p

ylor

ic c

hann

el o

rdu

oden

al u

lcer

with

in 3

0 da

ys p

rior

tore

ceiv

ing

first

dos

e of

stu

dy m

edic

atio

n;ac

tive

GI d

iseas

e (e

.g. i

nfla

mm

ator

y bo

wel

dise

ase)

; hist

ory

of g

astr

ic o

r du

oden

alsu

rger

y ot

her

than

sim

ple

over

sew

of a

nul

cer

or p

erfo

ratio

n; s

igni

fican

t re

nal o

rhe

patic

dys

func

tion

or a

sig

nific

ant

coag

ulat

ion

defe

ct c

onsid

ered

by

the

Com

pari

son:

cele

coxi

b (c

) vs

dicl

ofen

ac (b

), vs

ibup

rofe

n (a

) D

urat

ion:

26–6

5 w

eeks

Inte

rven

tion

s:c,

cel

ecox

ib80

0m

g/20

0–40

0m

g (4

00m

g ×2

dai

ly);

b, d

iclo

fena

c,15

0m

g/75

–150

mg

(75

mg

×2 d

aily

); a,

ibup

rofe

n24

00m

g/60

0–24

00m

g (8

00m

g ×3

dai

ly)

Oth

er m

edic

atio

n:pa

tient

sen

cour

aged

to

take

onl

y st

udy

drug

s if

poss

ible

, oth

er N

SAID

s,an

ti-ul

cer

drug

s, a

ntib

iotic

s,an

tineo

plas

tics

(exc

ept

met

hotr

exat

e at

25

mg

per

wee

kor

less

or

azat

hiop

rine)

wer

epr

ohib

ited;

ant

acid

s an

d ca

lciu

msu

pple

men

ts a

llow

ed a

nd o

ral,

intr

amus

cula

r an

d in

tra-

artic

ular

cort

icos

tero

ids

perm

itted

Asp

irin

allo

wed

:yes

, 325

mg

daily

or le

ss: a

383

, b 4

29, c

833

Ana

lges

ic a

llow

ed:y

es,

para

ceta

mol

up

to 2

000

mg

daily

alon

e or

in c

ombi

natio

n w

ithpr

opox

yphe

ne h

ydro

chlo

ride

orna

psal

ate,

hyd

rom

orph

one

hydr

ochl

orid

e, o

xyco

done

hydr

ochl

orid

e or

cod

eine

phos

phat

ePa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:n

o de

tails

Num

ber

and

freq

uenc

y of

vis

its:

6–7

(0, 4

, 13,

26,

39,

52

and

som

eat

65

wee

ks)

Allo

cate

d:a

2009

,b

2019

, c 4

031

Com

plet

ed:a

691

, b

939,

c 1

779

Dro

p-ou

t:a

1318

,b

1080

, c 2

252

Ass

esse

d:a

1985

,b

1996

, c 3

987

Out

com

es r

epor

ted:

mor

talit

y, s

erio

us G

Ico

mpl

icat

ions

,sy

mpt

omat

ic u

lcer

s,se

rious

car

diov

ascu

lar

orre

nal i

llnes

s, q

ualit

y of

life,

GI s

ympt

oms,

GI

drop

-out

s, a

naem

ia,

tota

l dro

p-ou

tsH

ow w

ere

adve

rse

even

ts a

sses

sed:

part

icip

ants

ask

ed ‘d

oyo

u ha

ve a

ny s

ympt

oms

that

are

not

ass

ocia

ted

with

you

r ar

thrit

is?’ i

fsu

gges

tive

of C

SUG

IE(C

linic

ally

Sig

nific

ant

Upp

er G

astr

oint

estin

alEv

ent)

the

n in

itiat

edw

orku

p of

pot

entia

lev

ents

acc

ordi

ng t

opr

edef

ined

alg

orith

m,

code

d ac

cord

ing

toW

HO

ART

(Wor

ldH

ealth

Org

aniz

atio

nA

dver

se R

eact

ions

Term

inol

ogy)

Ris

k fa

ctor

s:hi

stor

y of

ulc

ers:

a

151,

b

170,

c33

4hi

stor

y of

ble

eds:

a 2

8,b

30, c

68

conc

omita

nt u

se o

fan

ti-co

agul

ants

: a

20, b

24 c

42

cort

icos

tero

ids:

a 6

07,

b 56

8, c

121

9>

1NSA

ID: a

0, b

0,

c0;

CVD

: a 7

94,

b 80

5, c

160

2re

nal/h

epat

ic d

iseas

e:

a 0,

b 0

FU

ND

ING

Fund

ed b

y:ph

arm

acia

Affi

liati

on o

f con

tact

auth

or:P

harm

acia

A

ffilia

tion

of

stat

isti

cian

:unc

lear

,bu

t na

med

as

Cle

mM

aura

thA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:6/

16 w

ork

for

Phar

mac

ia, a

llot

her

auth

ors

have

been

pai

d co

nsul

tant

sfo

r Ph

arm

acia

Appendix 6

264

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

inve

stig

ator

to

be c

linic

ally

sig

nific

ant;

abno

rmal

scr

eeni

ng la

bora

tory

tes

t va

lues

mor

e th

an 1

.5 t

imes

the

upp

er li

mit

ofno

rmal

for

eith

er A

ST o

r A

LT o

r an

y ot

her

labo

rato

ry a

bnor

mal

ity a

t sc

reen

ing

cons

ider

ed b

y th

e in

vest

igat

or t

o be

clin

ical

ly s

igni

fican

t; po

sitiv

e sc

reen

ing

faec

aloc

cult

bloo

d re

sult;

kno

wn

hype

rsen

sitiv

ityto

Cox

-2 in

hibi

tors

, sul

fona

mid

es, i

bupr

ofen

or d

iclo

fena

c; r

ecei

ved

any

inve

stig

atio

nal

med

icat

ion

with

in 3

0 da

ys b

efor

e th

e fir

stdo

se o

f stu

dy m

edic

atio

n or

was

sch

edul

edto

rec

eive

an

inve

stig

atio

nal d

rug

othe

r th

ance

leco

xib

durin

g th

e co

urse

of t

he s

tudy

;ha

d pr

evio

usly

bee

n ad

mitt

ed t

o ei

ther

of

thes

e pr

otoc

ols

or a

prio

r st

udy

with

cele

coxi

b

How

was

com

plia

nce

asse

ssed

:tab

let

coun

t,no

n-co

mpl

ianc

e de

fined

as t

akin

g le

ss t

han

70%

stud

y m

edic

atio

n, d

iary

card

use

d to

list

any

med

icat

ion

take

n in

last

30 d

ays


265


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Day

, 200

090,2

24

Loca

tion

: 49

sites

in 2

6 co

untr

ies

inN

orth

and

Sou

thA

mer

ica,

Eur

ope,

Aus

tral

ia a

nd N

ewZ

eala

nd (n

ot U

K)

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’, c

ompu

ter-

gene

rate

d ra

ndom

isatio

nsc

hedu

le, m

aske

dal

loca

tion

sche

dule

gene

rate

d by

an

indi

vidu

al n

ot o

ther

wise

invo

lved

in t

he s

tudy

and

kept

con

ceal

ed fr

om a

llst

udy

part

icip

ants

,al

loca

tion

sche

dule

unbl

inde

d on

ce a

ll da

taw

as e

nter

ed, r

ecei

ved

and

cert

ified

Allo

cati

onco

ncea

lmen

t:ad

equa

teB

asel

ine

com

para

bilit

y:ye

sPa

rtic

ipan

t bl

indi

ng:

yes

Ass

esso

r bl

indi

ng:

uncl

ear

Inte

ntio

n-to

-tre

at:n

oA

pri

ori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

low

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

y, n

ofu

rthe

r de

tails

Ty

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A: a

9.0

, b 8

.3, c

8.5

Age

:a 6

4.1

b 64

.9 c

62.

8Se

x: M

/F: a

54/

195,

b 4

6/19

8, c

51/

191

Incl

usio

n cr

iter

ia:4

0 ye

ars

or m

ore,

clin

ical

and

radi

ogra

phic

evi

denc

e of

OA

(joi

nt s

pace

narr

owin

g an

d os

teop

hyte

s fo

r kn

ee a

nd jo

int

spac

e na

rrow

ing

for

hip)

, fun

ctio

nal c

lass

I, II

or

III(S

tein

broc

ker)

, sym

ptom

atic

for

at le

ast

6 m

onth

s,kn

ee o

r hi

p th

e pr

imar

y so

urce

of p

ain

ordi

sabi

lity

and

wom

en p

ostm

enop

ausa

l or

dem

onst

rabl

y no

n-gr

avid

, NSA

ID u

sers

: fol

low

ing

was

hout

, par

ticip

ants

’ pai

n on

wal

king

(fla

t) w

asas

sess

ed u

sing

ques

tion

1 of

WO

MA

C in

dex

and

if40

mm

or

mor

e an

d an

incr

ease

of 1

5m

m o

rm

ore

on t

he V

AS

com

pare

d w

ith p

re-w

asho

ut,

and

if th

e in

vest

igat

or’s

glo

bal a

sses

smen

t of

dise

ase

stat

us w

orse

ned

by a

t le

ast

1 po

int

on a

0–4

Like

rt s

cale

; ace

tam

inop

hen

user

s: if

met

all

3of

the

follo

win

g cr

iteria

at

both

the

scr

eeni

ng a

ndra

ndom

isatio

n vi

sits:

40

mm

or

mor

e on

the

pai

nVA

S (q

uest

ion

1 of

WO

MA

C),

repo

rted

40

mm

or

mor

e on

a V

AS

eval

uatin

g pa

tient

’s g

loba

las

sess

men

t of

dise

ase

stat

us a

nd t

he in

vest

igat

orra

ted

the

glob

al a

sses

smen

t of

dise

ase

stat

us a

sfa

ir, p

oor

or v

ery

poor

Excl

usio

n cr

iter

ia: s

igni

fican

t re

nal i

mpa

irmen

t,cl

inic

ally

sig

nific

ant

abno

rmal

res

ults

of p

hysic

alex

amin

atio

n or

labo

rato

ry s

cree

ning

, pos

itive

faec

al o

ccul

t bl

ood

test

, mal

abso

rptio

n, c

lass

III/I

Van

gina

or

cong

estiv

e he

art

failu

re, u

ncon

trol

led

hype

rten

sion,

str

oke

or t

rans

ient

isch

aem

ic a

ttac

kw

ithin

2 y

ears

, act

ive

hepa

tic d

iseas

e, h

istor

y of

rece

nt n

eopl

astic

dise

ase

or a

llerg

y to

NSA

IDs

orac

etam

inop

hen,

req

uirin

g as

pirin

(any

dos

e),

cort

icos

tero

ids,

war

farin

sod

ium

or

ticlo

pidi

nehy

droc

hlor

ide

Com

pari

son:

rofe

coxi

b (b

,c)

vs

ibup

rofe

n (a

) D

urat

ion:

6 w

eeks

Inte

rven

tion

s:b,

rof

ecox

ib12

.5m

g/12

.5–2

5m

g (o

nce

daily

); c,

rof

ecox

ib25

mg/

12.5

–25

mg

(onc

eda

ily);

a, ib

upro

fen

2400

mg/

600–

2400

mg

(800

mg

×3 d

aily

), do

uble

dum

mie

s us

ed

Oth

er m

edic

atio

n:co

rtic

oste

roid

s, w

arfa

rin a

ndtic

lopi

dine

pro

hibi

ted

Asp

irin

allo

wed

:no

Ana

lges

ic a

llow

ed:y

es,

acet

amin

ophe

n 26

00m

g/da

yor

less

Part

icip

ant

educ

atio

n:no

tst

ated

Was

hout

:yes

, lon

ger

than

5 pl

asm

a ha

lf-liv

es o

f prio

rN

SAID

use

Num

ber

and

freq

uenc

y of

visi

ts:4

(0, 2

, 4 a

nd6

wee

ks)

Allo

cate

d:a

249,

b

244,

c 2

42

Com

plet

ed:a

214

,b

224,

c 2

19D

rop-

out:

a 30

, b 1

8,c

16A

sses

sed:

a 24

4, b

242

,c

235

Out

com

es r

epor

ted:

sym

ptom

atic

ulc

ers,

GI

sym

ptom

sH

ow w

ere

adve

rse

even

ts a

sses

sed:

spon

tane

ously

rep

orte

dH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:co

ncom

itant

use

of

cort

icos

tero

ids:

a 0

, b

0C

VD: a

0, b

0re

nal/h

epat

ic d

iseas

e:

a 0,

b 0

FUN

DIN

GFu

nded

by:

Mer

ckA

ffilia

tion

of c

onta

ctau

thor

:Mer

ckA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

7 ou

t of

13

auth

ors

empl

oyed

by

Mer

ck

Appendix 6

266

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Haw

key,

200

091,2

23

Loca

tion

:5 U

SAsit

es a

nd 3

1in

tern

atio

nal s

ites

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d’,

rand

omisa

tion

stra

tifie

dby

pre

senc

e or

abs

ence

of h

istor

y of

GI e

vent

s(P

UBs

), 95

% o

fpa

rtic

ipan

ts t

akin

gpl

aceb

o an

d 5%

of

part

icip

ants

in t

he o

ther

grou

ps w

ere

rand

omly

sele

cted

and

disc

ontin

ued

from

the

tria

l in

a bl

inde

dm

anne

r at

wee

k 16

Allo

cati

onco

ncea

lmen

t:un

clea

rB

asel

ine

com

para

bilit

y:ye

sPa

rtic

ipan

t bl

indi

ng:

yes

Ass

esso

r bl

indi

ng:

uncl

ear

Inte

ntio

n-to

-tre

at:n

oA

pri

ori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd p

artic

ipan

ts e

xclu

ded

ifpy

loric

obs

truc

tion,

ero

sive

oeso

phag

itis

oroe

soph

agea

l, ga

stric

or

duod

enal

ulc

ers,

part

icip

ants

with

gas

trod

uode

nal e

rosio

nsw

ere

perm

itted

to

ente

r tr

ial

Bas

elin

e N

SAID

sta

tus:

49.4

% o

f all

part

icip

ants

rep

orte

d pr

ior

NSA

ID u

seTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A: n

o ot

her

deta

ilsA

ge:a

61

(49–

89),

b 62

(50–

85)

c 61

(50–

81)

Sex:

M/F

: a 5

0/14

3, b

45/

150,

c 5

4/13

9In

clus

ion

crit

eria

: OA

, 50

year

s or

mor

e,re

quire

d tr

eatm

ent

for

at le

ast

6 m

onth

sEx

clus

ion

crit

eria

:end

osco

pic

evid

ence

of

eros

ive

oeso

phag

itis,

oes

opha

geal

, gas

tric

or

duod

enal

ulc

erat

ion

or p

ylor

ic o

bstr

uctio

n,pr

evio

us U

GI s

urge

ry, i

nfla

mm

ator

y bo

wel

dise

ase,

ser

um c

reat

inin

e le

vels

mor

e th

an2.

0m

g/dl

, est

imat

ed c

reat

inin

e cl

eara

nce

30m

l/min

or

less

, fae

cal o

ccul

t bl

ood,

unst

able

med

ical

dise

ase,

hist

ory

ofm

alig

nanc

y in

prio

r 5

year

s, p

regn

ancy

,ce

rebr

ovas

cula

r ev

ents

in t

he p

rior

2 ye

ars,

blee

ding

dia

thes

is, r

equi

rem

ent

for

antic

oagu

lant

the

rapy

, cor

ticos

tero

ids,

ticlo

pidi

ne o

r as

pirin

Com

pari

son:

rofe

coxi

b (b

, c) v

sib

upro

fen

(a)

Dur

atio

n: 1

6–24

wee

ksIn

terv

enti

ons:

b, r

ofec

oxib

25m

g/12

.5–2

5m

g (o

nce

daily

);c,

rofe

coxi

b 50

mg/

12.5

–25

mg

(onc

e da

ily),

a, ib

upro

fen

2400

mg/

600–

2400

mg

(800

mg

3×da

ily);

doub

le d

umm

ies

used

Endo

scop

y: b

asel

ine,

6, 1

2 an

d24

wee

ks, a

t un

sche

dule

ddi

scon

tinua

tion

or t

o ev

alua

tem

oder

ate/

seve

re u

pper

GI

sym

ptom

s oc

curr

ing

for

2 da

ys o

rm

ore

Oth

er m

edic

atio

n: a

ntac

idsu

pplie

d as

nee

ded,

non

-stu

dyN

SAID

s, c

ortic

oste

roid

s,an

ticoa

gula

nts,

tic

lopi

dine

, H2R

As,

sucr

alfa

te, p

rost

agla

ndin

s, P

PIs

orun

appr

oved

ant

acid

s no

t pe

rmitt

edA

spir

in a

llow

ed:n

oA

nalg

esic

allo

wed

:yes

,ac

etam

inop

hen

2600

mg

daily

or

less

and

non

-NSA

ID p

ain

med

icat

ion

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:2 w

eeks

for

NSA

IDs,

antis

ecre

taor

y m

edic

atio

ns,

cyto

prot

ectiv

e dr

ugs

and

antib

iotic

sN

umbe

r an

d fr

eque

ncy

of v

isit

s:4

(0, 6

, 12

and

24 w

eeks

)

Allo

cate

d:a

193,

b19

5, c

193

Com

plet

ed:a

80,

b

138,

c 1

27D

rop-

out:

a 11

3, b

57,

c 66

Ass

esse

d:a

187,

b 1

87,

c 18

2O

utco

mes

rep

orte

d:se

rious

GI

com

plic

atio

ns, G

Isy

mpt

oms,

end

osco

pic

ulce

rsH

ow w

ere

adve

rse

even

ts a

sses

sed:

not

stat

edH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d bu

tm

ore

than

95%

com

plia

nce

repo

rted

inal

l stu

dy g

roup

s

Ris

k fa

ctor

s:hi

stor

y of

of P

UBs

: a

24, b

23

c 19

>1

NSA

IDs:

a 0

, b 0

conc

omita

nt u

se o

fan

ticoa

gula

nts:

a 0

, b

0co

rtic

oste

roid

s: a

0,

b 0

FUN

DIN

GFu

nded

by:

uncl

ear

Affi

liati

on o

f con

tact

auth

or:M

erck

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:5

of 1

0au

thor

s em

ploy

ed b

yM

erck


267


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Saag

, 200

0A92

Loca

tion

:62

clin

ical

cen

tres

inU

SA

Met

hod

ofra

ndom

isat

ion:

‘com

pute

r-ge

nera

ted

allo

catio

n sc

hedu

le’

Allo

cati

onco

ncea

lmen

t:un

clea

rB

asel

ine

com

para

bilit

y:ye

sPa

rtic

ipan

t bl

indi

ng:

yes

Ass

esso

r bl

indi

ng:y

es,

inve

stig

ator

s m

akin

gas

sess

men

ts w

ere

blin

ded

to t

reat

men

tst

atus

Inte

ntio

n-to

-tre

at:

uncl

ear

A p

riori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ype

rfor

med

but

pat

ient

s ex

clud

ed if

had

evid

ence

of a

ctiv

e G

I ble

edin

gTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A: a

9 (1

–47)

, b 8

(1–5

7), c

9 (1

–37)

Age

: a 6

3 (3

8–85

), b

62 (3

9-85

), c

62 (3

9–79

)Se

x: M

/F: a

42/

188,

b 4

4/18

7, c

52/

180

Incl

usio

n cr

iter

ia:4

0 ye

ars

or m

ore,

OA

(kne

e or

hip

), m

et c

linic

al a

nd r

adio

grap

hic

crite

ria fo

r O

A a

nd w

ere

ARA

func

tiona

lcl

asse

s I,

II or

III,

hist

ory

of p

ositi

veth

erap

eutic

ben

efit

from

NSA

IDs

(90%

of

patie

nts)

or

acet

amin

ophe

n (1

0%),

elig

ible

patie

nts

who

use

d a

pre-

stud

y N

SAID

had

to d

emon

stra

te w

orse

ning

of s

igns

and

sym

ptom

s of

OA

afte

r w

asho

ut p

erio

d,el

igib

le p

atie

nts

who

use

d ac

etam

inop

hen

wer

e re

quire

d to

hav

e co

nsist

ently

at

leas

tm

oder

ate

sym

ptom

s of

OA

Excl

usio

n cr

iter

ia: u

sing

cort

icos

tero

ids,

topi

cal a

nalg

esic

s, lo

w-d

ose

aspi

rin, r

egul

aran

taci

d, H

2bl

ocke

r, PP

Is, w

arfa

rin o

rtic

lopi

dine

, sig

nific

ant

rena

l im

pairm

ent,

evid

ence

of a

ctiv

e G

I ble

edin

g, G

Im

alab

sorp

tion

synd

rom

e, c

lass

III/I

V an

gina

or c

onge

stiv

e he

art

failu

re, u

ncon

trol

led

hype

rten

sion,

str

oke,

tra

nsie

nt is

chae

mic

atta

ck w

ithin

2ye

ars,

act

ive

hepa

tic d

iseas

e,re

cent

neo

plas

tic d

iseas

e, a

llerg

y to

acet

amin

ophe

n or

NSA

IDs,

any

con

ditio

nth

at c

ould

inte

rfer

e w

ith s

tudy

par

ticip

atio

n,co

nfou

nd r

esul

ts, o

r po

se a

n un

acce

ptab

leris

k to

the

pat

ient

Com

pari

son:

rofe

coxi

b (b

, c) v

sib

upro

fen

(a)

Dur

atio

n:1

year

Inte

rven

tion

s:b,

rof

ecox

ib12

.5m

g/12

.5–2

5m

g (o

nce

daily

inth

e m

orni

ng);

c, r

ofec

oxib

25m

g/12

.5–2

5m

g (o

nce

daily

inth

e m

orni

ng);

a, d

iclo

fena

c15

0m

g/75

–150

mg

(50

mg

×3 d

aily

), do

uble

dum

mie

s us

edO

ther

med

icat

ion:

cort

icos

tero

ids,

top

ical

ana

lges

ics,

regu

lar

anta

cid,

H2

bloc

ker,

PPIs

,w

arfa

rin o

r tic

lopi

dine

exc

lude

dA

spir

in a

llow

ed:n

oA

nalg

esic

allo

wed

:yes

,ac

etam

inop

hen

prov

ided

(325

mg)

for

brea

kthr

ough

pai

n, a

fter

first

26w

eeks

of s

tudy

top

ical

or

syst

emic

ana

lges

ics

orco

rtic

oste

roid

s w

ere

allo

wed

for

brea

kthr

ough

pai

nPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

es, n

o fu

rthe

r de

tails

Num

ber

and

freq

uenc

y of

vis

its:

8 (0

, 2, 4

, 8, 1

2, 2

4, 3

9, 5

2 w

eeks

)

Allo

cate

d:a

230,

b23

1, c

232

Com

plet

ed:a

154

,b

149,

c 1

58D

rop-

out:

a 76

, b 8

2,c

74A

sses

sed:

?a 2

30, b

231

c 23

2O

utco

mes

rep

orte

d:m

orta

lity,

car

diov

ascu

lar

even

ts, G

I sym

ptom

s, G

Idr

op-o

uts

How

wer

e ad

vers

eev

ents

ass

esse

d:no

n-di

rect

ed in

terv

iew

, all

adve

rse

even

tsev

alua

ted

as m

ild,

mod

erat

e, s

ever

e,re

latio

nshi

p to

stu

dydr

ug, o

utco

me

and

actio

n ta

ken

reco

rded

How

was

com

plia

nce

asse

ssed

:tab

let

coun

t

Ris

k fa

ctor

s:C

VD: a

0, b

0di

abet

es: t

otal

n=

35hy

pert

ensio

n: t

otal

n=

236;

ren

al/h

epat

icdi

seas

e: a

0, b

0FU

ND

ING

Fund

ed b

y:M

erck

Affi

liati

on o

f con

tact

auth

or:M

erck

Rese

arch

Lab

orat

orie

sA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f stu

dyad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

4 of

8 m

ain

auth

ors

empl

oyed

by

Mer

ck

Appendix 6

268

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Saag

, 200

0B92

Loca

tion

:62

clin

ical

cen

tres

inU

SA

Met

hod

ofra

ndom

isat

ion:

‘com

pute

r-ge

nera

ted

allo

catio

n sc

hedu

le’

Allo

cati

onco

ncea

lmen

t:un

clea

rB

asel

ine

com

para

bilit

y:un

clea

rPa

rtic

ipan

t bl

indi

ng:

yes

Ass

esso

r bl

indi

ng:y

es,

inve

stig

ator

s m

akin

gas

sess

men

ts w

ere

blin

ded

to t

reat

men

tst

atus

Inte

ntio

n-to

-tre

at:

uncl

ear

A p

riori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ype

rfor

med

but

pat

ient

s ex

clud

ed if

had

evid

ence

of a

ctiv

e G

I ble

edin

gTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A: a

10

(1–4

7), b

10

(0–4

8), c

11

(0–4

9)A

ge:a

61

(41–

82),

b 60

(39–

91),

c 62

(39–

85)

Sex:

M/F

: a 5

8/16

3, b

52/

167,

c 6

5/16

2In

clus

ion

crit

eria

:40

year

s or

mor

e, O

A(k

nee

or h

ip),

met

clin

ical

and

rad

iogr

aphi

ccr

iteria

for

OA

and

wer

e A

RA fu

nctio

nal

clas

ses

I, II

or II

I, hi

stor

y of

pos

itive

ther

apeu

tic b

enef

it fr

om N

SAID

s (9

0% o

fpa

tient

s) o

r ac

etam

inop

hen

(10%

), el

igib

lepa

tient

s w

ho u

sed

a pr

e-st

udy

NSA

ID h

adto

dem

onst

rate

wor

seni

ng o

f sig

ns a

ndsy

mpt

oms

of O

A a

fter

was

hout

per

iod,

elig

ible

pat

ient

s w

ho u

sed

acet

amin

ophe

nw

ere

requ

ired

to h

ave

cons

isten

tly a

t le

ast

mod

erat

e sy

mpt

oms

of O

AEx

clus

ion

crit

eria

:usin

g co

rtic

oste

roid

s,to

pica

l ana

lges

ics,

low

-dos

e as

pirin

, reg

ular

anta

cid,

H2

bloc

ker,

PPIs

, war

farin

or

ticlo

pidi

ne, s

igni

fican

t re

nal i

mpa

irmen

t,ev

iden

ce o

f act

ive

GI b

leed

ing,

GI

mal

abso

rptio

n sy

ndro

me,

cla

ss II

I/IV

angi

naor

con

gest

ive

hear

t fa

ilure

, unc

ontr

olle

dhy

pert

ensio

n, s

trok

e, t

rans

ient

isch

aem

icat

tack

with

in 2

yea

rs, a

ctiv

e he

patic

dise

ase,

rece

nt n

eopl

astic

dise

ase,

alle

rgy

toac

etam

inop

hen

or N

SAID

s, a

ny c

ondi

tion

that

cou

ld in

terf

ere

with

stu

dy p

artic

ipat

ion,

conf

ound

res

ults

, or

pose

an

unac

cept

able

risk

to t

he p

atie

nt

Com

pari

son:

rofe

coxi

b (b

, c) v

sib

upro

fen

(a)

Dur

atio

n:6

wee

ksIn

terv

enti

ons:

b, r

ofec

oxib

12.5

mg/

12.5

–25

mg

(onc

e da

ily in

the

mor

ning

); c,

rof

ecox

ib25

mg/

12.5

–25

mg

(onc

e da

ily in

the

mor

ning

); a,

ibup

rofe

n24

00m

g/60

0–24

00m

g (8

00m

g ×3

dai

ly);

doub

le d

umm

ies

used

Oth

er m

edic

atio

n:co

rtic

oste

roid

s, t

opic

al a

nalg

esic

s,re

gula

r an

taci

d, H

2bl

ocke

r, PP

Is,

war

farin

or

ticlo

pidi

ne e

xclu

ded

Asp

irin

allo

wed

:no

Ana

lges

ic a

llow

ed:y

es,

acet

amin

ophe

n pr

ovid

ed (3

25m

g)fo

r br

eakt

hrou

gh p

ain

Part

icip

ant

educ

atio

n: n

ot s

tate

dW

asho

ut:y

es, n

o fu

rthe

r de

tails

Num

ber

and

freq

uenc

y of

vis

its:

4 (0

, 2, 4

and

6 w

eeks

)

Allo

cate

d:a

221,

b

219,

c 2

27C

ompl

eted

:a 1

89,

b 18

6, c

200

Dro

p-ou

t:a

32, b

33,

c27

Ass

esse

d:?a

: 221

, b

219,

c 2

27O

utco

mes

rep

orte

d:m

orta

lity,

GI s

ympt

oms,

GI d

rop-

outs

How

wer

e ad

vers

eev

ents

ass

esse

d:no

n-di

rect

ed in

terv

iew

, all

adve

rse

even

tsev

alua

ted

as m

ild,

mod

erat

e, s

ever

e,re

latio

nshi

p to

stu

dydr

ug, o

utco

me

and

actio

n ta

ken

reco

rded

How

was

com

plia

nce

asse

ssed

:tab

let

coun

t

Ris

k fa

ctor

s:co

ncom

itant

use

of

cort

icos

tero

ids:

a 0

,b

0C

VD: a

0, b

0di

abet

es: t

otal

n=

44hy

pert

ensio

n: t

otal

n=

316

rena

l/hep

atic

dise

ase:

a0,

b 0

FUN

DIN

GFu

nded

by:

Mer

ckA

ffilia

tion

of c

onta

ctau

thor

: Mer

ckRe

sear

ch L

abor

ator

ies

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:4

of 8

mai

nau

thor

s em

ploy

ed b

yM

erck


269


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Dou

gado

s, 2

00193

Loca

tion

:76

rheu

mat

olog

yce

ntre

s in

Fra

nce

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:yes

A p

riori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ype

rfor

med

but

par

ticip

ants

wer

e ex

clud

ed if

had

ulce

r in

pre

viou

s ye

arTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:A

S: a

11,

b 1

1A

ge:a

38,

b 3

8 Se

x:M

/F: a

60/

30, b

56/

24In

clus

ion

crit

eria

:out

patie

nts

fulfi

lling

the

mod

ified

New

Yor

k cr

iteria

for

AS,

dai

lyN

SAID

inta

ke d

urin

g th

e pr

eced

ing

mon

th,

NSA

ID w

asho

ut 2

–14

days

bef

ore

base

line

visit

, a fl

are

at b

asel

ine

defin

ed b

oth

by p

ain

(40

mm

or

mor

e on

a 1

00m

m V

AS)

and

by

an in

crea

se in

pai

n of

at

leas

t 30

% b

etw

een

scre

enin

g an

d ba

selin

e vi

sits

Excl

usio

n cr

iter

ia:p

erip

hera

l art

icul

ardi

seas

e de

fined

by

the

pres

ence

of a

ctiv

e(w

ith s

wel

ling)

per

iphe

ral a

rthr

itis

(exc

ludi

nghi

p an

d sh

ould

er) a

t sc

reen

ing

visit

, act

ive

infla

mm

ator

y bo

wel

dise

ase,

con

com

itant

seve

re m

edic

al il

lnes

s, c

ortic

oste

roid

s w

ithin

prev

ious

mon

th a

nd/o

r an

y D

MA

RD w

ith a

chan

ge o

f dos

age

durin

g pr

evio

us 6

mon

ths,

pept

ic u

lcer

con

firm

ed b

y en

dosc

opy

with

inpr

evio

us y

ear;

at

scre

enin

g co

ncom

itant

ther

apie

s w

ith G

I pro

tect

ive

effe

cts

(miso

pros

tol,

PPIs

) wer

e st

oppe

d w

here

no

hist

ory

of g

astr

oduo

dena

l ulc

ers

and

initi

ated

/con

tinue

d w

hen

a po

sitiv

e hi

stor

yof

gas

trod

uode

nal u

lcer

s

Com

pari

son:

cele

coxi

b (b

) vs

keto

prof

en (a

) D

urat

ion:

6 w

eeks

Inte

rven

tion

s:b,

cel

ecox

ib20

0m

g/20

0–40

0m

g (1

00m

g ×2

dai

ly);

a, k

etop

rofe

n20

0m

g/10

0–20

0m

g (1

00m

g ×2

dai

ly),

doub

le d

umm

ies

used

(4ca

psul

es/d

ay, 2

at

brea

kfas

t, 2

at d

inne

r)O

ther

med

icat

ion:

conc

omita

ntth

erap

ies

with

GI p

rote

ctiv

e ef

fect

s(m

isopr

osto

l, PP

Is) w

ere

stop

ped

whe

re n

o hi

stor

y of

gas

trod

uode

nal

ulce

rs a

nd in

itiat

ed/c

ontin

ued

whe

na

posit

ive

hist

ory

of g

astr

oduo

dena

lul

cers

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:y

es,

acet

amin

ophe

n, m

ax. 6

×50

0m

gta

blet

s/da

yPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

es, 2

–14

days

, par

t of

incl

usio

n cr

iteria

Num

ber

and

freq

uenc

y of

vis

its:

4 (0

, 1, 3

and

6 w

eeks

)

Allo

cate

d:a

90, b

80

Com

plet

ed:a

67,

b 5

4D

rop-

out:

a 23

, b 2

6A

sses

sed:

a 90

, b 8

0 O

utco

mes

rep

orte

d:m

orta

lity,

ser

ious

GI

com

plic

atio

ns,

sym

ptom

atic

ulc

er,

serio

us c

ardi

ac o

r re

nal

illne

ss, G

I sym

ptom

s,an

aem

ia, G

I dro

p-ou

tsH

ow w

ere

adve

rse

even

ts a

sses

sed:

not

stat

edH

ow w

as c

ompl

ianc

eas

sess

ed:c

apsu

leco

unt,

a 10

0% m

ean

caps

ule

inta

ke; b

97.

5%m

ean

caps

ule

inta

ke

Ris

k fa

ctor

s:co

ncom

itant

use

of

cort

icos

tero

ids:

a 0

, b

0 FU

ND

ING

Fund

ed b

y:in

par

t by

a gr

ant

from

Sea

rleA

ffilia

tion

of c

onta

ctau

thor

:Uni

vers

itéRé

né D

esca

rtes

, Par

is,Fr

ance

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:1

of 8

auth

ors

wor

ked

for

Sear

leO

ther

:GI p

rote

ctiv

eef

fect

s (m

isopr

osto

l,PP

Is) w

ere

initi

ated

and/

or c

ontin

ued

whe

nth

ere

was

a p

ositi

vehi

stor

y of

gast

rodu

oden

al u

lcer

s,no

furt

her

deta

ils g

iven

Appendix 6

270

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Gol

dste

in, 2

00139

Loca

tion

:m

ultic

entr

e, 7

5sit

es in

USA

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d’ac

cord

ing

to a

com

pute

r-ge

nera

ted

rand

omisa

tion

sche

dule

(sep

arat

esc

hedu

les

wer

e pr

epar

edfo

r O

A a

nd R

A),

patie

nts

wer

e as

signe

d in

the

orde

r in

whi

ch t

hey

enro

lled

into

the

stu

dy a

tea

ch s

ite t

o re

ceiv

eal

loca

ted

trea

tmen

tac

cord

ing

to t

he s

pons

or-

prep

ared

(GD

Sea

rle)

Allo

cati

onco

ncea

lmen

t:un

clea

rB

asel

ine

com

para

bilit

y:ye

sPa

rtic

ipan

t bl

indi

ng:

yes

Ass

esso

r bl

indi

ng:y

esIn

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd e

xclu

ded

part

icip

ants

with

ulce

rs

Type

and

dur

atio

n of

art

hrit

is (

year

s):

OA

: a n

=19

5 (1

1.0

year

s), b

n =

194

(9.5

year

s); R

A: a

n =

72

(8.9

yea

rs),

b n

= 7

6 (1

1.6

year

s)A

ge:a

57.

7 (2

2–84

), b

56.7

(23–

86)

Sex:

M/F

: a 9

1/17

9, b

89/

181

Incl

usio

n cr

iter

ia: l

egal

age

of c

onse

nt,

activ

e O

A o

r RA

for

at le

ast

3 m

onth

s an

dre

quire

d ch

roni

c N

SAID

s, fu

nctio

nal

capa

city

cla

ssifi

catio

n I t

o III

, con

firm

ed u

seof

ade

quat

e co

ntra

cept

ion

and

nega

tive

preg

nanc

y te

st w

ithin

7 d

ays

of fi

rst

dose

of

stud

y m

edic

atio

nEx

clus

ion

crit

eria

: lar

gely

or

who

llyin

capa

cita

ted

perm

ittin

g lit

tle o

r no

sel

f-ca

re, a

ny o

ther

infla

mm

ator

y ar

thrit

is, a

cute

gout

, act

ive

GI d

iseas

e, d

iagn

osis

of a

nyac

ute

UG

I ulc

erat

ion

with

in 3

0 da

ys b

efor

eth

e fir

st d

ose

of s

tudy

med

icat

ion

(or

if th

eyha

d ta

ken

1000

mg/

day

or m

ore

ofna

prox

en w

ithin

30

days

of f

irst

dose

of

stud

y m

edic

atio

n); t

hose

with

ulc

ers

of3

mm

or

mor

e at

pre

-enr

olm

ent

endo

scop

y

Com

pari

son:

cele

coxi

b (b

) vs

Nap

roxe

n (a

)D

urat

ion:

12 w

eeks

Inte

rven

tion

s: b

, cel

ecox

ib40

0m

g/20

0–40

0m

g (2

00m

g ×2

dai

ly);

a, n

apro

xen

1000

mg/

500–

1250

mg

(500

mg

×2 d

aily

); do

uble

dum

mie

s us

ed, a

llm

edic

atio

n ta

ken

with

bre

akfa

stan

d di

nner

Endo

scop

y: 0

, 4, 8

and

12

wee

ksan

d if

sym

ptom

atic

Oth

er m

edic

atio

n:us

e of

oth

erdr

ugs

disc

oura

ged,

NSA

IDs,

ant

i-ul

cer

drug

s (e

.g. m

isopr

osto

l,an

tibio

tics

to t

reat

H. p

ylor

i,an

ticoa

gula

nts,

ant

acid

s,an

tineo

plas

tics)

wer

e pr

ohib

ited,

oral

cor

ticos

tero

ids

allo

wed

on

stab

le d

ose

only

Asp

irin

allo

wed

:yes

, 325

mg/

day

or le

ss

Ana

lges

ics

allo

wed

:yes

,ac

etam

inop

hen

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:yes

, NSA

IDs

disc

ontin

ued

7 da

ys b

efor

e fir

stdo

se o

f stu

dy m

edic

atio

nN

umbe

r an

d fr

eque

ncy

of v

isit

s:4

(0, 4

, 8, 1

2 w

eeks

)

Allo

cate

d:a

267,

b 2

70C

ompl

eted

:a 1

49,

b21

0D

rop-

out:

a 11

8, b

60

Ass

esse

d:a

267,

b 2

69O

utco

mes

rep

orte

d:m

orta

lity,

ser

ious

GI

com

plic

atio

ns,

sym

ptom

atic

ulc

ers,

serio

us c

ardi

ovas

cula

r or

rena

l illn

ess

(ext

ra d

ata)

GI s

ympt

oms,

endo

scop

ic u

lcer

s, G

Idr

op-o

uts

How

wer

e ad

vers

eev

ents

ass

esse

d:no

tst

ated

Ris

k fa

ctor

s:hi

stor

y of

ulc

ers:

a 5

3,b

57

hist

ory

of b

leed

s: a

13,

b 11

>1

NSA

IDs:

a 0

, b 0

CVD

: a 1

34, b

151

FUN

DIN

GFu

nded

by:

GD

Sea

rlean

d Pf

izer

Affi

liati

on o

f con

tact

auth

or:U

nive

rsity

of

Illin

ois

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:at

leas

t 1

auth

or e

mpl

oyed

by

GD

Sea

rleO

ther

:1 o

f 267

napr

oxen

par

ticip

ants

had

base

line

gast

ricul

cer


271


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Kiv

itz, 2

00194

Loca

tion

:m

ultic

entr

e, 1

76sit

es in

USA

and

Can

ada

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d’,

stra

tifie

d by

site

in b

lock

sof

10

Allo

cati

onco

ncea

lmen

t: u

ncle

arB

asel

ine

com

para

bilit

y:ye

sPa

rtic

ipan

t bl

indi

ng:

yes

Ass

esso

r bl

indi

ng:

uncl

ear

Inte

ntio

n-to

-tre

at:n

oA

pri

ori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ype

rfor

med

but

pat

ient

s ex

clud

ed if

the

y ha

dbe

en d

iagn

osed

with

or

trea

ted

for

oeso

phag

eal/g

astr

oduo

dena

l ulc

erat

ion

with

in 3

0 da

ys o

f rec

eivi

ng t

he s

tudy

dru

gTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A: a

7.3

, b 7

.2, c

6.9

Age

:a 6

4 (3

2–87

), b

62 (3

0–86

), c

61 (2

8–88

)Se

x:M

/F: a

70/

137,

b 7

2/13

5, c

70/

143

Incl

usio

n cr

iter

ia: a

dult

outp

atie

nts,

AC

Rcl

inic

al a

nd r

adio

grap

hic

crite

ria d

iagn

osis

ofpr

imar

y O

A (h

ip),

func

tiona

l cla

ss I,

II, o

r III

and

sym

ptom

atic

OA

flar

e at

bas

elin

e vi

sit

Excl

usio

n cr

iter

ia:r

ecei

ved

oral

,in

tram

uscu

lar,

intr

a-ar

ticul

ar o

r so

ft-tis

sue

inje

ctio

ns o

f cor

ticos

tero

ids

with

in 4

wee

ksof

the

firs

t do

se o

f stu

dy m

edic

atio

n,hy

pers

ensit

ivity

to

Cox

-2 in

hibi

tors

,su

lfona

mid

es o

r N

SAID

s, r

ecei

ved

any

inve

stig

atio

nal m

edic

atio

n w

ithin

30

days

of

the

first

stu

dy d

ose,

tak

en a

ny N

SAID

s or

anal

gesic

s w

ithin

48

h of

bas

elin

eas

sess

men

ts, o

r re

ceiv

ed p

iroxi

cam

and

/or

oxap

rozi

n w

ithin

4 d

ays

of b

asel

ine

asse

ssm

ent;

activ

e co

ncom

itant

GI t

ract

,re

nal,

hepa

tic o

r co

agul

atio

n di

sord

ers,

mal

igna

ncy,

oes

opha

geal

/gas

trod

uode

nal

ulce

ratio

n w

ithin

30

days

of r

ecei

ving

the

stud

y dr

ug, i

nfla

mm

ator

y ar

thrit

is, g

out,

orac

ute

join

t tr

aum

a at

the

hip

or

anan

ticip

ated

nee

d fo

r su

rger

y du

ring

the

stud

y pe

riod

Com

pari

son:

cele

coxi

b (b

, c) v

sna

prox

en (a

)D

urat

ion:

12 w

eeks

Inte

rven

tion

s:b,

cel

ecox

ib20

0m

g/20

0–40

0m

g (1

00m

g ×2

dai

ly);

c, c

elec

oxib

400

mg/

200–

400

mg

(200

mg

x2 d

aily

); a,

nap

roxe

n10

00m

g/50

0–12

50m

g (5

00m

g x2

dai

ly);

doub

le m

aske

dO

ther

med

icat

ion:

cor

ticos

tero

ids

not

allo

wed

in fi

rst

4 w

eeks

, oth

erm

edic

atio

n pe

rmitt

edA

spir

in a

llow

ed:y

es, 3

25m

g/da

yor

less

A

nalg

esic

allo

wed

:yes

,ac

etam

inop

hen

less

tha

n 3

g da

ilyfo

r 3

cons

ecut

ive

days

or

less

(exc

ept

with

in 4

8 h

of a

sses

smen

t)Pa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

es, 2

–4 d

ays

for

NSA

IDs

and

othe

r an

alge

sics

(4da

ys fo

r pi

roxi

cam

and

/or

oxap

rozi

nN

umbe

r an

d fr

eque

ncy

of v

isit

s:4

(0, 2

, 4, 1

2 an

d 24

wee

ks a

nd b

yte

leph

one

at 8

, 16

and

20 w

eeks

)

Allo

cate

d:a

207,

b

207,

c 2

13C

ompl

eted

:a 1

18,

b11

1, c

119

Dro

p-ou

t:a

89, b

96,

c94

Ass

esse

d:a

207,

b 2

07,

c 21

3O

utco

mes

rep

orte

d:se

rious

GI

com

plic

atio

ns, G

Isy

mpt

oms,

GI d

rop-

outs

How

wer

e ad

vers

eev

ents

ass

esse

d:no

tst

ated

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:hi

stor

y of

ulc

ers:

9–18

% in

eac

h gr

oup;

hist

ory

of b

leed

s:1–

3% in

eac

h gr

oup;

conc

omita

nt u

se o

fco

rtic

oste

roid

s: a

0, b

0 rena

l/hep

atic

dise

ase:

a

0, b

0FU

ND

ING

Fund

ed b

y:un

clea

rbu

t w

ritin

g of

the

artic

le w

as s

uppo

rted

by P

harm

acia

and

Pfiz

erA

ffilia

tion

of c

onta

ctau

thor

:Alto

ona

Cen

ter

for

Clin

ical

Rese

arch

, PA

, USA

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:5

of 7

auth

ors

empl

oyed

by

Phar

mac

iaO

ther

:cel

ecox

ib10

0m

g da

ily a

ndpl

aceb

o ar

ms

wer

eex

clud

ed fr

om a

naly

ses

Appendix 6

272

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

McK

enna

, 200

195

Loca

tion

:m

ultic

entr

e, 5

4sit

es in

USA

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

uncl

ear

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:un

clea

rA

pri

ori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ype

rfor

med

but

par

ticip

ants

exc

lude

d if

had

activ

e G

I dise

ase

Bas

elin

e N

SAID

sta

tus:

78.4

% d

iclo

fena

cgr

oup,

77.

6% c

elec

oxib

gro

up h

ad p

rior

NSA

ID u

seTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A: a

8.5

, b 8

.4A

ge:a

62.

7 (2

9–87

), b

61.9

(32–

85)

Sex:

M/F

: a 7

6/12

3, b

64/

137

Incl

usio

n cr

iter

ia: O

A (k

nee,

AC

R cr

iteria

),sy

mpt

omat

ic a

s ev

iden

ced

by w

orse

ning

of

signs

and

sym

ptom

s of

the

dise

ase

follo

win

gdi

scon

tinua

tion

of t

reat

men

t w

ith N

SAID

sor

oth

er a

nalg

esic

med

icat

ions

Excl

usio

n cr

iter

ia:a

ctiv

e G

I dise

ase,

chro

nic

or a

cute

ren

al o

r he

patic

dise

ase

Com

pari

son:

cele

coxi

b (b

) vs

dicl

ofen

ac (a

)D

urat

ion:

6 w

eeks

Inte

rven

tion

s:b,

cel

ecox

ib20

0m

g/20

0–40

0m

g (1

00m

g 2×

daily

); a,

dic

lofe

nac

150

mg/

75–1

50m

g (5

0m

g 3×

daily

)O

ther

med

icat

ion:

con

com

itant

cort

icos

tero

ids,

NSA

IDs

or in

tra-

artic

ular

inje

ctio

ns o

f hal

uron

ic a

cid

proh

ibite

dA

spir

in a

llow

ed:y

es fo

r no

n-ar

thrit

is in

dica

tions

if d

ose

stab

leA

nalg

esic

allo

wed

: not

sta

ted

Part

icip

ant

educ

atio

n: n

ot s

tate

dW

asho

ut:y

es, f

lare

nee

ded

ondi

scon

tinua

tion

of N

SAID

s or

oth

eran

alge

sics

Num

ber

and

freq

uenc

y of

vis

its:

3 (0

, 2 a

nd 6

wee

ks)

Allo

cate

d:a

199,

b 2

01C

ompl

eted

: a 1

62,

b 15

9D

rop-

out:

a 37

, b 4

2A

sses

sed:

a 19

9, b

199

Out

com

es r

epor

ted:

serio

us c

ardi

ovas

cula

r or

rena

l illn

ess,

GI

sym

ptom

s, a

naem

ia, G

Idr

op-o

uts

How

wer

e ad

vers

eev

ents

ass

esse

d:sp

onta

neou

sly r

epor

ted,

serio

us a

dver

se e

vent

sw

ere

reco

rded

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:hi

stor

y of

ulc

ers:

a 1

2,b

16hi

stor

y of

ble

eds:

a 4

,b

2 co

ncom

itant

use

of

cort

icos

tero

ids:

a 0

, b

0>

1 N

SAID

s: a

0, b

0C

VD: a

133

, b

131;

ren

al/h

epat

icdi

seas

e: a

0, b

0FU

ND

ING

Fund

ed b

y:Ph

arm

acia

Affi

liati

on o

f con

tact

auth

or: P

harm

acia

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:5

of 6

auth

ors

empl

oyed

by

Phar

mac

ia


273


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Kiv

itz, 2

00296

Loca

tion

:85

cent

res

in U

SA a

ndC

anad

a

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:yes

Inte

ntio

n-to

-tre

at:n

o A

pri

ori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd e

xclu

ded

part

icip

ants

with

10 o

r m

ore

oeso

phag

eal,

gast

ric o

rdu

oden

al e

rosio

ns o

r oe

soph

agea

l, ga

stric

,py

loric

cha

nnel

or

duod

enal

ulc

er

Type

and

dur

atio

n of

art

hrit

is (

year

s):

OA

: a 9

.4, b

9.8

, c 8

.7, d

9.2

A

ge:a

60.

4, b

58.

7, c

59.

8, d

59.

6Se

x:M

/F: a

76/

129,

b 7

3/12

8, c

72/

134,

d66

/136

Incl

usio

n cr

iter

ia:a

mbu

lato

ry p

atie

nts

diag

nose

d w

ith m

oder

ate

to s

ever

e O

A(k

nee,

AC

R cr

iteria

), ba

selin

e sc

ores

of

40m

m o

r m

ore

on t

he P

atie

nts

Ass

essm

ent

of A

rthr

itis

Pain

VA

S sc

ale

and

base

line

cate

goric

al s

core

s of

poo

r to

ver

y po

or o

nth

e Pa

tient

and

Phy

sicia

n G

loba

l Ass

essm

ent

of A

rthr

itis

Excl

usio

n cr

iter

ia:i

nfla

mm

ator

y ar

thrit

is,go

ut, p

seud

o-go

ut, P

aget

dise

ase,

any

chro

nic

pain

syn

drom

e th

at m

ight

inte

rfer

ew

ith a

sses

smen

t of

the

inde

x kn

ee, s

ever

ean

serin

e bu

rsiti

s, a

cute

join

t tr

aum

a or

com

plet

e lo

ss o

f art

icul

ar c

artil

age

on t

hein

dex

knee

, act

ive

GI d

iseas

e, G

I tra

ctul

cera

tion

with

in 3

0 da

ys, s

igni

fican

tbl

eedi

ng d

isord

er o

r hi

stor

y of

gas

tric

or

duod

enal

sur

gery

, oes

opha

geal

, gas

tric

,py

loric

cha

nnel

or

duod

enal

ulc

er o

r a

scor

eof

10

or m

ore

for

oeso

phag

eal,

gast

ric o

rdu

oden

al e

rosio

ns a

t th

e pr

etre

atm

ent

endo

scop

y

Com

pari

son:

Val

deco

xib

(b, c

, d)

vs n

apro

xen

(a)

Dur

atio

n:12

wee

ksIn

terv

enti

ons:

b, v

alde

coxi

b5

mg/

? (on

ce d

aily

); c,

Val

deco

xib

10m

g/? (

once

dai

ly);

d, V

alde

coxi

b20

mg/

? (on

ce d

aily

); a,

nap

roxe

n10

00m

g/50

0–12

50m

g (5

00m

g ×2

dai

ly)

Endo

scop

y:0

and

12 w

eeks

or

early

ter

min

atio

n or

any

tim

e if

sym

ptom

atic

Oth

er m

edic

atio

n:no

t st

ated

A

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:not

sta

ted

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:48

h fo

r N

SAID

s(in

clud

ing

aspi

rin a

t 32

5m

g/da

y or

less

), 4

wee

ks fo

r co

rtic

oste

roid

inje

ctio

ns, 3

mon

ths

for

intr

a-ar

ticul

ar in

ject

ions

of c

ortic

oste

roid

,6

mon

ths

for

intr

a-ar

ticul

arin

ject

ion

of h

yalu

roni

c ac

id, 2

4 h

for

H2R

As,

PPI

s, m

isopr

osto

l, su

cral

fate

Num

ber

and

freq

uenc

y of

vis

its:

4 (0

, 2, 6

, 12

wee

ks)

Allo

cate

d:a

205,

b20

1, c

206

, d 2

02C

ompl

eted

:a 1

49,

b16

2, c

150

, d 1

68D

rop-

out:

a 56

, b 3

9,c

56, d

44

Ass

esse

d:a

204,

b 2

01,

c 20

5, d

201

Out

com

es r

epor

ted:

sym

ptom

atic

ulc

ers,

GI

sym

ptom

s, e

ndos

copi

cul

cers

How

wer

e ad

vers

eev

ents

ass

esse

d:no

tst

ated

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:hi

stor

y of

ulc

ers:

a 3

1,b

21, c

24,

d 2

8hi

stor

y of

ble

eds:

a 3

,b

0, c

3, d

2FU

ND

ING

Fund

ed b

y:Ph

arm

acia

and

Pfiz

erA

ffilia

tion

of c

onta

ctau

thor

:has

act

ed in

past

as

cons

ulta

nt fo

rPh

arm

acia

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:3

empl

oyee

sof

Pha

rmac

ia a

nd h

ave

stoc

k in

tere

st w

ithin

the

com

pany

Appendix 6

274

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

McK

enna

200

297

Loca

tion

:m

ultic

entr

e,in

tern

atio

nal

(mai

nly

Euro

pean

,no

USA

)

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:un

clea

rA

pri

ori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ype

rfor

med

but

pep

tic u

lcer

atio

n an

d G

Ibl

eedi

ng e

xclu

ded

Type

and

dur

atio

n of

art

hrit

is (

year

s):

OA

: a 6

.6, b

7.3

Age

:a 6

4.1

b 63

.3Se

x:M

/F a

95/

246

b 99

/247

Incl

usio

n cr

iter

ia: a

dults

with

OA

(hip

and/

or k

nee)

for

at le

ast

6 m

onth

s an

ddi

agno

sed

acco

rdin

g to

AC

R cr

iteria

, Pat

ient

Glo

bal A

sses

smen

t sc

ore

of fa

ir, p

oor

orve

ry p

oor,

sym

ptom

atic

dise

ase

at b

asel

ine

and

a Fu

nctio

nal C

apac

ity C

lass

ifica

tion

of I,

II or

III

Excl

usio

n cr

iter

ia:a

ny o

ther

rhe

umat

icco

nditi

on, a

cute

tra

uma

of jo

ints

und

erex

amin

atio

n, p

eptic

ulc

erat

ion,

GI b

leed

ing,

infla

mm

ator

y bo

wel

dise

ase,

ren

al o

r he

patic

failu

re, a

sig

nific

ant

coag

ulat

ion

defe

ct,

mal

igna

ncy

Com

pari

son:

cele

coxi

b (b

) vs

dicl

ofen

ac (a

)D

urat

ion:

6 w

eeks

Inte

rven

tion

s:b,

cel

ecox

ib20

0m

g/20

0–40

0m

g (1

00m

g×2

daily

); a,

dic

lofe

nac

100

mg/

75–1

50m

g (5

0m

g ×2

dai

ly);

othe

r m

edic

atio

n:

no d

etai

lsA

spir

in a

llow

ed:y

es, l

ow-d

ose

Ana

lges

ic a

llow

ed:n

ot s

tate

dPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:n

ot s

tate

dN

umbe

r an

d fr

eque

ncy

of v

isit

s:4

(0, 2

, 4 a

nd 6

wee

ks)

Allo

cate

d:un

clea

rC

ompl

eted

:a ?3

09,

b?3

20D

rop-

out:

a ?3

2, b

?26

Ass

esse

d:a

341

b 34

6O

utco

mes

rep

orte

d:G

I sym

ptom

s,

GI d

rop-

outs

How

wer

e ad

vers

eev

ents

ass

esse

d:‘s

ince

your

last

visi

t, ha

ve y

ouex

perie

nced

or

do y

oucu

rren

tly h

ave

any

sym

ptom

s th

at a

re n

otas

soci

ated

with

you

rar

thrit

is?’ S

umm

arise

d in

case

rep

ort

form

as

mild

, mod

erat

e or

seve

re a

ccor

ding

to

WH

OA

RT c

lass

ifica

tion

with

sta

rt a

nd s

top

date

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:hi

stor

yof

ulc

ers:

a 9

, b 9

;co

ncom

itant

use

of

cort

icos

tero

ids:

a 1

7,b

19; r

enal

/hep

atic

dise

ase;

a 0

, b 0

FUN

DIN

GFu

nded

by:

uncl

ear

Affi

liati

on o

f con

tact

auth

or:T

raffo

rdG

ener

al H

ospi

tal,

Man

ches

ter,

UK

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:3

of 5

auth

ors

empl

oyed

by

Phar

mac

iaO

ther

:pub

lishe

d as

part

of p

oole

d da

taan

alys

is


275


(e)

Cox

-2 p

refe

rent

ial N

SAID

ver

sus

Cox

-1 N

SAID

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Foss

aluz

za, 1

98998

Loca

tion

:City

Hos

pita

l of U

dine

,Ita

ly

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

con

ceal

men

t:un

clea

r B

asel

ine

com

para

bilit

y:un

clea

r Pa

rtic

ipan

t bl

indi

ng:y

esA

sses

sor

blin

ding

:unc

lear

In

tent

ion-

to-t

reat

:yes

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

y bu

t th

ose

with

act

ive

pept

icul

cer

wer

e ex

clud

edTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A: n

o ot

her

deta

ilsA

ge:a

71.

3 (6

6–76

), b

72.8

(68–

77)

Sex:

M/F

: a 0

/20,

b 0

/20

Incl

usio

n cr

iter

ia:f

emal

e ou

tpat

ient

sw

ith h

ip a

nd/o

r kn

ee O

AEx

clus

ion

crit

eria

:kno

wn

hype

rsen

sitiv

ity t

o N

SAID

s, a

ctiv

e pe

ptic

ulce

r or

sev

ere

liver

, ren

al o

r he

art

failu

re,

unde

rgoi

ng s

urgi

cal t

reat

men

t of

join

ts,

non-

coop

erat

ive

or n

on-c

ompl

iant

patie

nts,

alre

ady

on n

imes

ulid

e or

napr

oxen

, con

curr

ent

trea

tmen

ts w

ithot

her

NSA

IDs,

ana

lges

ics

orco

rtic

oste

roid

age

nts

wer

e no

t al

low

ed

Com

pari

son:

nim

esul

ide

(b) v

sna

prox

en (a

) D

urat

ion:

28 d

ays

Inte

rven

tion

s:b,

nim

esul

ide

200

mg/

? (10

0m

g gr

anul

es

×2 d

aily

); a,

nap

roxe

n50

0m

g/50

0–12

50 (2

50m

g gr

anul

es×2

dai

ly).

All

med

icat

ion

take

n ea

chm

orni

ng a

nd e

veni

ng a

fter

mea

lsO

ther

med

icat

ion:

conc

urre

ntus

e of

oth

er N

SAID

s, o

rco

rtic

oste

roid

age

nts

not

allo

wed

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:n

oPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

es, 7

day

s fo

r N

SAID

sN

umbe

r an

d fr

eque

ncy

of v

isit

s:4

(0, 7

, 14

and

28 d

ays)

Allo

cate

d:a

20, b

20

Com

plet

ed:a

18,

b 1

9D

rop-

out:

a 2,

b 1

Ass

esse

d:a

20, b

20

Out

com

es r

epor

ted:

GI s

ympt

oms,

occ

ult

blee

ding

, GI d

rop-

outs

How

wer

e ad

vers

eev

ents

ass

esse

d:pa

tient

diso

rder

sre

port

ed o

n da

taco

llect

ion

form

sH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:co

ncom

itant

use

of

cort

icos

tero

ids:

a 0

,b

0>

1 N

SAID

: a 0

, b0

seve

re r

enal

/hep

atic

dise

ase:

a 0,

b 0

FUN

DIN

GFu

nded

by:

not

stat

edA

ffilia

tion

of c

onta

ctau

thor

:LBP

Inst

ituto

Farm

aceu

tico

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:1

of 2

auth

ors

empl

oyed

by

LBP

Inst

ituto

Farm

aceu

tico

Appendix 6

276

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Plat

t, 19

89A

99

Loca

tion

:10

coun

trie

s, in

clud

ing

the

UK

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

assig

ned’

Allo

cati

on c

once

alm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

uncl

ear

Part

icip

ant

blin

ding

:yes

Ass

esso

r bl

indi

ng:u

ncle

arIn

tent

ion-

to-t

reat

:unc

lear

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

y bu

t th

ose

with

pep

tic u

lcer

dise

ase

or h

istor

y of

GI b

leed

in t

he la

st5

year

s w

ere

excl

uded

Type

and

dur

atio

n of

art

hrit

is (

year

s):

OA

kne

e, n

o ot

her

deta

ilsA

ge:a

61,

b 6

1Se

x:M

/F: a

17/

29, b

7/2

9In

clus

ion

crit

eria

:OA

of t

he k

nee

with

at le

ast

2 of

the

follo

win

g ra

diol

ogic

alcr

iteria

: asy

mm

etric

join

t sp

ace

narr

owin

gw

ith s

ubch

ondr

al s

cler

osis,

mar

gina

los

teop

hyte

form

atio

n, o

r su

bcho

ndra

lps

eudo

cyst

s w

ith s

cler

otic

wal

ls; p

ain

inth

e af

fect

ed k

nee

and

at le

ast

one

of t

hefo

llow

ing

cond

ition

s: li

mita

tion

of m

otio

n,te

nder

ness

on

pres

sure

, sw

ellin

g, c

repi

tus

on m

otio

n, m

orni

ng s

tiffn

ess

or s

tiffn

ess

afte

r in

activ

ity; 1

8–75

yea

rs, r

espo

nded

inth

e pa

st t

o N

SAID

s, fr

ee o

f pep

tic u

lcer

dise

ase,

had

had

no

GI b

leed

ing

in t

he la

st5

year

s, n

o sig

nific

ant

rena

l,ha

emat

olog

ical

or

card

iova

scul

ar d

iseas

e,no

sev

ere

com

plic

atio

ns o

r di

abet

es, n

oot

her

dise

ase

that

cou

ld a

ffect

the

join

ts,

no s

ever

e in

fect

ion

or t

uber

culo

sis, n

osig

nific

ant

rheu

mat

oid

fact

or, n

ot t

akin

gN

SAID

s an

d ha

d ac

tive

knee

join

tsy

mpt

oms

(as

prev

ious

ly d

escr

ibed

) or

ifth

eir

dise

ase

wor

sene

d af

ter

a w

asho

utpe

riod

free

of a

ny N

SAID

sEx

clus

ion

crit

eria

:pre

viou

sly t

reat

edw

ith N

SAID

s w

ithou

t ef

fect

or

who

had

expe

rienc

ed a

dver

se r

eact

ions

to

NSA

IDs,

pat

ient

s ta

king

ora

l or

pare

nter

alan

ticoa

gula

nts,

ora

l hyp

ogly

caem

ics

ordr

ugs

know

n to

cau

se h

epat

ic e

nzym

ech

ange

s or

dru

g-in

duce

d he

patit

is,pr

egna

nt o

r br

east

-fee

ding

wom

en

Com

pari

son:

etod

olac

(b) v

sdi

clof

enac

(a)

Dur

atio

n:8

wee

ksIn

terv

enti

ons:

b, e

todo

lac

600

mg/

600

mg

daily

(200

mg

×3 d

aily

); a,

dic

lofe

nac

150

mg/

75–1

50m

g da

ily (5

0m

g ×3

dai

ly)

Oth

er m

edic

atio

n:or

al o

rpa

rent

eral

ant

icoa

gula

nts,

ora

lhy

pogl

ycae

mic

s or

dru

gs k

now

n to

caus

e he

patic

enz

yme

chan

ges

ordr

ug-in

duce

d he

patit

is, c

oncu

rren

tus

e of

oth

er N

SAID

s, o

rco

rtic

oste

roid

age

nts

not

allo

wed

,ty

pe o

r in

tens

ity o

f phy

sioth

erap

yre

mai

ned

unch

ange

dA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:yes

,ac

etam

inop

hen

durin

g w

asho

ut a

ndup

to

day

14

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:yes

, 1 w

eek

for

aspi

rinan

d m

ost

othe

r N

SAID

s, 2

wee

ksfo

r pi

roxi

cam

and

SR

indo

met

haci

nN

umbe

r an

d fr

eque

ncy

of v

isit

s:5

(0, 2

, 4, 6

and

8 w

eeks

)

Allo

cate

d:a,

47,

b 3

8C

ompl

eted

:a 4

0, b

32

Dro

p-ou

t:a,

7, b

6A

sses

sed:

uncl

ear

Out

com

es r

epor

ted:

tota

l dro

p-ou

tsH

ow w

ere

adve

rse

even

ts a

sses

sed:

node

tails

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:co

ncom

itant

use

of

antic

oagu

lant

s: a

0,

b 0

CVD

: a 0

, b 0

re

nal/h

epat

ic d

iseas

e:

a 0,

b 0

FUN

DIN

GFu

nded

by:

not

stat

edA

ffilia

tion

of c

onta

ctau

thor

:Fre

eman

Hos

pita

l, N

ewca

stle

,U

KA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f stu

dyad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

0/1

Oth

er:t

his

is an

inte

rim r

epor

t


277


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Plat

t, 19

89B99

Loca

tion

: 10

coun

trie

s, in

clud

ing

the

UK

Met

hod

ofra

ndom

isat

ion:

‘ran

dom

lyas

signe

d’A

lloca

tion

con

ceal

men

t:un

clea

rB

asel

ine

com

para

bilit

y:un

clea

rPa

rtic

ipan

t bl

indi

ng:y

esA

sses

sor

blin

ding

:unc

lear

Inte

ntio

n-to

-tre

at:u

ncle

arA

pri

ori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

y bu

t th

ose

with

pep

tic u

lcer

dise

ase

or h

istor

y of

GI b

leed

in t

he la

st5

year

s w

ere

excl

uded

Type

and

dur

atio

n of

art

hrit

is (

year

s):

OA

: kne

e, n

o ot

her

deta

ilsA

ge:a

61,

b 5

9Se

x:M

/F: a

7/1

0, b

5/1

0 In

clus

ion

crit

eria

:OA

of t

he k

nee

with

at le

ast

2 of

the

follo

win

g ra

diol

ogic

alcr

iteria

: asy

mm

etric

join

t sp

ace

narr

owin

gw

ith s

ubch

ondr

al s

cler

osis,

mar

gina

los

teop

hyte

form

atio

n or

sub

chon

dral

pseu

docy

sts

with

scl

erot

ic w

alls;

pai

n in

the

affe

cted

kne

e an

d at

leas

t on

e of

the

follo

win

g co

nditi

ons:

lim

itatio

n of

mot

ion,

tend

erne

ss o

n pr

essu

re, s

wel

ling,

cre

pitu

son

mot

ion,

mor

ning

stif

fnes

s or

stif

fnes

saf

ter

inac

tivity

; 18–

75ye

ars,

res

pond

ed in

the

past

to

NSA

IDs,

free

of p

eptic

ulc

erdi

seas

e, h

ad h

ad n

o G

I ble

edin

g in

the

last

5ye

ars,

no

signi

fican

t re

nal,

haem

atol

ogic

al o

r ca

rdio

vasc

ular

dise

ase,

no s

ever

e co

mpl

icat

ions

or

diab

etes

, no

othe

r di

seas

e th

at c

ould

affe

ct t

he jo

ints

,no

sev

ere

infe

ctio

n or

tub

ercu

losis

, no

signi

fican

t rh

eum

atoi

d fa

ctor

, not

tak

ing

NSA

IDs

and

had

activ

e kn

ee jo

int

sym

ptom

s (a

s pr

evio

usly

des

crib

ed) o

r if

thei

r di

seas

e w

orse

ned

afte

r a

was

hout

perio

d fr

ee o

f any

NSA

IDs

Excl

usio

n cr

iter

ia:p

revi

ously

tre

ated

with

NSA

IDs

with

out

effe

ct o

r w

ho h

adex

perie

nced

adv

erse

rea

ctio

ns t

oN

SAID

s, p

atie

nts

taki

ng o

ral o

r pa

rent

eral

antic

oagu

lant

s, o

ral h

ypog

lyca

emic

s or

drug

s kn

own

to c

ause

hep

atic

enz

yme

chan

ges

or d

rug-

indu

ced

hepa

titis,

preg

nant

or

brea

st-f

eedi

ng w

omen

Com

pari

son:

etod

olac

(b) v

sna

prox

en (a

) D

urat

ion:

6 w

eeks

Inte

rven

tion

s:b,

eto

dola

c60

0m

g/60

0m

g da

ily (3

00m

g ×2

daily

); a,

nap

roxe

n10

00m

g/50

0–12

50m

g da

ily(5

00m

g ×2

dai

ly)

Oth

er m

edic

atio

n:or

al o

rpa

rent

eral

ant

icoa

gula

nts,

ora

lhy

pogl

ycae

mic

s or

dru

gs k

now

n to

caus

e he

patic

enz

yme

chan

ges

ordr

ug-in

duce

d he

patit

is, c

oncu

rren

tus

e of

oth

er N

SAID

s or

cort

icos

tero

id a

gent

s no

t al

low

ed,

type

or

inte

nsity

of p

hysio

ther

apy

rem

aine

d un

chan

ged

Asp

irin

allo

wed

: not

sta

ted

Ana

lges

ic a

llow

ed: y

es,

acet

amin

ophe

n du

ring

was

hout

and

up t

o da

y 14

Pa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

es, 1

wee

k fo

r as

pirin

and

mos

t ot

her

NSA

IDs,

2 w

eeks

for

piro

xica

m a

nd S

R in

dom

etha

cin

Num

ber

and

freq

uenc

y of

vis

its:

4 (0

, 2, 4

and

6 w

eeks

)

Allo

cate

d:a

19, b

18

Com

plet

ed:a

18,

b 1

7D

rop-

out:

a 1,

b 1

Ass

esse

d:un

clea

r O

utco

mes

rep

orte

d:to

tal d

rop-

outs

How

wer

e ad

vers

eev

ents

ass

esse

d: n

ode

tails

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:co

ncom

itant

use

of

antic

oagu

lant

s: a

0, b

0C

VD: a

0, b

0re

nal/h

epat

ic d

iseas

e:

a 0,

b 0

FUN

DIN

GFu

nded

by:

not

stat

edA

ffilia

tion

of c

onta

ctau

thor

:Fre

eman

Hos

pita

l, N

ewca

stle

,U

KA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f stu

dyad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

0/1

Oth

er:t

his

is an

inte

rim r

epor

t

Appendix 6

278

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Plat

t, 19

89C

99

Loca

tion

:10

coun

trie

s, in

clud

ing

the

UK

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

assig

ned’

Allo

cati

on c

once

alm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

uncl

ear

Part

icip

ant

blin

ding

:yes

Ass

esso

r bl

indi

ng:u

ncle

arIn

tent

ion-

to-t

reat

:unc

lear

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

y, b

ut t

hose

with

pep

tic u

lcer

dise

ase

or h

istor

y of

GI b

leed

in t

he la

st5

year

s w

ere

excl

uded

Type

and

dur

atio

n of

art

hrit

is (

year

s):

OA

kne

e, n

o ot

her

deta

ilsA

ge:a

59,

b 5

9Se

x:M

/F: a

20/

57, b

17/

63

Incl

usio

n cr

iter

ia:O

A o

f the

kne

e w

ith a

tle

ast 2

of t

he fo

llow

ing

radi

olog

ical

crit

eria

:as

ymm

etric

al jo

int s

pace

nar

row

ing

with

subc

hond

ral s

cler

osis,

mar

gina

l ost

eoph

yte

form

atio

n or

sub

chon

dral

pse

udoc

ysts

with

scle

rotic

wal

ls; p

ain

in th

e af

fect

ed k

nee

and

at le

ast o

ne o

f the

follo

win

g co

nditi

ons:

limita

tion

of m

otio

n, te

nder

ness

on

pres

sure

, sw

ellin

g, c

repi

tus

on m

otio

n,m

orni

ng s

tiffn

ess

or s

tiffn

ess

afte

r in

activ

ity;

18–7

5ye

ars,

res

pond

ed in

the

past

toN

SAID

s, fr

ee o

f pep

tic u

lcer

dise

ase,

had

had

no G

I ble

edin

g in

the

last

5 y

ears

, no

signi

fican

t ren

al, h

aem

atol

ogic

al o

rca

rdio

vasc

ular

dise

ase,

no

seve

reco

mpl

icat

ions

or

diab

etes

, no

othe

r di

seas

eth

at c

ould

affe

ct th

e jo

ints

, no

seve

rein

fect

ion

or tu

berc

ulos

is, n

o sig

nific

ant

rheu

mat

oid

fact

or, n

ot ta

king

NSA

IDs

and

had

activ

e kn

ee jo

int s

ympt

oms

(as

prev

ious

ly d

escr

ibed

) or

if th

eir

dise

ase

wor

sene

d af

ter

a w

asho

ut p

erio

d fr

ee o

fan

y N

SAID

sEx

clus

ion

crit

eria

:pre

viou

sly t

reat

edw

ith N

SAID

s w

ithou

t ef

fect

or

who

had

expe

rienc

ed a

dver

se r

eact

ions

to

NSA

IDs,

pat

ient

s ta

king

ora

l or

pare

nter

alan

ticoa

gula

nts,

ora

l hyp

ogly

caem

ics

ordr

ugs

know

n to

cau

se h

epat

ic e

nzym

ech

ange

s or

dru

g in

duce

d he

patit

is,pr

egna

nt o

r br

east

-fee

ding

wom

en

Com

pari

son:

eto

dola

c (b

) vs

piro

xica

m (a

) D

urat

ion:

12 w

eeks

Inte

rven

tion

s:b,

eto

dola

c60

0m

g/60

0m

g da

ily (3

00m

g ×2

dai

ly);

a, p

iroxi

cam

20m

g/10

–30

mg

daily

(20

mg

once

dai

ly)

Oth

er m

edic

atio

n:or

al o

rpa

rent

eral

ant

icoa

gula

nts,

ora

lhy

pogl

ycae

mic

s or

dru

gs k

now

n to

caus

e he

patic

enz

yme

chan

ges

ordr

ug-in

duce

d he

patit

is, c

oncu

rren

tus

e of

oth

er N

SAID

s or

cort

icos

tero

id a

gent

s no

t al

low

ed,

type

or

inte

nsity

of p

hysio

ther

apy

rem

aine

d un

chan

ged

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:y

es,

acet

amin

ophe

n du

ring

was

hout

and

up t

o da

y 14

Pa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

es, 1

wee

k fo

r as

pirin

and

mos

t ot

her

NSA

IDs,

2 w

eeks

for

piro

xica

m a

nd S

R in

dom

etha

cin

Num

ber

and

freq

uenc

y of

vis

its:

7 (0

, 2, 4

, 6, 8

, 10

and

12 w

eeks

)

Allo

cate

d:a

77, b

80

Com

plet

ed:a

70,

b 7

1D

rop-

out:

a 7,

b 9

Ass

esse

d:un

clea

r O

utco

mes

rep

orte

d:to

tal d

rop-

outs

How

wer

e ad

vers

eev

ents

ass

esse

d:no

deta

ilsH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:co

ncom

itant

use

of

antic

oagu

lant

s: a

0, b

0C

VD: a

0, b

0re

nal/h

epat

ic d

iseas

e:

a 0,

b 0

FUN

DIN

GFu

nded

by:

not

stat

edA

ffilia

tion

of c

onta

ctau

thor

:Fre

eman

Hos

pita

l, N

ewca

stle

,U

KA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f stu

dyad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

0/1

Oth

er:t

his

is an

inte

rim r

epor

t


279


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Frei

tas,

199

0100

Loca

tion

:Bra

zil

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

assig

ned’

Allo

cati

on c

once

alm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

uncl

ear

Part

icip

ant

blin

ding

:yes

Ass

esso

r bl

indi

ng:u

ncle

arIn

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

y, n

o fu

rthe

r de

tails

Ty

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A k

nee,

no

othe

r de

tails

Age

:a 5

0 (2

3–71

), b

53 (3

7–71

)Se

x:M

/F: a

6/2

6, b

1/3

2In

clus

ion

crit

eria

:rad

iolo

gica

lly p

rove

nO

A o

f the

kne

e w

ith a

t le

ast

2 of

the

follo

win

g ra

diol

ogic

al c

riter

ia: a

sym

met

ricjo

int

spac

e na

rrow

ing

with

sub

chon

dral

scle

rosis

, mar

gina

l ost

eoph

yte

form

atio

n,or

sub

chon

dral

pse

udoc

ysts

with

scl

erot

icw

alls;

pai

n in

the

affe

cted

kne

e an

d at

leas

t on

e of

the

follo

win

g co

nditi

ons:

limita

tion

of m

otio

n, t

ende

rnes

s on

pres

sure

, sw

ellin

g, c

repi

tus

or s

tiffn

ess

afte

r in

activ

ity o

r sle

ep; 1

8–75

yea

rs,

hist

ory

of a

pos

itive

res

pons

e to

NSA

IDth

erap

y w

ith n

o hy

pers

ensit

ivity

rea

ctio

ns,

flare

of d

iseas

e sy

mpt

oms

afte

r w

asho

utof

NSA

IDs

(pre

senc

e of

3 o

f the

follo

win

g: m

oder

ate

to v

ery

seve

re p

ain

whe

n pe

rfor

min

g a

wei

ght-

bear

ing

activ

ity, m

oder

ate

to v

ery

seve

re p

ain

atni

ght,

at le

ast

10 m

inut

es o

f stif

fnes

s af

ter

inac

tivity

or

sleep

, pai

n in

tens

ity r

ecor

ded

as m

oder

ate

to v

ery

seve

re a

nd t

hepa

tient

s gl

obal

eva

luat

ion

repo

rted

as

fair

to v

ery

poor

)Ex

clus

ion

crit

eria

:pre

gnan

t or

bre

ast-

feed

ing

wom

en, s

erio

us d

iseas

e, p

atie

nts

taki

ng m

edic

atio

n w

ith a

pot

entia

l for

inte

ract

ion

with

NSA

IDs

Com

pari

son:

etod

olac

(b) v

spi

roxi

cam

(a)

Dur

atio

n:8

wee

ksIn

terv

enti

ons:

b et

odol

ac60

0m

g/60

0m

g da

ily (3

00m

g ×2

dai

ly);

a, p

iroxi

cam

20m

g/10

–30

mg

daily

(20

mg

once

daily

) O

ther

med

icat

ion:

no d

etai

lsA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:yes

,pa

race

tam

ol d

urin

g w

asho

ut

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:yes

, pat

ient

s to

ret

urn

for

base

line

visit

whe

n sy

mpt

oms

ofO

A h

ad fl

ared

Num

ber

and

freq

uenc

y of

vis

its:

5 (0

, 2, 4

, 6 a

nd 8

wee

ks)

Allo

cate

d:a

32, b

33

Com

plet

ed: a

27,

b 3

0D

rop-

out:

a 5,

b 3

Ass

esse

d:a

30, b

33

Out

com

es r

epor

ted:

mor

talit

y, s

erio

usca

rdio

vasc

ular

or

rena

lill

ness

, tot

al d

rop-

outs

,G

I dro

p-ou

tsH

ow w

ere

adve

rse

even

ts a

sses

sed:

node

tails

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:no

deta

ilsFU

ND

ING

Fund

ed b

y:W

yeth

-A

yers

t La

bora

torie

sA

ffilia

tion

of c

onta

ctau

thor

:Clin

ical

prac

tice,

Rec

ife-

Pern

ambu

co, B

razi

lA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f stu

dyad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

0/1

Appendix 6

280

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Taha

, 199

0101,

225,

226

Loca

tion

:Gla

sgow

Roya

l Inf

irmar

y, U

K

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

con

ceal

men

t:un

clea

rB

asel

ine

com

para

bilit

y:no Pa

rtic

ipan

t bl

indi

ng:y

esA

sses

sor

blin

ding

:unc

lear

Inte

ntio

n-to

-tre

at:n

oA

pri

ori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

high

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd d

efin

ite o

r pr

esum

ptiv

epe

ptic

ulc

erat

ion

excl

uded

B

asel

ine

NSA

ID s

tatu

s:12

of 1

5 in

each

gro

up h

ad p

revi

ous

NSA

ID u

seTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:RA

: a 6

(4–8

), b

11 (5

–17)

Age

:a 5

7 (4

5–65

), b

50 (4

1–63

)Se

x: M

/F: a

5/1

0, b

4/1

1 In

clus

ion

crit

eria

:ARA

crit

eria

for

RA,

func

tiona

l cla

ss I,

II o

r III

, sho

wed

evid

ence

of d

iseas

e ac

tivity

as

sugg

este

dby

all

of t

he fo

llow

ing:

5 o

r m

ore

tend

eror

pai

nful

join

ts o

n m

otio

n, 3

or

mor

esw

olle

n jo

ints

, mor

ning

stif

fnes

s of

30m

inut

es o

r m

ore;

pat

ient

s re

ceiv

ing

gold

sal

ts, a

ntim

alar

ials

or p

enic

illam

ine

wer

e ad

mitt

ed p

rovi

ded

that

the

y w

ere

star

ted

at le

ast

6 m

onth

s pr

ior

to t

he s

tart

of t

he s

tudy

, the

dos

age

regi

men

had

been

con

stan

t fo

r 2

mon

ths

and

wou

ldno

t be

cha

nged

dur

ing

the

stud

y, t

he d

ose

of h

ydro

xych

loro

quin

e di

d no

t ex

ceed

400

mg

daily

Excl

usio

n cr

iter

ia:a

rthr

itis

whi

ch s

tart

edbe

fore

the

age

of 1

6 ye

ars,

any

oth

erdi

seas

e of

the

kid

neys

, liv

er o

rca

rdio

vasc

ular

sys

tem

s; a

llerg

ic r

eact

ions

or d

iseas

e, d

efin

ite o

r pr

esum

ptiv

e pe

ptic

ulce

ratio

n, p

atie

nts

taki

ng s

ulfa

sala

zine

,sy

stem

ic o

r in

trar

ticlu

ar s

tero

ids,

cyto

toxi

cs, a

nd p

eptic

ulc

er h

ealin

g ag

ents

Com

pari

son:

etod

olac

(b) v

sna

prox

en (a

) D

urat

ion:

4 w

eeks

Inte

rven

tion

s:b,

eto

dola

c60

0m

g/60

0m

g da

ily (3

00m

g×2

dai

ly);

a, n

apro

xen

1000

mg/

500–

1250

mg

daily

(500

mg

×2 d

aily

) O

ther

med

icat

ion:

sulfa

sala

zine

,sy

stem

ic o

r in

trar

ticlu

ar s

tero

ids,

cyto

toxi

cs, a

nd p

eptic

ulc

er h

ealin

gag

ents

wer

e no

t al

low

ed, g

old

salts

,an

timal

aria

ls an

d pe

nici

llam

ine

coul

dbe

con

tinue

d un

chan

ged

Asp

irin

allo

wed

: not

sta

ted

Ana

lges

ic a

llow

ed:y

es,

para

ceta

mol

pro

vide

dPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

es, 4

–7 d

ays

Num

ber

and

freq

uenc

y of

vis

its:

2 (0

and

4 w

eeks

)

Allo

cate

d:32

in t

otal

C

ompl

eted

:a 1

5, b

15

Dro

p-ou

t: 2

in t

otal

Ass

esse

d: a

15,

b 1

5O

utco

mes

rep

orte

d:m

orta

lity,

GI s

ympt

oms,

endo

scop

ic u

lcer

sH

ow w

ere

adve

rse

even

ts a

sses

sed:

node

tails

How

was

com

plia

nce

asse

ssed

:tab

let

coun

t,na

prox

en g

roup

too

km

edia

n of

90%

tab

lets

,et

odol

ac g

roup

too

km

edia

n of

87%

tab

lets

Ris

k fa

ctor

s:co

ncom

itant

use

of

cort

icos

tero

ids:

a 0

,b

0C

VD: a

0, b

0re

nal/h

epat

ic d

iseas

e:

a 0,

b 0

FUN

DIN

GFu

nded

by:

Wye

th-

Aye

rst

Labo

rato

ries

Affi

liati

on o

f con

tact

auth

or:R

oyal

Infir

mar

y, G

lasg

ow, U

KA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f stu

dyad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

0/4


281


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Ast

orga

Pau

lsen,

1991

102

Loca

tion

:Sou

thA

mer

ica

and

Port

ugal

Met

hod

ofra

ndom

isat

ion:

‘ass

igne

d at

rand

om’

Allo

cati

on c

once

alm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

uncl

ear

Part

icip

ant

blin

ding

: yes

Ass

esso

r bl

indi

ng:u

ncle

arIn

tent

ion-

to-t

reat

: no

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

y, n

o fu

rthe

r de

tails

Type

and

dur

atio

n of

art

hrit

is (

year

s):

OA

kne

e, n

o fu

rthe

r de

tails

Age

:a 5

8 (2

3–75

), b

58 (2

0–79

)Se

x:M

/F: a

25/

83, b

25/

87

Incl

usio

n cr

iter

ia:r

adio

logi

cally

pro

ven

OA

of t

he k

nee

with

at

leas

t 2

of t

hefo

llow

ing

radi

olog

ical

crit

eria

dem

onst

rate

d w

ithin

the

pre

viou

s6

mon

ths:

asy

mm

etric

join

t sp

ace

narr

owin

g w

ith s

ubch

ondr

al s

cler

osis,

mar

gina

l ost

eoph

yte

form

atio

n or

subc

hond

ral p

seud

ocys

ts w

ith s

cler

otic

wal

ls; p

ain

in t

he a

ffect

ed k

nee

on m

otio

nor

at

rest

with

at

leas

t on

e of

the

follo

win

g co

nditi

ons:

lim

itatio

n of

mot

ion,

tend

erne

ss o

n pr

essu

re, s

wel

ling,

cre

pitu

sor

stif

fnes

s af

ter

prol

onge

d in

activ

ity o

rsle

ep; p

atie

nts

who

wer

e no

thy

pers

ensit

ive

to N

SAID

s, in

clud

ing

aspi

rin, a

nd w

ho h

ad e

xper

ienc

ed a

ther

apeu

tic r

espo

nse

to N

SAID

s in

the

past

Excl

usio

n cr

iter

ia:h

istor

y of

ser

ious

med

ical

or

psyc

holo

gica

l diso

rder

s or

any

conc

omita

nt d

iseas

e th

at a

ffect

ed t

hejo

ints

or

conn

ectiv

e tis

sue,

wom

en w

how

ere

preg

nant

or

brea

st-f

eedi

ng, t

hose

who

had

rec

ently

und

ergo

ne s

urge

ry o

rw

ho h

ad a

clin

ical

ly s

igni

fican

t po

sitiv

efin

ding

for

rheu

mat

oid

fact

or, p

atie

nts

who

use

d an

ticoa

gula

nt, o

ral

hypo

glyc

aem

ic, h

epat

otox

ic o

rco

rtic

oste

roid

dru

gs, t

hose

who

had

tak

enin

vest

igat

iona

l NSA

IDs

with

in 1

mon

th o

fth

e st

udy,

tho

se w

ho h

ad p

revi

ously

tak

enet

odol

ac

Com

pari

son:

etod

olac

(b) v

spi

roxi

cam

(a)

Dur

atio

n:8

wee

ksIn

terv

enti

ons:

b, e

todo

lac

600

mg/

600

mg

daily

(300

mg

×2 d

aily

); a,

piro

xica

m20

mg/

10–3

0m

g da

ily (2

0m

g on

ceda

ily)

Oth

er m

edic

atio

n:an

ticoa

gula

nt,

oral

hyp

ogly

caem

ic, h

epat

otox

ic o

rco

rtic

oste

roid

dru

gs n

ot a

llow

edA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:yes

,ac

etam

inop

hen

for

was

hout

and

first

7 d

ays

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:yes

, 1–2

wee

ks fo

ras

pirin

or

NSA

IDs

Num

ber

and

freq

uenc

y of

vis

its:

5 (0

, 2, 4

, 6 a

nd 8

wee

ks)

Allo

cate

d:a

108,

b 1

12C

ompl

eted

: a 9

5, b

100

Dro

p-ou

t:a

13, b

12

Ass

esse

d:a

106,

b 1

12O

utco

mes

rep

orte

d:m

orta

lity,

ser

ious

GI

com

plic

atio

ns, s

erio

usca

rdio

vasc

ular

or

rena

lill

ness

, GI s

ympt

oms,

GI

drop

-out

s, t

otal

dro

p-ou

tsH

ow w

ere

adve

rse

even

ts a

sses

sed:

node

tails

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:co

ncom

itant

use

of

antic

oagu

lant

s: a

0,

b 0

cort

icos

tero

ids:

a 0

, b

0FU

ND

ING

Fund

ed b

y:W

yeth

-A

yers

t La

bora

torie

sA

ffilia

tion

of c

onta

ctau

thor

:Uni

vers

idad

de C

hile

Affi

liati

on o

fst

atis

tici

an: u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:0/

5 by

Wye

th-A

yers

t

Appendix 6

282

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Bras

eur,

1991

103

Loca

tion

:Bel

gium

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

eco

mpa

rabi

lity:

uncl

ear

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

y,no

furt

her

deta

ilsTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A k

nee,

no

furt

her

deta

ilsA

ge:a

60.

2 (3

9–72

), b

63.3

(44–

81)

Sex:

M/F

: a 9

/20,

b 6

/26

Incl

usio

n cr

iter

ia:p

ain

in t

he a

ffect

ed k

nee

on m

otio

n or

at

rest

with

at

leas

t on

e of

the

follo

win

g co

nditi

ons:

lim

itatio

n of

mot

ion,

tend

erne

ss o

n pr

essu

re, s

wel

ling,

cre

pitu

s or

stiff

ness

(eith

er in

the

mor

ning

or

afte

rpr

olon

ged

inac

tivity

), ra

diol

ogic

ally

pro

ven

OA

of t

he k

nee

with

at

leas

t 2

of t

hefo

llow

ing

cond

ition

s: a

sym

met

ric jo

int

spac

ena

rrow

ing

with

sub

chon

dral

scl

eros

is,m

argi

nal o

steo

phyt

e fo

rmat

ion

orsu

bcho

ndra

l pse

udoc

ysts

with

scl

erot

ic w

alls

Excl

usio

n cr

iter

ia:p

atie

nts

who

wer

ehy

pers

ensit

ive

to N

SAID

s in

clud

ing

aspi

rin o

rw

hose

sym

ptom

s ha

d no

t be

en r

elie

ved

byN

SAID

s in

the

pas

t, hi

stor

y of

ser

ious

med

ical

or

psyc

holo

gica

l diso

rder

s or

any

conc

omita

nt d

iseas

e af

fect

ing

the

join

ts o

rco

nnec

tive

tissu

e, w

omen

who

wer

epr

egna

nt o

r nu

rsin

g, t

hose

who

had

rec

ently

unde

rgon

e su

rger

y, p

atie

nts

with

a c

linic

ally

signi

fican

t po

sitiv

e fin

ding

for

rheu

mat

oid

fact

or, p

atie

nts

who

use

d an

ticoa

gula

nt, o

ral

hypo

glyc

aem

ic, h

epat

otox

ic o

r co

rtic

oste

roid

drug

s, t

hose

who

had

tak

en in

vest

igat

iona

lN

SAID

s w

ithin

1m

onth

of t

he s

tudy

, tho

sew

ho h

ad p

revi

ously

tak

en e

todo

lac

Com

pari

son:

etod

olac

(b) v

sdi

clof

enac

SR

(a)

Dur

atio

n:6

wee

ksIn

terv

enti

ons:

b et

odol

ac60

0m

g/60

0m

g da

ily (3

00m

g×2

dai

ly);

a, d

iclo

fena

c SR

100

mg/

75–1

50m

g da

ily (1

00m

gon

ce d

aily

) O

ther

med

icat

ion:

antic

oagu

lant

,or

al h

ypog

lyca

emic

, hep

atot

oxic

or

cort

icos

tero

id d

rugs

exc

lude

dA

spir

in a

llow

ed:n

o, fr

om

1–2

wee

ks p

rior

to s

tudy

Ana

lges

ic a

llow

ed:y

es,

acet

amin

ophe

n co

uld

be c

ontin

ued

durin

g w

asho

ut a

nd fi

rst

7 da

ysPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

es, 1

–2 w

eeks

for

aspi

rin o

r N

SAID

sN

umbe

r an

d fr

eque

ncy

of v

isit

s:4

(0, 2

, 4 a

nd 6

wee

ks)

Allo

cate

d:a

29, b

32

Com

plet

ed:a

23,

b 2

6D

rop-

out:

a 6,

b 6

Ass

esse

d:a

29, b

32

Out

com

es r

epor

ted:

GI d

rop-

outs

, tot

aldr

op-o

uts

How

wer

e ad

vers

eev

ents

ass

esse

d:pa

tient

s co

mpl

aint

sre

cord

edH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:co

ncom

itant

use

of

antic

oagu

lant

s; a

0, b

0co

rtic

oste

roid

s: a

0,

b 0

FUN

DIN

GFu

nded

by:

Wye

th-

Aye

rst

Labo

rato

ries

Affi

liati

on o

f con

tact

auth

or:U

nive

rsity

of

Louv

ain,

Bel

gium

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:0/

3


283


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Karb

owsk

i, 19

9110

4

Loca

tion

:G

erm

any

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

eco

mpa

rabi

lity:

uncl

ear

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

y,no

furt

her

deta

ilsTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A k

nee,

no

furt

her

deta

ilsA

ge:a

53.

8 (3

3–74

), b

53.5

(22–

76)

Sex:

M/F

: a 1

3/20

, b 1

2/19

In

clus

ion

crit

eria

:OA

of t

he k

nee

with

at

leas

t 2 o

f the

follo

win

g co

nditi

ons

show

n by

radi

olog

ical

stu

dy: a

sym

met

ric jo

int s

pace

narr

owin

g w

ith s

ubch

ondr

al s

cler

osis,

mar

gina

l ost

eoph

yte

form

atio

n or

sub

chon

dral

pseu

docy

sts

with

scl

erot

ic w

alls;

clin

ical

sig

nsof

OA

def

ined

by

pain

in th

e af

fect

ed k

nee

onm

otio

n or

at r

est a

nd a

t lea

st o

ne o

f the

follo

win

g co

nditi

ons:

lim

itatio

n of

mot

ion,

tend

erne

ss o

n pr

essu

re, s

wel

ling,

cre

pitu

s or

stiff

ness

(eith

er in

the

mor

ning

or

afte

rpr

olon

ged

inac

tivity

), pa

tient

s w

ho w

ere

not

hype

rsen

sitiv

e to

NSA

IDs

incl

udin

g as

pirin

or

who

had

res

pond

ed th

erap

eutic

ally

toN

SAID

s in

the

past

, a fl

are

of d

iseas

e ac

tivity

and

a w

orse

ning

of t

he p

atie

nt’s

eval

uatio

n of

his

or h

er o

vera

ll co

nditi

on w

ere

requ

ired

for

patie

nts

with

draw

n fr

om N

SAID

s (d

efin

ed a

sw

orse

ning

of a

t lea

st 2

of t

he fo

llow

ing

varia

bles

: wei

ght-

bear

ing

pain

act

ivity

, nig

htpa

in, s

tiffn

ess

upon

aris

ing

or a

fter

prol

onge

dac

tivity

and

pai

n in

tens

ity)

Excl

usio

n cr

iter

ia:h

istor

y of

ser

ious

med

ical

or p

sych

olog

ical

diso

rder

s or

any

con

com

itant

dise

ase

affe

ctin

g th

e jo

ints

or

conn

ectiv

etis

sue,

wom

en w

ho w

ere

preg

nant

or

lact

atin

g, th

ose

who

had

rec

ently

und

ergo

nesu

rger

y, p

atie

nts

with

a c

linic

ally

sig

nific

ant

posit

ive

findi

ng fo

r rh

eum

atoi

d fa

ctor

, pat

ient

sw

ho u

sed

antic

oagu

lant

, ora

l hyp

ogly

caem

ic,

hepa

toto

xic

or c

ortic

oste

roid

dru

gs, t

hose

who

had

take

n in

vest

igat

iona

l NSA

IDs

with

in1

mon

th o

f the

stu

dy, t

hose

who

had

prev

ious

ly ta

ken

etod

olac

Com

pari

son:

etod

olac

(b) v

sin

dom

etha

cin

(a)

Dur

atio

n:6

wee

ksIn

terv

enti

ons:

b et

odol

ac60

0m

g/60

0m

g da

ily (3

00m

g×2

dai

ly);

a, in

dom

etha

cin

150

mg/

50–2

00m

g da

ily (5

0m

g ×3

dai

ly)

Oth

er m

edic

atio

n:an

ticoa

gula

nt,

oral

hyp

ogly

caem

ic, h

epat

otox

ic o

rco

rtic

oste

roid

dru

gs e

xclu

ded

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:y

es,

para

ceta

mol

for

was

hout

and

firs

t7

days

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:yes

, 1–2

wee

ks fo

ras

pirin

or

NSA

IDs

Num

ber

and

freq

uenc

y of

vis

its:

4 (0

, 2, 4

and

6 w

eeks

)

Allo

cate

d:a

33, b

31

Com

plet

ed:a

27,

b 2

8D

rop-

out:

a 6,

b 3

Ass

esse

d:a

33, b

31

Out

com

es r

epor

ted:

serio

us G

Ico

mpl

icat

ions

,sy

mpt

omat

ic u

lcer

s, G

Idr

op-o

uts,

tot

al d

rop-

outs

, occ

ult

blee

ding

How

wer

e ad

vers

eev

ents

ass

esse

d:no

deta

ilsH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:co

ncom

itant

use

of

antic

oagu

lant

s: a

0, b

0co

rtic

oste

roid

s: a

0,

b 0

FUN

DIN

GFu

nded

by:

Wye

th-

Aye

rst

Labo

rato

ries

Affi

liati

on o

f con

tact

auth

or:K

linik

und

Polik

linik

fur

Alle

gem

eine

Abt

eilu

ngO

rtho

padi

e de

rW

WU

, Mun

ster

,G

erm

any

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:0/

1

Appendix 6

284

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Palfe

rman

, 199

1105

Loca

tion

:3 s

ites

inU

K

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

eco

mpa

rabi

lity:

uncl

ear

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ybu

t ex

clud

ed if

GI b

leed

ing

or p

eptic

ulc

erdi

seas

eTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A, n

o fu

rthe

r de

tails

Age

:a 6

4.5

(47–

76),

b 61

.6 (2

7–74

)Se

x:M

/F: a

9/1

8, b

12/

17

Incl

usio

n cr

iter

ia:1

8–76

yea

rs, O

A o

f the

knee

with

act

ive

dege

nera

tive

join

t di

seas

eco

nfirm

ed b

y th

e fo

llow

ing

roen

tgen

olog

ical

and

clin

ical

crit

eria

: rad

iogr

aphs

of t

heaf

fect

ed t

aken

with

in t

he p

revi

ous

6 m

onth

sha

d to

sho

w a

t le

ast

2 of

the

follo

win

gco

nditi

ons:

asy

mm

etric

join

t sp

ace

narr

owin

gw

ith s

ubch

ondr

al s

cler

osis,

mar

gina

los

teop

hyte

form

atio

n or

sub

chon

dral

pseu

docy

sts

with

scl

erot

ic w

alls;

clin

ical

crite

ria fo

r O

A in

clud

ed p

ain

in t

he a

ffect

edkn

ee o

n m

otio

n or

at

rest

and

at

leas

t on

e of

the

follo

win

g co

nditi

ons:

lim

itatio

n of

mot

ion,

tend

erne

ss o

n pr

essu

re, s

wel

ling,

cre

pitu

s, o

rst

iffne

ss (e

ither

in t

he m

orni

ng o

r af

ter

prol

onge

d in

activ

ity),

only

pat

ient

s w

ho h

ad a

hist

ory

of p

ositi

ve t

hera

peut

ic r

espo

nse

with

no h

yper

sens

itivi

ty t

o N

SAID

s w

ere

incl

uded

,cr

iteria

for

activ

e O

A r

equi

red

at le

ast

3 of

the

follo

win

g co

nditi

ons

to b

e m

et: s

core

of

at le

ast

3 in

wei

ght-

bear

ing

pain

act

ivity

, in

nigh

t pa

in, i

n pa

in in

tens

ity, i

n pa

tient

’sov

eral

l eva

luat

ion

of h

is or

her

con

ditio

n of

dise

ase

activ

ity o

r in

stif

fnes

s of

at

leas

t10

min

utes

’ dur

atio

n on

aris

ing

or a

fter

prol

onge

d in

activ

ity; a

flar

e of

dise

ase

and

aw

orse

ning

of a

t le

ast

2 of

the

abo

ve c

riter

iaw

ere

requ

ired

for

patie

nts

with

draw

n fr

omN

SAID

sEx

clus

ion

crit

eria

:hist

ory

of s

erio

us r

enal

,he

patic

or

card

iova

scul

ar d

iseas

e; c

hron

ic s

kin

dise

ase;

GI b

leed

ing

or p

eptic

ulc

er d

iseas

e;

Com

pari

son:

etod

olac

(b) v

sna

prox

en (a

) D

urat

ion:

6 w

eeks

Inte

rven

tion

s:b,

eto

dola

c60

0m

g/60

0m

g da

ily (3

00m

g×2

dai

ly);

a, n

apro

xen

1000

mg/

500–

1250

mg

daily

(500

mg

×2 d

aily

); “d

oubl

e du

mm

y”O

ther

med

icat

ion:

hypo

glyc

aem

icag

ents

, ant

icoa

gula

nt t

hera

py, a

nym

edic

atio

n th

at c

ause

d liv

eren

zym

e ab

norm

aliti

es,

cort

icos

tero

ids

excl

uded

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:y

es,

acet

amin

ophe

n fo

r w

asho

ut a

ndfir

st 7

day

sPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

es, 1

–2 w

eeks

for

aspi

rin o

r N

SAID

sN

umbe

r an

d fr

eque

ncy

of v

isit

s:4

(0, 2

, 4 a

nd 6

wee

ks)

Allo

cate

d:a

27, b

29

Com

plet

ed:a

22,

b 2

4D

rop-

out:

a 5,

b 5

Ass

esse

d:a

27, b

29

Out

com

es r

epor

ted:

GI s

ympt

oms,

GI d

rop-

outs

, tot

al d

rop-

outs

How

wer

e ad

vers

eev

ents

ass

esse

d:pa

tient

com

plai

nts

reco

rded

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:co

ncom

itant

use

of

antic

oagu

lant

s: a

0,

b0;

cor

ticos

tero

ids:

a

0, b

0; C

VD: a

0, b

0re

nal/h

epat

ic d

iseas

e:

a 0,

b 0

FUN

DIN

GFu

nded

by:

not

stat

edA

ffilia

tion

of c

onta

ctau

thor

:Yeo

vil D

istric

tG

ener

al H

ospi

tal,

UK

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:0/

3


285


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

subs

tanc

e ab

use;

mal

igna

ncy

exce

pt r

esec

ted

basa

l cel

l car

cino

ma;

maj

or s

urge

ry in

the

last

6 m

onth

s; o

r se

rious

psy

chol

ogic

al d

isord

ers;

clin

ical

ly s

igni

fican

t lev

els

of r

heum

atoi

dfa

ctor

, con

com

itant

dise

ase

affe

ctin

g th

e jo

ints

or c

onne

ctiv

e tis

sue,

cur

rent

or

seve

rein

fect

ions

or

any

cond

ition

that

inte

rfer

edw

ith ta

king

the

stud

y m

edic

atio

n; w

omen

who

wer

e pr

egna

nt o

r la

ctat

ing,

pat

ient

s w

how

ere

rece

ivin

g hy

pogl

ycae

mic

age

nts,

antic

oagu

lant

ther

apy,

any

med

icat

ion

that

caus

ed li

ver

enzy

me

abno

rmal

ities

,co

rtic

oste

roid

s w

ithin

the

prev

ious

6 m

onth

s,in

vest

igat

iona

l NSA

IDs

with

in th

e pr

evio

usm

onth

or

etod

olac

at a

ny ti

me

prev

ious

ly

Pena

, 199

1106

Loca

tion

:C

olum

bia

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

eco

mpa

rabi

lity:

uncl

ear

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:yes

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

y,no

furt

her

deta

ilsB

asel

ine

NSA

ID s

tatu

s:5

in n

apro

xen

grou

p an

d 3

in e

todo

lac

grou

p di

d no

t ha

ve‘fl

are’

dur

ing

was

hout

Type

and

dur

atio

n of

art

hrit

is (

year

s):

OA

kne

e, n

o fu

rthe

r de

tails

Age

:a 6

2.3

(48–

75),

b 62

.7 (4

2–74

)Se

x:M

/F: a

3/2

8, b

5/2

6 In

clus

ion

crit

eria

:18–

75 y

ears

, rad

iolo

gica

lev

iden

ce o

f OA

of t

he k

nee

with

pai

n in

the

affe

cted

kne

e an

d at

leas

t on

e of

the

follo

win

g: li

mita

tion

of m

otio

n, t

ende

rnes

s on

pres

sure

, sw

ellin

g, c

repi

tus,

or

stiff

ness

(eith

er in

the

mor

ning

or

afte

r pr

olon

ged

inac

tivity

), hi

stor

y of

a p

ositi

ve t

hera

peut

icre

spon

se t

o N

SAID

sEx

clus

ion

crit

eria

:wom

en o

f chi

ldbe

arin

gpo

tent

ial,

patie

nts

who

had

rec

eive

d or

alco

rtic

oste

roid

s in

the

pre

viou

s 6

mon

ths

orin

ject

ion

of c

ortic

oste

roid

s w

ithin

the

last

4w

eeks

Com

pari

son:

eto

dola

c (b

) vs

napr

oxen

(a)

Dur

atio

n:8

wee

ksIn

terv

enti

ons:

b, e

todo

lac

600

mg/

600

mg

daily

(300

mg

×2 d

aily

); a,

nap

roxe

n10

00m

g/50

0–12

50m

g da

ily(5

00m

g ×2

dai

ly)

Oth

er m

edic

atio

n:co

rtic

oste

roid

sno

t al

low

edA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:yes

,ac

etam

inop

hen

durin

g w

asho

ut o

nly

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:yes

, 2 w

eeks

Num

ber

and

freq

uenc

y of

vis

its:

5x (0

, 2, 4

, 6 a

nd 8

wee

ks)

Allo

cate

d:a

31, b

31

Com

plet

ed:a

31,

b 3

0D

rop-

out:

a 0,

b 1

Ass

esse

d:a

30, b

30

Out

com

es r

epor

ted:

GI s

ympt

oms,

tot

aldr

op-o

uts

How

wer

e ad

vers

eev

ents

ass

esse

d:pa

tient

com

plai

nts

reco

rded

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:co

ncom

itant

use

of

cort

icos

tero

ids:

a 0

,b

0FU

ND

ING

Fund

ed b

y:W

yeth

-A

yers

t La

bora

torie

sA

ffilia

tion

of c

onta

ctau

thor

:Hos

pita

l San

Juan

de

Dio

s,C

olom

bia

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:0/

2

Appendix 6

286

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Perp

igna

no,

1991

107

Loca

tion

:Ita

ly

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

allo

cate

d’(p

rede

term

ined

rand

omisa

tion

list)

Allo

cati

onco

ncea

lmen

t:un

clea

rB

asel

ine

com

para

bilit

y:no Pa

rtic

ipan

t bl

indi

ng:y

esA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:un

clea

rA

pri

ori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

high

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd p

atie

nts

with

less

tha

ner

osio

ns w

ere

incl

uded

Type

and

dur

atio

n of

art

hrit

is (

year

s):

OA

hip

or

knee

, no

furt

her

deta

ilsA

ge:a

55.

7, b

51.

9 Se

x:M

/F: a

3/7

, b 6

/4

Incl

usio

n cr

iter

ia:3

9–65

yea

rs, O

A o

f the

hip

or k

nee

whi

ch r

equi

red

trea

tmen

t w

ithN

SAID

s, a

cute

OA

def

ined

as

spon

tane

ous

pain

agg

rava

ted

by m

ovem

ent,

pain

on

pres

sure

, fun

ctio

nal l

imita

tions

, sw

olle

n jo

int,

rigid

gre

ater

tha

n 30

°Ex

clus

ion

crit

eria

:end

osco

pic

scor

e of

grea

ter

than

2, h

istor

y of

pep

tic u

lcer

or

grav

e liv

er, r

enal

or

card

iova

scul

ar d

isord

ers;

bron

chia

l ast

hmas

, pre

gnan

t w

omen

,hy

pert

ensio

n tr

eate

d w

ith n

ifedi

pine

Com

pari

son:

eto

dola

c (b

) vs

napr

oxen

(a)

Dur

atio

n:4

wee

ksIn

terv

enti

ons:

b, e

todo

lac

600

mg/

600

mg

daily

; a, n

apro

xen

750

mg/

500–

1250

mg

daily

Oth

er m

edic

atio

n:no

det

ails

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:n

ot s

tate

dPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

es, 7

day

sN

umbe

r an

d fr

eque

ncy

of v

isit

s:2

(0 a

nd 4

wee

ks)

Allo

cate

d:a

10, b

10

Com

plet

ed:a

8, b

10

Dro

p-ou

t:a

2, b

0A

sses

sed:

a 10

, b 1

0O

utco

mes

rep

orte

d:G

I dro

p-ou

ts, t

otal

drop

-out

s, e

ndos

copi

cul

cers

How

wer

e ad

vers

eev

ents

ass

esse

d:no

tst

ated

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:C

VD:

a 0,

b 0

rena

l/hep

atic

dise

ase:

a

0, b

0FU

ND

ING

Fund

ed b

y: n

ot s

tate

dA

ffilia

tion

of c

onta

ctau

thor

:Uni

vers

ity o

fde

Cag

liari,

Ital

yA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f stu

dyad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

0/3

Oth

er:p

aper

tran

slate

d

Dic

k, 1

99210

8

Loca

tion

:fou

rsit

es in

clud

ing

The

Net

herla

nds

and

the

UK

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’(p

rede

term

ined

rand

omisa

tion

sche

dule

)A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

no, ‘

mor

e se

vere

art

hriti

csy

mpt

oms’

in e

todo

lac

grou

pPa

rtic

ipan

t bl

indi

ng:y

esA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:yes

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

high

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ybu

t ex

clud

ed s

erio

us s

ympt

omat

ic d

iseas

e B

asel

ine

NSA

ID s

tatu

s:ex

clud

ed p

atie

nts

with

no

NSA

ID e

xper

ienc

eTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:de

gene

rativ

e jo

int

dise

ase

of t

he k

nee,

no

furt

her

deta

ilsA

ge:a

57.

3 (3

2–77

), b

59.5

(38–

80)

Sex:

M/F

: a 2

1/38

, b 1

6/41

In

clus

ion

crit

eria

:18–

75 y

ears

, act

ive

OA

of

the

knee

con

firm

ed b

y X

-ray

find

ings

and

clin

ical

crit

eria

and

had

prio

r po

sitiv

eth

erap

eutic

res

pons

e to

one

or

mor

e N

SAID

sin

clud

ing

aspi

rinEx

clus

ion

crit

eria

:no

NSA

ID e

xper

ienc

e,hy

pers

ensit

ivity

to

NSA

IDs,

pre

viou

s no

resp

onse

or

adve

rse

reac

tion

with

piro

xica

m,

unac

cept

able

con

com

itant

med

icat

ion,

serio

us s

ympt

omat

ic d

iseas

e, o

r ne

urol

ogic

alor

psy

chol

ogic

al d

isord

ers;

wom

en o

fch

ildbe

arin

g po

tent

ial

Com

pari

son:

etod

olac

(b) v

spi

roxi

cam

(a)

Dur

atio

n:6

wee

ksIn

terv

enti

ons:

b, e

todo

lac

600

mg/

600

mg

daily

(300

mg

×2 d

aily

); a,

piro

xica

m20

mg/

10–3

0m

g da

ily (2

0m

g on

ceda

ily)

Oth

er m

edic

atio

n:ph

ysic

alth

erap

y an

d w

alki

ng a

ids

coul

d be

cont

inue

dA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:yes

,ac

etam

inop

hen

650

mg

×4 d

aily

for

was

hout

and

firs

t 7

days

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:yes

, 2 w

eeks

N

umbe

r an

d fr

eque

ncy

of v

isit

s:4

(0, 2

, 4 a

nd 6

wee

ks)

Allo

cate

d:a

59, b

57

Com

plet

ed:a

52,

b 4

2D

rop-

out:

a 7,

b 1

5A

sses

sed:

a 59

, b 5

7O

utco

mes

rep

orte

d:G

I sym

ptom

s, G

I dro

p-ou

ts, t

otal

dro

p-ou

tsH

ow w

ere

adve

rse

even

ts a

sses

sed:

patie

nt c

ompl

aint

sre

cord

edH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:no

deta

ilsFU

ND

ING

Fund

ed b

y:W

yeth

-A

yers

t La

bora

torie

sA

ffilia

tion

of c

onta

ctau

thor

:Roy

al V

icto

riaIn

firm

ary,

New

cast

le,

UK

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:0/

4


287


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Gris

anti,

199

2109

Loca

tion

:Po

rtug

al, B

razi

lan

d C

hile

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

uncl

ear

Part

icip

ant

blin

ding

:yes

Ass

esso

r bl

indi

ng:

uncl

ear

Inte

ntio

n-to

-tre

at:n

oA

pri

ori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ybu

t ex

clud

ed p

atie

nts

with

a h

istor

y of

pep

ticul

cer

dise

ase

or G

I ble

ed in

the

last

5 y

ears

Bas

elin

e N

SAID

sta

tus:

excl

uded

pat

ient

sw

ho h

ad n

ever

rec

eive

d an

NSA

IDTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A k

nee,

no

furt

her

deta

ilsA

ge:a

59

(35–

75),

b 59

(17–

73)

Sex:

M/F

: a 1

2/75

, b 1

2/73

In

clus

ion

crit

eria

: roe

ntge

nogr

am w

ithin

prev

ious

6 m

onth

s th

at c

onfir

med

dege

nera

tive

join

t di

seas

e of

the

kne

e, X

-ray

film

had

to

show

at

leas

t tw

o of

the

follo

win

gth

ree

signs

: asy

mm

etric

join

t sp

ace

narr

owin

gw

ith s

ubch

ondr

al s

cler

osis,

mar

gina

los

teop

hyte

form

atio

n or

sub

chon

dral

pseu

docy

sts

with

scl

erot

ic w

alls;

kne

e pa

inei

ther

dur

ing

mot

ion

or a

t re

st a

nd a

t le

ast

one

of t

he fo

llow

ing

sym

ptom

s: li

mite

dm

otio

n, t

ende

rnes

s du

ring

pres

sure

, sw

ellin

g,cr

epitu

s, m

orni

ng s

tiffn

ess

or s

tiffn

ess

afte

rpr

olon

ged

activ

ity; p

atie

nts

who

had

with

draw

n fr

om N

SAID

s ha

d to

sho

w a

flar

eat

bas

elin

e de

fined

as

a w

orse

ning

of a

t le

ast

two

of t

he fo

llow

ing

varia

bles

: wei

ght-

bear

ing

activ

ity, n

ight

pai

n, s

tiffn

ess

afte

r sle

epin

g or

afte

r pr

olon

ged

activ

ity o

r pa

in in

tens

ityEx

clus

ion

crit

eria

:nev

er r

ecei

ved

anN

SAID

to

trea

t O

A, p

revi

ously

tak

endi

clof

enac

and

had

not

res

pond

ed w

ell t

otr

eatm

ent,

prev

ious

ly t

aken

eto

dola

c, t

aken

inve

stig

atio

nal d

rugs

with

in t

he la

st m

onth

,pe

ptic

ulc

er d

iseas

e or

GI b

leed

ing

in t

he la

st5

year

s; w

omen

who

wer

e pr

egna

nt o

rbr

east

-fee

ding

or

inte

nded

to

brea

st-f

eed;

patie

nts

rece

ivin

g or

al h

ypog

lyca

emic

,he

pato

toxi

c or

ora

l or

pare

nter

alan

ticoa

gula

nt d

rugs

Com

pari

son:

etod

olac

(b) v

sdi

clof

enac

(a)

Dur

atio

n:8

wee

ksIn

terv

enti

ons:

b, e

todo

lac

600

mg/

600

mg

daily

(200

mg

×3 d

aily

); a,

dic

lofe

anc

150

mg/

75–1

50m

g da

ily (5

0m

gx3

daily

) O

ther

med

icat

ion:

oral

hypo

glyc

aem

ic, h

epat

otox

ic o

r or

alor

par

ente

ral a

ntic

oagu

lant

dru

gsex

clud

edA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:yes

,ac

etam

inop

hen

for

was

hout

and

first

7 d

ays

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:yes

, 1 w

eek

for

aspi

rinan

d 2

wee

ks fo

r pi

roxi

cam

N

umbe

r an

d fr

eque

ncy

of v

isit

s:5

(0, 2

, 4, 6

and

8 w

eeks

)

Allo

cate

d:a

87, b

85

Com

plet

ed:a

79,

b 7

8D

rop-

out:

a 8

, b 7

Ass

esse

d:a

84, b

84

Out

com

es r

epor

ted:

GI d

rop-

outs

, tot

aldr

op-o

uts

How

wer

e ad

vers

eev

ents

ass

esse

d:pa

tient

com

plai

nts

reco

rded

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:co

ncom

itant

use

of

antic

oagu

lant

s: a

0, b

0

FUN

DIN

GFu

nded

by:

Wye

th-

Aye

rst

Labo

rato

ries

Affi

liati

on o

f con

tact

auth

or:U

nive

rsity

of

Chi

leA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f stu

dyad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

0/3

Appendix 6

288

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Jubb

, 199

2110

Loca

tion

:UK

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

uncl

ear

Part

icip

ant

blin

ding

:yes

Ass

esso

r bl

indi

ng:

uncl

ear

Inte

ntio

n-to

-tre

at:y

esA

pri

ori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ybu

t ex

clud

ed h

istor

y of

gas

tric

ulc

er o

rha

emor

rhag

eB

asel

ine

NSA

ID s

tatu

s:ex

clud

ed p

atie

nts

who

had

nev

er r

ecei

ved

an N

SAID

Type

and

dur

atio

n of

art

hrit

is (

year

s):

RA, n

o fu

rthe

r de

tails

Age

: a 5

4 (2

4–73

), b

58 (2

9–76

)Se

x:M

/F: a

8/1

7, b

5/1

9 In

clus

ion

crit

eria

:act

ive

RA w

ith a

t le

ast

five

of t

he A

RA d

iagn

ostic

crit

eria

and

with

inSt

einb

rock

er p

rogr

essio

n (a

nato

mic

) sta

ges

I,II

or II

I and

in fu

nctio

nal c

lass

es I,

II o

r III

;ac

tive

RA c

onfir

med

by

the

pres

ence

of a

tle

ast

thre

e of

the

follo

win

g fo

ur c

riter

ia: s

ixor

mor

e te

nder

or

pain

ful j

oint

s on

mot

ion,

thre

e or

mor

e sw

olle

n jo

ints

, mor

ning

stiff

ness

dur

atio

n of

45

min

utes

or

mor

e,W

este

rgen

ery

thro

cyte

sed

imen

tatio

n ra

te o

f28

mm

/h o

r m

ore;

sev

eral

join

t sig

ns a

ndsy

mpt

oms,

suc

h as

mor

ning

stif

fnes

s, p

ain

onm

otio

n or

ten

dern

ess,

sw

ellin

g in

at

leas

t on

ejo

int

and

sym

met

rical

join

t sw

ellin

gin

volv

emen

t, ha

d to

be

pres

ent

cont

inuo

usly

for

at le

ast

6 w

eeks

; hist

ory

of a

pos

itive

ther

apeu

tic r

espo

nse

to o

ne o

r m

ore

NSA

IDs,

incl

udin

g as

pirin

, pat

ient

sdi

scon

tinui

ng N

SAID

s w

ere

requ

ired

to h

ave

a w

orse

ning

in a

t le

ast

two

of t

he c

riter

ia fo

rac

tive

dise

ase

at t

he e

nd o

f the

was

hout

Excl

usio

n cr

iter

ia:S

tein

broc

ker

prog

ress

ion

stag

e IV

or

func

tiona

l cla

ss IV

, or

met

any

of

the

ARA

exc

lusio

n cr

iteria

, hyp

erse

nsiti

vity

to

NSA

IDs

incl

udin

g as

pirin

or

who

had

nev

erre

ceiv

ed a

n N

SAID

for

the

trea

tmen

t of

RA

,ac

tive

pept

ic u

lcer

, hist

ory

of G

I ulc

er o

rha

emor

rhag

e, s

erio

us s

ympt

omat

ic d

iseas

e or

neur

olog

ical

or

psyc

holo

gica

l diso

rder

s;pr

egna

nt o

r nu

rsin

g w

omen

Com

pari

son:

etod

olac

SR

(b) v

spi

roxi

cam

(a)

Dur

atio

n:4

wee

ksIn

terv

enti

ons:

b, e

todo

lac

SR60

0m

g/60

0m

g da

ily; a

, piro

xica

m20

mg/

10–3

0m

g da

ily (2

0m

g on

ceda

ily)

Oth

er m

edic

atio

n:no

det

ails

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:y

es,

para

ceta

mol

up

to 5

00m

g ×4

dai

lydu

ring

was

hout

and

firs

t 7

days

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:yes

, up

to 2

wee

ksN

umbe

r an

d fr

eque

ncy

of v

isit

s:3

(0, 2

and

4 w

eeks

)

Allo

cate

d:a

25, b

24

Com

plet

ed:a

20,

b 2

1D

rop-

out:

a 5,

b 3

Ass

esse

d:a

25, b

24

Out

com

es r

epor

ted:

GI s

ympt

oms,

GI d

rop-

outs

, tot

al d

rop-

outs

How

wer

e ad

vers

eev

ents

ass

esse

d:pa

tient

com

plai

nts

reco

rded

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:hi

stor

y of

ulc

ers:

a 0

, b

0hi

stor

y of

ble

eds:

a 0

,b

0FU

ND

ING

Fund

ed b

y:W

yeth

-A

yers

t La

bora

torie

sA

ffilia

tion

of c

onta

ctau

thor

:Gre

enw

ich

Dist

rict

Hos

pita

l, U

KA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f stu

dyad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

0/3

Oth

er:t

his

is an

inte

rim r

epor

t


289


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Kha

n, 1

99211

1

Loca

tion

:Wal

es,

UK

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

eco

mpa

rabi

lity:

uncl

ear

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ybu

t ex

clud

ed p

atie

nts

with

act

ive

pept

ic u

lcer

or h

aem

orrh

age

Type

and

dur

atio

n of

art

hrit

is (

year

s):

dege

nera

tive

join

t di

seas

e of

the

kne

e, n

ofu

rthe

r de

tails

Age

:a 6

4 (5

2–76

), b

60 (4

6–76

)Se

x:M

/F: a

10/

22, b

13/

19

Incl

usio

n cr

iter

ia:4

6–76

yea

rs d

iagn

osed

as

suffe

ring

from

deg

ener

ativ

e jo

int

dise

ase

ofth

e kn

ee, X

-ray

rad

iogr

aphs

of t

he k

nee

wer

ere

quire

d to

sho

w a

t le

ast

two

of t

hefo

llow

ing

cond

ition

s: a

sym

met

ric jo

int

spac

ena

rrow

ing

with

sub

chon

dral

scl

eros

is,m

argi

nal o

steo

phyt

e fo

rmat

ion

orsu

bcho

ndra

l pse

udoc

ysts

with

scl

erot

ic w

alls;

clin

ical

crit

eria

wer

e pa

in o

f the

affe

cted

kne

eon

mot

ion

or a

t re

st, p

lus

at le

ast

one

of t

hefo

llow

ing

cond

ition

s: li

mita

tion

of m

otio

n,te

nder

ness

on

pres

sure

, sw

ellin

g, c

repi

tus,

stiff

ness

eith

er in

the

mor

ning

or

afte

rpr

olon

ged

inac

tivity

; at

base

line

activ

e di

seas

ew

as d

efin

ed a

s an

y th

ree

of t

he fo

llow

ing

five

crite

ria: a

sco

re o

f mod

erat

e or

gre

ater

for

wei

ght-

bear

ing

pain

, nig

ht p

ain

and

pain

inte

nsity

, stif

fnes

s of

at

leas

t 10

min

utes

dura

tion

on a

risin

g or

afte

r pr

olon

ged

inac

tivity

and

a r

atin

g of

fair

or w

orse

for

the

over

all a

sses

smen

t of

his/

her

cond

ition

;hi

stor

y of

pos

itive

the

rape

utic

res

pons

e to

one

or m

ore

NSA

ID, i

nclu

ding

asp

irin;

rout

ine

labo

rato

ry t

ests

wer

e re

quire

d to

be

with

in t

he n

orm

al r

ange

exc

ept

for

mild

elev

atio

n of

ery

thro

cyte

sed

imen

tatio

n ra

te;

patie

nts

disc

ontin

uing

NSA

IDs

wer

e re

quire

dto

hav

e a

flare

at

the

end

of t

he w

asho

utde

fined

as

a w

orse

ning

in t

he p

atie

nt’s

ove

rall

asse

ssm

ent

of h

is/he

r co

nditi

on a

nd a

wor

seni

ng in

tw

o of

the

follo

win

g fo

ur

Com

pari

son:

etod

olac

SR

(b) v

sdi

clof

enac

SR

(a)

Dur

atio

n:4

wee

ksIn

terv

enti

ons:

b, e

todo

lac

600

mg/

600

mg

daily

; a, d

iclo

fena

c10

0m

g/75

–150

mg

daily

O

ther

med

icat

ion:

no d

etai

lsA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:no

deta

ilsPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

es, u

p to

14

days

for

NSA

IDs

Num

ber

and

freq

uenc

y of

vis

its:

3 (0

, 2 a

nd 4

wee

ks)

Allo

cate

d:a

?32,

b ?3

2C

ompl

eted

:a: ?

28,

b ?2

7D

rop-

out:

a ?4

, b ?5

Ass

esse

d:a

32, b

32

Out

com

es r

epor

ted:

mor

talit

y, s

erio

usca

rdio

vasc

ular

or

rena

lill

ness

, GI d

rop-

outs

How

wer

e ad

vers

eev

ents

ass

esse

d:pa

tient

com

plai

nts

and

stud

y ev

ent

(any

adv

erse

expe

rienc

e, t

reat

men

tem

erge

nt s

ign

orsy

mpt

om, n

ewin

terc

urre

nt il

lnes

s or

clin

ical

ly s

igni

fican

tla

bora

tory

abn

orm

ality

)re

cord

edH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:hi

stor

y of

ulc

er: a

0,

b 0;

hist

ory

of b

leed

: a

0, b

0; C

VD: a

0, b

0;

rena

l/hep

atic

dise

ase:

a

0, b

0FU

ND

ING

Fund

ed b

y:no

t st

ated

Affi

liati

on o

f con

tact

auth

or:B

ridge

ndG

ener

al H

ospi

tal,

UK

Affi

liati

on o

fst

atis

tici

an: u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:0/

2O

ther

:thi

s is

anin

terim

rep

ort

Appendix 6

290

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

crite

ria: w

eigh

t-be

arin

g pa

in, n

ight

pai

n, p

ain

inte

nsity

and

stif

fnes

s du

ratio

nEx

clus

ion

crit

eria

:hyp

erse

nsiti

vity

toN

SAID

s, a

ctiv

e pe

ptic

ulc

er, h

istor

y of

GI

ulce

r or

hae

mor

rhag

e, s

igni

fican

t ren

al,

hepa

tic, h

aem

otol

ogic

al o

r ca

rdio

vasc

ular

dise

ase,

con

com

itant

dise

ase

affe

ctin

g th

ejo

ints

or

the

conn

ectiv

e tis

sue,

hist

ory

of s

kin

diso

rder

s pr

ecip

itate

d or

agg

rava

ted

by d

rugs

,cl

inic

ally

sig

nific

ant l

evel

s of

rhe

umat

oid

fact

or,

preg

nant

or

lact

atin

g w

omen

Wat

erw

orth

,19

9211

2

Loca

tion

:New

Zea

land

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

eco

mpa

rabi

lity:

noPa

rtic

ipan

t bl

indi

ng:

yes

Ass

esso

r bl

indi

ng:

uncl

ear

Inte

ntio

n-to

-tre

at:

uncl

ear

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

high

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ybu

t ex

clud

ed p

atie

nts

with

def

inite

pep

ticul

cer

dise

ase

in t

he la

st 5

yea

rsB

asel

ine

NSA

ID s

tatu

s:ex

clud

ed p

atie

nts

if ne

ver

take

n an

NSA

ID

Type

and

dur

atio

n of

art

hrit

is (

year

s):

OA

of t

he k

nee,

no

furt

her

deta

ilsA

ge:a

59.

3 (4

7–70

), b

59.8

(33–

72)

Sex:

M/F

: a 9

/20,

b 1

6/12

In

clus

ion

crit

eria

:18–

75 y

ears

with

radi

olog

ical

ly a

nd c

linic

ally

con

firm

ed O

A o

fth

e kn

ee a

nd w

ith a

hist

ory

of a

pos

itive

ther

apeu

tic r

espo

nse

to o

ne o

r m

ore

NSA

IDs,

X-r

ay fi

ndin

gs in

clud

ed t

wo

of t

hefo

llow

ing

with

in t

he p

revi

ous

6m

onth

s:as

ymm

etric

join

t sp

ace

narr

owin

g w

ithsu

bcho

ndra

l scl

eros

is, m

argi

nal o

steo

phyt

efo

rmat

ion,

or

subc

hond

ral p

seud

ocys

ts w

ithsc

lero

tic w

alls;

at

leas

t on

e of

the

follo

win

gcl

inic

al c

ondi

tions

was

req

uire

d: li

mita

tion

ofm

otio

n, t

ende

rnes

s on

pre

ssur

e, s

wel

ling,

crep

itus,

stif

fnes

s af

ter

sleep

or

prol

onge

din

activ

ity; p

atie

nts

who

had

with

draw

n fr

omN

SAID

s ha

d to

exh

ibit

a w

orse

ning

of a

t le

ast

Com

pari

son:

etod

olac

(b) v

spi

roxi

cam

(a)

Dur

atio

n: 6

wee

ksIn

terv

enti

ons:

b, e

todo

lac

600

mg/

600

mg

daily

(300

mg

×2 d

aily

); a

piro

xica

m20

mg/

10–3

0m

g da

ily (2

0m

g on

ceda

ily)

Oth

er m

edic

atio

n: a

ntic

oagu

lant

,or

al h

ypog

lyca

emic

, hep

atot

oxic

or

cort

icos

tero

id d

rugs

wer

e ex

clud

edA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:yes

,ac

etam

inop

hen

for

was

hout

and

the

first

wee

kPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

es, 2

wee

ks fo

r as

pirin

and

NSA

IDs

Num

ber

and

freq

uenc

y of

vis

its:

4 (0

, 2, 4

and

6 w

eeks

)

Allo

cate

d:a

29, b

28

Com

plet

ed:a

20,

b 2

3D

rop-

out:

a 9,

b 5

Ass

esse

d:a

29, b

28

Out

com

es r

epor

ted:

mor

talit

y, s

erio

us G

Ico

mpl

icat

ions

, ser

ious

card

iova

scul

ar o

r re

nal

illne

ss, G

I sym

ptom

s, G

Idr

op-o

uts,

ana

emia

How

wer

e ad

vers

eev

ents

ass

esse

d:pa

tient

com

plai

nts

reco

rded

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:hi

stor

y of

ulc

ers:

a 0

, b

0co

ncom

itant

use

of

antic

oagu

lant

s: a

0,

b 0

cort

icos

tero

ids:

a

0, b

0FU

ND

ING

Fund

ed b

y:W

yeth

-A

yers

t La

bora

torie

sA

ffilia

tion

of c

onta

ctau

thor

:Haw

kes

Bay

Are

a H

ealth

Boa

rd,

New

Zea

land

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:0/

2


291


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

two

of t

he fo

llow

ing

varia

bles

: wei

ght-

bear

ing

pain

act

ivity

, nig

ht p

ain,

stif

fnes

s af

ter

sleep

ing

or p

rolo

nged

inac

tivity

or

pain

inte

nsity

Excl

usio

n cr

iter

ia:p

atie

nts

who

had

nev

erre

ceiv

ed a

n N

SAID

, had

an

unsa

tisfa

ctor

yre

spon

se to

piro

xica

m, h

ad r

ecei

ved

etod

olac

at

any

time,

had

a h

istor

y of

ser

ious

med

ical

or

psyc

holo

gica

l diso

rder

s, h

ad d

efin

ite p

eptic

ulc

erdi

seas

e w

ithin

the

prev

ious

5 y

ears

or

had

any

conc

omita

nt d

iseas

e th

at a

ffect

ed th

e jo

ints

or

conn

ectiv

e tis

sue;

wom

en w

ho w

ere

preg

nant

or b

reas

t-fe

edin

g, p

atie

nts

who

had

und

ergo

nem

ajor

sur

gery

on

the

past

6w

eeks

and

thos

ew

ho u

sed

antic

oagu

lant

, ora

l hyp

ogly

caem

ic,

hepa

toto

xic

or c

ortic

oste

roid

dru

gs

Burs

sens

, 199

3113

Loca

tion

:5 s

ites

in B

elgi

um,

Ger

man

y an

dSw

itzer

land

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

no Part

icip

ant

blin

ding

:yes

Ass

esso

r bl

indi

ng:

uncl

ear

Inte

ntio

n-to

-tre

at:

uncl

ear

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

high

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ybu

t ex

clud

ed p

atie

nts

with

hist

ory

of a

ctiv

epe

ptic

ulc

er a

nd G

I hae

mor

rhag

eTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A, n

o fu

rthe

r de

tails

Age

:a 5

9 (4

4–73

), b

64 (4

7–80

)Se

x:M

/F: a

13/

23, b

14/

23In

clus

ion

crit

eria

:clin

ical

and

rad

iogr

aphi

cev

iden

ce o

f OA

of t

he k

nee,

dia

gnos

is of

activ

e O

A r

equi

red

any

thre

e of

the

follo

win

gfiv

e cr

iteria

: a s

core

whi

ch w

as a

t le

ast

mod

erat

e fo

r w

eigh

t-be

arin

g pa

in, n

ight

pai

nan

d pa

in in

tens

ity, s

tiffn

ess

of a

t le

ast

10m

inut

es d

urat

ion

on a

risin

g or

afte

rpr

olon

ged

inac

tivity

and

a p

atie

nt r

atin

g of

fair

or w

orse

for

the

over

all a

sses

smen

t of

his/

her

cond

ition

; hist

ory

of p

ositi

veth

erap

eutic

res

pons

e to

one

or

mor

e N

SAID

,in

clud

ing

aspi

rin; r

outin

e la

bora

tory

tes

tsw

ere

requ

ired

to b

e w

ithin

the

nor

mal

ran

geex

cept

for

mild

ele

vatio

n of

ery

thro

cyte

Com

pari

son:

etod

olac

SR

(b) v

ste

noxi

cam

(a)

Dur

atio

n:4

wee

ksIn

terv

enti

ons:

b, e

todo

lac

600

mg/

600

mg

daily

; a, t

enox

icam

20m

g/20

mg

daily

O

ther

med

icat

ion:

no d

etai

lsA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:no

deta

ilsPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

es, u

p to

14

days

for

NSA

IDs

Num

ber

and

freq

uenc

y of

vis

its:

3 (0

, 2 a

nd 4

wee

ks)

Allo

cate

d:a

36, b

37

Com

plet

ed:a

34,

b 3

5D

rop-

out:

a 2,

b 2

Ass

esse

d:a

36, b

37

Out

com

es r

epor

ted:

GI s

ympt

oms,

GI d

rop-

outs

, tot

al d

rop-

outs

How

wer

e ad

vers

eev

ents

ass

esse

d:no

deta

ilsH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:hi

stor

y of

ulc

ers:

a 0

, b

0hi

stor

y of

ble

eds:

a 0

,b

0C

VD: a

0, b

0re

nal/h

epat

ic d

iseas

e:

a 0,

b 0

FUN

DIN

GFu

nded

by:

not

stat

edA

ffilia

tion

of c

onta

ctau

thor

:Uni

vers

ityH

ospi

tal P

elte

nber

g,Be

lgiu

mA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f stu

dyad

min

istr

ator

:unc

lear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:0/

3 O

ther

:thi

s is

anin

terim

rep

ort

Appendix 6

292

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

sedi

men

tatio

n ra

te; p

atie

nts

disc

ontin

uing

NSA

IDs

wer

e re

quire

d to

hav

e a

flare

or

aw

orse

ning

in t

heir

over

all a

sses

smen

t, at

the

end

of t

he w

asho

ut d

efin

ed a

s a

wor

seni

ng in

the

patie

nts

over

all a

sses

smen

t of

his/

her

cond

ition

and

a w

orse

ning

in t

wo

of t

hefo

llow

ing

four

crit

eria

: wei

ght-

bear

ing

pain

,ni

ght

pain

, pai

n in

tens

ity a

nd s

tiffn

ess

dura

tion

Excl

usio

n cr

iter

ia:h

yper

sens

itivi

ty t

oN

SAID

s, a

ctiv

e pe

ptic

ulc

er, h

istor

y of

pep

ticul

cer,

GI h

aem

orrh

age,

sig

nific

ant

rena

l,he

patic

, hae

mot

olog

ical

or

card

iova

scul

ardi

seas

e, c

linic

ally

sig

nific

ant

leve

ls of

rheu

mat

oid

fact

or, p

regn

ant

or la

ctat

ing

wom

en

Dre

iser,

1993

A11

4

Loca

tion

:Fra

nce

Met

hod

ofra

ndom

isat

ion:

‘rand

omal

loca

tion’

Allo

cati

onco

ncea

lmen

t:un

clea

rB

asel

ine

com

para

bilit

y:no Pa

rtic

ipan

t bl

indi

ng:

uncl

ear

Ass

esso

r bl

indi

ng:

uncl

ear

Inte

ntio

n-to

-tre

at:

uncl

ear

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

high

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ybu

t ex

clud

ed p

atie

nts

with

act

ive

ulce

rTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A, h

ip/k

nee,

no

furt

her

deta

ilsA

ge:a

61.

2, b

67.

2Se

x:M

/F: a

12/

18, b

12/

17In

clus

ion

crit

eria

:30–

80 y

ears

, OA

of t

hehi

p or

kne

e co

nfirm

ed b

y ra

diol

ogy

Excl

usio

n cr

iter

ia:p

rese

nce

of n

on-

dege

nera

tive

join

t di

seas

es (e

.g. i

nfec

tious

,m

icro

crys

talli

ne),

seve

re a

nd d

isabl

ing

arth

ritis

and/

or e

ligib

ility

for

surg

ical

inte

rven

tion;

tre

atm

ent

with

intr

a-ar

ticul

arin

ject

ions

of c

ortic

oste

roid

s w

ithin

the

mon

thpr

eced

ing

the

stud

y; t

reat

men

t w

ithan

ticoa

gula

nts,

hyd

anto

in o

r an

tidia

betic

drug

s; h

istor

y of

sev

ere

hepa

tic, r

enal

or

haem

opoi

etic

dise

ase;

hist

ory

ofhy

pers

ensit

ivity

to

NSA

IDs;

pre

senc

e of

an

activ

e pe

ptic

ulc

er; p

regn

ancy

or

lact

atio

n

Com

pari

son:

nim

esul

ide

(b) v

spi

roxi

cam

(a)

Dur

atio

n:3

wee

ksIn

terv

enti

ons:

b, n

imes

ulid

e20

0m

g/?m

g da

ily (1

00m

g ×2

dai

ly);

a, p

iroxi

cam

20m

g/10

–30

mg

daily

(20

mg

once

daily

)O

ther

med

icat

ion:

intr

a-ar

ticul

arin

ject

ions

of c

ortic

oste

roid

s,an

ticoa

gula

nts,

hyd

anto

in o

ran

tidia

betic

dru

gs e

xclu

ded,

no

othe

r m

edic

atio

n lik

ely

to in

terf

ere

with

the

inve

stig

atio

nal d

rugs

was

perm

itted

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:p

arac

etam

olpr

escr

ibed

to

all p

atie

nts

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:no

deta

ilsN

umbe

r an

d fr

eque

ncy

of v

isit

s:3

(0, u

ncle

ar a

nd a

t 3

wee

ks)

Allo

cate

d: a

30,

b 2

9C

ompl

eted

:a 2

6, b

26

Dro

p-ou

t:a

4, b

3A

sses

sed:

a 30

, b 2

9O

utco

mes

rep

orte

d:to

tal d

rop-

outs

How

wer

e ad

vers

eev

ents

ass

esse

d:na

ture

and

sev

erity

of a

llad

vers

e ev

ents

rec

orde

dw

heth

er s

pont

aneo

usly

repo

rted

by

patie

nt o

rel

icite

d by

indi

rect

non

-sp

ecifi

c qu

estio

ning

by

inve

stig

ator

or

12pr

esel

ecte

d qu

estio

nsan

d ra

ted

on a

4-p

oint

verb

al r

atin

g sc

ale

byin

vest

igat

or a

nd p

atie

ntH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:co

ncom

itant

use

of

antic

oagu

lant

s: a

0,

b 0

cort

icos

tero

ids:

a 0

, b

0re

nal/h

epat

ic d

iseas

e: a

0, b

0FU

ND

ING

Fund

ed b

y:no

t st

ated

Affi

liati

on o

f con

tact

auth

or:2

5 Ru

eC

lape

yron

, Par

is,Fr

ance

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:1/

2 by

Hel

sinn

Hea

lthca

re


293


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Dre

iser,

1993

B114

Loca

tion:

Fra

nce

Met

hod

ofra

ndom

isat

ion:

‘rand

omal

loca

tion’

Allo

cati

onco

ncea

lmen

t:un

clea

rB

asel

ine

com

para

bilit

y:no Pa

rtic

ipan

t bl

indi

ng:

uncl

ear

Ass

esso

r bl

indi

ng:

uncl

ear

Inte

ntio

n-to

-tre

at:

uncl

ear

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

high

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ybu

t ex

clud

ed p

atie

nts

with

act

ive

ulce

rTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A, h

ip/k

nee,

no

furt

her

deta

ilsA

ge:a

60.

3, b

60.

2Se

x:M

/F: a

9/1

8, b

15/

13In

clus

ion

crit

eria

:30–

80 y

ears

, OA

of t

hehi

p or

kne

e co

nfirm

ed b

y ra

diol

ogy

Excl

usio

n cr

iter

ia:p

rese

nce

ofno

ndeg

ener

ativ

e jo

int

dise

ases

(e.g

.in

fect

ious

, mic

rocr

ysta

lline

), se

vere

and

disa

blin

g ar

thrit

is an

d/or

elig

ibili

ty fo

r su

rgic

alin

terv

entio

n; t

reat

men

t w

ith in

tra-

artic

ular

inje

ctio

ns o

f cor

ticos

tero

ids

with

in t

he m

onth

prec

edin

g th

e st

udy;

tre

atm

ent

with

antic

oagu

lant

s, h

ydan

toin

or

antid

iabe

ticdr

ugs;

hist

ory

of s

ever

e he

patic

, ren

al o

rha

emop

oiet

ic d

iseas

e; h

istor

y of

hype

rsen

sitiv

ity t

o N

SAID

s; p

rese

nce

of a

nac

tive

pept

ic u

lcer

; pre

gnan

cy o

r la

ctat

ion

Com

pari

son:

nim

esul

ide

(b) v

ske

topr

ofen

(a)

Dur

atio

n:8

wee

ksIn

terv

enti

ons:

b, n

imes

ulid

e20

0m

g/?m

g da

ily (1

00m

g ×2

dai

ly);

a, k

etop

rofe

n20

0m

g/10

0–20

0m

g da

ily (1

00m

g×2

dai

ly)

Oth

er m

edic

atio

n:in

tra-

artic

ular

inje

ctio

ns o

f cor

ticos

tero

ids,

antic

oagu

lant

s, h

ydan

toin

or

antid

iabe

tic d

rugs

exc

lude

d, n

oot

her

med

icat

ion

likel

y to

inte

rfer

ew

ith t

he in

vest

igat

iona

l dru

gs w

aspe

rmitt

edA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:par

acet

amol

pres

crib

ed t

o al

l pat

ient

sPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:n

o de

tails

Num

ber

and

freq

uenc

y of

vis

its:

4 (0

, unc

lear

, unc

lear

and

at

8w

eeks

)

Allo

cate

d:a

?27,

b ?2

8C

ompl

eted

:a: 2

5 b

24D

rop-

out:

a 2,

b 4

Ass

esse

d:a

27, b

28

Out

com

es r

epor

ted:

GI s

ympt

oms,

GI d

rop-

outs

, tot

al d

rop-

outs

How

wer

e ad

vers

eev

ents

ass

esse

d:na

ture

and

sev

erity

of a

llad

vers

e ev

ents

rec

orde

dw

heth

er s

pont

aneo

usly

repo

rted

by

patie

nt o

rel

icite

d by

indi

rect

non

-sp

ecifi

c qu

estio

ning

by

inve

stig

ator

or

12pr

esel

ecte

d qu

estio

nsan

d ra

ted

on a

4-p

oint

verb

al r

atin

g sc

ale

byin

vest

igat

or a

nd p

atie

ntH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:co

ncom

itant

use

of

antic

oagu

lant

s: a

0, b

0co

rtic

oste

roid

s:

a 0,

b 0

rena

l/hep

atic

dise

ase:

a

0, b

0FU

ND

ING

Fund

ed b

y:no

t st

ated

Affi

liati

on o

f con

tact

auth

or:2

5 Ru

eC

lape

yron

, Par

is,Fr

ance

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:1/

2 by

Hel

sinn

Hea

lthca

re

Appendix 6

294

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Eise

nkol

b, 1

99311

5

Loca

tion

:G

erm

any,

UK

and

Switz

erla

nd

Met

hod

of r

ando

mis

atio

n:‘ra

ndom

ised’

, pre

dete

rmin

edra

ndom

isatio

n sc

hedu

leA

lloca

tion

con

ceal

men

t:un

clea

rB

asel

ine

com

para

bilit

y:no

, eto

dola

c gr

oup

had

mor

e se

vere

art

hriti

csy

mpt

oms

Part

icip

ant

blin

ding

:yes

Ass

esso

r bl

indi

ng:u

ncle

arIn

tent

ion-

to-t

reat

:unc

lear

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

high

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

y, n

o fu

rthe

r de

tails

Ty

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A, k

nee,

no

furt

her

deta

ilsA

ge:a

60.

5 (3

7–76

), b

61.4

(37–

78)

Sex:

M/F

: a 2

4/45

, b 2

3/43

Incl

usio

n cr

iter

ia: 1

8–75

year

s w

ithac

tive

OA

of t

he k

nee

conf

irmed

by

X-r

ayst

udie

s an

d cl

inic

al c

riter

ia, p

rior

posit

ive

ther

apeu

tic r

espo

nse

to o

ne o

r m

ore

NSA

IDs

incl

udin

g as

pirin

Excl

usio

n cr

iter

ia:n

o de

tails

Com

pari

son:

etod

olac

(b) v

sdi

clof

enac

(a)

Dur

atio

n:6

wee

ksIn

terv

enti

ons:

b, e

todo

lac

600

mg/

600

mg

daily

(200

mg

×3 d

aily

); a,

dic

lofe

nac

150

mg/

75–1

50m

g da

ily (5

0m

g ×3

dai

ly)

Oth

er m

edic

atio

n:ph

ysic

alth

erap

y an

d w

alki

ng a

ids

coul

d be

cont

inue

dA

spir

in a

llow

ed:N

ot s

tate

dA

nalg

esic

allo

wed

:yes

,ac

etam

inop

hen

500

mg

×4 d

aily

durin

g w

asho

ut a

nd fi

rst

7 da

ysPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

es, 2

wee

ksN

umbe

r an

d fr

eque

ncy

of v

isit

s:4

(0, 2

, 4 a

nd 6

wee

ks)

Allo

cate

d:a

69, b

66

Com

plet

ed:a

52,

b 5

1D

rop-

out:

a 17

, b 1

5A

sses

sed:

a 69

, b 6

6O

utco

mes

rep

orte

d:G

I dro

p-ou

ts, t

otal

drop

-out

sH

ow w

ere

adve

rse

even

ts a

sses

sed:

node

tails

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:no

deta

ilsFU

ND

ING

Fund

ed b

y:W

yeth

-A

yers

t La

bora

torie

sA

ffilia

tion

of c

onta

ctau

thor

:Arz

t fu

rO

rhop

adie

,Rh

eum

atol

ogie

,C

hiro

ther

apie

,M

unst

er, G

erm

any

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:0/

4

Este

vez,

199

3116

Loca

tion

:U

rugu

ay

Met

hod

ofra

ndom

isat

ion:

‘ass

igne

dat

ran

dom

’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

no, r

egar

ding

age

Part

icip

ant

blin

ding

: yes

Ass

esso

r bl

indi

ng:

uncl

ear

Inte

ntio

n-to

-tre

at:

uncl

ear

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

high

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

y, n

o fu

rthe

r de

tails

Type

and

dur

atio

n of

art

hrit

is (

year

s):

OA

, no

furt

her

deta

ilsA

ge:a

64,

b 7

0Se

x:M

/F: a

1/9

, b 1

/9In

clus

ion

crit

eria

:OA

sta

ges

II–III

acco

rdin

g to

clin

ical

rad

iolo

gica

l eva

luat

ion

Excl

usio

n cr

iter

ia: O

A s

tage

s I a

nd IV

,ot

her

type

s of

art

hriti

s, s

ever

e re

nal o

rhe

patic

illn

esse

s, b

lood

pro

blem

s, a

llerg

ies

to d

iclo

fena

c or

nim

esul

ide

Com

pari

son:

nim

esul

ide

(b) v

sdi

clof

enac

(a)

Dur

atio

n:12

wee

ksIn

terv

enti

ons:

b, n

imes

ulid

e20

0m

g/?m

g da

ily, a

, dic

lofe

nac

100

mg/

75–1

50m

g da

ily

Oth

er m

edic

atio

n:no

det

ails

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:n

o de

tails

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:yes

, 1 w

eek

Num

ber

and

freq

uenc

y of

vis

its:

7 (0

, 2, 4

, 6, 8

, 10

and

12 w

eeks

)

Allo

cate

d:a

10, b

10

Com

plet

ed:a

9, b

10

Dro

p-ou

t:a

1, b

0A

sses

sed:

a 10

, b 1

0O

utco

mes

rep

orte

d:G

I sym

ptom

sH

ow w

ere

adve

rse

even

ts a

sses

sed:

node

tails

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:se

vere

rena

l/hep

atic

dise

ase:

a

0, b

0FU

ND

ING

Fund

ed b

y:no

t st

ated

Affi

liati

on o

f con

tact

auth

or:U

nive

rsid

adde

la R

epub

lica,

Mon

tevi

deo

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:4/

5 by

Labo

rato

ries

Gau

tier

Oth

er:t

rans

late

d


295


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Porz

io, 1

99311

7

Loca

tion

:G

erm

any

and

Italy

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

no Part

icip

ant

blin

ding

: yes

Ass

esso

r bl

indi

ng:

uncl

ear

Inte

ntio

n-to

-tre

at: y

esA

pri

ori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

high

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ybu

t ex

clud

ed p

atie

nts

with

act

ive

pept

ic u

lcer

,hi

stor

y of

GI u

lcer

or

haem

orrh

age

Bas

elin

e N

SAID

sta

tus:

excl

uded

pat

ient

sth

at h

ad n

ever

rec

eive

d N

SAID

sTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:RA

, no

furt

her

deta

ilsA

ge:a

55

(26–

73),

b 58

(18–

74)

Sex:

M/F

: a 7

/34,

b 8

/42

Incl

usio

n cr

iter

ia:e

xhib

ited

at le

ast

five

ofth

e A

RA d

iagn

ostic

crit

eria

and

wer

e w

ithin

Stei

nbro

cker

pro

gres

sion

(ana

tom

ic) s

tage

s I,

II or

III a

nd in

func

tiona

l cla

ss I,

II o

r III

; act

ive

RA c

onfir

med

by

at le

ast

thre

e of

the

follo

win

g fo

ur c

riter

ia: s

ix o

r m

ore

tend

er o

rpa

infu

l joi

nts

on m

otio

n, t

hree

or

mor

esw

olle

n jo

ints

, mor

ning

stif

fnes

s du

ratio

n of

45 m

inut

es o

r m

ore,

Wes

terg

en e

ryth

rocy

tese

dim

enta

tion

rate

of 2

8m

m/h

or

long

er;

seve

ral j

oint

sig

ns a

nd s

ympt

oms

such

as

mor

ning

stif

fnes

s, p

ain

on m

otio

n or

tend

erne

ss, s

wel

ling

in a

t le

ast

one

join

t an

dsy

mm

etric

al jo

int

swel

ling

invo

lvem

ent,

had

to b

e pr

esen

t co

ntin

uous

ly fo

r at

leas

t6

wee

ks; h

istor

y of

pos

itive

the

rape

utic

resp

onse

to

one

or m

ore

NSA

ID, i

nclu

ding

aspi

rin; p

atie

nts

disc

ontin

uing

NSA

IDs

wer

ere

quire

d to

hav

e a

wor

seni

ng in

at

leas

t tw

oof

the

crit

eria

for

activ

e RA

Excl

usio

n cr

iter

ia:S

tein

broc

ker

prog

ress

ion

stag

e IV

or

func

tiona

l cla

ss IV

or

thos

e w

hom

et a

ny o

f the

ARA

exc

lusio

n cr

iteria

;hy

pers

ensit

ivity

to

NSA

IDs

incl

udin

g as

pirin

,ha

d ne

ver

rece

ived

an

NSA

ID fo

r th

etr

eatm

ent

of R

A, a

ctiv

e pe

ptic

ulc

er, h

istor

yof

GI u

lcer

or

haem

orrh

agia

, ser

ious

sym

ptom

atic

dise

ases

, or

neur

olog

ical

or

psyc

holo

gica

l diso

rder

s; w

omen

who

wer

epr

egna

nt o

r la

ctat

ing

Com

pari

son:

eto

dola

c SR

(b) v

sdi

clof

enac

SR

(a)

Dur

atio

n:4

wee

ksIn

terv

enti

ons:

b, e

todo

lac

SR60

0m

g/60

0m

g da

ily; a

dic

lofe

nac

SR 1

00m

g/75

–100

mg

daily

O

ther

med

icat

ion:

no d

etai

lsA

spir

in a

llow

ed: n

ot s

tate

dA

nalg

esic

allo

wed

:yes

,pa

race

tam

ol u

p to

500

mg

×3 d

aily

durin

g w

asho

ut a

nd fi

rst

7 da

ysPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

es u

p to

2 w

eeks

Num

ber

and

freq

uenc

y of

vis

its:

3 (0

, 2 a

nd 4

wee

ks)

Allo

cate

d:a

41, b

50

Com

plet

ed:a

38,

b 4

3D

rop-

out:

a 3,

b 7

Ass

esse

d:a

41, b

50

Out

com

es r

epor

ted:

GI d

rop-

outs

, tot

aldr

op-o

uts

How

wer

e ad

vers

eev

ents

ass

esse

d:no

deta

ilsH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:hi

stor

y of

ulc

er: a

0,

b 0

hist

ory

of b

leed

s: a

0,

b 0

>65

yea

rsFU

ND

ING

Fund

ed b

y: W

yeth

-A

yers

t La

bora

torie

sA

ffilia

tion

of c

onta

ctau

thor

:Lud

wig

-M

axim

ilian

sU

nive

rsitä

t, M

unic

h,G

erm

any

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:0/

2O

ther

:thi

s is

anin

terim

rep

ort

Appendix 6

296

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Roth

, 199

378

Loca

tion

:6ce

ntre

s in

the

USA

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’, p

artic

ipan

tsas

signe

d a

trea

tmen

tnu

mbe

r th

atco

rres

pond

ed w

ithtr

eatm

ent

med

icat

ion

Allo

cati

onco

ncea

lmen

t:un

clea

r B

asel

ine

com

para

bilit

y:N

o, m

isopr

osto

l gro

upco

ntai

ned

youn

ger

part

icip

ants

and

mor

ew

ith n

orm

al e

ndos

copi

esPa

rtic

ipan

t bl

indi

ng:

uncl

ear

Ass

esso

r bl

indi

ng:y

esIn

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

high

Bas

elin

e G

I st

atus

:no

mor

e th

an 3

eros

ions

at

base

line

endo

scop

y, n

orm

alen

dosc

opy:

a 1

7, b

18,

c 2

7hy

pere

mia

: a 2

4, b

20,

c 1

7er

osio

ns: a

17,

b 1

5, c

13

Type

and

dur

atio

n of

art

hrit

is:

OA

: all

part

icip

ants

, no

othe

r de

tails

Age

:60–

64: a

15,

b 1

7, c

22;

65–

74: a

34,

b32

, c 3

5; ≥

75: a

9, b

4, c

3Se

x:F/

M: a

19/

39, b

12/

41, c

11/

49

Incl

usio

n cr

iter

ia:O

A a

ged

60 y

ears

or

olde

r, A

CR

func

tiona

l cla

ss II

or

III, u

sed

anN

SAID

for

at le

ast

3 m

onth

s be

fore

enro

lmen

t an

d ex

pect

ed t

o co

ntin

ue t

he u

seof

thi

s cl

ass

of m

edic

atio

n fo

r at

leas

t3

mon

ths

Excl

usio

n cr

iter

ia:h

istor

y of

hype

rsen

sitiv

ity r

eact

ion

to a

ny o

f the

stu

dydr

ugs,

inef

ficac

y or

into

lera

nce

to ib

upro

fen,

hist

ory

of M

I with

in la

st 6

mon

ths,

con

gest

ive

hear

t fa

ilure

, med

ical

ly u

ncon

trol

led

hype

rten

sion

or a

rrhy

thm

ias,

hist

ory

of a

nul

cer

or G

I tra

ct b

leed

ing

with

in 1

year

of

stud

y en

try,

hist

ory

of g

astr

oduo

dena

l or

eoso

phag

eal s

urge

ry, s

igni

fican

t lo

wer

-bow

eldi

seas

e (in

clud

ing

regi

onal

ent

eriti

s, u

lcer

ativ

eco

litis,

inte

stin

al b

ypas

s su

rger

y, fr

eque

ntly

blee

ding

hae

mor

rhoi

ds),

OA

whi

ch r

equi

red

trea

tmen

t w

ith m

ultip

le N

SAID

s w

ithin

3m

onth

s of

enr

olm

ent,

patie

nts

cons

ider

edto

be

cand

idat

es fo

r jo

int

repl

acem

ent

durin

gtim

e of

the

stu

dy, p

atie

nts

who

had

rec

eive

din

tra-

artic

ular

ste

roid

inje

ctio

ns o

r or

alst

eroi

ds w

ithin

1 m

onth

of e

nrol

men

t

Com

pari

son:

miso

pros

tol p

lus

ibup

rofe

n (c

) vs

ibup

rofe

n (b

) vs

nabu

met

one

(a)

Dur

atio

n:12

wee

ksIn

terv

enti

ons:

c, m

isopr

osto

l80

0µg

/400

–800

µg (4

×20

0 µg

daily

)N

SAID

s:c,

ibup

rofe

n24

00m

g/60

0–24

00m

g (4

×60

0m

gda

ily, a

dmin

ister

ed c

oncu

rren

tlyw

ith m

isopr

osto

l); b

, ibu

prof

en24

00m

g/60

0–24

00m

g (4

×60

0m

gda

ily);

a, n

abum

eton

e10

00m

g/50

0–20

00m

g da

ily (n

oot

her

deta

ils)

Endo

scop

y:0,

2, 6

, 12

wee

ks a

ndat

ear

ly w

ithdr

awal

Oth

er m

edic

atio

n:co

ncom

itant

med

icat

ion

was

allo

wed

with

the

exce

ptio

n of

ant

icoa

gula

nts,

oth

eran

ti-in

flam

mat

orie

s, c

ortic

oste

roid

s,im

mun

osup

pres

sant

the

rapy

, ulc

erth

erap

y (H

2RA

s, s

ucra

lfate

, lon

g-te

rm a

ntac

id t

hera

py)

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:p

arac

etam

olm

ax. 1

2×32

5m

g ta

blet

s in

24

hPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

es, 3

–10

days

dur

ing

whi

ch a

dmin

ister

ed p

lace

bo 3

xda

ilyN

umbe

r an

d fr

eque

ncy

of v

isit

s:7

(0, 2

, 4, 6

, 8, 1

0 an

d 12

wee

ks)

Allo

cate

d:a

58, b

53,

c60

C

ompl

eted

:a 4

6, b

25,

c 45

Dro

p-ou

t:a

12, b

28,

c15

Ass

esse

d fo

r G

Isy

mpt

oms:

a 5

8, b

53,

c 60

O

utco

mes

rep

orte

d:G

I sym

ptom

s,en

dosc

opic

ulc

ers,

anae

mia

, GI d

rop-

outs

H

ow w

ere

adve

rse

even

ts a

sses

sed:

part

icip

ants

ask

ed if

ther

e ha

d be

en a

nypr

oble

ms

since

last

visi

tH

ow w

as c

ompl

ianc

eas

sess

ed:t

able

t co

unt

Ris

k fa

ctor

s:hi

stor

y of

ulc

ers

(1 y

ear

or m

ore

ago)

: a

10, b

14,

c 1

4al

l par

ticip

ants

age

d60

year

s or

mor

eC

VD: a

0, b

0FU

ND

ING

Fund

ed b

y:Sm

ithK

line

Beec

ham

Phar

mac

eutic

als

Affi

liati

on o

f con

tact

auth

or:A

rthr

itis

Cen

ter,

Phoe

nix,

AZ

,U

SAA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

uncl

ear


297


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Perp

igna

no,

1994

118

Loca

tion

:Ita

ly

Met

hod

ofra

ndom

isat

ion:

pred

eter

min

edra

ndom

isatio

n sc

hedu

lepr

ovid

ed b

y W

yeth

Ital

iaA

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

uncl

ear

Part

icip

ant

blin

ding

:yes

Ass

esso

r bl

indi

ng:

uncl

ear

Inte

ntio

n-to

-tre

at:n

oA

pri

ori

sam

ple

size

:yes

Sum

mar

y ri

sk o

f bia

s:m

oder

ate

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ybu

t ex

clud

ed p

atie

nts

with

act

ive

pept

ic u

lcer

,hi

stor

y of

GI u

lcer

or

haem

orrh

age

eith

eras

soci

ated

with

NSA

ID u

se o

r in

the

last

3ye

ars

Bas

elin

e N

SAID

sta

tus:

excl

uded

pat

ient

sw

ho h

ad n

ever

rec

eive

d N

SAID

sTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A: o

f the

hip

or

knee

, no

furt

her

deta

ilsA

ge:a

71.

0 b

70.4

Sex:

M/F

a 5

/55

b 9/

51In

clus

ion

crit

eria

:65

year

s or

old

er w

ithac

tive

OA

of t

he h

ip o

r kn

ee c

onfir

med

by

roen

tgen

olog

ical

and

clin

ical

crit

eria

; pat

ient

sha

d to

sho

w a

gra

de 3

(red

uctio

n of

join

tsp

ace,

mod

erat

e m

argi

nal o

steo

phyt

osis)

or

grad

e 4

(red

uctio

n of

join

t sp

ace,

rem

arka

ble

mar

gina

l ost

eoph

ytos

is an

d su

bcho

ndra

lsc

lero

sis) i

n th

e Ke

llgre

n’s

scal

e; a

n X

-ray

exam

inat

ion

of t

he a

ffect

ed jo

int

mus

t ha

vebe

en d

one

in t

he p

revi

ous

12m

onth

s, c

linic

alcr

iteria

of t

he a

ctiv

ity o

f the

dise

ase

wer

e: a

scor

e of

at

leas

t 4

in t

he v

iso-a

nalo

gue

scal

eof

glo

bal p

ain

and

a sc

ore

of a

t le

ast

8 in

the

Lequ

esne

alg

ofun

ctio

nal i

ndex

, hist

ory

ofpo

sitiv

e th

erap

eutic

res

pons

e to

one

or

mor

eN

SAID

, inc

ludi

ng a

spiri

n; p

atie

nts

disc

ontin

uing

NSA

IDs

Excl

usio

n cr

iter

ia:h

yper

sens

itivi

ty t

oN

SAID

s in

clud

ing

aspi

rin, t

hose

who

had

neve

r re

ceiv

ed N

SAID

s fo

r th

e tr

eatm

ent

ofO

A, r

ecei

ved

inve

stig

atio

nal N

SAID

s w

ithin

the

prec

edin

g m

onth

; the

follo

win

g m

edic

alco

nditi

ons

and

med

icat

ions

also

pre

clud

eden

try

to t

he s

tudy

: act

ive

pept

ic u

lcer

, hist

ory

of G

I ulc

er o

r ha

emor

rhag

e, e

ither

ass

ocia

ted

with

NSA

ID u

se o

r w

ithin

the

last

3 y

ears

;sig

nific

ant

rena

l, he

patic

, hae

mat

olog

ical

or

card

iova

scul

ar d

iseas

e; a

ny c

ondi

tion

likel

y to

Com

pari

son:

etod

olac

SR

(b) v

ste

noxi

cam

(a)

Dur

atio

n:8

wee

ksIn

terv

enti

ons:

doub

le d

umm

y b,

eto

dola

c SR

600

mg/

600

mg

daily

; a, t

enox

icam

20

mg/

20m

gda

ilyO

ther

med

icat

ion:

no o

ther

NSA

IDs

or a

nalg

esic

s,co

rtic

oste

roid

s, a

ntic

oagu

lant

sex

clud

ed, m

edic

atio

n fo

r ch

roni

cco

nditi

ons

tole

rate

d if

not

disa

llow

ed in

the

pro

toco

l, ph

ysic

alth

erap

y no

t al

low

ed b

ut w

alki

ngai

ds p

erm

itted

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:y

es,

para

ceta

mol

up

to 5

00m

g ×4

dai

lydu

ring

was

hout

onl

yPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

es, a

t le

ast

7 da

ys fo

rN

SAID

s an

d 14

days

for

oxic

amde

rivat

ives

Num

ber

and

freq

uenc

y of

vis

its:

4 (0

, 2, 4

and

8 w

eeks

)

Allo

cate

d:a

60, b

60

Com

plet

ed:a

48,

b 4

8D

rop-

out:

a 12

, b 1

2A

sses

sed:

a 60

, b 6

0O

utco

mes

rep

orte

d:sy

mpt

omat

ic u

lcer

s, G

Idr

op-o

uts,

end

osco

pic

ulce

rs, t

otal

dro

p-ou

tsH

ow w

ere

adve

rse

even

ts a

sses

sed:

any

nega

tive

even

t w

ascl

asse

d as

an

adve

rse

even

t, sp

ecifi

c co

nditi

onw

as r

ecor

ded,

any

per

stud

y in

dica

tion,

dat

esan

d tim

es o

f occ

urre

nce,

seve

rity,

rel

atio

nshi

p to

stud

y m

edic

atio

n,co

unte

rmea

sure

s an

dou

tcom

eH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:hi

stor

yof

ulc

er: a

0, b

0;

hist

ory

of b

leed

s: a

0,

b 0;

co

ncom

itant

use

of

antic

oagu

lant

s: a

0,

b 0

cort

icos

tero

ids:

a0,

b

0>

1 N

SAID

: a0,

b 0

CVD

: a 0

, b 0

rena

l/hep

atic

dise

ase:

a0,

b 0

FUN

DIN

GFu

nded

by:

not

stat

edA

ffilia

tion

of c

onta

ctau

thor

:Uni

vers

ity o

fPi

sa, I

taly

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:0/

3 N

ote:

Wye

th p

rovi

ded

the

rand

omisa

tion

sche

dule

and

the

med

ical

mon

itorin

g of

the

stud

y

Appendix 6

298

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

inte

rfer

e w

ith d

rug

abso

rptio

n, d

istrib

utio

n,m

etab

olism

or

excr

etio

n; e

vide

nce

ofco

ncom

itant

dise

ase

that

cou

ld h

ave

affe

cted

join

ts, s

uch

as p

soria

sis, s

yphi

litic

neu

ropa

thy,

ochr

onos

is, m

etab

olic

bon

e di

seas

e,in

flam

mat

ory

bow

el d

iseas

e or

acu

te t

raum

a;co

exist

ence

of a

ny c

onne

ctiv

e-tis

sue

diso

rder

; maj

or s

urge

ry w

ithin

the

pas

t6

wee

ks; d

iabe

tes

trea

ted

with

hypo

glyc

aem

ic a

gent

s or

with

sig

nific

ant

com

plic

atio

ns; h

istor

y of

alc

ohol

ism a

nd/o

rdr

ug a

buse

with

in t

he p

ast

year

; sig

nific

ant

psyc

hiat

ric d

isord

er; p

ast

or p

rese

ntm

alig

nanc

y, e

xcep

t su

cces

sful

ly r

esec

ted

basa

l-cel

l car

cino

ma;

hist

ory

of s

kin

diso

rder

spr

ecip

itate

d or

agg

rava

ted

by d

rugs

; any

cond

ition

tha

t re

quire

d ne

w d

rug

ther

apy

atth

e tim

e of

ent

ry in

to t

he s

tudy

; clin

ical

lysig

nific

ant

posit

ive

resu

lts o

f tes

t fo

rrh

eum

atoi

d fa

ctor

; cur

rent

or

rece

nt s

ever

ein

fect

ions

, inc

ludi

ng t

uber

culo

sis, o

rpr

ophy

lact

ic t

reat

men

t w

ith a

nti-t

uber

culo

sisag

ents

; ora

l cor

ticos

tero

ids

with

in t

hepr

evio

us 6

mon

ths,

or

intr

a-ar

ticul

ar o

rpa

rent

eral

inje

ctio

n of

cor

ticos

tero

ids

with

inth

e pr

evio

us 4

wee

ks; o

ral o

r pa

rent

eral

antic

oagu

lant

s, a

nd s

igni

fican

t ab

norm

aliti

es in

labo

rato

ry p

erfo

rmed

prio

r to

the

sta

rt o

fth

erap

y


299


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Car

rabb

a,19

9511

9,22

7

Loca

tion

:21

cent

res

in It

aly,

3ce

ntre

s in

Ger

man

y

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:no,

piro

xica

m a

nd m

elox

icam

supp

osito

ries

diffe

red

insh

ape

and

colo

ur a

nd‘m

ay h

ave

been

reco

gnise

d by

som

epa

rtic

ipan

ts’

Ass

esso

r bl

indi

ng:n

oIn

tent

ion-

to-t

reat

:yes

A p

riori

sam

ple

size

:yes

Sum

mar

y ri

sk o

f bia

s:m

oder

ate

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

y,pa

rtic

ipan

ts e

xclu

ded

if ev

iden

ce o

f act

ive

pept

ic u

lcer

in p

revi

ous

6 m

onth

s Ty

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A: a

5.9

, b: 5

.8

Age

:a 6

2.5,

b: 6

1.4

Sex:

M/F

: a 1

7/92

, b: 3

3/18

3In

clus

ion

crit

eria

:35–

80 y

ears

with

clin

ical

ly d

efin

ed d

iagn

osis

of O

A (h

ip o

rkn

ee),

requ

ired

NSA

ID t

reat

men

t fo

rsy

mpt

oms,

sta

bilis

ed r

egim

en o

fco

rtic

oste

roid

s th

erap

y al

low

edEx

clus

ion

crit

eria

:mel

oxic

am p

revi

ously

take

n, o

r ot

her

stud

y dr

ugs

in la

st 4

wee

ks,

preg

nanc

y, la

ctat

ion

or o

f chi

ldbe

arin

gpo

tent

ial w

ithou

t ade

quat

e co

ntra

cept

ion,

live

rin

suffi

cien

cy, r

enal

insu

ffici

ency

, New

Yor

kH

eart

Ass

ocia

tion

clas

s III

or

IV h

eart

failu

re,

seve

re u

ncon

trol

led

hype

rten

sion,

any

sev

ere

met

abol

ic o

r ha

emat

olog

ical

dise

ase,

can

cer,

men

tal d

istur

banc

e or

bro

nchi

al a

sthm

a,cl

inic

al e

vide

nce

of a

ctiv

e pe

ptic

ulc

er d

urin

gth

e pr

evio

us 6

mon

ths,

Cro

hn’s

dise

ase,

ulce

rativ

e co

litis,

pro

ctiti

s, h

aem

orrh

oids

, any

dise

ase

whi

ch w

ould

inte

rfer

e w

ithsu

ppos

itory

abs

orpt

ion,

wor

sen

loca

l tol

eran

ceor

inte

rfer

e w

ith e

valu

atio

n of

loca

l tol

eran

ce,

clin

ical

ly s

igni

fican

t abn

orm

al la

bora

tory

inve

stig

atio

ns, h

istor

y of

hype

rsen

sitiv

ity to

anal

gesic

s, a

ntip

yret

ics

or N

SAID

s, h

istor

y of

poor

tole

ranc

e to

sup

posit

orie

s, tr

eatm

ent

with

oth

er N

SAID

s (s

yste

mic

or

topi

cal),

topi

cal a

nti-i

nfla

mm

ator

y pr

epar

atio

ns, m

uscl

ere

laxa

nts,

ant

icoa

gula

nts,

lith

ium

, hyd

anto

ins

or a

ny d

rug

adm

inist

ered

as

a su

ppos

itory

, due

to u

nder

go o

rtho

paed

ic s

urge

ry d

urin

g th

est

udy,

rece

ivin

g ch

ange

s in

phy

sioth

erap

y or

pres

entin

g w

ith a

ny o

ther

dise

ase

whi

ch c

ould

inte

rfer

e w

ith e

valu

atio

n of

saf

ety

or e

ffica

cy

Com

pari

son:

mel

oxic

amsu

ppos

itorie

s (b

) vs

piro

xica

msu

ppos

itorie

s (a

) D

urat

ion:

3 w

eeks

Inte

rven

tion

s:b,

mel

oxic

am15

mg/

7.5–

15m

g da

ily; a

, piro

xica

m20

mg/

10–3

0m

g da

ily; a

ll in

sert

edre

ctal

ly in

eve

ning

bef

ore

bed

Oth

er m

edic

atio

n:co

rtic

oste

roid

sal

low

ed if

sta

bilis

ed r

egim

en u

sed

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:y

es,

para

ceta

mol

up

to 4

g/da

yPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

es, h

alf l

ife o

f pre

viou

slyta

ken

NSA

IDs

Num

ber

and

freq

uenc

y of

vis

its:

3 (0

, day

7 a

nd d

ay 2

1)

Allo

cate

d: a

109

, b 2

16C

ompl

eted

:a 1

00,

b20

4D

rop-

out:

a 9,

b 1

2 A

sses

sed:

a 10

8, b

216

O

utco

mes

rep

orte

d:se

rious

GI

com

plic

atio

ns, G

Isy

mpt

oms

How

wer

e ad

vers

eev

ents

ass

esse

d:co

ded

acco

rdin

g to

WH

OA

RT,

no o

ther

det

ails

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:co

ncom

itant

use

of

antic

oagu

lant

s: a

0,

b 0

>1

NSA

ID: a

0, b

0C

VD: a

0, b

0;

rena

l/hep

atic

dise

ase:

a

0, b

0FU

ND

ING

Fund

ed b

y:no

t st

ated

Affi

liati

on o

f con

tact

auth

or:B

oehr

inge

rIn

gelh

eim

Ital

iaA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

2 ou

t of

6au

thor

s w

orke

d fo

rBo

ehrin

ger

Inge

lhei

mIta

lia

Appendix 6

300

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Dor

e, 1

99512

0

Loca

tion

:11

cent

res

in t

heU

SA

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

uncl

ear

Part

icip

ant

blin

ding

:yes

Ass

esso

r bl

indi

ng:

uncl

ear

Inte

ntio

n-to

-tre

at:y

esA

pri

ori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ybu

t ex

clud

ed p

atie

nts

with

hist

ory

of G

I ble

edTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A k

nee,

no

furt

her

deta

ilsA

ge:a

63.

7 b

63.8

Sex:

M/F

: a 3

0/52

, b 3

4/52

Incl

usio

n cr

iter

ia:o

utpa

tient

s, 4

0 ye

ars

orov

er, r

adio

logi

cally

con

firm

ed O

A o

f the

kne

eth

at r

equi

red

NSA

ID t

reat

men

t, pa

tient

s ha

dto

hav

e ac

tive

dise

ase

afte

r th

e w

asho

ut a

sde

fined

by

the

follo

win

g pr

imar

y ef

ficac

yva

riabl

es: o

vera

ll as

sess

men

t of

con

ditio

n by

both

the

pat

ient

and

the

inve

stig

ator

had

to

be fa

ir or

poo

r; jo

int

tend

erne

ss a

nd w

alki

ngpa

in h

ad t

o be

ass

esse

d as

mod

erat

e to

ver

yse

vere

; sec

onda

ry e

ffica

cy v

aria

bles

stu

died

incl

uded

inac

tivity

stif

fnes

s, n

ight

tim

e pa

inan

d qu

ality

of s

leep

Excl

usio

n cr

iter

ia:c

onne

ctiv

e tis

sue

diso

rder

; sch

edul

ed fo

r jo

int

repl

acem

ent

with

in 1

year

; had

a h

istor

y of

GI b

leed

ing,

rena

l or

hepa

tic im

pairm

ent,

drug

-indu

ced

skin

diso

rder

or

any

othe

r ill

ness

like

ly t

oin

terf

ere

with

the

eva

luat

ion

or d

ispos

ition

of

the

stud

y dr

ug; h

ad a

con

trai

ndic

atio

n to

NSA

IDs;

or

had

rece

nt c

ortic

oste

roid

,in

vest

igat

iona

l ant

icoa

gula

nt, o

rcy

topr

otec

tive

ther

apy;

wom

en w

ho w

ere

preg

nant

, bre

astfe

edin

g or

of c

hild

bear

ing

pote

ntia

l and

not

usin

g bi

rth

cont

rol

Com

pari

son:

etod

olac

(b) v

sna

prox

en (a

) D

urat

ion:

4 w

eeks

Inte

rven

tion

s:b,

eto

dola

c80

0m

g/60

0m

g da

ily (4

00m

g ×2

dai

ly);

a, n

apro

xen

1000

mg/

750–

1250

mg

daily

(500

mg

×2 d

aily

)O

ther

med

icat

ion:

othe

rco

ncom

itant

NSA

IDs,

cort

icos

tero

ids,

sal

icyl

ate-

cont

aini

ngto

pica

l pre

para

tions

and

new

or

alte

red

phys

ioth

erap

y w

ere

proh

ibite

dA

spir

in a

llow

ed:l

ow-d

ose

(5%

etod

olac

gro

up a

nd 1

0% n

apro

xen

grou

p to

ok a

spiri

n)A

nalg

esic

allo

wed

:yes

,ac

etam

inop

hen

(12%

eto

dola

cgr

oup

and

16%

nap

roxe

n gr

oup

took

ace

tam

inop

hen)

, occ

asio

nal

NSA

ID fo

r no

n-ar

thrit

ic p

ain

also

allo

wed

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:yes

, lon

g-ac

ting

NSA

IDs

requ

ired

7 da

ys a

nd o

ther

NSA

IDs

requ

ired

at le

ast

5 ha

lf-liv

esN

umbe

r an

d fr

eque

ncy

of v

isit

s:3

(0, 2

and

4 w

eeks

)

Allo

cate

d:a

82, b

86

Com

plet

ed:a

67,

b 6

6D

rop-

out:

a 1

5, b

20

Ass

esse

d:a

82, b

86

Out

com

es r

epor

ted:

serio

us G

Ico

mpl

icat

ions

, GI

sym

ptom

s, t

otal

dro

p-ou

tsH

ow w

ere

adve

rse

even

ts a

sses

sed:

reco

rded

any

neg

ativ

eev

ent,

stud

y ev

ents

and

vita

l sig

nsH

ow w

as c

ompl

ianc

eas

sess

ed: c

apsu

le c

ount

(mor

e th

an 9

0%co

mpl

ianc

e in

eac

hgr

oup)

Ris

k fa

ctor

s:hi

stor

y of

ble

eds:

a 0

,b

0co

ncom

itant

antic

oagu

lant

s: a

0,

b 0

cort

icos

tero

ids:

a

0, b

0>

1 N

SAID

: a 0

, b 0

rena

l/hep

atic

dise

ase:

a

0, b

0FU

ND

ING

Fund

ed b

y:W

yeth

-A

yers

t La

bora

torie

sA

ffilia

tion

of c

onta

ctau

thor

:priv

ate

prac

tice,

Ana

heim

, CA

,U

SAA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f stu

dyad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

3/4

byW

yeth

-Aye

rst


301


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Qua

ttrin

i, 19

9512

1

Loca

tion

:Ita

lyM

etho

d of

rand

omis

atio

n:‘ra

ndom

ly a

lloca

ted’

,do

uble

dum

my

tech

niqu

e,co

de fo

r ea

ch m

edic

atio

npa

ckag

e w

as s

uppl

ied

in a

seal

ed e

nvel

ope

and

open

ed a

t th

e en

d of

the

tria

lA

lloca

tion

conc

ealm

ent:

adeq

uate

Bas

elin

e co

mpa

rabi

lity:

uncl

ear

Part

icip

ant

blin

ding

:yes

Ass

esso

r bl

indi

ng:

uncl

ear

Inte

ntio

n-to

-tre

at:

uncl

ear

A p

riori

sam

ple

size

:yes

Sum

mar

y ri

sk o

f bia

s:m

oder

ate

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ype

rfor

med

but

exc

lude

d pa

tient

s w

ith h

istor

yof

pep

tic u

lcer

atio

n or

GI b

leed

ing

inpr

evio

us 1

2 m

onth

s Ty

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A, a

ppro

xim

atel

y 5

year

s du

ratio

n fo

r al

lpa

rtic

ipan

tsA

ge:a

65.

4, b

66.

4Se

x:M

/F: a

25/

35 b

25/

35In

clus

ion

crit

eria

:act

ive

OA

, hist

ory

of≥

12m

onth

s’ d

urat

ion

and

uni-

or b

ilate

ral h

ippa

in, p

atie

nts

with

diff

use

OA

pai

n w

ere

only

elig

ible

if t

he h

ip w

as t

he m

ain

sour

ce o

f all

sym

ptom

s, d

iseas

e, c

linic

al d

iagn

osis

conf

irmed

by

X-r

ay o

f affe

cted

join

t du

ring

last

12

mon

ths,

pai

n of

mod

erat

e to

sev

ere

inte

nsity

Excl

usio

n cr

iter

ia:k

now

n hy

pers

ensit

ivity

to a

ny N

SAID

, hist

ory

of p

eptic

ulc

erat

ion

orG

I ble

edin

g in

last

12

mon

ths,

ora

l, in

tra-

artic

ular

or

syst

emic

cor

ticos

tero

ids

up t

o2

wee

ks p

rior

to s

tudy

, clin

ical

ly s

igni

fican

t G

I,he

patic

and

/or

rena

l im

pairm

ent,

othe

rsy

stem

ic in

flam

mat

ory

dise

ases

, pre

gnan

cy o

rla

ctat

ion

Com

pari

son:

nim

esul

ide

(b) v

sna

prox

en (a

)D

urat

ion:

4 w

eeks

Inte

rven

tion

s:b,

nim

esul

ide

200

mg/

? (10

0m

g ×2

dai

ly);

a,na

prox

en 1

000

mg/

500–

1250

mg

(500

mg

×2 d

aily

), do

uble

dum

my

used

Oth

er m

edic

atio

n:co

ncur

rent

use

of a

nti-i

nfla

mm

ator

y an

alge

sicor

mus

cle-

rela

xant

dru

gs n

otpe

rmitt

edA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:yes

, occ

asio

nal

use

of p

arac

etam

ol u

p to

3g/

day

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:yes

, 7 d

ays

for

NSA

IDs

Num

ber

and

freq

uenc

y of

vis

its:

3 (0

, 2 a

nd 4

wee

ks)

Allo

cate

d:a

60, b

60

Com

plet

ed:a

51,

b 5

2D

rop-

out:

a 9,

b 8

Ass

esse

d:a

?60,

b ?6

0O

utco

mes

rep

orte

d:G

I sym

ptom

s, G

I dro

p-ou

tsH

ow w

ere

adve

rse

even

ts a

sses

sed:

aske

ddi

rect

ly w

heth

ertr

eatm

ent

had

upse

thi

m/h

er in

any

way

, all

subj

ectiv

e an

d ob

ject

ive

adve

rse

even

ts w

ere

reco

rded

(nat

ure,

seve

rity,

day

of o

nset

and

dura

tion)

How

was

com

plia

nce

asse

ssed

:tab

let

coun

t,4

of n

imes

ulid

e gr

oup

and

1 of

nap

roxe

n gr

oup

faile

d to

tak

e on

e or

both

dai

ly d

oses

(for

mor

e th

an 1

day

in o

nly

1 pa

tient

in n

imes

ulid

egr

oup)

Ris

k fa

ctor

s:hi

stor

y of

ulc

ers

(last

12 m

onth

s): a

0, b

0hi

stor

y of

ble

eds

(last

12m

onth

s): a

0, b

0co

ncom

itant

diso

rder

s(p

redo

min

antly

hea

rtdi

seas

e, e

mph

ysem

aan

d/or

hyp

erte

nsio

n):

a 20

, b 2

0>

1 N

SAID

: a 0

, b 0

rena

l/hep

atic

dise

ase:

a

0, b

0FU

ND

ING

Fund

ed b

y:H

elsin

nH

ealth

care

SA

Affi

liati

on o

f con

tact

auth

or:B

erga

mo

Hos

pita

l, Ita

lyA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f stu

dyad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

none

Appendix 6

302

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Deg

ner,

1996

122,

128

[abs

trac

t]Lo

cati

on:

Ger

man

y an

d U

K

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

conc

ealm

ent:

unc

lear

Bas

elin

e co

mpa

rabi

lity:

uncl

ear

Part

icip

ant

blin

ding

:yes

Ass

esso

r bl

indi

ng:

uncl

ear

Inte

ntio

n-to

-tre

at:

uncl

ear

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

y,no

furt

her

deta

ilsTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:RA

, no

furt

her

deta

ilsA

ge:n

o de

tails

Sex:

no d

etai

lsIn

clus

ion

crit

eria

:RA

(ARA

crit

eria

), no

furt

her

deta

ilsEx

clus

ion

crit

eria

:no

deta

ils

Com

pari

son:

mel

oxic

am (b

) vs

piro

xica

m (a

) D

urat

ion:

3 w

eeks

Inte

rven

tion

s:b,

mel

oxic

am15

mg/

7.5

mg–

15m

g da

ily;

a,pi

roxi

cam

20

mg/

10–3

0m

g da

ilyO

ther

med

icat

ion:

no d

etai

lsA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:not

sta

ted

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:not

sta

ted

Num

ber

and

freq

uenc

y of

vis

its:

uncl

ear

Allo

cate

d:a

135,

b 1

41C

ompl

eted

:no

deta

ilsD

rop-

out:

no d

etai

lsA

sses

sed:

a 1

35, b

141

Out

com

es r

epor

ted:

GI s

ympt

oms

How

wer

e ad

vers

eev

ents

ass

esse

d:no

deta

ilsH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:no

deta

ilsFU

ND

ING

Fund

ed b

y:no

t st

ated

Affi

liati

on o

f con

tact

auth

or:D

r Ka

rlT

hom

ae, B

iber

ach/

riss,

Ger

man

yA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f stu

dyad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

3 of

4em

ploy

ed b

y D

r Ka

rl T

hom

ae


303


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Hos

ie, 1

99612

3

Loca

tion

:52

GP

cent

res

in U

K

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d’A

lloca

tion

conc

ealm

ent:

unc

lear

Bas

elin

e co

mpa

rabi

lity:

no, r

egar

ding

dur

atio

n of

OA

acr

oss

trea

tmen

tgr

oups

Part

icip

ant

blin

ding

:yes

Ass

esso

r bl

indi

ng:

uncl

ear

Inte

ntio

n-to

-tre

at: y

esA

pri

ori

sam

ple

size

:yes

Sum

mar

y ri

sk o

f bia

s:hi

gh

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ype

rfor

med

, pat

ient

s ex

clud

ed if

evi

denc

e of

activ

e pe

ptic

ulc

erat

ion

in p

revi

ous

6 m

onth

sTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:RA

, a 7

.0, b

5.6

Age

:a 6

4.2,

b 6

4.3

Sex:

M/F

: a 6

8/98

, b 6

9/10

0In

clus

ion

crit

eria

:18

year

s or

mor

e,cl

inic

ally

and

rad

iogr

aphi

cally

con

firm

ed O

A(k

nee

or h

ip) w

ith s

ympt

oms

pres

ent

for

≥3

mon

ths

(X-r

ays

indi

cate

d na

rrow

ing

offe

mor

opat

ella

r an

d/or

fem

orot

ibia

l spa

ce in

the

knee

or

narr

owin

g of

the

acet

abul

ofem

oral

spa

ce in

the

hip

, plu

s kn

eeor

hip

mus

t sh

ow p

rese

nce

of o

steo

phyt

es,

subc

hond

ral s

cler

osis

and/

or c

ysts

), at

leas

tm

oder

ate

over

all p

ain

in a

ffect

ed jo

int

(sco

reof

35

mm

or

grea

ter

on p

atie

nt-a

sses

sed

100

mm

VA

S w

ith 0

mm

= n

o pa

in, 1

00m

m=

unb

eara

ble

pain

), re

quiri

ng t

reat

men

t w

ithN

SAID

, am

bula

ntEx

clus

ion

crit

eria

:pre

gnan

t, la

ctat

ing

or o

fch

ildbe

arin

g po

tent

ial w

ithou

t ad

equa

teco

ntra

cept

ion,

any

con

com

itant

clin

ical

lyun

stab

le d

iseas

e, c

linic

ally

rel

evan

t la

bora

tory

test

abn

orm

aliti

es, c

linic

al e

vide

nce

of a

ctiv

epe

ptic

ulc

erat

ion

in p

revi

ous

6 m

onth

s,hy

pers

ensit

ivity

to

anal

gesic

s, a

ntip

yret

ics

orN

SAID

s, a

ny d

rug

or p

roce

dure

whi

ch m

ight

inte

ract

with

or

obsc

ure

effe

cts

of t

he s

tudy

med

icat

ion

Com

pari

son:

mel

oxic

am (b

) vs

dicl

ofen

ac s

odiu

m S

R (a

)D

urat

ion:

6 m

onth

sIn

terv

enti

ons:

b, m

elox

icam

7.5

mg/

7.5–

15 m

g (o

nce

daily

); a,

dic

lofe

nac

sodi

um S

R10

0m

g/75

–150

mg

(onc

e da

ily),

doub

le d

umm

y us

edO

ther

med

icat

ion:

mas

sage

and

exer

cise

con

tinue

d un

chan

ged,

med

icat

ions

not

con

sider

ed t

oaf

fect

stu

dy o

utco

me

wer

e al

low

edto

con

tinue

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:y

es,

para

ceta

mol

up

to 4

g da

ilyPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

es, 3

day

s or

mor

e fo

ran

y pr

evio

us N

SAID

Num

ber

and

freq

uenc

y of

vis

its:

6 (0

, 2 w

eeks

the

n at

1, 2

, 3 a

nd6

mon

ths)

Allo

cate

d:a

167,

b 1

69C

ompl

eted

:a 1

29,

b14

1D

rop-

out:

a 38

, b 2

8A

sses

sed:

a 16

6, b

169

Out

com

es r

epor

ted:

mor

talit

y, s

erio

us G

Ico

mpl

icat

ions

, ser

ious

card

iac

or r

enal

illn

ess,

QoL

, par

ticip

ant

satis

fact

ion,

GI

sym

ptom

s, G

I dro

p-ou

tsH

ow w

ere

adve

rse

even

ts a

sses

sed:

used

WH

O b

ody

syst

ems

orga

n cl

assif

icat

ion

How

was

com

plia

nce

asse

ssed

:pla

sma

leve

lof

mel

oxic

amde

term

ined

at

3 m

onth

san

d ta

blet

cou

nt

Ris

k fa

ctor

s:no

deta

ilsFU

ND

ING

Fund

ed b

y:un

clea

rA

ffilia

tion

of c

onta

ctau

thor

:Gre

atW

este

rn M

edic

al (G

Pce

ntre

), G

lasg

ow, U

KA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f stu

dyad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

2 of

3em

ploy

ed b

yBo

ehrin

ger

Inge

lhei

m,

Bibe

rach

/Riss

,G

erm

any

Appendix 6

304

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Lind

en, 1

99642

,228

Loca

tion

:22

cent

res

inSw

eden

,D

enm

ark,

Belg

ium

, The

Net

herla

nds

and

Ger

man

y

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’, s

eale

den

velo

pes

Allo

cati

onco

ncea

lmen

t:un

clea

rB

asel

ine

com

para

bilit

y:ye

sPa

rtic

ipan

t bl

indi

ng:

yes

Ass

esso

r bl

indi

ng:n

oIn

tent

ion-

to-t

reat

:yes

A p

riori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ype

rfor

med

, no

furt

her

deta

ilsTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A: a

5.5

, b 6

.2A

ge:a

67.

2 b

67.2

Sex:

M/F

: a 4

7/80

, b 4

8/81

Incl

usio

n cr

iter

ia:1

8 ye

ars

or m

ore,

clin

ical

diag

nosis

of O

A (h

ip) f

or a

t le

ast

3 m

onth

s(r

adio

logi

cal c

onfir

mat

ion

in t

he t

arge

t hi

p), a

tle

ast

mod

erat

e pa

in o

n ac

tive

mov

emen

t in

affe

cted

hip

(sco

re o

f 35

mm

or

mor

e on

patie

nt-a

sses

sed

VAS

with

0m

m =

no p

ain,

100

mm

= u

nbea

rabl

e pa

in),

able

to

perf

orm

thei

r da

ily r

outin

eEx

clus

ion

crit

eria

:no

deta

ils

Com

pari

son:

mel

oxic

am (b

) vs

piro

xica

m (a

)D

urat

ion:

6 w

eeks

Inte

rven

tion

s:b,

mel

oxic

am15

mg/

7.5–

15m

g (o

nce

daily

); a,

piro

xica

m 2

0m

g/10

–30

mg

(onc

eda

ily)

Oth

er m

edic

atio

n:co

ntin

ued

ther

apy

for

conc

omita

nt d

iseas

es,

othe

r N

SAID

s an

d an

alge

sics

exce

ptpa

race

tam

ol, a

nti-i

nfla

mm

ator

ies

wer

e no

t al

low

ed, m

assa

ge a

ndex

erci

se c

ontin

ued

unch

ange

dA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

: yes

,pa

race

tam

ol

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:yes

, 3–7

day

s fo

rpr

evio

us N

SAID

sN

umbe

r an

d fr

eque

ncy

of v

isit

s:4

(0, 7

, 21

and

42da

ys)

Allo

cate

d:a

127,

b 1

29

Com

plet

ed:a

112

,b

113

Dro

p-ou

t:a

15, b

16

Ass

esse

d:a

127,

b 1

29O

utco

mes

rep

orte

d:m

orta

lity,

ser

ious

GI

com

plic

atio

ns,

sym

ptom

atic

ulc

ers,

serio

us c

ardi

ovas

cula

r or

rena

l illn

ess

(ext

ra)

part

icip

ant

satis

fact

ion,

GI s

ympt

oms

How

wer

e ad

vers

eev

ents

ass

esse

d:no

tst

ated

How

was

com

plia

nce

asse

ssed

:tab

let

coun

t,pl

asm

a le

vels

at d

ay 2

1

Ris

k fa

ctor

s:>

1N

SAID

: a 0

, b 0

FUN

DIN

GFu

nded

by:

uncl

ear

Affi

liati

on o

f con

tact

auth

or:E

ksjo

Hos

pita

l, Sw

eden

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:at

leas

t 1

of3

auth

ors

empl

oyed

by

Dr

Karl

Tho

mae

,Bi

bera

ch/R

iss,

Ger

man

yO

ther

: mel

oxic

am30

mg

daily

arm

disc

ontin

ued


305


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Woj

tule

wsk

i,19

9612

4,22

9

Loca

tion

:48

cent

res,

in U

K,

Ger

man

y, F

ranc

e,Be

lgiu

m, M

exic

oan

d Sp

ain

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

uncl

ear

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:yes

A p

riori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:par

ticip

ants

exc

lude

dw

ith c

linic

al e

vide

nce

of p

eptic

ulc

erat

ion

Bas

elin

e N

SAID

sta

tus:

prev

ious

NSA

IDus

e:a,

93.

3%, b

86.

4%

Type

and

dur

atio

n of

art

hrit

is (

year

s):

RA: a

9.2

, b 9

.3A

ge:n

o de

tails

Sex:

no d

etai

lsIn

clus

ion

crit

eria

:18–

75 y

ears

with

RA

defin

ed a

ccor

ding

to

AC

R cr

iteria

and

belo

ngin

g to

func

tiona

l cla

ss I,

II o

r III

,re

quire

d N

SAID

the

rapy

and

dem

onst

rate

dac

tive

dise

ase

befo

re a

nd/o

r du

ring

was

hout

perio

d (a

ctiv

e di

seas

e de

fined

as

pres

ence

of

3 of

the

follo

win

g: 6

or

mor

e jo

ints

pai

nful

or

tend

er o

n m

otio

n, 3

or

mor

e sw

olle

n jo

ints

,du

ratio

n of

mor

ning

stif

fnes

s of

45

min

utes

or

mor

e, W

este

rgre

n se

dim

enta

tion

rate

of

28m

m/h

or

mor

e).

Excl

usio

n cr

iter

ia:p

artic

ipat

ion

in p

revi

ous

mel

oxic

am t

rial,

clin

ical

evi

denc

e of

pep

ticul

cera

tion

or a

ny o

ther

dise

ase

whi

ch w

ould

inte

rfer

e w

ith t

he e

valu

atio

n of

effi

cacy

and

safe

ty [i

nclu

ding

col

lage

nsos

is,de

rmat

omyo

sitis,

gou

t, in

fect

ious

art

hriti

s,sa

rcoi

dosis

, pso

riatic

art

hriti

s, A

S, S

till’s

dise

ase,

mix

ed c

onne

ctiv

e tis

sue

dise

ase,

arth

ritis

asso

ciat

ed w

ith in

flam

mat

ory

bow

eldi

seas

e, s

yste

mic

lupu

s er

ythe

mat

osus

,fib

rom

yalg

ia, R

eite

r’s

synd

rom

e, a

rter

itis

(gen

eral

), po

lym

yalg

ia r

heum

atic

and

scle

rode

rma]

, sec

ond-

line

anti-

rheu

mat

icth

erap

ies

if no

t st

able

for

at le

ast

3m

onth

spr

ior

to s

tudy

Com

pari

son:

mel

oxic

am (b

) vs

napr

oxen

(a)

Dur

atio

n:26

wee

ksIn

terv

enti

ons:

b, m

elox

icam

7.5

mg/

7.5–

15m

g (7

.5m

g on

ceda

ily);

a, n

apro

xen

750

mg/

500–

1250

mg

(250

mg

×2m

orni

ng p

lus

1×

250

mg

even

ing)

,do

uble

dum

mie

s us

ed, a

llm

edic

atio

n ta

ken

with

wat

er a

ndaf

ter

food

Oth

er m

edic

atio

n:gl

ucoc

ortic

oste

roid

s of

7.5

mg/

day

or le

ss o

f pre

dniso

lone

or

equi

vale

ntan

d st

abili

sed

for

a m

onth

cou

ld b

eco

ntin

ued,

con

com

itant

med

icat

ion

allo

wed

incl

udin

g se

cond

-line

ant

i-rh

eum

atic

ther

apie

s if

stab

le fo

r 3

mon

ths

prio

r to

stu

dy, o

ral

cort

icos

tero

id a

nd s

econ

d-lin

eth

erap

y do

ses

coul

d no

t be

incr

ease

d bu

t cou

ld b

e re

duce

d,ph

ysio

ther

apy

coul

d co

ntin

ue,

intr

amus

cula

r or

intr

aven

ous

inje

ctio

ns o

f glu

coco

rtic

oids

or

adre

noco

rtic

otro

phic

hor

mon

e an

dm

ore

than

2 in

tra-

artic

ular

inje

ctio

nsof

cor

ticos

tero

ids

in m

onth

bef

ore

or d

urin

g st

udy

not p

erm

itted

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:y

es,

para

ceta

mol

onl

y an

d no

mor

e th

an4

g da

ilyPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

es, 3

–11

days

for

NSA

IDs

Num

ber

and

freq

uenc

y of

vis

its:

7 (0

, 14

and,

28

days

, 8, 1

2, 1

9 an

d26

wee

ks)

Allo

cate

d:a

180,

b 1

99C

ompl

eted

:a 1

06,

b11

7D

rop-

out:

a 74

b 8

2A

sses

sed:

a 18

0, b

199

Out

com

es r

epor

ted:

serio

us G

Ico

mpl

icat

ions

,sy

mpt

omat

ic u

lcer

s, G

Isy

mpt

oms,

GI d

rop-

outs

How

wer

e ad

vers

eev

ents

ass

esse

d:in

cide

nce,

tim

e, s

ever

ityan

d ca

usal

rel

atio

nshi

por

adv

erse

eve

ntta

bula

ted

by b

ody

syst

ems

orga

ncl

assif

icat

ion

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:no

deta

ilsFU

ND

ING

Fund

ed b

y:un

clea

rA

ffilia

tion

of c

onta

ctau

thor

:Eas

tbou

rne

Dist

rict

Gen

eral

Hos

pita

l, U

KA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f stu

dyad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

1 of

7au

thor

s em

ploy

ed b

yBo

ehrin

ger

Inge

lhei

man

d 1

auth

or e

mpl

oyed

by D

r Ka

rl T

hom

ae

Appendix 6

306

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Goe

i Thé

, 199

7125

Loca

tion

:23

cent

res

inBe

lgiu

m,

Den

mar

k,G

erm

any

and

The

Net

herla

nds

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:un

clea

rA

sses

sor

blin

ding

:un

clea

r In

tent

ion-

to-t

reat

: yes

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

y,no

furt

her

deta

ilsTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A: a

7.3

, b 7

.6

Age

:a 7

1.4,

b 7

1.5

Sex:

M/F

: a 2

3/10

7 b

19/1

09In

clus

ion

crit

eria

:18

year

s or

mor

e,am

bula

tory

, clin

ical

ly a

nd r

adio

grap

hica

llyco

nfirm

ed d

iagn

osis

of O

A (k

nee)

for

at le

ast

3 m

onth

s (m

ovem

ent

of k

nee

by e

xtre

me

flexi

on a

nd e

xten

sion

elic

ited

pain

, X-r

ays

indi

ffere

nt p

roje

ctio

ns d

emon

stra

ted

at le

ast

narr

owin

g of

the

fem

orop

atel

lar

and/

orfe

mor

otib

ial s

pace

and

ost

eoph

ytes

and

/or

subc

hond

ral s

cler

osis

and/

or c

ysts

), ha

dex

perie

nced

≥m

oder

ate

pain

in t

he w

orst

affe

cted

kne

e, (s

core

of ≥

35m

m o

n pa

tient

asse

ssed

VA

S) ju

dged

by

inve

stig

ator

to

requ

ire t

reat

men

t w

ith N

SAID

s, p

atie

nts

rece

ivin

g th

erap

y fo

r co

ncom

itant

dise

ase

wer

e al

low

ed t

o co

ntin

ue t

heir

med

icat

ion.

Excl

usio

n cr

iter

ia:t

reat

men

t w

ith o

ral o

rin

tra-

artic

ular

ste

roid

s w

as n

ot p

erm

itted

durin

g or

3m

onth

s pr

eced

ing

stud

y

Com

pari

son:

mel

oxic

am (b

) vs

dicl

ofen

ac S

R (a

)D

urat

ion:

6 w

eeks

Inte

rven

tion

s:b,

mel

oxic

am15

mg/

7.5–

15m

g (o

nce

daily

); a,

dic

lofe

nac

SR 1

00m

g/75

–150

mg

(onc

e da

ily),

doub

le d

umm

y us

edO

ther

med

icat

ion:

ther

apy

for

conc

omita

nt d

iseas

e al

low

ed(e

xcep

t if

excl

uded

by

prot

ocol

),tr

eatm

ent

with

oth

er N

SAID

s an

dor

al o

r in

tra-

artic

ular

ste

roid

s no

tpe

rmitt

ed

Asp

irin

allo

wed

: not

sta

ted

Ana

lges

ic a

llow

ed: y

es,

para

ceta

mol

max

imum

4g/

day

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:yes

, 7 d

ays

for

piro

xica

man

d te

noxi

cam

, at

leas

t 3

days

for

othe

r N

SAID

sN

umbe

r an

d fr

eque

ncy

of v

isit

s:4

(0, 1

, 3 a

nd 6

wee

ks)

Allo

cate

d:a,

130

,b

128

Com

plet

ed:u

ncle

arD

rop-

out:

uncl

ear

Ass

esse

d:a

130,

b 1

28

Out

com

es r

epor

ted:

sym

ptom

atic

ulc

ers,

GI

sym

ptom

sH

ow w

ere

adve

rse

even

ts a

sses

sed:

not

stat

edH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:>

1N

SAID

: a 0

, b 0

FUN

DIN

GFu

nded

by:

not

stat

edA

ffilia

tion

of c

onta

ctau

thor

:De

Wev

erH

ospi

tal,

The

Net

herla

nds

Affi

liati

on o

fst

atis

tici

an: u

ncle

arA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:2

of 4

auth

ors

empl

oyed

by

Dr

Karl

Tho

mae

Gm

bH B

iber

ach/

ande

r Li

ssO

ther

: ?sa

me

popu

latio

n as

in L

inde

npa

per42


307


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Hos

ie, 1

99712

6

Loca

tion

:G

ener

al p

ract

ices

in U

K

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:yes

A

pri

ori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ybu

t pa

tient

s ex

clud

ed if

had

clin

ical

evi

denc

eof

pep

tic u

lcer

atio

n du

ring

the

last

6 m

onth

sTy

pe a

nd d

urat

ion

of a

rthr

itis

(m

edia

nan

d IQ

R, y

ears

):O

A: a

5 y

ears

(2.2

–10)

, b

5 ye

ars

(2–1

0)A

ge:a

64.

0 (5

7.4–

74.0

), b

65.5

(55.

1–73

.0)

Sex:

M/F

: a 6

9/80

, b 1

28/1

78In

clus

ion

crit

eria

:18

year

s or

mor

e,cl

inic

ally

and

rad

iogr

aphi

cally

con

firm

ed O

A(k

nee

or h

ip) f

or a

t le

ast

3 m

onth

s, a

mbu

lant

and

at le

ast

mod

erat

e ov

eral

l pai

n in

the

targ

et jo

int

(35

mm

or

mor

e on

VA

S sc

ale)

Excl

usio

n cr

iter

ia:p

regn

ant,

lact

atin

g or

wom

en n

ot u

sing

adeq

uate

con

trac

eptio

n,ev

iden

ce o

f hep

atic

, ren

al, c

ardi

ac,

haem

atol

ogic

al o

r m

etab

olic

dise

ase;

pat

ient

sre

ceiv

ing

ther

apy

for

bron

chia

l ast

hma;

clin

ical

evi

denc

e of

pep

tic u

lcer

atio

n du

ring

the

last

6 m

onth

s; h

yper

sens

itivi

ty t

oan

alge

sics,

ant

ipyr

etic

s or

NSA

IDs;

clin

ical

lyab

norm

al la

bora

tory

val

ues;

tre

atm

ent

with

oral

cor

ticos

tero

ids;

intr

a-ar

ticul

arco

rtic

oste

roid

inje

ctio

ns in

pre

viou

s3

mon

ths;

tre

atm

ent

with

top

ical

ant

i-in

flam

mat

ory

agen

ts, a

ntic

oagu

lant

s, li

thiu

mor

ant

i-ulc

er d

rugs

; the

pos

sibili

ty o

fun

derg

oing

ort

hopa

edic

sur

gery

dur

ing

stud

y;un

derg

oing

act

ive

phys

ioth

erap

y du

ring

stud

y;re

mov

al o

f flu

id fr

om e

ffusio

n of

the

affe

cted

join

t, ot

her

rheu

mat

olog

ical

dise

ases

Com

pari

son:

mel

oxic

am (b

) vs

piro

xica

m (a

) D

urat

ion:

6 w

eeks

Inte

rven

tion

s:b,

mel

oxic

am15

mg/

7.5–

15m

g (o

nce

daily

); a,

piro

xica

m 2

0m

g/10

–30

mg

(onc

eda

ily)

Oth

er m

edic

atio

n:no

t st

ated

A

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:yes

,pa

race

tam

ol u

p to

4g

daily

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:7 d

ays

for

piro

xica

m o

rte

noxi

cam

, at

leas

t 3

days

for

all

othe

r N

SAID

s N

umbe

r an

d fr

eque

ncy

of v

isit

s:6

(0, 2

, 4, 8

, 12,

24

wee

ks)

Allo

cate

d:a

149,

b 3

06

Com

plet

ed:a

118

,b

252

Dro

p-ou

t:a

31, b

54

Ass

esse

d: a

149

, b 3

06O

utco

mes

rep

orte

d:se

rious

GI

com

plic

atio

ns, Q

oL, G

Isy

mpt

oms,

ana

emia

,to

tal d

rop-

outs

, GI

drop

-out

sH

ow w

ere

adve

rse

even

ts a

sses

sed:

part

icip

ants

ask

ed ‘H

ave

you

expe

rienc

edan

ythi

ng u

nusu

al s

ince

your

last

visi

t?’

How

was

com

plia

nce

asse

ssed

:non

com

plia

nce

asse

ssed

as

taki

ng le

ss t

han

20%

stud

y m

edic

atio

n by

retu

rn o

f unu

sed

caps

ules

but

not

repo

rted

Ris

k fa

ctor

s:co

ncom

itant

use

of

antic

oagu

lant

s: a

:0,

b 0

cort

icos

tero

ids:

a

0, b

; 0C

VD: a

0, b

0re

nal/h

epat

ic d

iseas

e:

a 0,

b 0

FUN

DIN

GFu

nded

by:

Dr

Karl

Tho

mae

,Bi

bera

ch/R

iss,

Ger

man

yA

ffilia

tion

of c

onta

ctau

thor

: has

act

ed in

past

as

cons

ulta

nt fo

rPh

arm

acia

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:3

empl

oyee

sof

Pha

rmac

ia a

nd h

ave

stoc

k in

tere

st w

ithin

the

com

pany

Appendix 6

308

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Jenn

ings

, 199

7127

Loca

tion

:New

York

, USA

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

conc

ealm

ent:

unc

lear

Bas

elin

e co

mpa

rabi

lity:

no r

egar

ding

age

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:un

clea

rA

pri

ori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

high

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ybu

t ex

clud

ed p

atie

nts

with

sto

mac

h ul

cer

Type

and

dur

atio

n of

art

hrit

is (

year

s):

OA

of t

he fo

ot, n

o fu

rthe

r de

tails

Age

:a 5

0.8,

b 4

5.0

Sex:

M/F

: a 8

/23,

b 7

/22

Incl

usio

n cr

iter

ia:3

1–71

yea

rs,

sym

ptom

atic

OA

of t

he fo

ot o

r an

kle

or b

oth

as c

onfir

med

by

radi

ogra

phic

exa

min

atio

n;en

rolle

d at

the

Foo

t C

linic

s of

New

Yor

kEx

clus

ion

crit

eria

:pat

ient

s al

read

y st

able

with

eto

dola

c or

nap

roxe

n or

who

wou

ldha

ve b

een

trea

ted

with

oth

er N

SAID

s du

ring

the

stud

y in

terv

al; w

omen

who

wer

epr

egna

nt o

r la

ctat

ing;

pat

ient

s w

ith a

hist

ory

of a

naem

ia, l

iver

dise

ase,

ren

al d

iseas

e,st

omac

h ul

cer

or N

SAID

alle

rgy

Com

pari

son:

etod

olac

(b) v

sna

prox

en (a

) D

urat

ion:

5 w

eeks

Inte

rven

tion

s:b,

eto

dola

c80

0m

g/60

0m

g da

ily (4

00m

g×2

dai

ly),

a, n

apro

xen

1000

mg/

500–

1250

mg

daily

(500

mg

×2 d

aily

)O

ther

med

icat

ion:

no

deta

ilsA

spir

in a

llow

ed:n

o de

tails

A

nalg

esic

allo

wed

:no

deta

ilsPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

es, n

o de

tails

Num

ber

and

freq

uenc

y of

vis

its:

6 (0

, 1, 2

, 3, 4

and

5 w

eeks

)

Allo

cate

d:a

31, b

29

Com

plet

ed:a

: 18

b 16

Dro

p-ou

t:a

13, b

13

Ass

esse

d:un

clea

rO

utco

mes

rep

orte

d:to

tal d

rop-

outs

How

wer

e ad

vers

eev

ents

ass

esse

d: n

ode

tails

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:re

nal/h

epat

ic d

iseas

e:

a 0,

b 0

FUN

DIN

GFu

nded

by:

Wye

th-

Aye

rst

Labo

rato

ries

Affi

liati

on o

f con

tact

auth

or:N

ew Y

ork

Col

lege

of P

odia

tric

Med

icin

e, U

SAA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

0/2


309


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Ligh

tfoot

, 199

7128

Loca

tion

:28

sites

in U

SA a

ndEu

rope

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

uncl

ear

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ype

rfor

med

, no

furt

her

deta

ilsTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:RA

, no

othe

r de

tails

Age

:a 5

6 (2

8–76

), b

58 (3

4–76

)Se

x:M

/F: a

43/

96, b

44/

103

Incl

usio

n cr

iter

ia:1

8–75

yea

rs, d

efin

ite o

rcl

assic

al R

A a

s de

fined

by

ARA

of a

t le

ast

6m

onth

s’ d

urat

ion

(age

of o

nset

16 y

ears

or

over

), hi

stor

y of

pos

itive

res

pons

e to

NSA

IDth

erap

y w

ith n

o se

rious

adv

erse

rea

ctio

ns,

had

to h

ave

a fla

re o

f RA

reg

ardl

ess

of p

rior

NSA

ID u

se (i

ndic

ated

by

wor

seni

ng in

pat

ient

glob

al a

sses

smen

t of

pai

nful

join

ts, n

umbe

r of

swol

len

join

ts, W

este

rgre

n ES

R or

dur

atio

n of

mor

ning

stif

fnes

s), t

hose

tak

ing

DM

ARD

s or

cort

icos

tero

ids

wer

e el

igib

le if

tre

atm

ent

initi

ated

at

leas

t 6

mon

ths

prio

r to

stu

dy a

ndfix

ed d

osag

e m

aint

aine

d fo

r at

leas

t 2

mon

ths

Excl

usio

n cr

iter

ia:w

omen

of c

hild

bear

ing

pote

ntia

l, no

furt

her

deta

ils

Com

pari

son:

eto

dola

c (b

) vs

piro

xica

m (a

)D

urat

ion:

12

wee

ksIn

terv

enti

ons:

b, e

todo

lac

600

mg/

600

mg

(300

mg

×2 d

aily

);a,

piro

xica

m 2

0m

g/10

–30

mg

(onc

eda

ily) m

atch

ing

plac

ebos

Endo

scop

y:on

ly if

par

ticip

ant

sym

ptom

atic

Oth

er m

edic

atio

n: D

MA

RDs

and

cort

icos

tero

ids

only

if m

aint

aine

d at

cons

tant

dos

e, m

inim

um a

llow

able

cum

ulat

ive

dose

of m

etho

trex

ate

=2

g, o

ral c

ortic

oste

roid

7.5

mg/

day

or le

ss, n

o ot

her

anti-

infla

mm

ator

ies

allo

wed

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:y

es,

acet

amin

ophe

n up

to

650

mg

4×da

ily d

urin

g w

asho

ut a

nd fi

rst

wee

kof

tre

atm

ent

only

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:not

mor

e th

an 1

4 da

ysfo

r N

SAID

s, a

t le

ast

10 d

ays

for

SRor

long

act

ing

NSA

IDs

Num

ber

and

freq

uenc

y of

vis

its:

5 (0

, 1, 4

, 8, 1

2 w

eeks

)

Allo

cate

d:a

139,

b 1

47C

ompl

eted

:a 9

8, b

103

Dro

p-ou

t:a

41, b

44

Ass

esse

d:a

139,

b 1

47O

utco

mes

rep

orte

d:se

rious

GI

com

plic

atio

ns,

sym

ptom

atic

ulc

ers,

GI

sym

ptom

s, G

I dro

p-ou

tsH

ow w

ere

adve

rse

even

ts a

sses

sed:

not

stat

edH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:co

ncom

itant

use

of

cort

icos

tero

ids:

a 5

0,

b 55

FUN

DIN

GFu

nded

by:

Wye

th-

Aye

rst

Phar

mac

eutic

als

Affi

liati

on o

f con

tact

auth

or:U

nive

rsity

of

Kent

ucky

, USA

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:un

clea

rN

ote:

ther

e w

as a

lsoan

eto

dola

c 20

0m

g ×2

dai

ly, w

hich

was

excl

uded

from

thi

sre

view

Appendix 6

310

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Neu

stad

t, 19

9712

9

Loca

tion

:96

cent

res

in U

SA

Met

hod

ofra

ndom

isat

ion:

‘ass

igne

d ra

ndom

ly’

Allo

cati

onco

ncea

lmen

t:un

clea

rB

asel

ine

com

para

bilit

y:ye

sPa

rtic

ipan

t bl

indi

ng:

yes

Ass

esso

r bl

indi

ng:

uncl

ear

Inte

ntio

n-to

-tre

at:y

esA

pri

ori

sam

ple

size

:un

clea

r, st

udy

enro

lmen

tdi

scon

tinue

d af

ter

4.5

year

s du

e to

inad

equa

te p

ower

Sum

mar

y ri

sk o

f bia

s:m

oder

ate

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ype

rfor

med

, no

furt

her

deta

ilsB

asel

ine

NSA

ID s

tatu

s:90

% a

llpa

rtic

ipan

ts h

ad p

revi

ously

tak

en N

SAID

sTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:RA

, a 3

.6, b

3.5

Age

:a 5

3.1,

b 5

3.0

Sex:

M/F

: a 1

18/2

99, b

126

/283

Incl

usio

n cr

iter

ia:e

arly

sta

ge R

A, d

iseas

edu

ratio

n 1–

7 ye

ars,

Ste

inbr

ocke

r’s

stag

e of

dise

ase

clas

sific

atio

n as

wel

l as

func

tiona

l cla

ssra

ting

of I

or II

for

prog

ress

ion

of r

adio

logi

cal

chan

ges,

tho

se n

ot t

akin

g N

SAID

at

scre

enin

gvi

sit w

ere

requ

ired

to m

eet

the

crite

ria fo

rac

tive

dise

ase,

tho

se t

akin

g N

SAID

s at

scre

enin

g w

ere

requ

ired

to d

iscon

tinue

the

mfo

r up

to

21 d

ays

durin

g w

hich

tim

e th

eyw

ere

requ

ired

to d

evel

op a

flar

e (fl

are

defin

ed a

s fir

st 3

of f

ollo

win

g, p

lus

at le

ast

1of

the

oth

er 2

had

to

be m

et: w

orse

ning

inth

e nu

mbe

r of

ten

der

or p

ainf

ul jo

ints

on

mot

ion,

join

t sw

ellin

g an

d m

orni

ng s

tiffn

ess

plus

wor

seni

ng o

f inv

estig

ator

’s o

r pa

tient

’sop

inio

n of

dise

ase

sym

ptom

s)Ex

clus

ion

crit

eria

:tre

atm

ent

with

aD

MA

RD w

ithin

6 m

onth

s of

sta

rt o

f stu

dy

Com

pari

son:

etod

olac

(b) v

sIb

upro

fen

(a)

Dur

atio

n: 3

yea

rsIn

terv

enti

ons:

b, e

todo

lac

1000

mg/

600

mg

(500

mg

×2 d

aily

)(fo

r in

itial

2 w

eeks

300

mg

daily

,ne

xt 2

wee

ks 6

00m

g da

ily);

a, ib

upro

fen

2400

mg/

600–

2400

mg

(600

mg

×4 d

aily

) (fo

r in

itial

2w

eeks

160

0m

g da

ily)

Oth

er m

edic

atio

n:D

MA

RDs

not

perm

itted

, low

-dos

e or

alco

rtic

oste

roid

s (e

.g. 5

mg/

day

orle

ss p

redn

isone

or

equi

vale

nt)

perm

itted

if d

osag

e co

nsta

nt fr

om4

wee

ks b

efor

e en

rolm

ent

to e

ndof

stu

dyA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:not

sta

ted

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:yes

, up

to 2

1 da

ys fo

ran

y N

SAID

sN

umbe

r an

d fr

eque

ncy

of v

isit

s:26

(12-

wee

k in

terv

als

in s

econ

d an

dth

ird y

ears

, mor

e fr

eque

nt in

firs

tye

ar)

Allo

cate

d:a

417,

b 4

09C

ompl

eted

:a 7

1, b

86

Dro

p-ou

t: a

346

, b 3

23A

sses

sed:

a 41

7, b

409

Out

com

es r

epor

ted:

tota

l dro

p-ou

tH

ow w

ere

adve

rse

even

ts a

sses

sed:

colle

cted

com

plai

nts

usin

g a

6 pa

ge c

heck

list

that

allo

wed

for

ques

tioni

ng o

f pre

senc

eof

mor

e th

an 7

0 sp

ecifi

csy

mpt

oms

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:ab

out

20%

of a

ll pa

rtic

ipan

tsto

ok lo

w-d

ose

cort

icos

tero

ids

thro

ugho

ut s

tudy

FUN

DIN

GFu

nded

by:

uncl

ear

Affi

liati

on o

f con

tact

auth

or:U

nive

rsity

of

Loui

svill

e, U

SAA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f stu

dyad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

none

Oth

er:e

todo

lac

300

mg

daily

arm

excl

uded

from

ana

lyse

sas

dos

e be

low

min

imum

reco

mm

ende

d in

BN

F


311


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Rogi

nd,

1997

130,

230

Loca

tion

:19

cent

res

inD

enm

ark

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

uncl

ear

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

: yes

Inte

ntio

n-to

-tre

at: y

esA

pri

ori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ybu

t ex

clud

ed p

atie

nts

with

hist

ory

of G

I ble

edor

pep

tic u

lcer

dise

ase

Type

and

dur

atio

n of

art

hrit

is (

year

s):

OA

of t

he h

ip o

r kn

ee, n

o fu

rthe

r de

tails

Age

:a 6

7.5

(37–

91),

b 67

.0 (3

9–88

)Se

x:M

/F: a

30/

103,

b 2

8/11

0In

clus

ion

crit

eria

:rad

iolo

gica

lly p

rove

n O

Aof

the

hip

or

knee

sho

win

g at

leas

t tw

o of

the

follo

win

g co

nditi

ons:

wei

ght-

bear

ing

pain

,jo

int

stiff

ness

, pai

n on

mot

ion;

40

year

s of

age

or o

ver,

wom

en o

f chi

ldbe

arin

g po

tent

ial

wer

e re

quire

d to

use

con

trac

eptio

nEx

clus

ion

crit

eria

:wom

en w

ho w

ere

brea

st-f

eedi

ng o

r pr

egna

nt, i

mpa

ired

rena

l or

liver

func

tion,

hist

ory

of G

I ble

edin

g or

pep

ticul

cer

dise

ase;

infla

mm

ator

y jo

int

dise

ase;

alle

rgy

tow

ards

asp

irin

or o

ther

NSA

IDs;

patie

nts

rece

ivin

g lit

hium

; H2R

A a

ntag

onist

s;an

ticoa

gula

nts;

sys

tem

ic o

r in

tra-

artic

ular

cort

icos

tero

ids

with

in t

he p

revi

ous

2 m

onth

s;pe

nici

llam

ine,

gol

d, im

mun

osup

pres

sive

drug

sor

cyt

otox

ic a

gent

s w

ithin

the

pre

viou

s6

mon

ths

Com

pari

son:

etod

olac

(b) v

spi

roxi

cam

(a)

Dur

atio

n:8

wee

ksIn

terv

enti

ons:

b, e

todo

lac

600

mg/

600

mg

daily

(300

mg

×2 d

aily

); a,

piro

xica

m20

mg/

10–3

0m

g da

ily (2

0m

g on

ceda

ily

Oth

er m

edic

atio

n:lit

hium

; H2R

Aan

tago

nist

s; a

ntic

oagu

lant

s; s

yste

mic

or in

tra-

artic

ular

cor

ticos

tero

ids;

peni

cilla

min

e, g

old,

imm

unos

uppr

essiv

e dr

ugs

orcy

toto

xic

drug

s w

ere

excl

uded

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:y

es,

para

ceta

mol

up

to 4

000

mg

daily

durin

g w

asho

ut a

nd e

ntire

stu

dyPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

es, 1

wee

kN

umbe

r an

d fr

eque

ncy

of v

isit

s:3

(0, 4

and

8 w

eeks

)

Allo

cate

d:a

133,

b 1

38C

ompl

eted

:a 1

02,

b10

9D

rop-

out:

a 3

1, b

29

Ass

esse

d:a

133,

b 1

38O

utco

mes

rep

orte

d:se

rious

GI

com

plic

atio

ns,

sym

ptom

atic

ulc

ers,

GI

sym

ptom

s, G

I dro

p-ou

ts, t

otal

dro

p-ou

tsH

ow w

ere

adve

rse

even

ts a

sses

sed:

adve

rse

even

ts a

ndpa

tient

com

plai

nts

reco

rded

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:hi

stor

y of

ulc

er: a

0,

b 0

hist

ory

of b

leed

s: a

0,

b 0;

hist

ory

of H

2RA

use:

a 0

, b 0

conc

omita

nt u

se o

fan

ticoa

gula

nts:

a 0

, b

0co

rtic

oste

roid

s:

a 0,

b 0

>1

NSA

ID: a

0, b

0re

nal/h

epat

ic d

iseas

e:

a 0,

b 0

FUN

DIN

GFu

nded

by:

LEO

Phar

mac

eutic

alPr

oduc

tsA

ffilia

tion

of c

onta

ctau

thor

:Cop

enha

gen

Mun

icip

al H

ospi

ta,

Den

mar

kA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f stu

dyad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

1/2

by

LEO

Appendix 6

312

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Deq

ueke

r,19

9838

,231

,232

SELE

CT

Loca

tion

:12

coun

trie

s (E

urop

ean

d A

ustr

alia

,A

rgen

tina,

Sou

thA

fric

a, in

clud

ing

UK

)

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’ s

eale

den

velo

pes

Allo

cati

onco

ncea

lmen

t:un

clea

r B

asel

ine

com

para

bilit

y:ye

sPa

rtic

ipan

t bl

indi

ng:

yes

Ass

esso

r bl

indi

ng:n

oIn

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ype

rfor

med

but

exc

lude

d pa

rtic

ipan

ts w

ithac

tive

pept

ic u

lcer

B

asel

ine

NSA

ID s

tatu

s:79

% in

eac

h ar

mw

ere

prev

ious

ly t

akin

g N

SAID

sTy

pe a

nd d

urat

ion

of a

rthr

itis

(m

onth

s):

OA

: a 4

8, b

45

Age

:a 6

1.6,

b 6

1.3

Sex:

M/F

: a 1

431/

2905

, b 1

382/

2938

Incl

usio

n cr

iter

ia:1

8 ye

ars

or m

ore,

acu

tean

d pa

infu

l exa

cerb

atio

n of

OA

(hip

, kne

e,ha

nd o

r ve

rteb

ral s

pine

), pa

in o

n ac

tive

mov

emen

t (3

5m

m o

r m

ore

on a

100

mm

VAS,

0m

m =

no

pain

, 100

mm

= u

nbea

rabl

epa

in) a

nd c

onsid

ered

sui

tabl

e fo

r tr

eatm

ent

with

NSA

ID, d

iagn

osis

of O

A b

ased

on

clin

ical

judg

emen

t of

tria

list

(but

rad

iolo

gica

ldi

agno

sis r

equi

red

for

OA

of v

erte

bral

spi

ne),

OA

in m

ultip

le s

ites

elig

ible

pro

vide

d th

esp

ecifi

ed jo

ints

wer

e al

so a

ffect

edEx

clus

ion

crit

eria

:act

ive

pept

ic u

lcer

,hy

pers

ensit

ivity

to

anal

gesic

s, a

ntip

yret

ics

orN

SAID

s, a

sthm

a, n

asal

pol

yps,

ang

ione

urot

icoe

dem

a or

urt

icar

ia fo

llow

ing

NSA

IDad

min

istra

tion,

con

com

itant

ant

icoa

gula

nts,

lithi

um, m

etho

trex

ate,

oth

er N

SAID

s or

anal

gesic

age

nts,

sig

nific

ant

impa

irmen

t of

rena

l fun

ctio

n, s

ever

e liv

er in

jury

,ha

emat

olog

ical

diso

rder

, pre

gnan

t,br

east

feed

ing,

any

dise

ase

whi

ch c

ould

inte

rfer

e w

ith e

valu

atio

n of

effi

cacy

or

tole

rabi

lity,

cor

ticos

tero

id t

reat

men

t w

ithin

2m

onth

s, p

rior

repl

acem

ent

of, t

raum

a to

,or

infe

ctio

n of

the

eva

luat

ed jo

int,

conf

inem

ent

to b

ed, p

revi

ous

part

icip

atio

n in

a cl

inic

al t

rial i

n th

e pr

evio

us m

onth

Com

pari

son:

mel

oxic

am (b

) vs

piro

xica

m (a

) D

urat

ion:

28

days

Inte

rven

tion

s:b,

mel

oxic

am7.

5m

g/7.

5–15

mg

(onc

e da

ily);

a, p

iroxi

cam

20

mg/

10–3

0m

g (o

nce

daily

)O

ther

med

icat

ion:

conc

omita

ntus

e of

oth

er g

astr

opro

tect

ive

drug

s:a

5.6%

, b 4

.6%

A

spir

in a

llow

ed:y

es, l

ow d

ose

allo

wed

Ana

lges

ic a

llow

ed:n

ot s

tate

d Pa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut: y

es, 3

day

s fo

r N

SAID

sN

umbe

r an

d fr

eque

ncy

of v

isit

s:2

(0 a

nd 4

wee

ks)

Allo

cate

d:a

4641

,b

4645

Com

plet

ed:a

381

6,b

3845

Dro

p-ou

t:a

520,

b 4

75A

sses

sed:

a 4

336,

b43

20

Out

com

es r

epor

ted:

mor

talit

y, s

erio

us G

Ico

mpl

icat

ions

,sy

mpt

omat

ic u

lcer

s,se

rious

car

diov

ascu

lar

orre

nal i

llnes

s, (e

xtra

dat

a)G

I sym

ptom

s, G

I dro

p-ou

ts

How

wer

e ad

vers

eev

ents

ass

esse

d:no

tst

ated

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:hi

stor

y of

PU

Bs: a

243

,b

276

>1

NSA

ID: a

0, b

0co

ncom

itant

use

of

antic

oagu

lant

s: a

0,

b 0

cort

icos

tero

ids:

a

0, b

0re

nal/h

epat

ic d

iseas

e:

a 0,

b 0

FUN

DIN

GFu

nded

by:

Boeh

ringe

r In

gelh

eim

Affi

liati

on o

f con

tact

auth

or:U

nive

rsity

Hos

pita

l Que

en’s

Med

ical

Cen

tre,

UK

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of t

rial

adm

inis

trat

or:t

rial

prot

ocol

was

deve

lope

d an

d th

e tr

ial

was

mon

itore

d by

ast

eerin

g co

mm

ittee

cons

istin

g of

the

auth

ors

with

the

repr

esen

tativ

es fr

omBo

ehrin

ger

Inge

lhei

mN

o. o

f aut

hors

empl

oyed

by

spon

sor:

none


313


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Haw

key,

1998

231–

233

MEL

ISSA

Loca

tion

:27

coun

trie

s (S

outh

Am

eric

a, E

urop

e,N

orth

Am

eric

a,A

ustr

alia

and

New

Zea

land

,A

fric

a, A

sia,

incl

udin

g U

K)

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’, s

eale

den

velo

pes

Allo

cati

onco

ncea

lmen

t:un

clea

rB

asel

ine

com

para

bilit

y:ye

sPa

rtic

ipan

t bl

indi

ng:

yes

Ass

esso

r bl

indi

ng:n

oIn

tent

ion-

to-t

reat

: no

A p

riori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ype

rfor

med

but

exc

lude

d pa

rtic

ipan

ts w

ithac

tive

pept

ic u

lcer

B

asel

ine

NSA

ID s

tatu

s:a

3847

/468

8,b

3796

/463

5 ha

d us

ed N

SAID

pre

viou

s to

the

stud

yTy

pe a

nd d

urat

ion

of a

rthr

itis

(m

edia

nm

onth

s): O

A: a

48,

b 5

2A

ge:a

61.

7, b

61.

5Se

x:M

/F: a

153

8/31

44 (?

6), b

153

6/30

96 (?

3)

Incl

usio

n cr

iter

ia:1

8 ye

ars

or m

ore,

acu

tean

d pa

infu

l exa

cerb

atio

n of

OA

(hip

, kne

e,ha

nd o

r ve

rteb

ral s

pine

), pa

in o

n ac

tive

mov

emen

t (3

5m

m o

r m

ore

on 1

00m

mVA

S), a

nd c

onsid

ered

sui

tabl

e fo

r tr

eatm

ent

with

NSA

ID, d

iagn

osis

of O

A b

ased

on

clin

ical

judg

emen

t of

the

tria

list

(but

radi

olog

ical

dia

gnos

is al

so r

equi

red

for

OA

of

the

vert

ebra

l spi

ne),

part

icip

ants

with

OA

inm

ultip

le s

ites

wer

e el

igib

le p

rovi

ded

one

ofth

e sp

ecifi

ed jo

ints

was

affe

cted

Excl

usio

n cr

iter

ia:e

xact

ly t

he s

ame

as fo

rD

eque

ker38

Com

pari

son:

mel

oxic

am (b

) vs

dicl

ofen

ac (a

)D

urat

ion:

28 d

ays

Inte

rven

tion

s:b,

mel

oxic

am7.

5m

g/7.

5–15

mg

(onc

e da

ily);

adi

clof

enac

SR

100

mg/

75–1

50m

g(o

nce

daily

), do

uble

dum

my

used

Oth

er m

edic

atio

n:an

ticoa

gula

nts,

met

hotr

exat

e, li

thiu

m a

nd o

ther

NSA

IDs

proh

ibite

dA

spir

in a

llow

ed:y

es, l

ow d

ose

Ana

lges

ic a

llow

ed:n

oPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

es, 3

day

s fo

r th

ose

prev

ious

ly t

akin

g N

SAID

sN

umbe

r an

d fr

eque

ncy

of v

isit

s:2

(0 a

nd 4

wee

ks)

Allo

cate

d: a

505

1,b

5000

Com

plet

ed:a

413

8,b

4186

Dro

p-ou

t:a

550,

b 4

49A

sses

sed:

a 46

88,

b46

35O

utco

mes

rep

orte

d:m

orta

lity,

ser

ious

GI

com

plic

atio

ns,

sym

ptom

atic

ulc

ers,

serio

us c

ardi

ovas

cula

r or

rena

l illn

ess,

(ext

ra d

ata)

GI s

ympt

oms,

GI d

rop-

outs

How

wer

e ad

vers

eev

ents

ass

esse

d:no

tst

ated

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:hi

stor

y of

PU

Bs: a

249

, b

222

conc

omita

nt u

se o

fdr

ugs

for

gast

ropr

otec

tion:

a

301,

b 2

60

conc

omita

nt u

se o

fan

ticoa

gula

nts:

a 0

, b

0co

rtic

oste

roid

s:

a 0,

b 0

>1

NSA

IDs:

a 0

, b 0

rena

l/hep

atic

dise

ase:

a

0, b

0

FUN

DIN

GFu

nded

by:

Boeh

ringe

r In

gelh

eim

Affi

liati

on o

f con

tact

auth

or:U

nive

rsity

Hos

pita

l Not

tingh

amA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

fad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

0/11

Appendix 6

314

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Port

o, 1

99813

1,23

4

Loca

tion

:m

ultic

entr

e,Po

rtug

al

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d in

bloc

ks o

f 10’

, com

pute

r-ge

nera

ted

allo

catio

nA

lloca

tion

conc

ealm

ent:

unc

lear

Bas

elin

eco

mpa

rabi

lity:

uncl

ear

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:un

clea

rA

pri

ori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd p

atie

nts

only

incl

uded

in s

tudy

with

nor

mal

muc

osa

or 1

0 pe

tech

iae

or le

ssTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A: l

ess

than

1 y

ear

dura

tion

Age

:50

year

s or

mor

e, n

o fu

rthe

r de

tails

Sex:

M/F

: 14/

75 in

tot

alIn

clus

ion

crit

eria

: 50

year

s or

mor

e, O

A(h

ip o

r kn

ee),

unde

rgon

e w

asho

ut fr

ompr

evio

us N

SAID

, nor

mal

gas

trod

uode

nal

muc

osa

or 1

0 pe

tech

iae

or le

ss o

n ba

selin

een

dosc

opy,

OA

with

pai

nful

exa

cerb

atio

n fo

rgr

eate

r th

an 1

wee

k or

req

uire

men

t fo

rtr

eatm

ent

for

1 m

onth

with

NSA

ID, a

nd w

ithda

ily p

ain

(spo

ntan

eous

or

on m

ovem

ent)

and

func

tiona

l im

pairm

ent

of t

he in

fect

ed jo

int,

spon

tane

ous

pain

(4.9

cm o

r m

ore

on 1

0cm

VAS,

Hus

kiss

on t

ype)

, les

ions

rat

ed 1

to

3 on

radi

olog

ical

exa

min

atio

n 1

year

or

less

bef

ore

stud

yEx

clus

ion

crit

eria

:OA

: pre

sent

for

1 ye

aror

mor

e, s

ever

e or

inca

paci

tatin

g O

A (u

nabl

eto

wal

k), n

eces

sitat

ing

surg

ical

inte

rven

tion

durin

g th

e st

udy

perio

d, b

eing

tre

ated

with

intr

a-ar

ticul

ar c

ortic

oids

dur

ing

the

4 w

eeks

prio

r to

stu

dy e

ntry

, sev

ere

rena

l, he

patic

,ca

rdio

vasc

ular

, end

ocrin

e or

hae

mat

olog

ical

dise

ases

or

bron

chia

l ast

hma,

kno

wn

hist

ory

of h

yper

sens

itivi

ty t

o N

SAID

s, p

regn

ant

wom

en, n

ursin

g m

othe

rs o

r w

omen

who

mig

ht b

ecom

e pr

egna

nt

Com

pari

son:

nim

esul

ide

(b) v

sdi

clof

enac

(a)

Dur

atio

n:30

day

sIn

terv

enti

ons:

b, n

imes

ulid

e20

0m

g/?m

g (1

00m

g ×2

dai

ly);

a, d

iclo

fena

c 15

0m

g/75

–150

mg

(50

mg

×3 d

aily

) ‘do

uble

dum

my’

Endo

scop

y:be

fore

ran

dom

isatio

nan

d da

y 30

Oth

er m

edic

atio

n:us

e of

antic

oagu

lant

s, h

ydan

toin

, cen

tral

or

perip

hera

l ana

lges

ics,

imm

unos

uppr

essiv

e ag

ents

, ora

lan

tidia

betic

s, a

ntim

alar

ials,

oth

erN

SAID

s, s

yste

mic

or

intr

a-ar

ticul

arco

rtic

oids

, mus

cle

rela

xant

s,ne

urol

eptic

s, a

ntid

epre

ssan

tspr

ohib

ited

thro

ugho

ut s

tudy

, all

othe

r m

edic

atio

ns w

ere

perm

itted

.Ph

ysio

-the

rape

utic

mea

sure

sin

itiat

ed a

t le

ast

1 m

onth

prio

r to

stud

y al

low

ed t

o co

ntin

ueA

spir

in a

llow

ed:n

oA

nalg

esic

allo

wed

:yes

,ac

etam

inop

hen

up t

o 50

0m

g 6×

daily

Pa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:4

8–72

hN

umbe

r an

d fr

eque

ncy

of v

isit

s:2

(0 a

nd d

ay 3

0)

Allo

cate

d:a

45, b

44

Com

plet

ed:a

39,

b 3

9D

rop-

out:

a 6,

b 5

Ass

esse

d:a

45, b

44

Out

com

es r

epor

ted:

sym

ptom

atic

ulc

ers,

GI

sym

ptom

s, e

ndos

copi

cul

cers

How

wer

e ad

vers

eev

ents

ass

esse

d:pa

rtic

ipan

ts a

sked

non

-le

adin

g qu

estio

nsre

gard

ing

adve

rse

even

tsw

hich

wer

e th

en g

rade

din

sev

erity

, fre

quen

cy,

rela

tions

hip

to s

tudy

med

icat

ion

and

outc

ome

How

was

com

plia

nce

asse

ssed

: tab

let

coun

t, 6

or le

ss t

able

ts r

etur

ned

= g

ood,

7–1

2 ta

blet

sre

turn

ed =

fair,

mor

eth

an 1

2 ta

blet

s re

turn

ed=

poo

r, no

ne in

dicl

ofen

ac g

roup

and

one

in n

imes

ulid

e gr

oup

wer

e po

orly

com

plia

nt

Ris

k fa

ctor

s:co

ncom

itant

use

of

antic

oagu

lant

s: a

0, b

0

cort

icos

tero

ids:

a 0

, b

0 >

1 N

SAID

: a 0

, b 0

C

VD: a

0, b

0

diab

etes

: a 0

, b 0

rena

l/hep

atic

dise

ase:

a

0, b

0FU

ND

ING

Fund

ed b

y:Rh

one-

Poul

enc

Rore

r, Li

sbon

,Po

rtug

alA

ffilia

tion

of c

onta

ctau

thor

:Hel

sinn

Hea

lthca

re,

Switz

erla

ndA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f stu

dyad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

1 of

6em

ploy

ed b

y Rh

one-

Poul

enc

Rore

r, 1

of 6

empl

oyed

by

Hel

sinn

Hea

lthca

re


315


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Dou

gado

s,19

9913

2,23

5

Loca

tion

:Be

lgiu

m, F

ranc

e,G

erm

any

and

UK

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d’A

lloca

tion

conc

ealm

ent:

unc

lear

B

asel

ine

com

para

bilit

y:un

clea

rPa

rtic

ipan

t bl

indi

ng:

yes

Ass

esso

r bl

indi

ng:

uncl

ear

Inte

ntio

n-to

-tre

at:y

esA

pri

ori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

y,no

furt

her

deta

ilsTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:A

S: a

12,

b 1

3, c

12

Age

:a 4

4, b

44,

c 4

2Se

x:M

/F: a

25/

83, b

25/

95, c

19/

105

Incl

usio

n cr

iter

ia:o

utpa

tient

s fu

lfilli

ngm

odifi

ed N

ew Y

ork

crite

ria fo

r A

S, d

aily

NSA

ID in

take

dur

ing

the

mon

th p

rece

ding

the

sele

ctio

n vi

sit, N

SAID

was

hout

per

iod

of2–

15 d

ays

befo

re b

asel

ine

visit

, fla

re o

fdi

seas

e at

bas

elin

e de

fined

bot

h by

pai

n(4

0m

m o

r m

ore

on a

100

mm

VA

S) a

nd b

yin

crea

se in

pai

n of

at

leas

t 30

% b

etw

een

scre

enin

g an

d ba

selin

e vi

sits

Excl

usio

n cr

iter

ia:p

erip

hera

l art

icul

ardi

seas

e de

fined

by

the

pres

ence

of a

ctiv

e(p

ainf

ul o

r sw

olle

n) p

erip

hera

l art

hriti

s(e

xclu

ding

hip

and

sho

ulde

r) a

t sc

reen

ing

visit

, act

ive

infla

mm

ator

y bo

wel

dise

ase,

seve

re c

onco

mita

nt m

edic

al il

lnes

s, r

ecei

ved

cort

icos

tero

ids

with

in p

revi

ous

mon

th a

nd/o

ran

y slo

w-a

ctin

g dr

ug in

itiat

ed (o

r al

tere

ddo

se) i

n pr

evio

us 6

mon

ths

Com

pari

son:

mel

oxic

am (b

, c) v

spi

roxi

cam

(a)

Dur

atio

n:52

wee

ksIn

terv

enti

ons:

b m

elox

icam

15m

g/7.

5–15

mg

(onc

e da

ily);

c, m

elox

icam

22.

5m

g/7.

5–15

mg

(onc

e da

ily);

a, p

iroxi

cam

20m

g/10

–30

mg

(onc

e da

ily),

all

took

2 c

apsu

les

(indi

stin

guish

able

)ea

ch e

veni

ngO

ther

med

icat

ion:

not

sta

ted

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:y

es,

para

ceta

mol

500

-mg

tabl

ets

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

: yes

, 2–1

5 da

ys, p

art

ofin

clus

ion

crite

riaN

umbe

r an

d fr

eque

ncy

of v

isit

s:8

(0, 1

, 3, 6

, 13,

26,

39,

52

wee

ks)

Allo

cate

d: a

108

, b12

0, c

124

Com

plet

ed:a

51,

b 5

7,c

78D

rop-

out:

a 57

, b 6

3,c

46A

sses

sed:

a 10

8, b

120

,c

124

Out

com

es r

epor

ted:

serio

us G

Ico

mpl

icat

ions

,sy

mpt

omat

ic u

lcer

s, G

Isy

mpt

oms

How

wer

e ad

vers

eev

ents

ass

esse

d:no

tst

ated

How

was

com

plia

nce

asse

ssed

:tab

let

coun

t,re

sult

not

repo

rted

Ris

k fa

ctor

s:co

ncom

itant

use

of

cort

icos

tero

ids:

a 0

, b

0 FU

ND

ING

Fund

ed b

y:in

par

tBo

ehrin

ger

Inge

lhei

mA

ffilia

tion

of c

onta

ctau

thor

:Hop

ital

Coc

hin,

Par

is, F

ranc

eA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

1 of

7au

thor

s em

ploy

edBo

ehrin

ger

Inge

lhei

mD

ose:

22.5

mg

mel

oxic

am a

rm is

abov

e re

com

men

ded

dose

Oth

er:p

lace

bo a

rmex

clud

ed fr

om a

naly

sis

Appendix 6

316

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Hus

kiss

on,

1999

133

Loca

tion

:12

rheu

mat

olog

you

tpat

ient

clin

ics

in t

he U

K a

ndIr

elan

d an

d 3

GPs

in t

he U

K

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:un

clea

rA

pri

ori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ype

rfor

med

but

pat

ient

s ex

clud

ed if

hist

ory

orsy

mpt

oms

of g

astr

ic o

r du

oden

al u

lcer

Ty

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A h

ip o

r kn

ee, n

o ot

her

deta

ilsA

ge:a

64.

9 b

64.6

Sex:

M/F

: a 4

7/97

, b 5

1/84

Incl

usio

n cr

iter

ia:4

5–79

yea

rs, O

A (k

nee

or h

ip) o

f 6 m

onth

s or

long

er d

urat

ion

and

with

mod

erat

e to

sev

ere

pain

, wom

en o

fch

ildbe

arin

g po

tent

ial r

equi

red

to u

sead

equa

te b

irth

cont

rol

Excl

usio

n cr

iter

ia:t

arge

t jo

int

requ

ired

arth

ropl

astic

sur

gery

dur

ing

stud

y, s

ever

ein

terc

urre

nt il

lnes

s, k

now

n hy

pers

ensit

ivity

to

NSA

IDs,

a h

istor

y of

or

sym

ptom

s of

gas

tric

or d

uode

nal u

lcer

, clin

ical

ly s

igni

fican

tla

bora

tory

abn

orm

aliti

es, p

artic

ipat

ion

inan

othe

r cl

inic

al t

rial w

ithin

the

pre

cedi

ng3

mon

ths,

pre

gnan

t or

bre

ast-

feed

ing

Com

pari

son:

nim

esul

ide

(b) v

sdi

clof

enac

(a)

Dur

atio

n:24

wee

ksIn

terv

enti

ons:

b, n

imes

ulid

e20

0mg/

? (10

0m

g ×2

dai

ly);

a, d

iclo

fena

c 15

0m

g/75

–150

mg

(50

mg

×3 d

aily

), do

uble

dum

my

desig

nO

ther

med

icat

ion:

oth

er t

hera

pyfo

r O

A n

ot p

erm

itted

Asp

irin

allo

wed

:no

Ana

lges

ic a

llow

ed:y

es,

acet

amin

ophe

n up

to

4g

daily

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:yes

, no

furt

her

deta

ilsN

umbe

r an

d fr

eque

ncy

of v

isit

s:4

(0, 2

, 4, 1

2 an

d 24

wee

ks a

nd b

yte

leph

one

at 8

, 16

and

20 w

eeks

)

Allo

cate

d:a

144,

b 1

35C

ompl

eted

:a 9

9, b

88

Dro

p-ou

t:a

45 b

47

Ass

esse

d:a

144,

b 1

35O

utco

mes

rep

orte

d:m

orta

lity,

GI s

ympt

oms,

anae

mia

, GI d

rop-

outs

,to

tal d

rop-

outs

How

wer

e ad

vers

eev

ents

ass

esse

d:pa

rtic

ipan

ts w

ere

tele

phon

ed b

etw

een

visit

s re

gard

ing

adve

rse

even

tsH

ow w

as c

ompl

ianc

eas

sess

ed: d

efin

ed a

sm

issin

g fe

wer

tha

n9

dose

s in

any

4-w

eek

perio

d, 7

0% o

fpa

rtic

ipan

ts in

eac

hgr

oup

had

good

to

exce

llent

com

plia

nce

(N.B

.oth

er 3

0% d

id n

otre

turn

use

d m

edic

atio

npa

cks

and

so e

xact

com

plia

nce

data

are

unav

aila

ble)

Ris

k fa

ctor

s:hi

stor

y of

ulc

ers:

a 0

, b

0 FU

ND

ING

Fund

ed b

y:M

erck

Affi

liati

on o

f con

tact

auth

or:U

nive

rsity

of

Sout

hern

Cal

iforn

iaSc

hool

of M

edic

ine,

USA

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:4

of 9

auth

ors

empl

oyed

by

Mer

ck, 1

of 9

by

Hill

Top

Rese

arch


317


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Roy,

199

9134

Loca

tion

:Lok

Nay

ak H

ospi

tal,

New

Del

hi, I

ndia

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

adm

inist

ered

’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

no Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

high

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ype

rfor

med

but

exc

lude

d pa

rtic

ipan

ts w

ithac

tive

pept

ic u

lcer

Type

and

dur

atio

n of

art

hrit

is (

mon

ths)

:O

A: a

44.

9, b

33.

2A

ge:a

47.

3 b

46.7

Sex:

M/F

: unc

lear

Incl

usio

n cr

iter

ia: 4

2–80

yea

rs, n

ewly

diag

nose

d O

A (k

nee)

for

6 m

onth

s or

long

er(A

CR

crite

ria w

ith c

linic

al a

nd r

adio

logi

cal

conf

irmat

ion)

, Ste

inbr

ocke

r fu

nctio

nal

capa

city

of c

lass

I or

IIEx

clus

ion

crit

eria

:pre

senc

e of

non

-de

gene

rativ

e jo

int

dise

ases

(inf

ectio

us,

mic

rocr

ysta

lline

), se

vere

and

disa

blin

gar

thrit

is w

ith e

ligib

ility

for

surg

ical

inte

rven

tion,

tre

atm

ent

with

intr

a-ar

ticul

arin

ject

ions

of c

ortic

oste

roid

s w

ithin

the

mon

thpr

eced

ing

the

stud

y, h

istor

y of

hype

rsen

sitiv

ity t

o N

SAID

s, p

rese

nce

of a

nac

tive

ulce

r, pr

egna

ncy,

lact

atio

n, h

istor

y of

hepa

tic, r

enal

or

haem

atop

oiet

ic d

iseas

e,re

ceiv

ing

othe

r N

SAID

s or

any

oth

erm

edic

atio

ns, h

istor

y of

alc

ohol

inta

ke

Com

pari

son:

nim

esul

ide

(b) v

spi

roxi

cam

(a)

Dur

atio

n: 8

wee

ksIn

terv

enti

ons:

b, n

imes

ulid

e20

0m

g/?m

g (1

00m

g ×2

dai

ly);

a, p

iroxi

cam

20

mg/

10–3

0m

g (o

nce

daily

) plu

s id

entic

al p

lace

bo, t

aken

afte

r m

eals

Oth

er m

edic

atio

n:no

oth

erm

edic

atio

n lik

ely

to in

terf

ere

with

stud

y dr

ug w

as a

llow

edA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:yes

,pa

race

tam

ol, 5

00-m

g ta

blet

s Pa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:n

ot s

tate

dN

umbe

r an

d fr

eque

ncy

ofvi

sits

:5 (0

, 2, 4

, 6 a

nd 8

wee

ks)

Allo

cate

d:a

49, b

41

Com

plet

ed:a

40,

b 3

0D

rop-

out:

a 9,

b 1

1A

sses

sed:

a 40

, b 3

0O

utco

mes

rep

orte

d:sy

mpt

omat

ic u

lcer

s, G

Isy

mpt

oms,

GI d

rop-

outs

How

wer

e ad

vers

eev

ents

ass

esse

d:gl

obal

eval

uatio

n of

tol

erab

ility

as r

epor

ted

by t

hepa

rtic

ipan

t w

as d

one

ona

4-po

int

verb

al r

atin

gsc

ale

at e

ach

follo

w-u

pvi

sitH

ow w

as c

ompl

ianc

eas

sess

ed:t

able

t co

unt

Ris

k fa

ctor

s:>

1 N

SAID

: a 0

, b 0

rena

l/hep

atic

dise

ase:

a

0, b

0FU

ND

ING

Fund

ed b

y:Pa

nace

aBi

otec

Affi

liati

on o

f con

tact

auth

or:M

AM

Col

lege

,N

ew D

elhi

, Ind

iaA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f stu

dyad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

none

Oth

er:1

0 pa

rtic

ipan

tske

pt in

tria

l for

24w

eeks

and

had

MRI

, Tab

le 1

app

ears

inac

cura

te; d

esig

nid

entic

al w

ith s

tudy

by

Shar

ma44

Appendix 6

318

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Shar

ma,

199

944

Loca

tion

:All

Indi

a In

stitu

te o

fM

edic

al S

cien

ces,

New

Del

hi, I

ndia

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d’,

stra

tifie

d in

to 2

gro

ups

(par

ticip

ants

bel

ongi

ng t

ofu

nctio

nal c

lass

II w

ere

chos

en fo

r M

RIev

alua

tion,

n=

14),

cent

ral c

ompu

ter

Allo

cati

onco

ncea

lmen

t: u

ncle

arB

asel

ine

com

para

bilit

y:no Pa

rtic

ipan

t bl

indi

ng:

yes

Ass

esso

r bl

indi

ng:n

oIn

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

high

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ype

rfor

med

, no

furt

her

deta

ilsTy

pe a

nd d

urat

ion

of a

rthr

itis

(m

onth

s):

OA

: a 6

–144

, b 6

–140

Age

:a 5

2.3,

b 5

0.2

Sex:

M/F

: a 1

0/18

, b 9

/12

Incl

usio

n cr

iter

ia: 4

2–80

yea

rs, n

ewly

diag

nose

d O

A (k

nee)

for

6 m

onth

s or

long

er(A

CR

crite

ria w

ith c

linic

al a

nd r

adio

logi

cal

conf

irmat

ion)

, Ste

inbr

ocke

r fu

nctio

nal

capa

city

of c

lass

I, II

or

III (d

iagn

osis

requ

ired

at le

ast

3 hi

stor

ical

crit

eria

and

at

leas

t 1

ofth

e ra

diol

ogic

al fi

ndin

gs t

o be

pre

sent

: hist

ory

of p

ain

aggr

avat

ed b

y m

otio

n an

d at

leas

tpa

rtly

rel

ieve

d by

res

t, lim

itatio

ns o

f the

rang

e of

mov

emen

t, in

activ

ity s

tiffn

ess,

tend

erne

ss o

n pr

essu

re, s

ynov

itis

indi

cativ

e of

OA

by

join

t flu

id a

naly

sis w

hen

effu

sion

pres

ent,

radi

olog

y sh

owin

g jo

int

spac

ena

rrow

ing,

sub

chon

dral

bon

y sc

lero

sis(e

burn

atio

n), b

one

cyst

s, g

ross

def

orm

ity a

ndsu

blux

atio

n an

d/or

loos

e bo

dies

).Ex

clus

ion

crit

eria

:rec

eivi

ng a

ntin

eopl

astic

agen

ts, c

ortic

oste

roid

s, g

old

salts

,pe

nici

llam

ine,

col

chic

ine,

ant

icoa

gula

nts,

hyda

ntoi

n, a

ntid

iabe

tic d

rugs

, ant

imal

aria

lsw

ithin

1 m

onth

pre

cedi

ng t

he s

tudy

or

attim

e of

incl

usio

n, o

ther

typ

es o

f art

hriti

cco

nditi

ons,

sch

edul

ed fo

r ho

spita

lisat

ion

orbe

d re

st o

r fo

r jo

int

repl

acem

ent

surg

ery

beca

use

of a

rthr

itis

with

evi

denc

e of

act

ive

GI

dise

ase,

pre

gnan

t an

d nu

rsin

g w

omen

Com

pari

son:

nim

esul

ide

(b) v

spi

roxi

cam

(a)

Dur

atio

n:8

wee

ksIn

terv

enti

ons:

b, n

imes

ulid

e20

0m

g/?m

g (1

00m

g ×2

dai

ly);

a, p

iroxi

cam

20

mg/

10–3

0m

g (in

the

mor

ning

plu

s id

entic

al p

lace

boin

the

eve

ning

)O

ther

med

icat

ion:

no

othe

rN

SAID

s pe

rmitt

ed a

ntin

eopl

astic

agen

ts, c

ortic

oste

roid

s, g

old

salts

,pe

nici

llam

ine,

col

chic

ine,

antic

oagu

lant

s, h

ydan

toin

,an

tidia

betic

dru

gs, a

ntim

alar

ials

excl

uded

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:y

es,

para

ceta

mol

adm

inist

ered

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:yes

, 15

days

for

prio

rN

SAID

s du

ring

whi

ch id

entic

alpl

aceb

o w

as a

dmin

ister

edN

umbe

r an

d fr

eque

ncy

of v

isit

s:5

(0, 2

, 4, 6

and

8 w

eeks

)

Allo

cate

d:a

40, b

25

Com

plet

ed:a

28,

b 2

1D

rop-

out:

a 12

, b 4

Ass

esse

d:a

28, b

21

Out

com

es r

epor

ted:

mor

talit

y, s

ympt

omat

icul

cers

, ser

ious

card

iova

scul

ar o

r re

nal

illne

ss, (

extr

a da

ta)

serio

us G

Ico

mpl

icat

ions

, GI

sym

ptom

s, G

I dro

p-ou

tsH

ow w

ere

adve

rse

even

ts a

sses

sed:

not

stat

edH

ow w

as c

ompl

ianc

eas

sess

ed:t

able

t co

unt,

part

icip

ants

who

did

n’t

take

stu

dy m

edic

atio

nfo

r m

ore

than

3 d

ays

wer

e co

nsid

ered

as

drop

-out

s

Ris

k fa

ctor

s:co

ncom

itant

use

of

antic

oagu

lant

s: a

0, b

0co

rtic

oste

roid

s; a

0,

b 0

>1N

SAID

s: a

0, b

0FU

ND

ING

Fund

ed b

y:Pa

nace

aBi

otec

Affi

liati

on o

f con

tact

auth

or:I

nstit

ute

ofH

uman

Beh

avio

ur a

ndA

llied

Sci

ence

s, D

elhi

,In

dia

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:1

or 5

auth

ors

empl

oyed

by

Pana

cea

Biot

ecO

ther

:11

part

icip

ants

kept

in t

rial f

or

24 w

eeks

and

had

MRI

, des

ign

iden

tical

with

stu

dy b

y Ro

y134


319


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Zgr

adie

, 199

9135

Loca

tion

:Yu

gosla

via

Mili

tary

Med

ical

Aca

dem

y,Be

lgra

de a

ndU

nive

rsity

of

Prish

tina

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

uncl

ear

Part

icip

ant

blin

ding

:un

clea

rA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:un

clea

rA

pri

ori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

yTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A, n

o fu

rthe

r de

tails

Age

:18–

80Se

x:M

/F: a

44/

46, b

34/

56In

clus

ion

crit

eria

: OA

of t

he h

ip, k

nee

orlu

mba

r sp

ine,

18–

80 y

ears

, mod

erat

e to

mar

ked

evid

ent

sym

ptom

s of

OA

Ex

clus

ion

crit

eria

:no

deta

ils

Com

pari

son:

nim

esul

ide

(b) v

sdi

clof

enac

sod

ium

(a)

Dur

atio

n:4

wee

ksIn

terv

enti

ons:

b, n

imes

ulid

e20

0m

g/?m

g (1

00m

g ×2

dai

ly);

a, d

iclo

fena

c 15

0m

g/75

–150

mg

(50

mg

×3 d

aily

) O

ther

med

icat

ion:

no d

etai

lsA

spir

in a

llow

ed: n

ot s

tate

dA

nalg

esic

allo

wed

: not

sta

ted

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

: not

sta

ted

Num

ber

and

freq

uenc

y of

vis

its:

3 (0

, 2 a

nd 4

wee

ks)

Allo

cate

d:a

90, b

90

Com

plet

ed:u

ncle

arD

rop-

out:

uncl

ear

Ass

esse

d:un

clea

rO

utco

mes

rep

orte

d:G

I sym

ptom

s, G

I dro

p-ou

tsH

ow w

ere

adve

rse

even

ts a

sses

sed:

‘did

you

expe

rienc

e an

yun

plea

sant

sen

satio

ndu

ring

the

last

2 w

eeks

?’If

yes,

the

n pa

rtic

ipan

tsas

ked

to e

valu

ate

degr

eeof

tha

t ad

vers

e ev

ent

and

deriv

e fin

alev

alua

tion

of t

he d

rug

tole

ranc

eH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:no

deta

ilsFU

ND

ING

Fund

ed b

y:un

clea

rA

ffilia

tion

of c

onta

ctau

thor

:Yug

osla

via

Mili

tary

Med

ical

Aca

dem

y, B

elgr

ade

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

Pana

cea

Biot

ecN

o. o

f aut

hors

empl

oyed

by

spon

sor:

none

Appendix 6

320

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Pate

l, 20

0013

6

Loca

tion

:Set

hG

S M

edic

alC

olle

ge, M

umba

i,In

dia

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

allo

tted

’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

no r

egar

ding

age

Part

icip

ant

blin

ding

:un

clea

rA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:un

clea

rA

pri

ori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

high

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ype

rfor

med

, no

furt

her

deta

ilsTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

: RA

: a 1

6, b

15

OA

: a 2

4, b

22

Age

:a 4

5.4,

b 5

1.4

Sex:

M/F

: a 3

5/31

, b 3

2/29

Incl

usio

n cr

iter

ia:a

dults

, art

icul

ar r

heum

atic

diso

rder

s (O

A o

r RA

) or

non-

artic

ular

cond

ition

s su

ch a

s lu

mba

go, s

ciat

ica

and

othe

r su

bacu

te/c

hron

ic m

uscu

losk

elet

alco

nditi

ons

Excl

usio

n cr

iter

ia:k

now

n hy

pers

ensit

ivity

to s

tudy

dru

gs, a

cid

pept

ic d

iseas

e, s

ever

ehe

patic

and

/or

rena

l dise

ase,

pre

gnan

cy,

cort

icos

tero

id t

hera

py fo

r an

y ot

her

cond

ition

Com

pari

son:

mel

oxic

am (b

) vs

dicl

ofen

ac s

ubsy

de C

R (a

)D

urat

ion:

28 d

ays

Inte

rven

tion

s:b,

mel

oxic

am7.

5m

g O

R 15

mg/

7.5–

15m

g da

ily;

a, d

iclo

fena

c su

bsyd

e C

R10

0m

g/75

–150

mg

daily

Oth

er m

edic

atio

n:no

det

ails

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed: n

ot s

tate

dPa

rtic

ipan

t ed

ucat

ion:

not

sta

ted

Was

hout

:not

sta

ted

Num

ber

and

freq

uenc

y of

vis

its:

7 (0

, 1, 3

, 7, 1

4, 2

1 an

d 28

day

s)

Allo

cate

d:un

clea

rC

ompl

eted

:unc

lear

Dro

p-ou

t:un

clea

rA

sses

sed:

a 66

, b 6

1O

utco

mes

rep

orte

d:G

I sym

ptom

sH

ow w

ere

adve

rse

even

ts a

sses

sed:

not

stat

edH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:re

nal/h

epat

ic d

iseas

e:

a 0,

b 0

FUN

DIN

GFu

nded

by:

uncl

ear

Affi

liati

on o

f con

tact

auth

or:S

eth

GS

Med

ical

Col

lege

,M

umba

i, In

dia

Affi

liati

on o

fst

atis

tici

an: u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:un

clea

rO

ther

:dos

age

ofdi

clof

enac

arm

not

stat

ed in

stu

dy b

ut in

adve

rtise

men

tfo

llow

ing

stud

y


321


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Yocu

m, 2

00013

7

Loca

tion

:61

stud

y ce

ntre

s in

USA

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

e co

mpa

rabi

lity:

no Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

high

Bas

elin

e G

I st

atus

:par

ticip

ants

exc

lude

d if

uppe

r G

I per

fora

tions

, ulc

ers

or p

eptic

ulc

erbl

eedi

ng in

6 m

onth

s pr

ior

to e

nrol

men

tB

asel

ine

NSA

ID s

tatu

s:al

l par

ticip

ants

wer

e re

quire

d to

be

curr

ent

NSA

ID u

sers

,m

ean

dura

tion

of N

SAID

use

: a 3

.9 y

ears

, b

3.8

year

s, c

3.8

yea

rsTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A: a

9, b

8 c

7A

ge:a

63.

0, b

62.

4, c

64.

3Se

x:M

/F: a

49/

104,

b 5

7/97

, c 5

6/10

0In

clus

ion

crit

eria

: cur

rent

NSA

ID u

ser,

40ye

ars

or m

ore,

at l

east

3-m

onth

hist

ory

ofO

A (h

ip o

r kn

ee) c

onfir

med

by

X-r

ay a

ndcl

inic

al s

igns

and

sym

ptom

s, a

nd p

ain

onm

ovem

ent o

f the

targ

et jo

int;

NSA

ID-fr

eepe

riod

of a

t lea

st 3

day

s du

ring

whi

ch fl

are

was

requ

ired

(def

ined

as

wor

seni

ng o

f dise

ase

activ

ity fr

om in

itial

scr

eeni

ng th

at m

et th

efo

llow

ing

crite

ria: a

t lea

st 1

gra

de d

eter

iora

tion

in th

e in

vest

igat

or g

loba

l ass

essm

ent o

f dise

ase

activ

ity, a

n in

crea

se o

f 10

mm

or

grea

ter

on a

100

mm

VA

S fo

r th

e pa

tient

glo

bal a

sses

smen

tof

dise

ase

activ

ity, a

nd a

n in

crea

se g

reat

er th

an35

mm

on

a 10

0m

m V

AS

in th

e pa

tient

ove

rall

asse

ssm

ent o

f pai

nEx

clus

ion

crit

eria

:int

oler

ance

of a

nyN

SAID

, asp

irin,

ana

lges

ic o

r an

tipyr

etic

or

any

dise

ase

that

cou

ld in

terf

ere

with

eval

uatio

n of

effi

cacy

or

safe

ty, a

bnor

mal

rena

l, ha

emat

olog

ical

or

hepa

tic fu

nctio

n,hi

stor

y of

ble

edin

g di

sord

er o

r cu

rren

tth

erap

y w

ith a

n an

ticoa

gula

nt, r

ecen

t(2

mon

ths)

use

of c

ortic

oste

roid

s, t

reat

men

tw

ith in

tra-

artic

ular

inje

ctio

ns o

f hya

luro

nic

acid

in p

rior

3 m

onth

s, lo

ng-t

erm

use

of G

Im

edic

atio

ns (H

2bl

ocke

rs, m

isopr

osto

l, PP

Is)

that

cou

ld n

ot b

e di

scon

tinue

d, h

istor

y of

narc

otic

and

/or

alco

hol a

buse

Com

pari

son:

mel

oxic

am (b

, c) v

sdi

clof

enac

(a)

Dur

atio

n:12

wee

ksIn

terv

enti

ons:

b: m

elox

icam

7.5

mg/

7.5–

15m

g (o

nce

in t

hem

orni

ng a

fter

food

); c,

mel

oxic

am15

mg/

7.5–

15m

g (o

nce

in t

hem

orni

ng a

fter

food

); a,

dic

lofe

nac

100

mg/

75–1

50m

g (5

0m

g ×2

dai

lym

orni

ng a

nd e

veni

ng a

fter

food

),do

uble

dum

mie

s us

ed

Oth

er m

edic

atio

n:an

ticoa

gula

nts,

cort

icos

tero

ids,

intr

a-ar

ticul

arin

ject

ions

of h

yalu

rinat

e, H

2RA

s,m

isopr

osto

l and

PPI

s w

ere

not

perm

itted

A

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:not

sta

ted

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:yes

, at

leas

t 3

days

for

NSA

IDs

Num

ber

and

freq

uenc

y of

vis

its:

5 (0

, 2, 4

, 8 a

nd 1

2 w

eeks

)

Allo

cate

d:a

153,

b

154,

c 1

56(5

part

icip

ants

miss

ing

from

5 a

rms)

Com

plet

ed:a

108

,b

101,

c 1

07D

rop-

out:

a 45

, b 5

3,

c 49

Ass

esse

d:a

153,

b 1

54,

c 15

6O

utco

mes

rep

orte

d:m

orta

lity,

ser

ious

GI

com

plic

atio

ns,

sym

ptom

atic

ulc

ers,

serio

us c

ardi

ac o

r re

nal

illne

ss, G

I sym

ptom

s, G

Idr

op-o

uts

How

wer

e ad

vers

eev

ents

ass

esse

d:re

cord

ed in

cide

nce,

dura

tion

and

inte

nsity

and

rela

tion

to s

tudy

drug

, nee

d fo

rtr

eatm

ent

and

actio

nta

ken

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:hi

stor

y of

ble

eds

(not

in p

revi

ous

6 m

onth

s):

a 16

, b 1

1, c

8co

ncom

itant

use

of

antic

oagu

lant

s: a

0, b

0co

rtic

oste

roid

s: a

0,

b 0

rena

l/hep

atic

dise

ase:

a

0, b

0FU

ND

ING

Fund

ed b

y:Bo

ehrin

ger

Inge

lhei

mA

ffilia

tion

of c

onta

ctau

thor

:Uni

vers

ity o

fA

rizon

a, U

SAA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f stu

dyad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

2 of

6au

thor

s em

ploy

ed b

yBo

ehrin

ger

Inge

lhei

m

Oth

er:p

lace

bo a

rman

d m

elox

icam

3.75

mg

daily

arm

wer

e ex

clud

ed fr

oman

alys

es

Appendix 6

322

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Cha

ng, 2

00137

Loca

tion

:Tri

Serv

ice

Gen

eral

Hos

pita

l, Ta

iwan

Met

hod

ofra

ndom

isat

ion:

‘con

secu

tivel

yra

ndom

ised’

cen

tral

com

pute

r an

d ce

ntra

lpe

rson

nel

Allo

cati

onco

ncea

lmen

t:ad

equa

te

Bas

elin

e co

mpa

rabi

lity:

no Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:yes

Inte

ntio

n-to

-tre

at:n

oA

pri

ori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd e

xclu

ded

part

icip

ants

with

pept

ic u

lcer

s Ty

pe a

nd d

urat

ion

of a

rthr

itis

:O

A: a

5.9

, b 2

.8

Age

:a 6

3.1

(36–

77),

b 60

.8 (4

5–78

)Se

x:M

/F: a

9/2

7, b

4/3

2 In

clus

ion

crit

eria

: 18

year

s or

mor

e w

ith a

conf

irmed

OA

(kne

e) o

f at l

east

3 m

onth

s’du

ratio

n, d

efin

ed c

linic

ally

and

rad

iogr

aphi

cally

(kne

e pa

in o

n m

ost d

ays

of th

e pr

evio

usm

onth

with

per

iart

icul

ar o

r re

ferr

ed p

ain

excl

uded

on

exam

inat

ion,

mor

ning

stif

fnes

s of

less

than

30

min

utes

’ dur

atio

n pl

us p

rese

nce

of o

steo

phyt

es r

adio

grap

hica

lly p

lus

crep

itus

or 5

0 ye

ars

or m

ore,

req

uire

d co

ntin

uous

NSA

ID th

erap

y fo

r du

ratio

n of

tria

lEx

clus

ion

crit

eria

:end

osco

py-d

etec

ted

pept

ic u

lcer

atio

n, t

reat

men

t w

ith a

ny s

tudy

drug

in p

revi

ous

4w

eeks

, pre

gnan

cy o

rla

ctat

ion,

hist

ory

of g

astr

ic, d

uode

nal o

r sm

all

inte

stin

e su

rger

y, s

ever

e ca

rdia

c, h

epat

ic,

rena

l, ha

emat

olog

ical

or

met

abol

ic d

iseas

e,ca

ncer

, men

tal d

istur

banc

e, u

lcer

ativ

e co

litis,

bron

chia

l ast

hma

indu

cibl

e by

asp

irin

or o

ther

NSA

IDs,

kno

wn

hype

rsen

sitiv

ity t

o an

alge

sics,

antip

yret

ics

or N

SAID

s, c

onco

mita

nttr

eatm

ent

with

ant

icoa

gula

nts,

incl

udin

ghe

parin

and

asp

irin,

con

com

itant

inta

ke o

fN

SAID

s, in

clud

ing

aspi

rin e

ven

in lo

w d

oses

,co

ncom

itant

tre

atm

ent

with

lith

ium

,hy

dant

oins

, clin

ical

ly s

igni

fican

t ab

norm

alla

bora

tory

inve

stig

atio

ns, t

reat

men

t w

ithco

rtic

oste

roid

s (in

clud

ing

intr

a-ar

ticul

arin

ject

ions

) in

prev

ious

mon

th o

r du

ring

stud

y,tr

eatm

ent

with

4g/

day

or m

ore

para

ceta

mol

,an

y co

ncom

itant

dise

ase

whi

ch m

ight

lead

to

prem

atur

e te

rmin

atio

n of

stu

dy, a

ny o

ther

dise

ase

that

wou

ld in

terf

ere

with

the

eval

uatio

n of

effi

cacy

and

saf

ety

Com

pari

son:

mel

oxic

am (b

) vs

piro

xica

m (a

) D

urat

ion:

4 w

eeks

Inte

rven

tion

s:b,

mel

oxic

am7.

5m

g/7.

5–15

mg

(onc

e da

ily);

a, p

iroxi

cam

20

mg/

10–3

0m

g (o

nce

daily

), do

uble

dum

mie

s us

edEn

dosc

opy:

(0 a

nd a

t 4

wee

ks)

Oth

er m

edic

atio

n:an

taci

d(a

ntag

el) w

as p

resc

ribed

for

both

arm

s th

roug

hout

the

tria

l,an

ticoa

gula

nts,

con

com

itant

inta

keof

NSA

IDs,

lith

ium

, hyd

anto

ins,

cort

icos

tero

ids

(incl

udin

g in

tra-

artic

ular

inje

ctio

ns) t

reat

men

t w

ith4

g/da

y or

mor

e pa

race

tam

olex

clud

edA

spir

in a

llow

ed:n

oA

nalg

esic

allo

wed

:yes

,pa

race

tam

ol d

istrib

uted

, max

imum

4g/

day

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:yes

, 7 d

ays

for

NSA

IDs

and

anti-

ulce

r dr

ugs

Num

ber

and

freq

uenc

y of

vis

its:

2 (0

and

4 w

eeks

)

Allo

cate

d:a

36, b

36

Com

plet

ed:a

27,

b 2

6 D

rop-

out:

a 9,

b 1

0 A

sses

sed:

a 36

, b 3

6 O

utco

mes

rep

orte

d:m

orta

lity,

ser

ious

GI

com

plic

atio

ns,

sym

ptom

atic

ulc

ers,

(ext

ra d

ata)

ser

ious

card

iova

scul

ar o

r re

nal

illne

ss, G

I sym

ptom

s,en

dosc

opy,

GI

with

draw

als

How

wer

e ad

vers

eev

ents

ass

esse

d:no

tst

ated

How

was

com

plia

nce

asse

ssed

:tab

let

coun

t,no

t re

port

ed

Ris

k fa

ctor

s:co

ncom

itant

use

of

antic

oagu

lant

s: a

0, b

0co

rtic

oste

roid

s: a

0, b

0>

1 N

SAID

s: a

0, b

0C

VD: a

0, b

0

diab

etes

: a 0

, b 0

rena

l/hep

atic

dise

ase:

a

0, b

0FU

ND

ING

Fu

nded

by:

supp

orte

din

par

t by

gra

nts

from

NSC

, dru

gs p

rovi

ded

by B

oehr

inge

rIn

gelh

eim

Affi

liati

on o

f con

tact

auth

or:T

ri Se

rvic

eG

ener

al H

ospi

tal,

Taiw

anA

ffilia

tion

of

stat

isti

cian

: Nat

iona

lC

heng

-Kun

g U

nive

rsity

,Ta

iwan

Affi

liati

on o

f tri

alad

min

istr

ator

:G

enel

abs

Biot

ech

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:no

ne


323


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

cont

inue

d

Krie

gel,

2001

138

Loca

tion

: 37

cent

res

inG

erm

any

and

The

Net

herla

nds

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

conc

ealm

ent:

unc

lear

Bas

elin

e co

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:un

clea

rA

pri

ori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ype

rfor

med

but

act

ive

GI d

iseas

e ex

clud

edTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A: a

4.1

, b 4

.7A

ge:a

65.

0 (4

4–80

), b

64.0

(42–

81)

Sex:

M/F

: a 4

7/14

0, b

57/

126

Incl

usio

n cr

iter

ia: o

utpa

tient

s, 4

5–80

yea

rs,

hist

ory

of O

A (k

nee

or h

ip) f

or a

t le

ast

6m

onth

s, m

oder

ate

or s

ever

e pa

in o

n a

four

-po

int

scal

e (0

= n

o pa

in, 1

= s

light

, 2

= m

oder

ate,

3=

seve

re),

radi

ogra

phic

evid

ence

of c

hron

ic O

A in

the

affe

cted

join

tdo

cum

ente

d in

pre

viou

s 12

mon

ths

and

seve

rity

of d

iseas

e be

twee

n 5

and

12 o

n th

eLe

ques

ne fu

nctio

nal i

ndex

(ran

ge 0

–26)

Excl

usio

n cr

iter

ia: a

cute

OA

(una

ble

tow

alk)

and

/or

requ

iring

art

hrop

last

ic s

urge

rydu

ring

the

stud

y, t

reat

men

t w

ith in

tra-

artic

ular

cor

ticos

tero

ids

in t

he 3

wee

ksbe

fore

stu

dy s

tart

or

use

of s

yste

mic

cort

icos

tero

ids

in t

he p

revi

ous

wee

k, h

istor

yof

or

pres

ence

of s

igni

fican

t G

I dise

ase,

pres

ence

of o

ther

sev

ere

conc

omita

ntdi

seas

es, u

se o

f ant

icoa

gula

nt m

edic

atio

n

Com

pari

son:

nim

esul

ide

(b) v

sna

prox

en (a

)D

urat

ion:

52 w

eeks

Inte

rven

tion

s:b,

nim

esul

ide

200m

g/?m

g (1

00m

g ×2

, mor

ning

and

even

ing,

dai

ly);

a, n

apro

xen

750

mg/

500–

1250

mg

(250

mg

×3,

1 m

orni

ng a

nd 2

eve

ning

), do

uble

dum

mie

s us

ed

Oth

er m

edic

atio

n:ot

her

NSA

IDs,

anal

gesic

s, a

ntic

oagu

lant

s,pr

ophy

lact

ic t

reat

men

t fo

r pe

ptic

ulce

r, m

yore

laxa

nts,

oth

ertr

eatm

ent

for

OA

, cor

ticos

tero

ids

not

allo

wed

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed: y

es,

para

ceta

mol

Pa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut: n

ot s

tate

dN

umbe

r an

d fr

eque

ncy

of v

isit

s:10

(0, 2

, 4, 8

, 12,

18,

26,

34,

42

and

52w

eeks

)

Allo

cate

d:a

187,

b 1

83C

ompl

eted

: unc

lear

Dro

p-ou

t:un

clea

rA

sses

sed:

a 1

87, b

183

Out

com

es r

epor

ted:

GI s

ympt

oms,

ana

emia

How

wer

e ad

vers

eev

ents

ass

esse

d:no

tst

ated

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:co

ncom

itant

use

of

antic

oagu

lant

s: a

0, b

0,

cort

icos

tero

ids:

a 0

, b 0

>1

NSA

IDs:

a 0

, b 0

FUN

DIN

GFu

nded

by:

Hel

sinn

Hea

lthca

reA

ffilia

tion

of c

onta

ctau

thor

:Hel

sinn

Hea

lthca

reA

ffilia

tion

of

stat

isti

cian

: unc

lear

Affi

liati

on o

f stu

dyad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

2 of

7au

thor

s em

ploy

ed b

yH

elsin

n H

ealth

care

,Sw

itzer

land

Appendix 6

324

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

Furs

t, 20

0213

9

Loca

tion

:m

ultic

entr

e, U

SA

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’

Allo

cati

onco

ncea

lmen

t: u

ncle

ar

Bas

elin

e co

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:no

A p

riori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

y,no

furt

her

deta

ils

Type

and

dur

atio

n of

art

hrit

is:

RA, a

10.

3, b

10.

3, c

10.

2, d

9.6

Age

:a 5

4.7,

b 5

6.3,

c 5

5.6,

d 5

6.7

Sex:

M/F

: a 4

0/14

1, b

37/

138,

c 4

5/13

9,d

47/1

30In

clus

ion

crit

eria

:18

to 8

0 ye

ars,

cur

rent

lyus

ing

NSA

ID t

hera

py fo

r RA

, and

met

at

leas

t3

of t

he fo

llow

ing:

6 o

r m

ore

tend

er jo

ints

, 3or

mor

e sw

olle

n jo

ints

, pat

ient

’s a

sses

smen

tof

pai

n 20

mm

or

mor

e on

a 1

00m

m V

AS,

mor

ning

stif

fnes

s la

stin

g at

leas

t 45

min

utes

,ES

R m

ore

than

22

mm

or

C-r

eact

ive

prot

ein

mor

e th

an1.

2m

g/dl

; cou

ld b

e ta

king

and

cont

inue

to

take

DM

ARD

initi

ated

at

leas

t3

mon

ths

prio

r to

tria

l and

/or

pred

niso

ne10

mg/

day

or le

ss a

nd s

tabl

e fo

r at

leas

t3

mon

ths

prio

r to

tria

l, if

reta

ined

sta

ble

dose

thro

ugho

ut t

rial;

allo

wed

dic

lofe

nac

aspr

eced

ing

NSA

ID, a

flar

e w

ith 3

or

mor

e of

the

5 cr

iteria

was

obs

erve

d w

ithin

2 w

eeks

of

was

hout

: wor

seni

ng o

f at

leas

t 1

grad

e fr

omsc

reen

ing

on in

vest

igat

or’s

glo

bal a

sses

smen

tof

dise

ase

activ

ity, w

orse

ning

of 1

0m

m o

rm

ore

from

scr

eeni

ng o

n th

e 10

0m

m V

AS

patie

nt g

loba

l ass

essm

ent

of d

iseas

e ac

tivity

,w

orse

ning

of 1

0m

m o

r m

ore

from

scr

eeni

ngon

the

100

mm

VA

S pa

tient

ass

essm

ent

ofpa

in, 2

0% o

r m

ore

incr

ease

com

pare

d w

ithsc

reen

ing

visit

in t

he n

umbe

r of

sw

olle

n jo

ints

Excl

usio

n cr

iteria

: no

deta

ils

Com

pari

son:

mel

oxic

am (b

, c, d

)vs

dic

lofe

nac

(a)

Dur

atio

n: 1

2 w

eeks

Inte

rven

tion

s:b,

mel

oxic

am,

7.5

mg/

7.5–

15m

g da

ily,

c, m

elox

icam

15

mg/

7.5–

15m

gda

ily, d

, mel

oxic

am22

.5m

g/7.

5–15

mg

daily

; a,

dic

lofe

nac

150

mg/

75–1

50m

g(7

5m

g ×2

dai

ly)

Oth

er m

edic

atio

n:in

tra-

artic

ular

ster

oids

pro

hibi

ted

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:y

es,

acet

amin

ophe

n (b

ut n

ot w

ithin

12

hof

clin

ic v

isit)

Part

icip

ant

educ

atio

n:no

t st

ated

Was

hout

:fla

re n

eede

d to

be

obse

rved

with

in 2

wee

ks o

fdi

scon

tinui

ng N

SAID

s pr

ior

to s

tart

of s

tudy

Num

ber

and

freq

uenc

y of

vis

its:

4 (0

, 4, 8

and

12

wee

ks)

Allo

cate

d:a

181,

b

175,

c 1

84, d

177

C

ompl

eted

: a 1

28,

b10

5, c

121

, d 1

19

Dro

p-ou

t: a

53,

b 7

0,c

63, d

58

Ass

esse

d:a

180,

b 1

74,

c 18

4, d

177

O

utco

mes

rep

orte

d:m

orta

lity,

ser

ious

GI

com

plic

atio

ns,

sym

ptom

atic

ulc

ers,

QoL

, GI s

ympt

oms,

occu

lt bl

eedi

ng, G

Idr

op-o

uts

How

wer

e ad

vers

eev

ents

ass

esse

d:di

ary

card

sH

ow w

as c

ompl

ianc

eas

sess

ed:n

ot s

tate

d

Ris

k fa

ctor

s:hi

stor

y of

PU

Bs: a

18,

b

21, c

16, d

19

conc

omita

nt u

se o

fco

rtic

oste

roid

s: a

53,

b57

, c 6

5, d

47

FUN

DIN

G

Fund

ed b

y:Bo

ehrin

ger

Inge

lhei

mPh

arm

aceu

tical

sA

ffilia

tion

of c

onta

ctau

thor

:Virg

inia

Mas

onRe

sear

ch C

ente

r,Se

attle

, WA

, USA

Affi

liati

on o

fst

atis

tici

an: u

ncle

arA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r: 2

or

8au

thor

s em

ploy

ed b

yBo

ehrin

ger

Inge

lhei

mPh

arm

aceu

tical

sD

ose:

mel

oxic

am22

.5m

g da

ily a

rmab

ove

reco

mm

ende

ddo

seO

ther

:1 p

atie

nt in

dicl

ofen

ac a

rmre

ceiv

ed in

tra-

artic

ular

inje

ctio

n of

ste

roid

durin

g st

udy


325


(f)

H2R

A p

lus

NSA

ID v

ersu

s P

PI

plus

NSA

ID

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

Yeom

ans,

1998

140,

162,

165,

192

AST

RON

AU

T

Loca

tion

:73

cent

res

in 1

5co

untr

ies,

incl

udin

gU

K

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d’ in

bloc

ks o

f 2 p

er s

iteA

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

eco

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:no A

pri

ori

sam

ple

size

:ye

sSu

mm

ary

risk

of

bias

: mod

erat

e

Bas

elin

e G

I st

atus

:end

osco

py p

erfo

rmed

follo

win

g he

alin

g ph

ase

for

ulce

rs h

ad t

o sh

owtr

eatm

ent

succ

ess

defin

ed a

s th

e di

sapp

eara

nce

oful

cer

and

the

pres

ence

of f

ewer

tha

n 5

eros

ions

inth

e st

omac

h, fe

wer

tha

n 5

eros

ions

in t

hedu

oden

um a

nd n

ot m

ore

than

mild

dys

pept

icsy

mpt

oms

Type

and

dur

atio

n of

art

hrit

is (

year

s):

RA: c

99,

b 8

8O

A: c

67,

b 7

1Ps

oria

tic a

rthr

itis:

a 1

6, b

: 11

AS:

c 1

1, b

12

Oth

ers:

c 1

1, b

18

Com

bina

tion:

c 6

, b 1

5A

ge:c

: 56

(31–

78),

b 56

(20–

80)

Sex:

M/F

: c 6

4/14

6, b

66/

149

Incl

usio

n cr

iter

ia: 1

8–85

yea

rs, a

ny c

ondi

tion

requ

iring

con

tinuo

us t

hera

py w

ith N

SAID

s ab

ove

spec

ified

the

rape

utic

dos

es (n

o m

axim

um d

ose)

,an

d no

t m

ore

than

10

mg

of p

redn

isolo

ne o

r its

equi

vale

nt p

er d

ay (5

0m

g/da

y di

clof

enac

,50

mg/

day

indo

met

haci

n, 5

00m

g/da

y na

prox

en);

follo

win

g en

dosc

opy,

tho

se fo

und

to h

ave

any

oral

l of t

he fo

llow

ing

wer

e in

clud

ed: u

lcer

s 3

mm

or

mor

e in

dia

met

er, m

ore

than

10

eros

ions

in t

hest

omac

h, m

ore

than

10

eros

ions

in t

he d

uode

num

,su

cces

sful

tre

atm

ent

durin

g he

alin

g ph

ase,

usin

gth

erap

eutic

dos

es o

f NSA

IDs

at le

ast

5da

ys p

erw

eek

Excl

usio

n cr

iter

ia:n

eck

inst

abili

ty t

hat

wou

ldco

mpr

omise

end

osco

py, c

oncu

rren

t er

osiv

e or

ulce

rativ

e oe

soph

agiti

s, p

ylor

ic s

teno

sis, m

ajor

activ

e G

I ble

edin

g, o

r di

sord

ers

that

mig

ht m

odify

the

abso

rptio

n of

the

dru

g, n

o ab

norm

aliti

es in

labo

rato

ry t

ests

reg

arde

d as

clin

ical

ly im

port

ant

byth

e in

vest

igat

or

Com

pari

son:

omep

razo

lepl

us m

ixed

NSA

IDs

(b) v

sra

nitid

ine

plus

mix

ed N

SAID

s(c

)D

urat

ion:

26 w

eeks

Inte

rven

tion

s:c,

ran

itidi

ne30

0m

g/15

0–30

0m

g (1

50m

g×2

dai

ly);

b, o

mep

razo

le20

mg/

20m

g (2

0m

g ×

daily

)N

SAID

s:b

+ c

:na

prox

en: 1

6%in

dom

etha

cin:

23%

dicl

ofen

ac: 2

9%En

dosc

opy:

1, 3

and

6m

onth

sO

ther

med

icat

ion:

node

tails

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:n

otst

ated

Part

icip

ant

educ

atio

n:no

tst

ated

Was

hout

:not

sta

ted

Num

ber

and

freq

uenc

y of

visi

ts: 4

(0, 1

, 3 a

nd6

mon

ths)

Allo

cate

d:un

clea

rC

ompl

eted

:unc

lear

Dro

p-ou

t:b

30, c

: 29

Ass

esse

d:b

210,

c: 2

15O

utco

mes

rep

orte

d:se

rious

GI

com

plic

atio

ns,

endo

scop

ic u

lcer

s, t

otal

drop

-out

How

wer

e ad

vers

eev

ents

ass

esse

d:pa

rtic

ipan

ts a

sked

stan

dard

ised

ques

tions

rega

rdin

g ov

eral

l upp

erG

I sym

ptom

s an

ddy

spep

tic s

ympt

oms

inth

e pr

evio

us 7

day

s an

dth

ese

wer

e gr

aded

as

abse

nt, m

ild, m

oder

ate

or s

ever

eH

ow w

as c

ompl

ianc

eas

sess

ed:r

etur

ned

med

icat

ion,

res

ult

not

repo

rted

Ris

k fa

ctor

s:al

lpa

rtic

ipan

ts h

ad r

ecen

thi

stor

y of

ulc

ers

and/

orer

osio

nsFU

ND

ING

Fund

ed b

y:A

stra

Has

sleA

ffilia

tion

of c

onta

ctau

thor

:Uni

vers

ity o

fM

elbo

urne

, but

also

serv

es a

s co

nsul

tant

for

Sear

le A

ustr

alia

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:un

clea

rO

ther

:?0/

8 m

ain

auth

ors

Appendix 6

326 (g)

H2R

A p

lus

NSA

ID v

ersu

s m

isop

rost

ol p

lus

NSA

ID

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

Vale

ntin

i, 19

9514

1

Loca

tion

:Ita

lyM

etho

d of

rand

omis

atio

n:‘ra

ndom

ised’

Allo

cati

onco

ncea

lmen

t:un

clea

rB

asel

ine

com

para

bilit

y:un

clea

r, in

suffi

cien

tin

form

atio

nPa

rtic

ipan

t bl

indi

ng:

no Ass

esso

r bl

indi

ng:

yes,

end

osco

pist

blin

ded

Inte

ntio

n-to

-tre

at:

no A p

riori

sam

ple

size

:ye

sSu

mm

ary

risk

of

bias

: mod

erat

e

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd e

xclu

ded

patie

nts

with

mor

e th

an1

pete

chia

or

area

of h

aem

orrh

age

or e

rosio

n;al

so e

xclu

ded

patie

nts

with

hist

ory

of p

eptic

ulc

erdi

seas

eno

rmal

muc

osa:

a 2

8, b

28

Lanz

a sc

ore

of 1

: a 2

, b 3

Type

and

dur

atio

n of

art

hrit

is (

year

s):

Not

app

licab

le –

can

cer

patie

nts

Age

:a 5

9.8

(37–

82),

b 59

.2 (2

1–80

)Se

x: M

/F: a

: 12/

14, b

10/

13In

clus

ion

crit

eria

: pat

ient

s w

ho c

ompl

aine

d of

canc

er p

ain

and

who

nee

ded

high

-dos

e(2

00–3

00m

g/da

y) t

reat

men

t w

ith o

ral d

iclo

fena

c;in

goo

d ph

ysic

al c

ondi

tion

(Kar

nofs

ky p

erfo

rman

cest

atus

of 7

0 or

mor

e)

Excl

usio

n cr

iter

ia:h

istor

y of

pep

tic u

lcer

dise

ase,

GI m

alig

nanc

y, G

I sur

gery

, ble

edin

gdi

athe

sis, r

ecei

ving

tre

atm

ent

with

oth

er N

SAID

sor

gas

tric

ant

isecr

etor

y dr

ugs,

bas

elin

e en

dosc

opy

scor

e of

mor

e th

an 1

(1 p

etec

hia

or a

rea

ofha

emor

rhag

e or

ero

sion)

Com

pari

son:

miso

pros

tol

plus

dic

lofe

nac

(b) v

sra

nitid

ine

plus

dic

lofe

nac

(a)

Dur

atio

n:4

wee

ksIn

terv

enti

ons:

b,

miso

pros

tol 4

00 µ

g/4

00–8

00µg

(200

µg

×2da

ily);

a, r

aniti

dine

300

mg/

150–

300

mg

(150

mg

×2 d

aily

)N

SAID

s: a

+b:

dic

lofe

nac

200–

300

mg/

75–1

50m

g di

clof

enac

200

mg:

a 1

4, b

10

dicl

ofen

ac 3

00m

g: a

12,

b 1

3En

dosc

opy:

4 w

eeks

Oth

er m

edic

atio

n:ch

emot

hera

py, r

adia

tion,

cort

icos

tero

ids,

antin

eopl

astic

s al

low

edA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:not

stat

edPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:n

ot s

tate

dN

umbe

r an

d fr

eque

ncy

ofvi

sits

: 5 (0

, 1, 2

, 3 a

nd4

wee

ks)

Allo

cate

d:a

31, b

30

Com

plet

ed:a

26,

b 2

3D

rop-

out:

a 5

, b 7

Ass

esse

d:a

26, b

23

Out

com

es r

epor

ted:

sym

ptom

atic

ulc

ers,

GI

sym

ptom

s, e

ndos

copi

cul

cers

, GI d

rop-

outs

,to

tal d

rop-

outs

How

wer

e ad

vers

eev

ents

ass

esse

d:no

tst

ated

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:hi

stor

y of

ulc

ers:

a 0

, b

0 co

ncom

itant

use

of

cort

icos

tero

ids:

a 4

, b

4>

1 N

SAID

: a 0

, b 0

FUN

DIN

GFu

nded

by:

uncl

ear

Affi

liati

on o

f con

tact

auth

or:C

entr

o di

Rife

rimen

toO

ncol

ogic

o–Is

titut

oN

azio

nale

Tum

ori

Cen

troe

urop

eo, I

taly

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:un

clea

r bu

tat

leas

t 1

auth

orem

ploy

ed b

y Se

arle

Farm

aceu

tici

cont

inue

d


327


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

Rask

in, 1

99614

2

Loca

tion

:m

ultic

entr

e, U

SA

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’A

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

eco

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:un

clea

rIn

tent

ion-

to-t

reat

:no A

pri

ori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of

bias

: mod

erat

e

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd e

xclu

ded

patie

nts

with

evi

denc

e of

an u

lcer

of t

he g

astr

ic o

r du

oden

al m

ucos

a,de

fined

as

a le

sion

of t

he m

ucos

a of

at

leas

t 3

mm

in d

iam

eter

with

per

cept

ible

dep

th; a

lso e

xclu

ded

patie

nts

with

hist

ory

of r

ecur

rent

pep

tic u

lcer

dise

ase

(mor

e th

an o

ne e

piso

de in

pre

viou

s12

mon

ths)

; had

to

be e

xper

ienc

ing

UG

I pai

nth

ough

t to

be

rela

ted

to t

heir

NSA

ID t

hera

pyB

asel

ine

NSA

ID s

tatu

s: m

ean

dura

tion

NSA

IDus

e: a

9.2

mon

ths,

b 9

.8 m

onth

sTy

pe o

f art

hrit

is: O

A: a

: 201

, b 1

98; R

A: a

40,

b

48; b

oth:

a 1

3, b

7; o

ther

: a 1

3, b

16

Age

:a: 6

0 (2

3–86

), b

61 (2

3–85

)Se

x:M

/F: a

116

/153

, b 1

26/1

43In

clus

ion

crit

eria

: rec

eivi

ng d

aily

dos

es o

fib

upro

fen,

piro

xica

m, n

apro

xen,

sul

inda

c, t

olm

etin

or in

dom

etha

cin

for

one

of t

he fo

llow

ing

cond

ition

s: o

steo

arth

ritis,

rhe

umat

oid

arth

ritis,

psor

iatic

art

hriti

s, A

S, o

r Re

iters

syn

drom

e, a

ndw

ere

expe

cted

to

requ

ire a

t le

ast

2 co

nsec

utiv

em

onth

s of

con

tinue

d N

SAID

the

rapy

; had

to

beex

perie

ncin

g U

GI p

ain

thou

ght

to b

e re

late

d to

thei

r N

SAID

the

rapy

Excl

usio

n cr

iter

ia:p

atie

nts

with

evi

denc

e of

an

ulce

r of

the

gas

tric

or

duod

enal

muc

osa,

def

ined

as a

lesio

n of

the

muc

osa

of a

t le

ast

3m

m in

diam

eter

with

per

cept

ible

dep

th; p

atie

nts

with

hist

ory

of r

ecur

rent

pep

tic u

lcer

dise

ase

(mor

eth

an o

ne e

piso

de in

pre

viou

s 12

mon

ths)

; any

UG

Itr

act

mal

igna

ncy

or m

etas

tasis

, pyl

oric

or

duod

enal

obs

truc

tion,

acu

te h

epat

itis,

pan

crea

titis,

infla

mm

ator

y bo

wel

dise

ase,

ble

edin

g di

athe

sis;

rece

ived

miso

pros

tol,

H2R

A o

r an

y in

vest

igat

iona

ldr

ug o

r an

tineo

plas

tic a

gent

with

in 3

0 da

ys p

rior

to e

ntry

into

stu

dy; r

enal

impa

irmen

t ju

dged

by

inve

stig

ator

to

be a

t ris

k of

NSA

ID-in

duce

d re

nal

failu

re; a

ntic

ipat

ed n

eed

for

anti-

ulce

r m

edic

atio

nsot

her

than

stu

dy m

edic

atio

n, a

ntin

eopl

astic

dru

gs,

Com

pari

son:

miso

pros

tol

plus

mix

ed N

SAID

s (b

) vs

rani

tidin

e pl

us m

ixed

NSA

IDs

(a)

Dur

atio

n:8

wee

ksIn

terv

enti

ons:

b, m

isopr

osto

l80

0µg

/400

–800

µg (2

00 µ

g×4

dai

ly);

a, r

aniti

dine

300

mg/

150–

300

mg

(150

mg

×2 d

aily

), do

uble

dum

my

NSA

IDs:

ibup

rofe

n: a

73,

b 7

3na

prox

en: a

78,

b 6

5pi

roxi

cam

: a 5

4, b

56

sulin

dac:

a 2

4, b

32

othe

r: a

40,

b 4

3En

dosc

opy:

8 w

eeks

Oth

er m

edic

atio

n:28

×60

0m

g an

taci

d to

be

take

n as

req

uire

d fo

r re

lief o

fU

GI p

ain

wer

e pr

escr

ibed

for

first

wee

k on

ly; a

nti-u

lcer

med

icat

ions

oth

er t

han

stud

ym

edic

atio

n, a

ntin

eopl

astic

drug

s, a

ntic

oagu

lant

s,pr

edni

sone

gre

ater

tha

n7.

5m

g/da

y,cy

clop

hosp

ham

ide

orm

etho

trex

ate

wer

e ex

clud

edA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:not

stat

edPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:n

ot s

tate

dN

umbe

r an

d fr

eque

ncy

ofvi

sits

: 3 (0

, 4 a

nd 8

wee

ks)

Allo

cate

d:a

269,

b 2

69C

ompl

eted

:a 2

19,

b 20

6D

rop-

out:

a 5

0, b

63

Ass

esse

d:a

269,

b 2

69O

utco

mes

rep

orte

d:m

orta

lity,

ser

ious

GI

com

plic

atio

ns, s

erio

usca

rdio

vasc

ular

or

rena

lill

ness

(ext

ra d

ata)

, GI

sym

ptom

s, e

ndos

copi

cul

cers

, GI d

rop-

outs

,to

tal d

rop-

outs

How

wer

e ad

vers

eev

ents

ass

esse

d: n

otst

ated

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:hi

stor

y of

ulc

ers:

a 5

6,b

62FU

ND

ING

Fund

ed b

y:G

D S

earle

Affi

liati

on o

f con

tact

auth

or:u

nive

rsity

of

Mia

mi,

USA

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:1

of 6 co

ntin

ued

Appendix 6

328

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

antic

oagu

lant

s, p

redn

isone

gre

ater

tha

n7.

5m

g/da

y, c

yclo

phos

pham

ide

or m

etho

trex

ate

durin

g th

e co

urse

of t

he s

tudy

Yild

iz, 1

99614

3

Loca

tion

:Tur

key

Met

hod

ofra

ndom

isat

ion:

‘div

ided

ran

dom

ly’

Allo

cati

onco

ncea

lmen

t:un

clea

rB

asel

ine

com

para

bilit

y:un

clea

rPa

rtic

ipan

t bl

indi

ng:

uncl

ear

Ass

esso

r bl

indi

ng:

uncl

ear

Inte

ntio

n-to

-tre

at:

uncl

ear

A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of

bias

:mod

erat

e

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd d

id n

ot e

xclu

de a

ny e

ndos

copi

csc

ore

(1 p

erso

n in

eac

h gr

oup

had

ulce

r at

base

line

and

excl

uded

from

ana

lyse

s by

rev

iew

ers)

Type

and

dur

atio

n of

art

hriti

s (y

ears

): ‘rh

eum

atic

sym

ptom

s’, n

o fu

rthe

r de

tails

Age

:a 3

9.2

(19–

70) b

37.

0 (2

0–55

)Se

x:M

/F: a

1/1

5, b

4/1

2In

clus

ion

crit

eria

:tak

ing

long

-ter

m N

SAID

s fo

rth

eir

prim

ary

rheu

mat

ic d

iseas

e, a

ny e

ndos

copi

csc

ore

at b

asel

ine

Excl

usio

n cr

iter

ia: n

o de

tails

Com

pari

son:

fam

otid

ine

plus

napr

oxen

sod

ium

and

indo

met

haci

n (b

) vs

miso

pros

tol p

lus

napr

oxen

sodi

um a

nd in

dom

etha

cin

(a)

Dur

atio

n:2

mon

ths

Inte

rven

tion

s: b

, fam

otid

ine

40m

g/20

mg

(20

mg

×2 d

aily,

a, m

isopr

osto

l 400

µg/

400–

800

µg (2

00 µ

g ×2

dai

ly)

NSA

IDs:

a+b:

nap

roxe

n so

dium

1100

mg/

500–

1250

mg

(550

mg

×2 d

aily

) plu

sin

dom

etha

cin

supp

osito

ries

100

mg/

100–

200

mg

(100

mg

×1 d

aily

)En

dosc

opy:

1 an

d 2

mon

ths

Oth

er m

edic

atio

n:no

deta

ilsA

spir

in a

llow

ed:n

ot s

tate

dA

nalg

esic

allo

wed

:not

stat

edPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:n

ot s

tate

dN

umbe

r an

d fr

eque

ncy

ofvi

sits

: 3 (0

, 1 a

nd 2

mon

ths)

Allo

cate

d:un

clea

rC

ompl

eted

:a 1

6, b

16

Dro

p-ou

t:un

clea

rA

sses

sed:

a 15

, b 1

5O

utco

mes

rep

orte

d:en

dosc

opy

How

wer

e ad

vers

eev

ents

ass

esse

d:no

tst

ated

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:no

deta

ilsFU

ND

ING

Fund

ed b

y:un

clea

rA

ffilia

tion

of c

onta

ctau

thor

:unc

lear

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:un

clea

rO

ther

:stu

dy in

Turk

ish, o

nly

Engl

ishab

stra

ct a

nden

dosc

opy

tabl

eex

trac

ted


329


(h)

PP

I pl

us N

SAID

ver

sus

mis

opro

stol

plu

s N

SAID

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

Haw

key,

1998

b62,6

5,16

0–16

4

OM

NIU

MLo

cati

on:9

3ce

ntre

s in

14

coun

trie

s in

clud

ing

UK

and

USA

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d’,

rand

omisa

tion

phas

eno

t fo

rmal

ly b

alan

ced

acco

rdin

g to

tre

atm

ent

assig

nmen

t in

the

heal

ing

phas

eA

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

eco

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:un

clea

r In

tent

ion-

to-t

reat

:no A

pri

ori

sam

ple

size

:ye

sSu

mm

ary

risk

of

bias

:mod

erat

e

Bas

elin

e G

I st

atus

:end

osco

py p

erfo

rmed

and

excl

uded

par

ticip

ants

with

out

trea

tmen

t su

cces

sfo

llow

ing

4–8-

wee

k he

alin

g ph

ase

(om

epra

zole

20m

g/da

y vs

om

epra

zole

40

mg/

day

vsm

isopr

osto

l 200

µg/

day)

; tre

atm

ent

succ

ess

defin

ed a

s ab

senc

e of

ulc

ers

in t

he s

tom

ach

ordu

oden

um a

nd t

he p

rese

nce

of fe

wer

tha

n fiv

ega

stric

ero

sions

, few

er t

han

five

duod

enal

ero

sions

and

not

mor

e th

an m

ild s

ympt

oms

of d

yspe

psia

(cor

resp

onde

d to

a 2

-poi

nt r

educ

tion

in L

anza

scal

e fr

om g

rade

4 t

o gr

ade

2)

Type

of a

rthr

itis

: O

A: a

70,

b 1

29, c

142

RA

: a 5

6, b

107

, c 1

18ot

her:

a 2

5, b

33,

c 3

0co

mbi

natio

n: a

5, b

5, c

6A

ge:a

57

(20–

80),

b 58

(23–

79),

c 58

(23–

85)

Sex:

M/F

: a 4

8/10

7, b

101

/173

, c 1

18/1

78In

clus

ion

crit

eria

:18–

85 y

ears

of a

ge a

nd w

hoha

d an

y co

nditi

on r

equi

ring

cont

inuo

us t

reat

men

tw

ith o

ral o

r re

ctal

NSA

IDs

abov

e a

pred

eter

min

ed m

inim

al d

ose

(no

max

imum

dos

e);

trea

tmen

t su

cces

s de

fined

as

abse

nce

of u

lcer

s in

the

stom

ach

or d

uode

num

and

the

pre

senc

e of

few

er t

han

five

gast

ric e

rosio

ns, f

ewer

tha

n fiv

edu

oden

al e

rosio

ns a

nd n

ot m

ore

than

mild

sym

ptom

s of

dys

peps

ia (c

orre

spon

ded

to a

2-

poin

t re

duct

ion

in L

anza

sca

le fr

om g

rade

4 t

ogr

ade

2)Ex

clus

ion

crit

eria

: con

curr

ent

reflu

xoe

soph

agiti

s at

sta

ge 3

or

4 ac

cord

ing

to t

heSa

vary

–Mill

er c

lass

ifica

tion,

clin

ical

ly im

port

ant

GI

blee

ding

, pyl

oric

ste

nosis

, hist

ory

of g

astr

icsu

rger

y or

GI d

isord

ers

that

mig

ht im

pair

the

abso

rptio

n of

the

stu

dy d

rugs

Com

pari

son:

miso

pros

tol

plus

mix

ed N

SAID

s (c

) vs

omep

razo

le p

lus

mix

edN

SAID

s (b

) vs

plac

ebo

plus

mix

ed N

SAID

s (a

)D

urat

ion:

6 m

onth

sIn

terv

enti

ons:

c, m

isopr

osto

l 40

0 µg

/400

–800

µg/d

ay

(200

µg

×2 d

aily

; b,

omep

razo

le 2

0m

g/20

mg

(20

mg

×1 d

aily

); a,

iden

tical

plac

ebo

Endo

scop

y:1,

3 a

nd6

mon

ths

NSA

IDs:

(min

imum

and

mea

n do

se):

dicl

ofen

ac(5

0m

g, 1

29m

g/da

y) 2

3%to

tal p

artic

ipan

tske

topr

ofen

(100

mg,

137

mg)

16%

tot

al p

artic

ipan

tsna

prox

en (5

00m

g, 8

44m

g)22

% t

otal

par

ticip

ants

Oth

er m

edic

atio

n:pa

tient

sco

uld

ente

r th

e st

udy

if th

eyw

ere

taki

ng g

luco

cort

icoi

ds a

ta

dose

≤10

mg

ofpr

edni

solo

ne (o

r its

equi

vale

nt)

Asp

irin

allo

wed

:not

sta

ted

Ana

lges

ic a

llow

ed:n

otst

ated

Part

icip

ant

educ

atio

n:no

tst

ated

Was

hout

:not

sta

ted

Num

ber

and

freq

uenc

y of

visi

ts:4

(0, 1

, 3 a

nd 6

mon

ths)

Allo

cate

d:a

155,

b27

4, c

296

(7

par

ticip

ants

unac

coun

ted

for)

Com

plet

ed:a

139

, b

242,

c 2

47D

rop-

out:

a 1

6, b

33,

c

50A

sses

sed:

a 15

5, b

275

,c

297

Out

com

es r

epor

ted:

serio

us G

Ico

mpl

icat

ions

, QoL

,en

dosc

opic

ulc

ers,

tot

aldr

op-o

utH

ow w

ere

adve

rse

even

ts a

sses

sed:

part

icip

ants

ask

ed if

had

spec

ific

dysp

eptic

sym

ptom

s du

ring

the

last

7 d

ays

and

tode

scrib

e an

y U

GI

sym

ptom

s on

tha

t da

y,sy

mpt

oms

grad

ed, a

lsosy

mpt

om d

iary

car

dus

ed d

urin

g in

itial

4w

eeks

How

was

com

plia

nce

asse

ssed

:tab

let

coun

t,re

sult

not

repo

rted

Ris

k fa

ctor

s:63

–64%

of p

artic

ipan

ts in

eac

hgr

oup

had

rece

nthi

stor

y of

ulc

ers

(rem

aini

ng p

artic

ipan

tsha

d re

cent

hist

ory

ofm

ore

than

10

gast

ricor

duo

dena

l ero

sions

)FU

ND

ING

Fund

ed b

y:A

stra

Has

sle, S

wed

enA

ffilia

tion

of c

onta

ctau

thor

:Not

tingh

amG

astr

oint

estin

al T

rials

Serv

ice,

Uni

vers

ityH

ospi

tal N

ottin

gham

,U

KA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

One

aut

hor

serv

es a

s a

cons

ulta

ntfo

r Se

arle

, Aus

tral

iaO

ther

:par

ticip

ants

wer

e di

scon

tinue

d an

dex

clud

ed fr

om a

naly

sisif

deve

lope

d m

ore

than

10

eros

ions

or

mor

e th

an m

oder

ate

dysp

epsia

or

adve

rse

even

ts

cont

inue

d

Appendix 6

330

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

Gra

ham

, 200

264,2

14

Loca

tion

:63

cent

res

in N

orth

Am

eric

a

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d in

bloc

ks o

f 4’,

‘rand

omisa

tion

sche

dule

was

gene

rate

d by

ast

atist

ical

spe

cial

istw

ho w

as n

ot in

volv

edin

the

tria

l des

ign,

the

rand

omisa

tion

was

code

d an

d st

ored

inse

aled

env

elop

es’

Allo

cati

onco

ncea

lmen

t:ad

equa

teB

asel

ine

com

para

bilit

y:ye

sPa

rtic

ipan

t bl

indi

ng:

yes

for

PPI a

ndpl

aceb

o gr

oups

, no

for

miso

pros

tol g

roup

A

sses

sor

blin

ding

:ye

s (s

tatis

ticia

n),

endo

scop

ist a

lsobl

inde

dIn

tent

ion-

to-t

reat

:no A

pri

ori

sam

ple

size

:ye

sSu

mm

ary

risk

of

bias

:low

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed, p

atie

nts

had

to b

e w

ithou

t H

. pyl

ori,

have

hist

ory

of e

ndos

copi

cally

doc

umen

ted

gast

ricul

cer

with

or

with

out

coex

istin

g du

oden

al u

lcer

or

GI b

leed

ing

(2/3

par

ticip

ants

had

pre

viou

slyco

mpl

eted

par

ticip

atio

n in

a h

ealin

g tr

ial f

orN

SAID

-ass

ocia

ted

gast

ric u

lcer

); ex

clud

ed p

atie

nts

with

gas

tric

or

duod

enal

ulc

er c

rate

r at

leas

t5

mm

in d

iam

eter

or

mor

e th

an 2

5 er

osio

ns o

rer

osiv

e re

flux

oeso

phag

itis

Bas

elin

e N

SAID

sta

tus:

trea

tmen

t w

ith s

tabl

efu

ll th

erap

eutic

dos

es o

f an

NSA

ID fo

r at

leas

t th

epr

evio

us m

onth

(exc

ept

nabu

met

one

or a

spiri

n at

1300

mg/

day

or m

ore)

Type

and

dur

atio

n of

art

hrit

is (

year

s):

no d

etai

lsA

ge:a

60.

5, b

59.

4, c

61.

6, d

60.

2Se

x:M

/F: a

46/

87, b

43/

91, c

50/

86, d

48/

84In

clus

ion

crit

eria

:18

year

s or

old

er, h

istor

y of

endo

scop

ical

ly d

ocum

ente

d ga

stric

ulc

er w

ith o

rw

ithou

t du

oden

al u

lcer

or

GI b

leed

ing,

tre

atm

ent

with

sta

ble

full

ther

apeu

tic d

oses

of a

n N

SAID

(with

the

exc

eptio

n of

nab

umet

one

or a

spiri

n at

1300

mg/

day

or m

ore;

low

-dos

e as

pirin

for

card

iova

scul

ar p

rote

ctio

n w

as p

erm

itted

) for

at

leas

t th

e pr

evio

us m

onth

Excl

usio

n cr

iter

ia: p

ositi

ve fo

r H

. pyl

ori,

gast

ricor

duo

dena

l ulc

er c

rate

r of

5m

m o

r m

ore

orse

vere

ero

sions

def

ined

as

mor

e th

an 2

5 er

osio

ns,

eros

ive

reflu

x oe

soph

agiti

s, u

se o

f PPI

,m

isopr

osto

l or

H2R

As

with

in 2

4 h

of s

tart

of s

tudy

Com

pari

son:

lans

opra

zole

(c, d

) plu

s m

ixed

NSA

IDs

vsm

isopr

osto

l (b)

plu

s m

ixed

NSA

IDs

vs m

ixed

NSA

IDs

(a)

Dur

atio

n: 1

2 w

eeks

Inte

rven

tion

s:d,

lans

opra

zole

30

mg/

15–3

0m

g(3

0m

g ×1

dai

ly);

c, la

nsop

razo

le15

mg/

15–3

0m

g (1

5m

g ×1

dai

ly);

b, m

isopr

osto

l80

0µg

/400

–800

µg (2

00 µ

g×4

dai

ly);

a, p

lace

boN

SAID

use

:ib

upro

fen:

40%

napr

oxen

: 35%

dicl

ofen

ac: 3

2%as

pirin

or

aspi

rinco

mbi

natio

ns: 2

2%pi

roxi

cam

: 17%

othe

r N

SAID

s: 3

4%en

dosc

opy:

1, 2

and

3m

onth

sO

ther

med

icat

ion:

anta

cid

prov

ided

for

use

as n

eede

dfo

r sy

mpt

om r

elie

f, in

stru

cted

to a

void

ant

iulc

er m

edic

atio

not

her

than

stu

dy m

edic

atio

n,ul

cero

geni

c m

edic

atio

n an

dag

ents

tha

t al

ter

haem

osta

sisA

spir

in a

llow

ed:y

esA

nalg

esic

allo

wed

: not

stat

edPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:n

ot s

tate

dN

umbe

r an

d fr

eque

ncy

ofvi

sits

:?4

(0, 4

, 8 a

nd12

wee

ks)

Allo

cate

d:a

134,

b13

4, c

136

, d 1

33C

ompl

eted

:a 1

11,

b11

1, c

122

, d:1

14D

rop-

out:

a 23

, b 2

3,c

14, d

19

Ass

esse

d:a

133,

b 1

34,

c 13

6, d

132

Out

com

es r

epor

ted:

mor

talit

y, s

erio

us G

Ico

mpl

icat

ions

, ser

ious

card

iova

scul

ar o

r re

nal

illne

ss, (

extr

a da

ta)

endo

scop

ic u

lcer

s, t

otal

drop

-out

sH

ow w

ere

adve

rse

even

ts a

sses

sed:

part

icip

ants

kep

t di

ary

ofda

ily s

ympt

oms

and

aske

d di

rect

que

stio

ns a

tea

ch v

isit

How

was

com

plia

nce

asse

ssed

: tab

let

coun

t,90

% in

gro

ups

a, c

and

d w

ere

com

plia

ntco

mpa

red

with

73%

ingr

oup

b (m

isopr

osto

l)

Ris

k fa

ctor

s:hi

stor

y of

ulc

ers:

all

part

icip

ants

FUN

DIN

GFu

nded

by:

TAP

Phar

mac

eutic

alPr

oduc

tsA

ffilia

tion

of c

onta

ctau

thor

:Vet

eran

sA

ffairs

Med

ical

Cen

ter,

Hou

ston

, TX

, USA

Affi

liati

on o

fst

atis

tici

an:A

bbot

tLa

bora

torie

sA

ffilia

tion

of s

tudy

adm

inis

trat

or:T

AP

Phar

mac

eutic

alPr

oduc

tsN

o. o

f aut

hors

empl

oyed

by

spon

sor:

2 of

7 cont

inue

d


331


(i)

PP

I pl

us N

SAID

ver

sus

Cox

-2 c

oxib

NSA

ID

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

Cha

n, 2

00223

6

Loca

tion

:En

dosc

opy

cent

re,

Prin

ce o

f Wal

esH

ospi

tal,

Hon

gKo

ng, C

hina

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d’,

com

pute

r-ge

nera

ted

list

of r

ando

mnu

mbe

rs, i

ndep

ende

ntst

aff a

ssig

ned

trea

tmen

ts a

ccor

ding

to c

onse

cutiv

enu

mbe

rs in

sea

led

enve

lope

s’A

lloca

tion

conc

ealm

ent:

adeq

uate

Bas

elin

eco

mpa

rabi

lity:

yes

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:ye

s, b

linde

den

dosc

opist

and

adju

dica

tion

com

mitt

eeIn

tent

ion-

to-t

reat

:no A

pri

ori

sam

ple

size

:ye

sSu

mm

ary

risk

of

bias

:low

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed, a

nd p

atie

nts

excl

uded

who

did

not

pres

ent

with

ulc

er b

leed

ing,

incl

usio

ncr

iteria

wer

e ul

cer

heal

ing

conf

irmed

by

follo

w u

p en

dosc

opy,

neg

ativ

e te

st fo

rH

.pyl

ori(

or s

ucce

ssfu

l era

dica

tion)

Type

and

dur

atio

n of

art

hrit

is (

year

s):

OA

: a 1

27, b

123

RA: a

2, b

5ot

her:

a 1

4, b

16

Age

:a 6

8.8,

b 6

6.5

Sex:

M/F

: a 6

5/78

, b 6

1/83

Incl

usio

n cr

iter

ia:u

lcer

hea

ling

asco

nfirm

ed b

y fo

llow

-up

endo

scop

y, n

egat

ive

test

for

H. p

ylor

ior

succ

essf

ul e

radi

catio

n of

H. p

ylor

iacc

ordi

ng t

o hi

stol

ogic

al fi

ndin

gs,

antic

ipat

ed r

egul

ar u

se o

f NSA

IDs

for

the

dura

tion

of t

he t

rial

Excl

usio

n cr

iter

ia: c

onco

mita

nt u

se o

fan

ticoa

gula

nt a

gent

s or

cor

ticos

tero

ids;

hist

ory

of g

astr

ic o

r du

oden

al s

urge

ry o

ther

than

a p

atch

rep

air;

pre

senc

e of

ero

sive

oeso

phag

itis,

gas

tric

out

let

obst

ruct

ion,

ren

alfa

ilure

(def

ined

by

a se

rum

cre

atin

ine

leve

l of

mor

e th

an 2

.2 m

g/dl

), te

rmin

al il

lnes

s or

canc

er

Com

pari

son:

cele

coxi

b (b

) vs

dicl

ofen

ac (e

xten

ded

rele

ase)

plu

som

epra

zole

(a)

Dur

atio

n:6

mon

ths

Inte

rven

tion

s:b,

cel

ecox

ib40

0m

g/20

0–40

0m

g (2

00m

g ×2

daily

); a,

dic

lofe

nac

(ext

ende

dre

leas

e) 1

50m

g/75

–150

mg

(75

mg

×2 d

aily

) + o

mep

razo

le20

mg/

20m

g (2

0m

g ×1

dai

ly),

dicl

ofen

ac a

nd c

elec

oxib

wer

eid

entic

al-a

ppea

ring

red

caps

ules

,om

epra

zole

and

its

plac

ebo

wer

eid

entic

al-a

ppea

ring

gree

n ca

psul

esO

ther

med

icat

ion:

per

mitt

ed t

ota

ke a

ntac

ids,

non

-NSA

IDan

alge

sics,

DM

ARD

s; N

SAID

sot

her

than

dic

lofe

nac,

miso

pros

tol,

H2R

As,

suc

ralfa

te, P

PIs

othe

r th

anom

epra

zole

wer

e pr

ohib

ited

Asp

irin

allo

wed

:yes

, 325

mg/

day

or le

ssA

nalg

esic

allo

wed

:yes

,ac

etam

inop

hen

and

non-

NSA

IDan

alge

sics

Part

icip

ant

educ

atio

n:no

tst

ated

Was

hout

:not

sta

ted

Num

ber

and

freq

uenc

y of

visi

ts:4

(tel

epho

ne c

all a

t m

onth

1, t

hen

visit

at

mon

ths

2, 4

and

6)

Allo

cate

d:a

143,

b 1

44C

ompl

eted

:a 1

24,

b12

3D

rop-

out:

a 19

, b 2

1A

sses

sed:

a 14

3, b

144

Out

com

es r

epor

ted:

mor

talit

y, s

erio

us G

Ico

mpl

icat

ions

,sy

mpt

omat

ic u

lcer

s,se

rious

car

diov

ascu

lar

orre

nal i

llnes

s, G

Isy

mpt

oms,

ana

emia

, GI

drop

-out

s, t

otal

dro

p-ou

tsH

ow w

ere

adve

rse

even

ts a

sses

sed:

obse

rved

or

repo

rted

,di

rect

tel

epho

ne li

ne fo

rpa

rtic

ipan

ts t

o re

port

serio

us a

dver

se e

vent

sin

bet

wee

n st

udy

visit

sH

ow w

as c

ompl

ianc

eas

sess

ed:t

able

t co

unt,

92%

in e

ach

arm

too

kat

leas

t 70

% o

f stu

dym

edic

atio

n

Ris

k fa

ctor

s:hi

stor

y of

ble

edin

gul

cers

: a

143,

b 1

44co

ncom

itant

use

of

antic

oagu

lant

s: a

0, b

0

cort

icos

tero

ids:

a 0

, b

0>

1 N

SAID

: a 0

, b 0

co

ncur

rent

use

of

aspi

rin: a

18,

b 9

FUN

DIN

GFu

nded

by:

Chi

nese

Uni

vers

ity o

f Hon

gKo

ng a

nd H

ealth

Serv

ices

Res

earc

hC

entr

e of

Hon

g Ko

ngA

ffilia

tion

of c

onta

ctau

thor

:Prin

ce o

fW

ales

Hos

pita

l, H

ong

Kong

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:0/

12

Appendix 6

332 (j)

Mis

opro

stol

plu

s N

SAID

ver

sus

Cox

-2 c

oxib

NSA

ID

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

Ace

vedo

, 200

1144

Loca

tion

:21

inve

stig

ativ

e sit

es in

Peru

, Arg

entin

a,C

anad

a, C

olum

bia,

Mex

ico,

USA

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d ac

cord

ing

to a

com

pute

r-ge

nera

ted

sche

dule

and

stra

tifie

d ac

cord

ing

to h

istor

y of

ulc

er o

rU

GI b

leed

ing’

Allo

cati

onco

ncea

lmen

t:un

clea

rB

asel

ine

com

para

bilit

y:ye

sPa

rtic

ipan

t bl

indi

ng:

yes

Ass

esso

r bl

indi

ng:

uncl

ear

Inte

ntio

n-to

-tre

at:

yes

A p

riori

sam

ple

size

:ye

sSu

mm

ary

risk

of

bias

:mod

erat

e

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ype

rfor

med

, 7.1

% (n

= 1

7) a

rthr

otec

gro

up(a

) and

7.4

% (n

= 1

8) r

ofec

oxib

gro

up (b

)ha

d pr

ior

hist

ory

of U

GI u

lcer

atio

n or

blee

ding

Type

and

dur

atio

n of

art

hrit

is (

year

s):

OA

: a 8

.5 (8

.0),

b 6.

8 (6

.0)

Age

:a 6

2.4,

b 6

1.8

Sex:

M/F

: a 4

5/19

6, b

50/

192

Incl

usio

n cr

iter

ia: a

t le

ast

40 y

ears

of a

ge,

clin

ical

ly e

stab

lishe

d di

agno

sis o

f OA

requ

iring

reg

ular

NSA

ID t

reat

men

tEx

clus

ion

crit

eria

:inf

lam

mat

ory

or p

ost-

trau

mat

ic a

rthr

itis;

GI d

iseas

es a

ssoc

iate

dw

ith d

iarr

hoea

(suc

h as

irrit

able

bow

eldi

seas

e); i

nfec

tious

dise

ase;

mal

abso

rptio

n;un

cont

rolle

d di

abet

es o

r ot

her

serio

usco

nditi

ons

(suc

h as

ren

al, c

ardi

ovas

cula

r, or

hepa

tic d

iseas

e); a

nd/o

r a

blee

ding

diso

rder

;al

lerg

ic t

o N

SAID

s or

par

acet

amol

, had

test

ed p

ositi

ve fo

r fa

ecal

occ

ult

bloo

d, h

adev

er u

sed

miso

pros

tol,

wer

e re

gula

r us

ers

ofas

pirin

, had

use

d co

rtic

oste

roid

s in

the

prev

ious

mon

th o

r ha

d a

hist

ory

of s

usta

ined

use

of G

I med

icat

ion

Com

pari

son:

rofe

coxi

b (b

) vs

arth

rote

c (a

)D

urat

ion:

6 w

eeks

Inte

rven

tion

s:b,

rof

ecox

ib12

.5m

g/12

.5–2

5m

g (1

2.5

mg

×1 d

aily

); a,

dic

lofe

nac

100

mg/

75m

g–15

0m

g (5

0m

g ×2

dai

ly) +

miso

pros

tol

400

µg/4

00 µ

g –8

00 µ

g (2

00 µ

g ×2

dai

ly),

mat

chin

g pl

aceb

o us

edO

ther

med

icat

ion:

cort

icos

tero

ids

excl

uded

Asp

irin

allo

wed

:no

Ana

lges

ic a

llow

ed:y

es,

para

ceta

mol

up

to 2

600

mg/

day

asre

quire

d Pa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:n

ot s

tate

dN

umbe

r an

d fr

eque

ncy

ofvi

sits

: 4 (0

, 2, 4

and

6 w

eeks

)

Allo

cate

d:a

241,

b 2

42C

ompl

eted

: a 2

15,

b22

5D

rop-

out:

a 2

6, b

17

Ass

esse

d:a

241,

b 2

42O

utco

mes

rep

orte

d:G

I sym

ptom

s, G

I dro

p-ou

ts, t

otal

dro

p-ou

tsH

ow w

ere

adve

rse

even

ts a

sses

sed:

‘spo

ntan

eous

ly r

epor

ted’

How

was

com

plia

nce

asse

ssed

:no

deta

ils

Ris

k fa

ctor

s:hi

stor

y of

ulc

ers

and/

orbl

eeds

: a 1

7, b

18

conc

omita

nt u

se o

fco

rtic

oste

roid

s: a

0,

b 0

CVD

: a 0

, b 0

Re

nal/h

epat

ic d

iseas

e:a:

0, b

: 0

FUN

DIN

GFu

nded

by:

Mer

ckRe

sear

ch L

abor

ator

ies

Affi

liati

on o

f con

tact

auth

or: M

erck

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:3

of 1

4


333


(k)

Mis

opro

stol

plu

s N

SAID

ver

sus

Cox

-2 p

refe

rent

ial N

SAID

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

Roth

, 199

378

Loca

tion

:6ce

ntre

s in

the

USA

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’,

part

icip

ants

ass

igne

d a

trea

tmen

t nu

mbe

r th

atco

rres

pond

ed w

ithtr

eatm

ent

med

icat

ion

Allo

cati

onco

ncea

lmen

t:un

clea

r B

asel

ine

com

para

bilit

y:no

,m

isopr

osto

l gro

upco

ntai

ned

youn

ger

part

icip

ants

and

mor

ew

ith n

orm

alen

dosc

opie

sPa

rtic

ipan

t bl

indi

ng:

uncl

ear

Ass

esso

r bl

indi

ng:

yes

Inte

ntio

n-to

-tre

at:

no A p

riori

sam

ple

size

:un

clea

rSu

mm

ary

risk

of

bias

: hig

h

Bas

elin

e G

I st

atus

:no

mor

e th

an 3

eros

ions

at

base

line

endo

scop

yno

rmal

end

osco

py: a

17,

b 1

8, c

27

hype

rem

ia: a

24,

b 2

0, c

17

eros

ions

: a 1

7, b

15,

c 1

3Ty

pe a

nd d

urat

ion

of a

rthr

itis

:O

A: a

ll pa

rtic

ipan

ts, n

o ot

her

deta

ilsA

ge:6

0–64

: a 1

5, b

17,

c 2

265

–74:

a 3

4, b

32,

c 3

5≥

75: a

9, b

4, c

3Se

x:F/

M: a

19/

39, b

12/

41, c

11/

49In

clus

ion

crit

eria

:OA

age

d 60

yea

rs o

rol

der,

AC

R fu

nctio

nal c

lass

II o

r III

, use

d an

NSA

ID fo

r at

leas

t 3

mon

ths

befo

reen

rolm

ent

and

expe

cted

to

cont

inue

the

use

of t

his

clas

s of

med

icat

ion

for

at le

ast

3m

onth

sEx

clus

ion

crit

eria

: hist

ory

ofhy

pers

ensit

ivity

rea

ctio

n to

any

of t

he s

tudy

drug

s, in

effic

acy

or in

tole

ranc

e to

ibup

rofe

n,hi

stor

y of

MI w

ithin

last

6m

onth

s, c

onge

stiv

ehe

art

failu

re, m

edic

ally

unc

ontr

olle

dhy

pert

ensio

n or

arr

hyth

mia

s, h

istor

y of

an

ulce

r or

GI t

ract

ble

edin

g w

ithin

1 y

ear

ofst

udy

entr

y, h

istor

y of

gas

trod

uode

nal o

reo

soph

agea

l sur

gery

, sig

nific

ant

low

er b

owel

dise

ase

(incl

udin

g re

gion

al e

nter

itis,

ulce

rativ

e co

litis,

inte

stin

al b

ypas

s su

rger

y,fr

eque

ntly

ble

edin

g ha

emor

rhoi

ds),

OA

whi

ch r

equi

red

trea

tmen

t w

ith m

ultip

leN

SAID

s w

ithin

3m

onth

s of

enr

olm

ent,

patie

nts

cons

ider

ed t

o be

can

dida

tes

for

join

tre

plac

emen

t du

ring

time

of t

he s

tudy

,pa

tient

s w

ho h

ad r

ecei

ved

intr

a-ar

ticul

arst

eroi

d in

ject

ions

or

oral

ste

roid

s w

ithin

1m

onth

of e

nrol

men

t

Com

pari

son:

miso

pros

tol p

lus

ibup

rofe

n (c

) vs

ibup

rofe

n (b

) vs

nabu

met

one

(a)

Dur

atio

n:12

wee

ksIn

terv

enti

ons:

c, m

isopr

osto

l80

0µg

/400

–800

µg

(4×

200

µgda

ily) p

lus

ibup

rofe

n24

00m

g/60

0–24

00m

g (4

×60

0m

gda

ily, a

dmin

ister

ed c

oncu

rren

tlyw

ith m

isopr

osto

l); b

, ibu

prof

en24

00m

g/60

0–24

00m

g (4

×60

0m

gda

ily);

a, n

abum

eton

e10

00m

g/50

0–20

00m

g da

ily (n

oot

her

deta

ils)

Endo

scop

y:0,

2, 6

, 12

wee

ks a

ndat

ear

ly w

ithdr

awal

Oth

er m

edic

atio

n:co

ncom

itant

med

icat

ion

was

allo

wed

with

the

exce

ptio

n of

ant

icoa

gula

nts,

oth

eran

ti-in

flam

mat

orie

s,co

rtic

oste

roid

s,im

mun

osup

pres

sant

the

rapy

, ulc

erth

erap

y (H

2RA

s, s

ucra

lfate

, lon

g-te

rm a

ntac

id t

hera

py)

Asp

irin

allo

wed

:Not

sta

ted

Ana

lges

ic a

llow

ed:p

arac

etam

olm

ax. 1

2×32

5m

g ta

blet

s in

24

hPa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

es, 3

–10

days

dur

ing

whi

ch a

dmin

ister

ed p

lace

bo 3

×da

ilyN

umbe

r an

d fr

eque

ncy

ofvi

sits

:7 (0

, 2, 4

, 6, 8

, 10

and

12w

eeks

)

Allo

cate

d:a

58, b

53,

c

60

Com

plet

ed:a

46,

b 2

5,c

45D

rop-

out:

a 12

, b 2

8,

c 15

Ass

esse

d fo

r G

Isy

mpt

oms:

a 5

8, b

53,

c 60

O

utco

mes

rep

orte

d:G

I sym

ptom

s,en

dosc

opic

ulc

ers,

anae

mia

, GI d

rop-

outs

H

ow w

ere

adve

rse

even

ts a

sses

sed:

part

icip

ants

ask

ed if

ther

e ha

d be

en a

nypr

oble

ms

since

last

visi

tH

ow w

as c

ompl

ianc

eas

sess

ed: t

able

t co

unt

Ris

k fa

ctor

s:hi

stor

y of

ulc

ers

(1 y

ear

or m

ore

ago)

;a

10, b

14,

c 1

4al

l par

ticip

ants

age

d60

year

s or

mor

e C

VD: a

0, b

0FU

ND

ING

Fu

nded

by:

Smith

Klin

e Be

echa

mPh

arm

aceu

tical

sA

ffilia

tion

of c

onta

ctau

thor

: Art

hriti

sC

ente

r, Ph

oeni

x, A

Z,

USA

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:un

clea

r

cont

inue

d

Appendix 6

334

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

Agr

awal

, 199

9145

Loca

tion

:Bra

zil,

Can

ada,

USA

and

Mex

ico

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

ass

igne

d’,

stra

tifie

d by

H. p

ylor

ist

atus

Allo

cati

onco

ncea

lmen

t:un

clea

r B

asel

ine

com

para

bilit

y: y

esPa

rtic

ipan

t bl

indi

ng:

yes

Ass

esso

r bl

indi

ng:

uncl

ear

Inte

ntio

n-to

-tre

at:

no A p

riori

sam

ple

size

:ye

sSu

mm

ary

risk

of

bias

:mod

erat

e

Bas

elin

e G

I st

atus

:bas

elin

e en

dosc

opy

perf

orm

ed a

nd e

xclu

ded

patie

nts

with

10

orm

ore

gast

ric a

nd/o

r du

oden

al e

rosio

ns,

part

icip

ants

had

hist

ory

of u

lcer

s or

ero

sions

Type

and

dur

atio

n of

art

hrit

is (

year

s):

OA

: 10.

3–11

.0 y

ears

a 4

26, b

393

Age

: a: 6

2.1

(32–

90),

b 61

.8 (3

0–85

)Se

x:M

/F a

132

/294

, b 1

38/2

55In

clus

ion

crit

eria

: adu

lts w

ith O

A h

ip o

rkn

ee (A

CR

crite

ria) o

f at

leas

t 6

mon

ths

dura

tion,

doc

umen

ted

hist

ory

ofen

dosc

opic

ally

con

firm

ed g

astr

ic, p

ylor

ic-

chan

nel o

r du

oden

al u

lcer

of 1

0 or

mor

eer

osio

ns in

the

sto

mac

h or

duo

denu

m,

expe

rienc

ing

OA

sym

ptom

s ra

nked

on

a 5-

poin

t sc

ale

as fa

ir, p

oor,

very

poo

r on

bot

hpa

tient

and

phy

sicia

n gl

obal

ass

essm

ent

ofar

thrit

is, a

s w

ell a

s hi

p or

kne

e pa

in o

nw

eigh

t-be

arin

g ra

nked

as

mod

erat

e, s

ever

eor

ver

y se

vere

Excl

usio

n cr

iter

ia:a

ctiv

e ul

cer

or m

ore

than

10

gast

ric a

nd/o

r du

oden

al u

lcer

s on

base

line

endo

scop

y, if

par

ticip

ant

had

rece

ived

NSA

ID o

r ot

her

anal

gesic

with

in3

days

of e

nrol

men

t, ha

d ta

ken

cort

icos

tero

ids

(incl

udin

g in

tra-

artic

ular

inje

ctio

ns) o

r an

ticoa

gula

nts

with

in 3

0da

ys o

fth

e fir

st d

ose

of a

ny s

tudy

med

icat

ion

or if

they

wer

e ex

pect

ed t

o re

quire

cort

icos

tero

ids

or a

ntic

oagu

lant

s du

ring

the

cour

se o

f the

stu

dy, a

ny in

flam

mat

ory

arth

ritis

othe

r th

an O

A, f

ibro

myl

agia

or

acut

ejo

int

trau

ma,

ans

erin

a or

tro

chan

teric

bur

sitis

at t

he s

ite o

f OA

, if t

heir

alan

ine

amin

otra

nsfe

rase

, asp

arta

te a

min

otra

nfer

ase

or c

reat

inin

e va

lues

wer

e gr

eate

r th

an1.

5tim

es t

he u

pper

lim

it of

nor

mal

, if t

hey

wer

e sc

hedu

led

to u

nder

go a

rthr

osco

py o

rjo

int

lava

ge o

f the

inde

x jo

int

or jo

int

Com

pari

son:

art

hrot

ec (b

) vs

nabu

met

one

(a)

Dur

atio

n:6

wee

ksIn

terv

enti

ons:

b, m

isopr

osto

l40

0 µg

/400

–800

µg

(2×

200

µgda

ily) p

lus

dicl

ofen

ac15

0m

g/75

–150

mg

(2×

75m

gda

ily) a

rthr

otec

75;

a,

nab

umet

one

1500

mg/

500–

2000

mg

(1×

1500

mg

daily

) O

ther

med

icat

ion:

6×

600

mg

alum

iniu

m h

ydro

xide

gel

tab

lets

per

day

for

relie

f of U

GI

sym

ptom

sA

spir

in a

llow

ed:y

es, i

f dos

e no

mor

e th

an 3

25m

g pe

r da

y an

dta

ken

for

30 o

r m

ore

days

bef

ore

first

dos

e of

stu

dy m

edic

atio

n A

nalg

esic

allo

wed

:not

sta

ted

Part

icip

ant

educ

atio

n:no

tst

ated

Was

hout

:3 d

ays

for

NSA

IDs,

30da

ys fo

r co

rtic

oste

roid

s or

antic

oagu

lant

s N

umbe

r an

d fr

eque

ncy

ofvi

sits

:2 (0

and

6 w

eeks

)En

dosc

opy:

(bas

elin

e an

d 6

wee

ks, o

r at

ear

lier

with

draw

al)

Allo

cate

d:a

426,

b 3

95C

ompl

eted

:unc

lear

Dro

p-ou

t:un

clea

rA

sses

sed

for

GI

sym

ptom

s: a

426

, b

393

Out

com

es r

epor

ted:

serio

us G

I eve

nts,

GI

sym

ptom

s, e

ndos

copi

cul

cers

How

wer

e ad

vers

eev

ents

ass

esse

d:no

tst

ated

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:hi

stor

y of

ulc

ers

orer

osio

ns: a

llpa

rtic

ipan

tsFU

ND

ING

Fund

ed b

y:no

t st

ated

A

ffilia

tion

of c

onta

ctau

thor

: Duk

eU

nive

rsity

Med

ical

Cen

ter,

USA

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of t

rial

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:5/

9 G

DSe

arle

Oth

er:n

apro

xen

arm

disc

ontin

ued

early

owin

g to

gast

rodu

oden

al u

lcer

rate

. A fu

rthe

r pl

aceb

oar

m is

not

rep

orte

dhe

re

cont

inue

d


335


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

repl

acem

ent

surg

ery,

if t

hey

had

activ

e G

Idi

seas

e (e

.g. i

nfla

mm

ator

y bo

wel

dise

ase)

, if

they

had

a h

istor

y of

gas

tric

or

duod

enal

surg

ery

othe

r th

an a

sim

ple

over

sew

, if t

hey

had

chro

nic

or a

cute

ren

al o

r he

patic

diso

rder

, a s

igni

fican

t co

agul

atio

n de

fect

, am

alig

nanc

y of

any

typ

e, o

r a

hist

ory

of a

mal

igna

ncy

or a

ny o

ther

con

ditio

n th

atpr

eclu

ded

part

icip

atio

n in

the

stu

dy

Cha

n, 2

00114

6

Loca

tion

:En

dosc

opy

Cen

tre,

Prin

ce o

f Wal

esH

ospi

tal,

Hon

gKo

ng, C

hina

Met

hod

ofra

ndom

isat

ion:

‘rand

omly

allo

cate

d,co

mpu

ter-

gene

rate

d lis

tof

ran

dom

num

bers

,se

aled

pac

kage

s of

stu

dym

edic

atio

ns in

cons

ecut

ive

num

bers

disp

ense

d by

stu

dynu

rse,

med

icin

es p

acke

dby

loca

l pha

rmac

y so

tha

tne

ither

pat

ient

s no

rin

vest

igat

ors

wer

e aw

are

of t

reat

men

t as

signm

ent’

Allo

cati

onco

ncea

lmen

t:ad

equa

te

Bas

elin

eco

mpa

rabi

lity:

uncl

ear

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

: yes

Inte

ntio

n-to

-tre

at:n

oA

pri

ori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

mod

erat

e

Bas

elin

e G

I st

atus

:com

plet

e ul

cer

heal

ing

follo

win

g 8

wee

ks o

f om

epra

zole

20

mg

daily

for

blee

ding

pep

tic u

lcer

sTy

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A: a

38,

b 2

9; R

A: a

1, b

3, n

o ot

her

deta

ilsA

ge:a

74

(42–

89),

b 75

(43–

92)

Sex:

M/F

: a 1

5/30

, b 1

7/28

Incl

usio

n cr

iter

ia:c

ompl

ete

ulce

r he

alin

gon

end

osco

py fo

llow

ing

8 w

eeks

of

omep

razo

le 2

0m

g da

ily fo

r bl

eedi

ng p

eptic

ulce

rs w

ith N

SAID

tre

atm

ent

with

in 7

day

sbe

fore

hos

pita

lisat

ion,

had

inad

equa

te p

ain

relie

f fro

m s

impl

e an

alge

sics

befo

reho

spita

lisat

ions

, neg

ativ

e fo

r h.

pyl

ori

Excl

usio

n cr

iter

ia:c

onco

mita

nt a

cid-

supp

ress

ing

drug

s, s

tero

ids,

ant

icoa

gula

nts

or p

roph

ylac

tic lo

w-d

ose

aspi

rin, h

adun

derg

one

prev

ious

gas

tric

sur

gery

, had

conc

urre

nt u

pper

gas

trod

uode

nal d

iseas

esin

clud

ing

eros

ive

oeso

phag

itis,

gra

de II

or

abov

e, o

esop

hage

al/g

astr

ic v

aric

es, g

astr

icou

tlet

obst

ruct

ion,

gas

tric

can

cer,

had

rece

ived

h. p

ylor

iera

dica

tion

ther

apy

in t

hepa

st, h

ad r

enal

impa

irmen

t (s

erum

crea

tinin

e >

200

mm

ol/l)

and

wer

em

orib

und,

had

und

erly

ing

mal

igna

ncy

orw

ere

unab

le t

o re

turn

for

follo

w-u

p

Com

pari

son:

napr

oxen

plu

sm

isopr

osto

l (b)

vs

nabu

met

one

plus

pla

cebo

miso

pros

tol (

a)

Dur

atio

n:24

wee

ksIn

terv

enti

ons:

b, m

isopr

osto

l40

0µg

/400

–800

µg

(2×

200

µgda

ily) p

lus

napr

oxen

500–

1000

mg/

500–

1250

mg

(n=

12 t

ook

1000

mg/

day)

; a,

pla

cebo

(2×

daily

) plu

sna

bum

eton

e10

00–1

500

mg/

500–

2000

mg

(n=

12 t

ook

1500

mg/

day)

En

dosc

opy:

bas

elin

e th

enre

peat

ed o

nly

if pa

tient

sde

velo

ped

sym

ptom

s of

rec

urre

ntul

cer

blee

ding

or

seve

re d

yspe

psia

O

ther

med

icat

ion:

not

stat

edA

spir

in a

llow

ed:n

oA

nalg

esic

allo

wed

:not

sta

ted

Part

icip

ant

educ

atio

n:no

tst

ated

Was

hout

:not

sta

ted

Num

ber

and

freq

uenc

y of

visi

ts:4

(0, 8

, 16

and

24 w

eeks

)

Allo

cate

d:un

clea

r, 96

in t

otal

Com

plet

ed:u

ncle

arD

rop-

out:

uncl

ear

Ass

esse

d fo

r G

Isy

mpt

oms:

a 4

5, b

45

Out

com

es r

epor

ted:

mor

talit

y, s

erio

us G

Ico

mpl

icat

ions

,sy

mpt

omat

ic u

lcer

s,se

rious

car

diov

ascu

lar

orre

nal i

llnes

s, G

Isy

mpt

oms

How

wer

e ad

vers

eev

ents

ass

esse

d:no

tst

ated

How

was

com

plia

nce

asse

ssed

:tab

let

coun

t,80

% o

r m

ore

(no

mor

ede

tails

) a 3

2/45

, b

38/4

5

Ris

k fa

ctor

s:al

l had

rece

nt h

istor

y of

blee

ding

gas

tric

and

/or

duod

enal

ulc

ers,

maj

orco

mor

bid

illne

ss:a

27,

b 29

FU

ND

ING

Fund

ed b

y:H

ealth

Serv

ices

Res

earc

hC

ounc

il G

rant

, Hon

g-Ko

ngA

ffilia

tion

of c

onta

ctau

thor

: Chi

nese

Uni

vers

ity o

f Hon

gKo

ngA

ffilia

tion

of

stat

isti

cian

:unc

lear

Affi

liati

on o

f tri

alad

min

istr

ator

:un

clea

rN

o. o

f aut

hors

empl

oyed

by

spon

sor:

0/10

?

Appendix 6

336 (l)

Cox

-2 c

oxib

NSA

ID v

ersu

s C

ox-2

pre

fere

ntia

l NSA

ID

Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

Trui

tt, 2

00114

7

Loca

tion

:22

cent

res

in S

wed

en,

Den

mar

k, B

elgi

um,

The

Net

herla

nds

and

Ger

man

y

Met

hod

ofra

ndom

isat

ion:

‘rand

omise

d’ b

yce

ntra

lised

com

pute

r-ge

nera

ted

allo

catio

nsc

hedu

le, s

trat

ified

by

low

-dos

e as

pirin

use

and

stud

y sit

eA

lloca

tion

conc

ealm

ent:

uncl

ear

Bas

elin

eco

mpa

rabi

lity:

no,

rega

rdin

g du

ratio

n of

OA

and

hist

ory

oful

cers

or

blee

ds

Part

icip

ant

blin

ding

:ye

sA

sses

sor

blin

ding

:yes

,bl

inde

d in

vest

igat

or,

labo

rato

ry t

estin

g at

cent

ral l

abor

ator

yIn

tent

ion-

to-t

reat

:ye

sA

pri

ori

sam

ple

size

:ye

sSu

mm

ary

risk

of b

ias:

high

Bas

elin

e G

I st

atus

:no

base

line

endo

scop

ype

rfor

med

but

par

ticip

ants

exc

lude

d if

activ

eG

I ble

edin

g in

pre

viou

s 3

mon

ths

Bas

elin

e N

SAID

sta

tus:

prev

ious

NSA

IDus

e: a

74.

8%, b

75.

4%, c

76.

8%Ty

pe a

nd d

urat

ion

of a

rthr

itis

(ye

ars)

:O

A: a

14.

6, b

17.

0, c

14.

0A

ge:a

83.

1, b

83.

3, c

83.

8Se

x:M

/F: a

41/

74, b

41/

77, c

24/

31In

clus

ion

crit

eria

:80

year

s or

mor

e, c

linic

alan

d ra

diog

raph

ic c

riter

ia fo

r th

e di

agno

sis o

fO

A (k

nee

or h

ip) (

mos

t pa

infu

l joi

ntde

signa

ted

as p

rimar

y st

udy

join

t), p

ain

in t

hest

udy

join

t to

be

pres

ent

for

at le

ast

6m

onth

s, c

linic

al s

ympt

oms

had

to b

eco

nfirm

ed b

y th

e pr

esen

ce o

f rad

iogr

aphi

cfin

ding

s (jo

int

spac

e na

rrow

ing

in a

hip

, and

join

t sp

ace

narr

owin

g an

d os

teop

hyte

s in

akn

ee),

AC

R fu

nctio

nal c

lass

es I,

II o

r III

,hi

stor

y of

pos

itive

the

rape

utic

ben

efit

from

NSA

IDs

(incl

udin

g sa

licyl

ates

) or

acet

amin

ophe

n, a

nd t

o ha

ve t

aken

the

rapy

on 2

0 or

mor

e of

the

pre

viou

s 30

day

s,re

quire

d to

sco

re 2

4 or

mor

e on

the

30-

ques

tion

(0–3

0) M

ini–

Men

tal S

tatu

sEx

amin

atio

n at

scr

eeni

ng, r

equi

red

tosw

allo

w a

tes

t do

se o

f pla

cebo

with

out

diffi

culty

, fla

re fo

llow

ing

3–5-

day

was

hout

for

thos

e on

pre

viou

s N

SAID

s, e

ligib

ility

to

ente

rw

asho

ut r

equi

red

an in

itial

Pat

ient

Glo

bal

Ass

essm

ent

of D

iseas

e St

atus

of l

ess

than

90m

m o

n a

100

mm

VA

S, fr

om 0

= v

ery

wel

l to

100

= v

ery

poor

, elig

ibili

ty fo

ral

loca

tion

requ

ired

a po

st-w

asho

ut P

atie

ntG

loba

l Ass

essm

ent

of D

iseas

e St

atus

of

40m

m o

r m

ore;

tho

se w

ho d

id n

ot t

ake

pre-

Com

pari

son:

rofe

coxi

b (b

, c) v

sna

bum

aton

eD

urat

ion:

6 w

eeks

plu

s 7–

10 d

ays

post

-stu

dy a

sses

smen

tIn

terv

enti

ons:

b: r

ofec

oxib

12.5

mg

/12.

5–25

mg

(onc

e da

ily);

c, r

ofec

oxib

25

mg/

12.5

–25

mg

(onc

e da

ily);

a, n

abum

eton

e15

00m

g/50

0–20

00m

g da

ily,

doub

le d

umm

ies

used

Oth

er m

edic

atio

n: n

ot s

tate

dA

spir

in a

llow

ed:y

es, 3

25m

gda

ily o

r le

ss p

erm

itted

, a 3

2, b

38,

c 23

Ana

lges

ic a

llow

ed:y

es,

acet

amin

ophe

n 32

5m

g/da

y or

less

Pa

rtic

ipan

t ed

ucat

ion:

not

stat

edW

asho

ut:y

es, 3

–5 d

ays

for

prev

ious

NSA

IDs

but

not

for

thos

eta

king

ace

tam

inop

hen

as N

SAID

N

umbe

r an

d fr

eque

ncy

ofvi

sits

:5 (0

, 1, 2

, 4 a

nd 6

wee

ks)

Allo

cate

d:a

115,

b11

8, c

56

Com

plet

ed:a

100

,b

101.

c 4

8D

rop-

out:

a 15

, b 1

7,c

8A

sses

sed:

a 11

5, b

118

,c

56O

utco

mes

rep

orte

d:se

rious

GI

com

plic

atio

ns,

sym

ptom

atic

ulc

ers,

serio

us c

ardi

ovas

cula

r or

rena

l illn

ess,

GI

sym

ptom

s, o

ccul

tbl

eedi

ng, G

I dro

p-ou

tsH

ow w

ere

adve

rse

even

ts a

sses

sed:

part

icip

ant

inte

rimhi

stor

ies,

det

erm

inat

ion

of a

dver

se e

vent

s w

as in

the

subj

ectiv

e op

inio

n of

the

blin

ded

inve

stig

ator

,ev

ents

rev

iew

ed, r

ated

by in

tens

ity a

ndre

latio

nshi

p to

stu

dytr

eatm

ent

How

was

com

plia

nce

asse

ssed

:not

sta

ted

Ris

k fa

ctor

s:hi

stor

y of

PU

Bs: a

7,

b 11

, c10

conc

omita

nt u

se o

fco

rtic

oste

roid

s:a

0,

b 0

hist

ory

of a

ngin

a: a

10,

b 11

, c 5

MI:

a: 9

, b 9

. c 1

0co

rona

ry a

rter

ydi

seas

e: a

9, b

5, c

:4hy

pert

ensio

n: a

56,

b55

, c 2

7FU

ND

ING

Fund

ed b

y:M

erck

Rese

arch

Lab

orat

orie

sA

ffilia

tion

of c

onta

ctau

thor

:Mer

ckRe

sear

ch L

abor

ator

ies

Affi

liati

on o

fst

atis

tici

an:u

ncle

arA

ffilia

tion

of s

tudy

adm

inis

trat

or:

uncl

ear

No.

of a

utho

rsem

ploy

ed b

ysp

onso

r:6

of 8

auth

ors

empl

oyed

by

Mer

ck R

esea

rch

Labo

rato

ries

Oth

er:p

lace

bo g

roup

not

data

ext

ract

ed

cont

inue

d


337


Stud

y id

enti

fier,

Met

hods

and

val

idit

yPa

rtic

ipan

t ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsO

utco

me

Ris

k fa

ctor

s,

loca

tion

asse

ssm

ent

fund

ing,

oth

er n

otes

stud

y N

SAID

s bu

t w

ere

taki

ng p

re-s

tudy

acet

amin

ophe

n w

ere

requ

ired

to g

ive

cons

isten

t Pa

tient

Glo

bal A

sses

smen

t of

Dise

ase

Stat

us (4

0m

m o

r m

ore

but

less

tha

n90

mm

) at

scre

enin

g an

d ba

selin

eEx

clus

ion

crit

eria

:prio

r hi

stor

y of

infla

mm

ator

y ar

thrit

is (in

clud

ing

RA),

acut

elig

amen

tous

or

men

iscal

inju

ry t

o st

udy

join

tw

ithin

18

mon

ths,

or

arth

rosc

opy

with

in4

mon

ths,

intr

a-ar

ticul

ar o

r sy

stem

icco

rtic

oste

roid

s w

ithin

3m

onth

s of

stu

dyen

try,

oth

er m

edic

al c

ondi

tions

or

labo

rato

ryab

norm

aliti

es w

hich

con

trai

ndic

ated

use

of

NSA

IDs

or w

ere

pote

ntia

l con

foun

ders

of

safe

ty e

valu

atio

n, a

ngin

a or

con

gest

ive

hear

tfa

ilure

with

sym

ptom

s at

res

t, se

rum

crea

tinin

e m

ore

than

2.0

mg/

dl o

r cr

eatin

ine

clea

ranc

es 3

0m

l/min

ute

or le

ss, u

ncon

trol

led

hype

rten

sion,

act

ive

GI b

leed

ing

with

in3

mon

ths,

hist

ory

of le

ukae

mia

, lym

phom

a or

mye

lopr

olife

rativ

e di

seas

e, h

yper

sens

itivi

ty t

oas

pirin

or

NSA

IDs,

any

one

of t

hree

pre

-al

loca

tion

stoo

l-gua

iac

test

s be

ing

posit

ive

Funnel plots and related inferential methodswere used to assess for evidence of small study

effects, including publication bias.34 These werecarried out on StatsDirect software, using Eggerand colleagues’35 and Begg and Mazumdar’s36

tests. All of these methods have low power todetect small study effects (which may include bias)where there are few studies reporting theoutcomes of interest.

(a) H2RA versus placebo,endoscopic ulcers

Not enough studies reported symptomatic ulcersfor this outcome to be used in assessment of bias.

Bias indicatorsFrom regression of normalised effect versusprecision (Egger and colleagues35): intercept (0 ifunbiased) = –0.375 (approximate 95% CI = –2.429 to 1.680), p = 0.679. From Kendall’stest on standardised effect versus variance (Beggand Mazumdar36): tau = –0.167, p = 0.477 (notrobust, small sample).

(b) PPI versus placebo, endoscopiculcers


Bias indicatorsFrom regression of normalised effect versusprecision (Egger and colleagues35): intercept (0 if

unbiased) = –0.619 (approximate 95% CI =–2.958 to 1.719) p = 0.503. From Kendall’s test onstandardised effect versus variance (Begg andMazumdar36): tau = –0.733, p = 0.0167 (notrobust, small sample).

(c) Misoprostol versus placebo,endoscopic ulcers


Bias indicatorsFrom regression of normalised effect versusprecision (Egger and colleagues35): intercept (0 ifunbiased) = –0.941699 (approximate 95% CI =–2.682789 to 0.799391), p = 0.2559. FromKendall’s test on standardised effect versusvariance (Begg and Mazumdar36):tau = –0.138462, p = 0.5815.


339


Appendix 7

Bias indicators

Bias assessment plot

–3 –2 –1 0 1 20.96

0.80

0.64

0.48

0.32

0.16

0.00

Log (relative risk)

Stan

dard

err

or


Stan

dard

err

or

–3 –2 –1 0 11.0

0.8

0.6

0.4

0.2

0.0

Log (relative risk)


Stan

dard

err

or

–3 –2 –1 0 10.8

0.6

0.4

0.2

0.0

Log (relative risk)

(d) Cox-2 coxibs NSAIDs versusCox-1 NSAIDs, symptomaticulcers

Bias indicatorsFrom regression of normalised effect versusprecision (Egger and colleagues35): intercept (0 ifunbiased) = 0.100571 (approximate 95% CI =–2.014181 to 2.215324), p = 0.9013. FromKendall’s test on standardised effect versusvariance (Begg and Mazumdar36): tau = 0.066667,p > 0.9999 (not robust, small sample).

(e) Cox-2 preferential NSAIDsversus Cox-1 NSAIDs,symptomatic ulcers

Bias indicatorsFrom regression of normalised effect versusprecision (Egger and colleagues35): intercept (0 ifunbiased) = –0.966622 (approximate 95% CI =–2.596344 to 0.663099), p = 0.1879. FromKendall’s test on standardised effect versusvariance (Begg and Mazumdar36): tau =–0.142857, p = 0.5619 (not robust, small sample).

Appendix 7

340


–100 100 300 500 7001.125

0.750

0.375

0.000

Log (relative risk)

Stan

dard

err

or


–100 100 300 500 7001.125

0.750

0.375

0.000

Log (relative risk)

Stan

dard

err

or


341


Appendix 8

Meta-regression results for direct comparisons

Comparison Outcome Covariate No. of Regression 95% CI of p-Valuestudies coefficient regression

coefficient

H2RA vs placebo Endoscopic ulcers Study duration 12 –0.011 –0.033 to 0.012 0.32(weeks)

% with history of 8 –0.002 –0.009 to 0.005 0.60ulcer or bleeds

Mean age (years) 12 –0.023 –0.068 to 0.020 0.29

PPI vs placebo Endoscopic ulcers Study duration, 6 –0.003 –0.033 to 0.026 0.82(weeks)

% with history of 4 0.004 –0.006 to 0.014 0.40ulcer or bleeds

Mean age (years) 6 0.073 –0.087 to 0.233 0.37

Misoprostol vs Endoscopic ulcers Study duration 19 0.014 0.001 to 0.027 0.03placebo (weeks)


Mean age (years) 18 –0.002 –0.053 to 0.049 0.94

Cox-2 coxibs vs Symptomatic ulcers Study duration 12 0.011 –0.010 to 0.032 0.32Cox-1 (weeks)


Mean age (years) 12 0.014 –0.032 to 0.060 0.56

Cox-2 preferentials Symptomatic ulcers Study duration 14 –0.016 –0.053 to 0.020 0.39vs Cox-1 (weeks)


Mean age (years) 12 0.013 -0.053 to 0.078 0.71


343


Absolute risk reduction (ARR) or risk difference is the risk in the intervention group minus the risk in thecontrol group.

(a) Overall ARRs for direct comparisons

Appendix 9

Absolute risk reductions (risk differences)

Outcome Events N Events N ARR 95% CI, 95% CI, Hetero-intervention intervention control control lower upper geneity

limit limit p-value

H2RA vs placeboSerious GI events 0 497 1 397 –0.004 –0.011 0.003Symptomatic ulcers 1 221 0 122 0.005 –0.005 0.015Serious CV or renal events 2 440 3 341 –0.007 –0.017 0.003Deaths 1 364 0 357 0.0002 –0.007 0.008GI symptoms 84 695 117 690 –0.037 –0.069 –0.006Endoscopic ulcers 105 987 145 760 –0.09 –0.13 –0.05Drop-outs, total 176 994 166 878 –0.002 –0.03 0.02Drop-outs, GI symptoms 25 668 32 557 –0.005 –0.04 0.03

PPI vs placeboSerious GI events 1 677 2 431 –0.001 –0.01 0.008Symptomatic ulcers 1 168 17 175 –0.09 –0.13 –0.04Serious CV or renal events 2 333 1 163 0.002 –0.015 0.019Deaths 0 268 1 133 –0.008 –0.022 0.007GI symptoms 13 85 32 90 –0.2 –0.33 –0.08Endoscopic ulcers 108 816 173 542 –0.18 –0.26 –0.11Drop-outs, total 73 600 43 346 0.001 –0.05 0.06Drop-outs, GI symptoms 15 155 33 124 –0.098 –0.378 0.182

Misoprostol vs placeboSerious GI events 26 5780 49 5727 –0.003 –0.006 –0.0001 0.46Symptomatic ulcers 14 4436 40 4477 –0.005 –0.008 –0.002 0.55Serious CV or renal events 3 1581 1 725 0.0002 –0.003 0.003 0.38Deaths 17 6452 18 5616 –0.0005 –0.002 0.001 1.0GI symptoms 863 1338 355 635 –0.0017 –0.11 0.11 0.004Endoscopic ulcers 220 3407 438 2675 –0.119 –0.135 –0.103 <0.0001Drop-outs, total 2655 8120 2117 7155 0.026 0.003 0.049 0.008Drop-outs, GI symptoms 1366 6373 966 5922 0.024 –0.006 0.054 <0.0001

Cox-2 coxibs vs Cox-1Serious GI events 41 11661 74 10082 –0.003 –0.005 –0.001 0.90Symptomatic ulcers 97 11896 184 10115 –0.007 –0.011 –0.002 0.03Serious CV or renal events 134 10181 108 9403 0.002 –0.002 0.006 0.22Deaths 40 9292 36 8821 –0.0002 –0.003 0.002 0.24GI symptoms 2554 6883 2630 5855 –0.06 –0.08 –0.04 0.70Endoscopic ulcers 162 2184 360 1159 –0.23 –0.34 –0.12 <0.0001Drop-outs, total 4967 13877 4583 11379 –0.055 –0.090 –0.021 <0.0001Drop-outs, GI symptoms 990 12912 1201 10883 –0.019 –0.032 –0.006 0.0002

continued

Appendix 9

344

Outcome Events N events N ARR 95% CI, 95% CI, Hetero-intervention intervention control control lower upper geneity

limit limit p-value

Cox-2 preferentials vs Cox-1Serious GI events 17 11797 26 10928 –0.0004 –0.0013 0.0006 0.55Symptomatic ulcers 23 10980 59 10391 –0.0033 –0.0074 0.0008 0.0004Serious CV or renal events 23 9824 25 9732 0.0002 –0.0012 0.0015 0.89Deaths 7 10510 12 10072 –0.0001 –0.0008 0.0006 0.48GI symptoms 1724 12263 2170 11396 –0.054 –0.068 –0.040 0.29Endoscopic ulcers 6 185 18 182 –0.06 –0.11 –0.002 0.29Drop-outs, total 2179 13920 2095 13047 –0.013 –0.022 –0.003 0.42Drop-outs, GI symptoms 455 12049 719 11727 –0.021 –0.029 –0.013 0.24

Comparison Outcome Factor Events/ Events/ Limits RRa 95% CIa Hetero-for participants participants geneity subgrouping in in control p-value

intervention group

H2RA vs Serious GI Baseline GI risk No usable data for subgroupingplacebo events Baseline age No usable data for subgrouping

Symptomatic Baseline GI risk No usable data for subgroupingulcers Baseline age No usable data for subgrouping

Endoscopic Baseline GI 16/197 27/176 1 0.52 0.29 to 0.94 0.90ulcers riskb 76/709 86/509 2 0.61 0.46 to 0.82 0.48

0/33 3/26 3 0.19 0.02 to 1.65 0.9313/48 29/49 4 0.45 0.27 to 0.76 0.66

Baseline age 94/883 121/658 <65 years 0.57 0.45 to 0.74 0.629/92 22/88 ≥ 65 years 0.39 0.20 to 0.77 0.90

PPI vs placebo Serious GI Baseline GI risk No usable data for subgroupingevents Baseline age No usable data for subgrouping

Symptomatic Baseline GI risk No usable data for subgroupingulcers Baseline age No usable data for subgrouping

Endoscopic Baseline 1/50 8/53 1 0.13 0.02 to 1.02 Not ulcers GI riskb relevant

16/139 23/111 2 0.42 0.14 to 1.31 0.103 No relevant studies

87/542 127/288 4 0.36 0.29 to 0.46 0.69Baseline age <65 years No included studies have a

≥ 65 years mean age over 65 years orappropriate subgrouping

Misoprostol vs Serious GI Baseline GI 1 One study only, no eventsplacebo events riskb 0/349 6/547 2 0.25 0.03 to 2.15 0.72

3 No studies0/431 1/288 4 0.17 0.01 to 4.26 Not

relevantBaseline age 1/1305 6/1209 <65 years 0.34 0.06 to 2.03 0.56

25/4444 42/4482 ≥ 65 years 0.60 0.37 to 0.98 Notrelevant

(b) Update April 2005, subgrouping RRs for direct comparisons bybaseline GI risk and by age

continued


345


Comparison Outcome Factor Events/ Events/ Limits RR* 95% CI* Hetero-for participants participants geneity subgrouping in in control p-value

intervention group

Symptomatic Baseline GI 1 No studiesulcers riskb 2 No studies

3 No studies4 No studies

Baseline age <65 years No studies14/4436 40/4477 ≥ 65 years 0.36 0.20 to 0.67 0.52

Endoscopic Baseline GI 0/45 5/45 1 0.09 0.01 to 1.60 Not ulcers riskbr relevant

47/1670 159/1739 2 0.31 0.23 to 0.44 0.6285/948 106/427 3 0.39 0.30 to 0.50 0.4273/430 127/288 4 0.34 0.17 to 0.67 0.02

Baseline age 215/3318 419/2584 <65 years 0.33 0.27 to 0.41 0.195/32 11/38 ≥ 65 years 0.54 0.21 to 1.39 Not

relevant

Cox-2 coxibs Serious GI Baseline GI 1 No studiesvs Cox-1 events riskb 23/5699 30/4846 2 0.72 0.42 to 1.22 0.51


Baseline age 41/11487 73/9967 <65 years 0.55 0.38 to 0.80 0.75≥ 65 years No studies

Symptomatic Baseline GI 1 No studiesulcers riskb 38/5877 56/4842 2 0.56 0.36 to 0.85 0.39



Endoscopic Baseline GI 1 No studiesulcers riskb 154/1972 327/941 2 0.25 0.21 to 0.30 0.52



Cox-2 Serious GI Baseline GI 1 No studiespreferentials vs events riskb 0/36 0/36 2 One study, no eventsCox-1 3 No studies

4 No studiesBaseline age 14/10891 22/10195 <65 years 0.59 0.31 to 1.12 0.98

3/707 4/553 ≥ 65 years 0.73 0.17 to 3.09 0.60

Symptomatic Baseline GI 1 No studiesulcers riskb 2/78 7/77 2 0.28 0.06 to 1.33 0.87


Baseline age 21/10321 48/9751 <65 years 0.43 0.26 to 0.71 0.881/418 6/419 ≥ 65 years 0.34 0.08 to 1.42 1.00

Endoscopic Baseline GI 1 No studiesulcers riskb 4/161 16/153 2 0.29 0.10 to 0.86 0.61


Baseline age 2/61 5/59 <65 years 0.47 0.10 to 2.18 0.482/24 2/29 ≥ 65 years 1.21 0.18 to 7.95 Not

relevant

a Using random effects meta-analysis.b By baseline risk of GI problems: 1, normal gut on endoscopy for all participants; 2, some participants normal, others have

some erosions and/or haemorrhages on endoscopy, but no frank ulcers; 3, all abnormal gut at baseline endoscopy (noulcers or up to 50% recently healed ulcers). 4, all recently healed from ulcers (at least 50% recently healed ulcers).


347


Appendix 10

Quality of life data

(a) Omeprazole versus misoprostol versus placebo

Study Interventions Measure of Baseline QoL Change in QoL Final QoLQoL useda

Hawkey, 199862

(OMNIUM),(reported inYeomans,200165)

Omeprazole 20 mg/day (n = 274)Misoprostol400 µg /day(n = 297)Placebo (n = 155)

NottinghamHealth Profile(NHP)

Baseline was before ulcerhealing. Only reported by typeof arthritis, not treatmentgroup, and includes those inmisoprostol, placebo andomeprazole arms:Total score part 1: RA n = 220mean score 32.3 (SD 19.5), OAn = 313, mean score 32.2 (SD 21.1)Total score part 2: RA n = 220mean score 93.8 (SD 18.1), OA n = 313, mean score 92.3(SD 19.0)

After healing therewas a slightimprovement onall dimensions ofthe NHP, inparticularregarding arthritispain relief (15%),improved sleep(6%), vitality (7%)and ability to lookafter the home(8%)

6 months:‘Duringprevention thehealth-relatedQoL assessed bythe NHP waspreserved.’ Nofurther data, ordata byinterventiongroup, werepresented

PsychologicalGeneral Well-Being Index(PGWB)

Mean score of 93 in the studycompared with 103 in thegeneral population, indicatingthat their well-being wasseverely compromised. Worstdimensions were general healthand vitality

After healing themean PGWBscore improvedfrom 93 to 98, aclinically relevantimprovement

The PGWB indexwas maintainedat ‘the samelevel’ as afterhealing

a Nottingham Health Profile: the NHP is a generic questionnaire that measures the perceived impact of chronic disease. Part 1 consists of 38 yes/no questions about distress and dysfunction in six dimensions (energy, sleep, social isolation, pain,emotions, physical mobility). Part 2 has seven yes/no statements about health-related problems in employment, housework,social life, home life, sex life, hobbies and holidays. The higher the score the worse is the QoL; an improvement in QoL isindicated by a decreased score. Psychological General Well-Being Index: the PGWB measures subjective well-being ordistress in terms of anxiety, depressed mood, positive well-being, self-control and general health and vitality on a six-pointLikert scale. The worst possible score is 22 and the best is 132.

Appendix 10

348

(b) Cox-2 coxib NSAIDs versus Cox-1 NSAIDs

Study Interventions Measure of QoL used Baseline QoL Change in QoL

Simon 1999,86

(reported inZhao, 2000240)

Cox-2: b celecoxib200 mg/day (n = 240)c celecoxib 400 mg/day(n = 235)d celecoxib 800 mg/day(n = 218)Cox-1: a naproxen1000 mg/day (n = 225)

Stanford Health AssessmentQuestionnaire (HAQ) Disability Index

Total functionaldisability index:b 1.40 (SD 0.65)c 1.50 (SD 0.73)d 1.40 (SD 0.72)a 1.50 (SD 0.67)

12 weeks: Totalfunctionaldisability indexb –0.17c –0.29d –0.28a –0.22

The Medical Outcomes Study Short Form with 36 Items (SF-36) is a general health measure. Measures health across threedimensions (functional status, well-being, overall evaluation of health) using eight domains (physical functioning, role physical,bodily pain, general health, vitality, social functioning, role emotional, mental health, plus health transition). Can be self-administered in 5–10 minutes. Higher scores indicate better QoL.a The Stanford Health Assessment Questionnaire (HAQ) Disability Index (the 20-item core instrument of the HAQ) is a

disease-specific instrument. Can be self-administered in less than 5 minutes and evaluates eight categories of dailyfunctioning: dressing, arising, eating, walking, hygiene, reach, grip, activities. A lower score represents better functionalstatus.

Medical Outcomes Study Short Formwith 36 Items (SF-36)

Physicalcomponentscore:b 29.7 (SD 8.0)c 29.5 (SD 7.9)d 29.5 (SD 8.3)a 29.9 (SD 8.9)Mentalcomponent scoreb 47.6 (SD 11.1)c 45.3 (SD 12.3)d 47.5 (SD 11.6)a 46.2 (SD 11.6)

12 weeks:Physicalcomponent score:b 2.5c 4.3d 4.4a 2.7Mentalcomponent score:b 1.8c 2.8d 1.8a 2.1


349


(c) Cox-2 preferential NSAIDs versus Cox-1 NSAID

Study Interventions Measure of QoL useda Baseline QoL Change in QoL

Hosie, 1996123 Cox-2: b meloxicam7.5mg/day (n = 169)Cox-1: a diclofenac100 mg/day (n = 166)

Modified Nottingham Health Profile b score 7.2 (SD 4.3)a score 7.0 (SD 4.3)

6 months:b mean –2.3 (SD 3.7)a mean –2.2 (SD 4.2)

Hosie, 1997126 Cox-2: b meloxicam15 mg/day (n = 306)Cox-1 a piroxicam20 mg/day (n = 149)

Modified Nottingham HealthProfile

No data provided 6 months:b median –1 (Interquartilerange –2 to 0)a median –1 (Interquartilerange –3 to 0)

Furst, 2002139 Cox-2: b meloxicam7.5 mg/day (n = 175)c meloxicam 15 mg/day(n = 184)d meloxicam22.5 mg/day (n = 177)Cox-1: a diclofenac150mg/day (n = 181)

Modified Health AssessmentQuestionnaire (mHAQ)

At flareb 1.02 (SD 0.59)c 1.06 (SD 0.66)d 1.09 (SD 0.61)a 1.02 (SD 0.60)

12 weeks:b –0.32c –0.37d –0.42a –0.33

a The Modified Nottingham Health Profile has 22 questions from 3 of 6 sections in part 1 and 3 of 6 sections from part 2covering physical mobility, social isolation, energy levels and influences on various aspects of life. An improvement in QoL isindicated by a decreased score. The Modified Health Assessment Questionnaire (mHAQ) for patient assessment of physicalfunction has maximum score = +3. This is more a measure of efficacy than of QoL.


351


(a) H2RA versus PPI meta-analysis (MA) and sensitivity analysis (SA)results

Appendix 11

Direct comparisons, meta-analysis and sensitivity analysis details

Outcome Analysis No. of No. of No. of RR 95% CI Heterogeneity included participants events (random p-valueRCTs effects)

Serious GI events MA 1 425 1 0.33 0.01 to 7.95 NRSA quality 1 425 0.33 0.01 to 7.95 NRSA dosage 1 425 0.33 0.01 to 7.95 NR

Symptomatic ulcers MA 1 425 1 0.33 0.01 to 7.95 NRSA quality 1 425 0.33 0.01 to 7.95 NRSA dosage 1 425 0.33 0.01 to 7.95 NR

Serious CV or MA 0renal events

QoL MA 0

Deaths MA 0

GI symptoms MA 0

Endoscopic ulcers MA 1 425 46 3.11 1.62 to 5.95 NRSA quality 1 425 3.11 1.62 to 5.95 NRSA dosage 1 425 3.11 1.62 to 5.95 NR

Anaemia MA 0

Occult bleed MA 0

Total drop-outs MA 1 425 59 0.94 0.59 to 1.52 NRSA quality 1 425 0.94 0.59 to 1.52 NRSA dosage 1 425 0.94 0.59 to 1.52 NR

Drop-outs due MA 0to GI symptoms

NR, not relevant (e.g. tests of heterogeneity when only one study is included in the analysis).

Appendix 11

352

(b) H2RA vs misoprostol meta-analysis (MA) and sensitivity analysis(SA)


Serious GI events MA 1 538 0 NE NE NRSA quality 1 538 NE NE NRSA dosage 1 538 NE NE NR

Symptomatic ulcers MA 1 49 1 2.67 0.11 to 62.42 NRSA quality 1 49 2.67 0.11 to 62.42 NRSA dosage 0

Serious CV or MA 1 538 0 NE NE NRrenal events SA quality 1 538 NE NE NR

SA dosage 1 538 NE NE NRSA naproxen 0

QoL 0

Deaths MA 1 538 0 NE NE NRSA quality 1 538 NE NE NRSA dosage 1 538 NE NE NRSA Naproxen 0

GI symptoms MA 2 587 345 0.85 0.74 to 0.97 0.46SA quality 2 587 0.85 0.74 to 0.97 0.46SA dosage 1 538 0.84 0.73 to 0.96

Endoscopic ulcers MA 3 454 23 4.35 1.51 to 12.55 0.82SA quality 3 454 4.35 1.51 to 12.55 0.82SA dosage 1 375 4.04 1.17 to 13.96 NR

Anaemia MA 0

Occult bleed MA 0

Total drop-outs MA 2 599 125 0.78 0.57 to 1.07 0.8SA quality 2 599 0.78 0.57 to 1.07 0.8SA dosage 1 538 0.79 0.57 to 1.10 NR

Drop-outs due MA 2 599 46 0.40 0.22 to 0.74 0.89to GI symptoms SA quality 2 599 0.40 0.22 to 0.74 0.89

SA dosage 1 538 0.41 0.22 to 0.76 NR

NE, no events, and so no data; NR, not relevant (e.g. tests of heterogeneity when only one study is included in the analysis).


353


(c) PPI versus misoprostol meta-analysis (MA) and sensitivity analysis(SA)



Symptomatic ulcers MA 0Serious CV or MA 1 402 4 0.50 0.07 to 3.51 NRrenal events SA quality 1 402 0.50 0.07 to 3.51 NR

SA dosage 1 402 0.50 0.07 to 3.51 NRSA naproxen 0

QoL 0

Deaths MA 1 402 1 0.17 0.01 to 4.08 NRSA quality 1 402 0.17 0.01 to 4.08 NRSA dosage 1 402 0.17 0.01 to 4.08 NRSA naproxen 0

GI symptoms MA 0

Endoscopic ulcers MA 2 972 160 1.08 0.50 to 2.32 0.021SA quality 2 972 1.08 0.50 to 2.32 0.021SA dosage 2 972 1.08 0.50 to 2.32 0.021

Anaemia MA 0

Occult bleed MA 0

Total drop-outs MA 2 972 139 0.71 0.52 to 0.98 0.99SA quality 2 972 0.71 0.52 to 0.98 0.99SA dosage 2 972 0.71 0.52 to 0.98 0.99

Drop-outs due to MA 0GI symptoms


Appendix 11

354

(d) PPI vs Cox-2 coxib meta-analysis (MA) and sensitivity analysis (SA)results



Symptomatic ulcers MA 1 287 16 1.29 0.50 to 3.38 NRSA quality 1 287 1.29 0.50 to 3.38 NRSA dosage 1 287 1.29 0.50 to 3.38 NR

Serious CV or MA 1 287 21 1.11 0.49 to 2.53 NRrenal events SA quality 1 287 1.11 0.49 to 2.53 NR

SA dosage 1 287 1.11 0.49 to 2.53 NRSA naproxen 1 287 1.11 0.49 to 2.53 NR

QoL 0

Deaths MA 1 287 2 1.01 0.06 to 15.95 NRSA quality 1 287 1.01 0.06 to 15.95 NRSA dosage 1 287 1.01 0.06 to 15.95 NRSA naproxen 1 287 1.01 0.06 to 15.95 NR

GI symptoms MA 1 287 37 0.61 0.33 to 1.14 NRSA quality 1 287 0.61 0.33 to 1.14 NRSA dosage 1 287 0.61 0.33 to 1.14 NR

Endoscopic ulcers MA 0

Anaemia MA 1 287 4 9.06 0.49 to 166.81 NRSA quality 1 287 9.06 0.49 to 166.81 NRSA dosage 1 287 9.06 0.49 to 166.81 NR

Occult bleeds MA 0

Total drop-outs MA 1 287 40 0.91 0.51 to 1.62 NRSA quality 1 287 0.91 0.51 to 1.62 NRSA dosage 1 287 0.91 0.51 to 1.62 NR

Drop-outs due to MA 1 287 11 0.84 0.26 to 2.69 NRGI symptoms SA quality 1 287 0.84 0.26 to 2.69 NR

SA dosage 1 287 0.84 0.26 to 2.69 NR



355


(e) Misoprostol versus Cox-2 coxib meta-analysis (MA) and sensitivityanalysis (SA) results


Serious GI events MA 0

Symptomatic ulcers MA 0

Serious CV or MA 1 483 24 0.72 0.32 to 1.58 NRrenal events SA quality 1 483 24 0.72 0.32 to 1.58 NR

SA dosage 1 483 24 0.72 0.32 to 1.58 NRSA naproxen 1 483 24 0.72 0.32 to 1.58 NR

QoL 0

Deaths MA 0

GI symptoms MA 1 483 187 1.68 1.32 to 2.13 NRSA quality 1 483 187 1.68 1.32 to 2.13 NRSA dosage 1 483 187 1.68 1.32 to 2.13 NR

Endoscopic ulcers MA 0

Anaemia MA 0

Occult bleed MA 0

Total drop-outs MA 1 483 43 1.54 0.86 to 2.76 NRSA quality 1 483 43 1.54 0.86 to 2.76 NRSA dosage 1 483 43 1.54 0.86 to 2.76 NR

Drop-outs due to MA 1 483 10 9.04 1.15 to 70.78 NRGI symptoms SA quality 1 483 10 9.04 1.15 to 70.8 NR

SA dosage 1 483 10 9.04 1.15 to 70.8 NR


Appendix 11

356

(f) Misoprostol versus Cox-2 preferential meta-analysis (MA) andsensitivity analysis (SA) results


Serious GI events MA 2 909 16 3.05 1.03 to 9.06 0.75SA quality 2 909 16 3.05 1.03 to 9.06 0.75SA dosage 2 909 16 3.05 1.03 to 9.06 0.75

Symptomatic ulcers MA 1 90 5 0.25 0.03 to 2.15 NRSA quality 1 90 5 0.25 0.03 to 2.15 NRSA dosage 1 90 5 0.25 0.03 to 2.15 NR

Serious CV or MA 1 90 2 1.00 0.06 to 15.50 NRrenal events SA quality 1 90 2 1.00 0.06 to 15.50 NR

SA dosage 1 90 2 1.00 0.06 to 15.50 NRSA naproxen 0

QoL 0

Deaths MA 1 90 4 1.00 0.15 to 6.79 NRSA quality 1 90 4 1.00 0.15 to 6.79 NRSA dosage 1 90 4 1.00 0.15 to 6.79 NRSA naproxen 0

GI symptoms MA 1 90 12 0.50 0.16 to 1.54 NRSA quality 1 90 12 0.50 0.16 to 1.54 NRSA dosage 1 90 12 0.50 0.16 to 1.54 NR

Endoscopic ulcers MA 2 934 60 0.37 0.21 to 0.65 0.96SA quality 1 819 59 0.37 0.21 to 0.65 NRSA dosage 2 934 60 0.37 0.21 to 0.65 0.96

Anaemia MA 1 118 1 2.90 0.12 to 69.8 NRSA quality 0SA dosage 1 118 1 2.90 0.12 to 69.8 NR

Occult bleed MA 0

Total drop-outs MA 2 208 63 1.00 0.67 to 1.50 0.48SA quality 1 90 36 0.89 0.54 to 1.49 NRSA dosage 2 208 63 1.00 0.67 to 1.50 0.48

Drop-outs due to MA 0GI symptoms



357


(g) Cox-2 (pooled coxib and preferential) NSAIDs versus Cox-1 NSAIDmeta-analysis (MA) and sensitivity analysis (SA) results


Serious GI events MA 31 44468 158 0.56 0.41,0.77 0.99SA quality 24 42547 0.56 0.41,0.78 0.96SA dosage 28 27369 0.55 0.33,0.92 1.00SA Cox-2 11 21454 0.55 0.38,0.80 0.75

preferentials

Symptomatic ulcers MA 28 43194 363 0.47 0.38,0.59 1SA quality 22 41576 0.48 0.38,0.60 0.99SA dosage 26 26445 0.44 0.30,0.63 1SA Cox-2 11 21534 0.49 0.39,0.63 0.83

preferentials

Serious CV or MA 20 39140 290 1.09 0.86,1.37 0.64renal events SA quality 14 37874 1.11 0.88,1.40 0.57

SA dosage 18 23096 0.93 0.62,1.41 0.78SA Cox-2 8 19295 1.19 0.80,1.75 0.27

preferentialsSA naproxen 18 30525 0.98 0.76,1.26 0.89

QoL 1 335 WMD –0.95,0.75 NR–0.10

Deaths MA 20 38695 97 0.99 0.66,1.48 0.56SA quality 14 37688 1.06 0.70,1.60 0.49SA dosage 18 22474 0.60 0.27,1.32 0.59SA Cox-2

preferentials 6 18113 1.02 0.55,1.92 0.26SA naproxen 17 30050 0.93 0.55,1.56 0.48

GI symptoms MA 38 36045 8996 0.77 0.72,0.84 <0.001SA quality 27 34108 0.77 0.71, 0.84 <0.001SA dosage 35 27330 0.73 0.69, 0.77 0.61SA Cox-2 9 12446 0.85 0.79, 0.91 0.32

preferentials

Endoscopic ulcers MA 11 3411 531 0.25 0.21,0.30 0.58SA quality 7 2861 0.25 0.21, 0.31 0.38SA dosage 10 2903 0.24 0.19, 0.29 0.64SA Cox-2 7 3173 0.25 0.21, 0.30 0.45

preferentials

Anaemia MA 8 10218 470 0.61 0.51,0.73 0.87SA quality 6 9506 0.61 0.51, 0.73 0.72SA dosage 7 2250 0.26 0.09, 0.74 1.00SA Cox-2 4 9191 0.62 0.51, 0.74 0.54

preferentials

Occult bleed MA 5 1328 18 0.92 0.37,2.31 0.89SA quality 4 1039 0.86 0.33, 2.24 0.83SA dosage 5 1151 0.92 0.37, 2.31 0.88SA Cox-2 0

preferentials

Total drop-outs MA 59 51739 13706 0.69 0.61,0.77 0.048SA quality 43 49134 0.88 0.83, 0.95 <0.001SA dosage 52 33562 0.88 0.81, 0.96 <0.001SA Cox-2 18 24848 0.83 0.74, 0.92 <0.001

preferentials

continued

Appendix 11

358


Drop-outs due to MA 47 47383 3365 0.89 0.84,0.95 <0.001GI symptoms SA quality 33 44866 0.69 0.61, 0.78 0.07

SA dosage 44 30924 0.66 0.57, 0.77 0.16SA Cox-2

preferentials 19 32867 0.71 0.60, 0.85 0.006

WMD, weighted mean difference.


359


Appendix 12

Economic evaluations

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cos

ts =

not

incl

uded

Reso

urce

use

=ep

idem

iolo

gica

l risk

stud

y;23

7Ex

pert

opi

nion

.

(US

dolla

rs, 1

987)

3 m

onth

sC

ost

of t

hera

py p

er p

atie

nt(3

mon

ths)

at

diffe

rent

pric

es o

fm

isopr

osto

l:

Miso

pros

tol p

rice

$1.7

0/da

y:M

isopr

osto

l pro

phyl

axis

=$2

98.9

1N

o pr

ophy

laxi

s =

$30

1.65

(cos

t sa

ving

= $

2.74

)

Miso

pros

tol p

rice

$1.9

3/da

y:M

isopr

osto

l pro

phyl

axis

=$3

15.6

3N

o pr

ophy

laxi

s =

$30

1.65

Miso

pros

tol p

rice

$2.1

0/da

y:M

isopr

osto

l pro

phyl

axis

=$3

27.5

8N

o pr

ophy

laxi

s =

$30

1.65

The

aut

hors

rep

orte

dm

isopr

osto

l was

cos

t sa

ving

at

any

pric

e be

low

$1.

74/d

ay in

thei

r ba

se-c

ase

3-m

onth

ana

lysis

The

aut

hors

con

clud

eth

at t

he u

se o

fm

isopr

osto

l in

the

trea

tmen

t of

pat

ient

sw

ith o

steo

arth

ritis

ispo

tent

ially

cos

t sa

ving

,de

pend

ing

on t

he p

rice

of m

edic

atio

n, t

he s

ilent

ulce

r ra

te a

nd t

he r

ate

of p

atie

nt c

ompl

ianc

e.In

rel

atio

n to

the

med

icat

ion

pric

e, t

heau

thor

s re

port

tha

tm

isopr

osto

l is

cost

savi

ng a

t an

y pr

ice

belo

w $

2.74

/day co

ntin

ued


361


Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

Car

rin, 1

99015

0

Belg

ium

(hos

pita

l)

To a

naly

se t

he c

ost-

effe

ctiv

enes

s of

miso

pros

tol f

orpr

even

tion

of g

astr

icul

cers

in O

A p

atie

nts

trea

ted

with

NSA

IDs

To c

ompa

re t

heco

sts

of p

roph

ylax

isw

ith m

isopr

osto

lw

ith t

he c

osts

of t

hepr

esen

t st

anda

rdtr

eatm

ent

A d

ecisi

on-a

naly

ticm

odel

was

use

d

SA w

as u

sed

toin

vest

igat

e un

cert

aint

y

Clin

ical

: bas

ic c

linic

al d

ata

wer

e de

rived

from

Gra

ham

et a

l.66D

ata

on in

cide

nce

ofga

stric

ulc

er d

iseas

e w

ere

deriv

ed fr

om a

nep

idem

iolo

gica

l sur

vey

(198

4) b

y th

e In

stitu

te o

fH

ygie

ne a

nd E

pide

mio

logy

of

Belg

ian

Min

istry

of P

ublic

Hea

lth

Econ

omic

: Clo

son,

238

expe

rtop

inio

n an

d a

data

bank

prep

ared

for

this

stud

yco

ntai

ning

dat

a fr

om 4

2,51

0pa

tient

s fr

om t

hree

Bel

gian

Uni

vers

ity H

ospi

tals.

(Bel

gian

fran

cs, J

une

1985

–8)

Soci

etal

In a

uni

vers

ity h

ospi

tal s

cena

rioth

e us

e of

miso

pros

tol w

ould

enta

il ne

t sa

ving

s pe

r pa

tient

of

1999

BEF

In a

gen

eral

hos

pita

l sce

nario

the

use

of m

isopr

osto

l wou

lden

tail

a sa

ving

for

soci

ety

Prev

enta

tive

trea

tmen

tw

ith m

isopr

osto

l ent

ails

net

savi

ngs

for

soci

ety

as a

who

le; h

owev

er,

the

size

of t

he n

etsa

ving

is s

ensit

ive

topa

ram

eter

s su

ch a

s th

epr

esen

ce o

fas

ympt

omat

ic u

lcer

san

d th

e co

st o

fm

isopr

osto

l

cont

inue

d

Appendix 12

362

Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

Edel

son,

199

0151

USA

Hea

lthca

re p

rovi

der

To c

ompa

re t

heco

st-e

ffect

iven

ess

ofpr

imar

y an

dse

cond

ary

prop

hyla

xis

with

miso

pros

tol a

gain

stno

pro

phyl

axis

in t

hepr

even

tion

ofN

SAID

-indu

ced

GI

trac

t bl

eedi

ng

The

tw

o he

alth

tech

nolo

gies

wer

eco

mpa

red

in t

hree

popu

latio

ns o

fN

SAID

use

rs: (

i) th

ege

nera

l pop

ulat

ion

(all

user

s); (

ii) u

sers

aged

60

year

s or

olde

r; (i

ii) u

sers

with

RA

A d

ecisi

on-a

naly

tic(d

ecisi

on-t

ree)

mod

elw

as u

sed

to d

eriv

e th

eco

st-e

ffect

iven

ess

ofth

e tw

o tr

eatm

ent

stra

tegi

es. T

his

was

calc

ulat

ed in

rel

atio

nto

the

cos

t pe

rad

ditio

nal y

ear

of li

fesa

ved,

the

cos

t pe

rad

ditio

nal b

leed

prev

ente

d an

d th

eco

st p

er fa

tal b

leed

prev

ente

d.

One

-way

SA

was

use

dto

tes

t un

cert

aint

y

Clin

ical

: syn

thes

is of

prev

ious

ly p

ublis

hed

stud

ies

Econ

omic

: dire

ct c

osts

=in

clud

ed: s

ourc

e: h

ospi

tal

char

ge d

ata

indi

rect

cos

ts =

not

incl

uded

Reso

urce

use

= h

ospi

tal

billi

ng

(US

dolla

rs, 1

989)

1 ye

arT

he a

vera

ge n

et c

ost

per

100,

000

patie

nts

trea

ted

with

miso

pros

tol p

roph

ylax

isco

mpa

red

with

no

prop

hyla

xis,

by p

opul

atio

n gr

oup:

gen

eral

popu

latio

n (a

ll us

ers)

=$5

3,87

9,00

0; u

sers

age

d ≥

60 y

ears

= $

49,8

14,0

00; u

sers

with

RA

= $

36,9

20,0

00

Incr

emen

tal/n

et c

ost

per

year

of

life

save

d, b

y po

pula

tion

grou

p:G

ener

al p

opul

atio

n (a

ll us

ers)

=$6

67,4

00U

sers

age

d ≥

60 y

ears

=$1

86,7

00U

sers

with

RA

= $

95,6

00

Cos

t-ef

fect

iven

ess

ofm

isopr

osto

l as

a se

cond

ary

prev

entio

n: IC

ERs

of le

ss t

han

$40,

00 p

er li

fe-y

ear

save

d w

ere

repo

rted

in a

ll pa

tient

gro

ups

The

aut

hors

con

clud

eth

at m

isopr

osto

l was

cost

ly a

s a

prim

ary

prev

entio

n fo

r N

SAID

-in

duce

d G

I ble

edin

g,bu

t st

ate

that

miso

pros

tol m

ay b

eco

st-e

ffect

ive

as a

seco

ndar

y pr

even

tion

inpa

tient

s w

ith a

hist

ory

of G

I tra

ct b

leed

ing

cont

inue

d


363


Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

Kni

ll-Jo

nes,

199

015

UK

(NH

S)

To c

ompa

re t

heco

sts

of m

isopr

osto

lpr

ophy

laxi

s ag

ains

tno

miso

pros

tol i

nth

e tr

eatm

ent

ofos

teoa

rthr

itis

rece

ivin

g N

SAID

s

A d

ecisi

on-a

naly

tic(d

ecisi

on-t

ree)

mod

elw

as u

sed

to c

ompa

reth

e co

sts

ofm

isopr

osto

l aga

inst

no

miso

pros

tol i

n pa

tient

sw

ith O

A

One

-way

SA

was

use

dto

tes

t fo

r un

cert

aint

y

Clin

ical

: Epi

dem

iolo

gica

l dat

afr

om E

ngla

nd a

nd S

cotla

nd;

CC

T (G

raha

m e

t al

., 19

88)66

Dire

ct c

osts

= in

clud

ed:

sour

ce =

nat

iona

l uni

t co

sts;

MIM

S

Indi

rect

cos

ts =

not

incl

uded

Reso

urce

use

= S

cott

ishM

orbi

dity

Rec

ords

(SM

R1);

Hea

lth A

ctiv

ity A

naly

sis(H

AA

) (W

est

Mid

land

s);

expe

rt o

pini

on (G

Ps)

(UK

pou

nds

ster

ling,

198

8)

3 m

onth

sT

he a

utho

rs r

epor

t th

at t

he n

etsa

ving

s pe

r pa

tient

to

the

NH

Sov

er t

he e

xpec

ted

3 m

onth

s of

care

wer

e £6

.10

in S

cotla

nd a

nd£8

.40

in E

ngla

nd

In r

elat

ion

to t

he S

A t

he a

utho

rsre

port

tha

t in

crea

sing

the

dose

of m

isopr

osto

l to

800

µg w

ould

resu

lt in

a n

et c

ost

of £

25.0

inSc

otla

nd a

nd £

22.7

0 in

Eng

land

The

oth

er v

aria

bles

tes

ted

show

ed t

hat

unde

r m

any

assu

mpt

ions

, miso

pros

tol

prop

hyla

xis

gene

rate

s a

net

savi

ng t

o th

e N

HS

or a

sm

all n

etco

st

The

aut

hors

con

clud

eth

at u

sing

cons

erva

tive

assu

mpt

ions

and

a d

aily

dose

of 4

00µg

of

miso

pros

tol r

esul

ts in

cost

sav

ings

per

pat

ient

to t

he N

HS

of £

5–8

over

a 3

-mon

th p

erio

d.T

he a

utho

rs a

lso r

epor

tth

at a

dai

ly d

ose

of80

0µg

miso

pros

tol

prop

hyla

xis

resu

lts in

ane

t co

st o

f £23

–25

per

patie

nt t

o th

e N

HS

cont

inue

d

Appendix 12

364

Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

Jons

son,

199

2152

Swed

en

(soc

ieta

l)

To c

ompa

re t

heco

st-e

ffect

iven

ess

ofpr

ophy

laxi

s w

ithm

isopr

osto

l aga

inst

no p

roph

ylax

is in

the

trea

tmen

t of

pat

ient

sw

ith o

steo

arth

ritis

and

NSA

ID-

asso

ciat

ed a

bdom

inal

pain

A d

ecisi

on-a

naly

tic(d

ecisi

on-t

ree)

mod

elw

as u

sed

to d

eriv

e th

eco

st-e

ffect

iven

ess

ofth

e tw

o tr

eatm

ent

stra

tegi

es. T

his

was

calc

ulat

ed in

ter

ms

ofth

e co

st p

er e

piso

deof

gas

tric

ulc

er d

iseas

eav

oide

d

One

-way

SA

was

use

dto

tes

t fo

r un

cert

aint

y

Clin

ical

: syn

thes

is of

prev

ious

ly p

ublis

hed

stud

ies.

Dire

ct c

osts

= in

clud

ed:

sour

ce =

Sw

edish

hos

pita

ls(s

econ

dary

) and

prim

ary

care

Indi

rect

cos

ts =

incl

uded

:so

urce

= s

ick

leav

e/da

ysba

sed

on a

vera

gein

com

e st

atist

ics

in S

wed

en

Reso

urce

use

= S

wed

ishho

spita

ls, a

nd M

edic

al In

dex

Swed

en

(Sw

edish

kro

ner,

1988

)

3 m

onth

sBa

se c

ase

anal

ysis

Cos

t pe

r pa

tient

(ind

irect

cos

tsno

t in

clud

ed):

Prop

hyla

xis

with

miso

pros

tol =

969

SEK

No

prop

hyla

xis

= 1

090

SEK

(D

iffer

ence

= 1

21 S

EK)

Cos

t pe

r pa

tient

(ind

irect

cos

tsin

clud

ed):

Prop

hyla

xis

with

miso

pros

tol =

1016

SEK

No

prop

hyla

xis

= 1

202

SEK

(Diff

eren

ce =

186

SEK

)

The

aut

hors

rep

orte

d th

e co

st-

effe

ctiv

enes

s of

pro

phyl

axis

with

miso

pros

tol a

t di

ffere

nt r

iskle

vels

of u

lcer

dise

ase

(35–

5%)

and

diffe

rent

effe

ctiv

enes

sas

sum

ptio

ns (1

00–5

0%).

The

max

imum

cos

t pe

r ep

isode

of

gast

ric u

lcer

avo

ided

with

in t

his

anal

ysis

= 3

8,00

0 SE

K(p

roba

bilit

y of

ulc

er =

5%

,ef

fect

iven

ess

= 1

00%

)

The

aut

hors

con

clud

eth

at in

pat

ient

s w

ithos

teoa

rthr

itis

and

NSA

ID-a

ssoc

iate

dab

dom

inal

pai

n,pr

ophy

laxi

s w

ithm

isopr

osto

l is

cost

-ef

fect

ive

in S

wed

en

cont

inue

d


365


Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

Kni

ll-Jo

nes,

199

2153

UK

(NH

S)

To c

ompa

re t

heia

trog

enic

cos

tfa

ctor

s of

10

NSA

IDs

in t

he U

K N

HS

agai

nst

thos

e of

the

Fren

ch n

atio

nal

heal

th in

sura

nce

syst

em (A

ssur

ance

Mal

adie

)

The

ten

NSA

IDs

wer

e di

clof

enac

,na

prox

en, s

ulin

dac,

ibup

rofe

n,in

dom

etha

cin,

piro

xica

m,

flurb

ipro

fen,

etod

olac

, ket

opro

fen

and

dicl

ofen

ac/

miso

pros

tol

The

aut

hor

repo

rts

that

the

iatr

ogen

icco

st fa

ctor

of N

SAID

sfo

r th

e U

K N

HS

wer

eca

lcul

ated

usin

g th

em

odel

of D

ePo

uvou

rvill

e an

dBa

der23

9

Clin

ical

: syn

thes

is of

prev

ious

ly p

ublis

hed

stud

ies

Dire

ct c

osts

= in

clud

ed:

sour

ce =

mon

thly

Inde

x of

Med

ical

Spe

cial

ities

(MIM

S),

Aug

ust

1991

Indi

rect

cos

ts =

not

incl

uded

Reso

urce

use

: not

rep

orte

d

(UK

pou

nds,

ste

rling

)

6 m

onth

sIa

trog

enic

cos

t fa

ctor

ran

ge b

yN

SAID

: D

iclo

fena

c =

1.4

2–1.

47N

apro

xen

= 1

.40–

1.44

Sulin

dac

= 1

.57–

1.63

Ibup

rofe

n =

2.3

8–2.

53In

dom

etha

cin

= 1

.80–

1.88

Piro

xica

m =

184

–1.9

3Fl

urbi

prof

en =

1.9

0–2.

00Et

odol

ac =

1.8

4–1.

93Ke

topr

ofen

= 1

.71–

1.79

Dic

lofe

nac/

miso

pros

tol =

1.08

–1.0

9

(Iatr

ogen

ic c

ost

fact

or =

rat

io o

fth

e sh

adow

pric

e to

the

NH

Spr

ice)

The

aut

hors

con

clud

eth

at N

HS

iatr

ogen

icco

st fa

ctor

s of

the

10

NSA

IDs

wer

e sim

ilar

toth

ose

calc

ulat

ed b

y D

ePo

uvou

rvill

e an

d Ba

der

for

the

Fren

chA

ssur

ance

Mal

adie

, and

rang

ed fr

om 1

.08

for

dicl

ofen

ac/m

isopr

osto

lto

2.3

8 fo

r ib

upro

fen

cont

inue

d

Appendix 12

366

Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

Gab

riel,

1993

154

Can

ada

(hos

pita

l)

To a

sses

s th

e co

st-

effe

ctiv

enes

s of

miso

pros

tol

prop

hyla

xis

in t

hepr

even

tion

ofN

SAID

-ass

ocia

ted

GI

adve

rse

even

ts in

OA

pat

ient

s in

thr

eedi

ffere

nt p

opul

atio

ns:

(i) p

roph

ylax

is fo

r al

lpa

tient

s ta

king

NSA

IDs;

(ii

) pro

phyl

axis

for

no p

atie

nts

taki

ngN

SAID

s;

(iii)

prop

hyla

xis

for

elde

rly p

erso

ns (a

ge≥

60ye

ars)

tak

ing

NSA

IDs

A d

ecisi

on-a

naly

tic(d

ecisi

on-t

ree)

mod

elw

as u

sed

to d

eriv

e th

eco

st-e

ffect

iven

ess

ofm

isopr

osto

lpr

ophy

laxi

s in

the

thre

e di

ffere

ntpo

pula

tions

. Thi

s w

asca

lcul

ated

inte

rms

of t

he c

ost

per

GI e

vent

ave

rted

One

- an

d tw

o-w

ay S

Aw

as u

sed

to t

est

for

unce

rtai

nty

Clin

ical

: syn

thes

is of

prev

ious

ly p

ublis

hed

stud

ies

Dire

ct c

osts

: inc

lude

dso

urce

: med

ical

war

d at

Wel

lesle

y H

ospi

tal,

Ont

ario

Indi

rect

cos

ts =

not

incl

uded

Reso

urce

use

= W

elle

sley

Hos

pita

l, O

ntar

io: m

edic

alre

cord

s of

pat

ient

s

(Can

adia

n do

llars

, 199

0)

3 m

onth

sBa

selin

e co

sts:

Hyp

othe

tical

coho

rt o

f 100

pat

ient

s:N

o pr

ophy

laxi

s =

$25

,662

Elde

rly p

roph

ylax

is =

$28

,971

All

user

s pr

ophy

laxi

s =

$32

,396

Cos

t pe

r G

I eve

nt a

vert

ed:

No

prop

hyla

xis

= $

297.

9El

derly

pro

phyl

axis

= $

317.

7 A

ll us

ers

prop

hyla

xis

= $

338.

0

The

aut

hors

con

clud

eth

at t

heir

resu

lts s

how

miso

pros

tol p

roph

ylax

isto

be

high

ly c

ost-

effe

ctiv

e in

the

Can

adia

n he

alth

care

sett

ing

cont

inue

d

Peac

ock,

199

3155

UK

(NH

S)

To c

ompa

re t

he t

otal

cost

of t

reat

ing

ahy

poth

etic

al c

ohor

tof

100

0 pa

tient

s w

itha

mon

th’s

sup

ply

ofon

e of

the

follo

win

gth

ree

inte

rven

tions

:(i)

an

oral

NSA

ID;

(ii) T

raxa

m (t

opic

alN

SAID

); (ii

i) A

rthr

otec

(dic

lofe

nac/

miso

pros

tol)

A d

ecisi

on-a

naly

tic(d

ecisi

on-t

ree)

mod

elw

as u

sed

to c

alcu

late

the

drug

cos

t, th

esh

adow

cos

t an

d to

tal

cost

of t

reat

ing

ahy

poth

etic

al c

ohor

t of

1000

pat

ient

s w

ith t

heth

ree

diffe

rent

inte

rven

tions

One

-way

SA

was

use

dto

tes

t fo

r un

cert

aint

y

Clin

ical

: syn

thes

is of

prev

ious

ly c

ompl

eted

stu

dies

Dire

ct c

osts

= in

clud

ed:

sour

ce =

Dru

g Ta

riff

(Oct

ober

199

3); M

IMS

(Sep

tem

ber

1993

)

Indi

rect

cos

ts =

not

incl

uded

Reso

urce

use

= h

ospi

tal a

ndam

bula

tory

(UK

pou

nds

ster

ling,

199

3)

1 ye

arTo

tal c

ost

of t

reat

ing

1000

patie

nts

for

1 m

onth

:A

n or

al N

SAID

=£3

9,67

8–58

,858

Trax

am =

£7,

139

Art

hrot

ec =

£17

,924

(Alth

ough

the

aut

hors

rep

ort

that

the

stu

dy w

as a

cos

t-ef

fect

iven

ess

anal

ysis,

no

sum

mar

y m

easu

re o

f hea

lthbe

nefit

was

rep

orte

d an

d no

synt

hesis

of c

osts

and

ben

efits

was

und

erta

ken.

The

stu

dysh

ould

the

refo

re b

e cl

assif

ied

asa

cost

–con

sequ

ence

s an

alys

is)

The

aut

hors

con

clud

eth

at p

resc

riptio

n of

the

topi

cal N

SAID

, in

plac

eof

an

oral

pre

para

tion,

wou

ld r

esul

t in

cos

tsa

ving

s to

bot

h G

P an

dho

spita

l bud

gets

,be

caus

e of

the

red

uced

cost

of t

reat

ing

side-

effe

cts


367


Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

Gab

riel,

1994

156

USA

Hea

lthca

re p

rovi

der

To c

ompa

re t

heco

st-

effe

ctiv

enes

s/ut

ility

of s

trat

egie

s fo

r th

etr

eatm

ent

of p

atie

nts

with

OA

The

thr

ee t

reat

men

tst

rate

gies

wer

e (i)

pro

phyl

axis

for

all

NSA

ID u

sers

, (ii

) pro

phyl

axis

for

elde

rly N

SAID

use

rsan

d (ii

i) no

prop

hyla

xis

for

NSA

ID u

sers

A d

ecisi

on-a

naly

tic(d

ecisi

on-t

ree)

mod

elw

as u

sed

to d

eriv

e th

eco

st–u

tility

of t

hetr

eatm

ent

optio

ns.

Thi

s w

as c

alcu

late

d in

term

s of

the

cos

t pe

rQ

ALY

sav

ed

One

-way

, tw

o-w

ayan

d pr

obab

ilist

ic S

Aw

as u

nder

take

n to

test

for

unce

rtai

nty

Clin

ical

: syn

thes

is of

prev

ious

ly p

ublis

hed

stud

ies

Dire

ct c

osts

= in

clud

ed:

sour

ce =

Hea

lthca

re =

Loca

l dat

a, M

inne

sota

Miso

pros

tol =

ave

rage

who

lesa

le p

rice

Indi

rect

cos

ts =

not

incl

uded

Reso

urce

use

= m

edic

alre

cord

s of

pat

ient

s

(US

dolla

rs, 1

992)

3 m

onth

sA

vera

ge c

ost

of t

reat

men

t:(I)

Bas

e ca

se:

No

prop

hyla

xis

for

NSA

ID u

sers

= $

142

Prop

hyla

xis

for

elde

rly N

SAID

user

s =

$17

0Pr

ophy

laxi

s fo

r al

lN

SAID

use

rs =

$20

2(ii

) Wor

st c

ase:

No

prop

hyla

xis

for

NSA

ID u

sers

= $

142

Prop

hyla

xis

for

elde

rly N

SAID

user

s =

$17

0Pr

ophy

laxi

s fo

r al

l NSA

ID u

sers

= $

202

(iii)

Best

cas

e:N

o pr

ophy

laxi

s fo

r N

SAID

use

rs=

$14

2 Pr

ophy

laxi

s fo

r el

derly

NSA

IDus

ers

= $

170

Prop

hyla

xis

for

all

NSA

ID u

sers

= $

202

Incr

emen

tal c

ost–

utili

ty r

atio

:Be

st c

ase:

Prop

hyla

xis

for

all N

SAID

use

rsvs

pro

phyl

axis

for

the

elde

rly =

$10,

666

per

QA

LY s

aved

The

aut

hors

con

clud

eth

at t

heir

resu

lts s

how

that

miso

pros

tol

prop

hyla

xis

resu

lts in

mod

est

addi

tiona

l cos

ts,

but

prov

ides

no

addi

tiona

l QoL

. The

auth

ors

stat

e th

at e

ven

for

thos

e pa

tient

sde

mon

stra

ting

am

arke

d po

sitiv

e ut

ility

for

prop

hyla

xis,

the

incr

emen

tal c

ost

per

QA

LY g

aine

d w

asre

lativ

ely

high

and

high

ly s

ensit

ive

toch

ange

s in

pre

fere

nce

scor

es

cont

inue

d

Appendix 12

368

Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

Al,

1996

157

The

Net

herla

nds

(soc

ieta

l)

To c

ompa

re t

heco

st-e

ffect

iven

ess

ofa

fixed

dos

eco

mbi

natio

n (F

DC

)of

dic

lofe

nac

and

miso

pros

tol w

ithdi

clof

enac

mon

othe

rapy

in t

hepr

even

tion

ofN

SAID

-indu

ced

ulce

rs in

pat

ient

sw

ith R

A

A d

ecisi

on-a

naly

ticm

odel

was

use

d to

deriv

e th

e co

st-

effe

ctiv

enes

s of

the

two

trea

tmen

tst

rate

gies

. Thi

s w

asca

lcul

ated

as

the

cost

per

sym

ptom

atic

ulce

r-fr

ee p

erio

dga

ined

Uni

varia

te a

ndm

ultiv

aria

te S

A w

asun

dert

aken

to

test

for

unce

rtai

nty

Clin

ical

: syn

thes

is of

prev

ious

ly p

ublis

hed

stud

ies

Dire

ct c

osts

= h

ospi

tal c

osts

and

tarif

fs

Indi

rect

cos

ts =

not

incl

uded

Reso

urce

use

= e

xper

top

inio

n, p

revi

ously

pub

lishe

dlit

erat

ure

and

2 ge

nera

lho

spita

ls in

The

Net

herla

nds.

(Dut

ch g

uild

ers,

199

5)

3 m

onth

sBa

selin

e re

sults

– t

otal

cos

ts fo

r10

0 pa

tient

s re

ceiv

ing

3m

onth

s’tr

eatm

ent:

dicl

ofen

ac m

onot

hera

py =

N

LG 1

9,82

5FD

C d

iclo

fena

c–m

isopr

osto

l =N

LG 2

0,59

8(In

crem

enta

l cos

t of

FD

Cdi

clof

enac

–miso

pros

tol =

N

LG 7

73)

Incr

emen

tal c

ost

per

sym

ptom

atic

ulc

er-f

ree

perio

dga

ined

usin

g FD

Cdi

clof

enac

–miso

pros

tol

com

pare

d w

ith d

iclo

fena

cm

onot

hera

py =

NLG

949

Incr

emen

tal c

ost

per

addi

tiona

lsu

rviv

or u

sing

FDC

dicl

ofen

ac–m

isopr

osto

lco

mpa

red

with

dic

lofe

nac

mon

othe

rapy

= N

LG 4

1,79

0

The

aut

hors

con

clud

eth

at t

reat

men

t w

ithdi

clof

enac

–miso

pros

tol

is co

st s

avin

g in

RA

patie

nts

at h

igh

risk

ofN

SAID

-indu

ced

ulce

rs,

and

that

for

RA p

atie

nts

in g

ener

al t

his

inte

rven

tion

com

pare

sfa

vour

ably

with

oth

erpr

ophy

lact

ic t

reat

men

tsin

ter

ms

of c

ost-

effe

ctiv

enes

s

cont

inue

d


369


Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

Mae

tzel

, 199

811

Can

ada

(pro

vinc

ial h

ealth

car

epl

an)

To r

e-ex

amin

e th

eco

st-e

ffect

iven

ess

ofm

isopr

osto

l usin

gda

ta fo

rm a

rec

ently

publ

ished

pla

cebo

-co

ntro

lled

tria

l in

patie

nts

with

rheu

mat

oid

arth

ritis

taki

ng N

SAID

s(M

UC

OSA

stu

dy)87

The

tre

atm

ent

regi

men

s w

ere

(1) N

SAID

and

plac

ebo

and

(2) N

SAID

and

miso

pros

tol (

up t

o80

0µg

dai

ly)

A d

ecisi

on t

ree

was

used

to

mod

el t

hecl

inic

al a

nd m

ajor

reso

urce

use

eve

nts

inth

e tw

o ar

ms

of t

hest

udy

App

roxi

mat

e C

Is fo

rth

e co

st-e

ffect

iven

ess

estim

ates

wer

eca

lcul

ated

usin

g M

onte

Car

lo s

imul

atio

ns

The

stu

dy p

opul

atio

npa

tient

s w

as a

hypo

thet

ical

coh

ort

ofpa

tient

s w

ithrh

eum

atoi

d ar

thrit

isov

er t

he a

ge o

f52

year

s an

d ta

king

NSA

ID fo

r m

ore

than

6m

onth

s

The

mod

el a

llow

edfo

r se

para

te a

naly

ses

to b

e pe

rfor

med

for

patie

nts

with

diff

eren

tle

vels

of b

asel

ine

risk

Clin

ical

: syn

thes

is of

prev

ious

ly p

ublis

hed

stud

ies

Dire

ct c

osts

= d

rugs

cos

ts,

use

of G

I-rel

ated

pro

cedu

res

incl

udin

g nu

mbe

r of

hosp

italis

atio

ns; n

umbe

r of

endo

scop

ies/

UG

Ira

diog

raph

ic s

erie

s; n

umbe

rof

sur

gica

l pro

cedu

res

Sour

ce: O

ntar

io C

ase

Cos

tPr

ojec

t (O

CC

P) d

atab

ase

Indi

rect

cos

ts =

not

incl

uded

Reso

urce

use

= c

olle

cted

from

pat

ient

s’ c

hart

s an

dst

udy

mon

itor

logs

.

(Can

adia

n do

llars

, 199

4)

6 m

onth

sT

he u

nit

cost

s w

ere:

miso

pros

tol =

Can

$0.5

1 pe

rta

blet

; gas

tric

ulc

er w

ithha

emor

rhag

e an

d pe

rfor

atio

n =

Can

$651

4; d

uode

nal u

lcer

with

haem

orrh

age

and

perf

orat

ion

=C

an$9

578;

gas

tric

ulc

er w

ithha

emor

rhag

e bu

t no

per

fora

tion

= C

an$3

580;

gas

tric

ulc

erw

ithou

t ha

emor

rhag

e =

Can

$280

7; d

uode

nal u

lcer

with

out

haem

orrh

age

=C

an$2

573

In t

he b

asel

ine

anal

ysis,

the

cos

tof

ave

rtin

g on

e se

rious

GI

com

plic

atio

n by

pre

scrib

ing

miso

pros

tol w

as e

stim

ated

to

beC

an$9

4,76

6 (9

5% C

I: 60

,286

to

137,

146)

In p

atie

nts

with

a m

ediu

m r

isk(p

revi

ous

pept

ic u

lcer

dise

ase)

,th

e co

st o

f ave

rtin

g on

e se

rious

GI c

ompl

icat

ion

by p

resc

ribin

gm

isopr

osto

l was

est

imat

ed t

o be

Can

$14,

943

(95%

CI:

10,9

12 t

o33

2,15

7)

In p

atie

nts

with

a h

igh

risk

(pre

viou

s pe

ptic

ulc

er d

iseas

ean

d ov

er 7

5 ye

ars

old)

, the

cos

tof

ave

rtin

g on

e se

rious

GI

com

plic

atio

n by

pre

scrib

ing

miso

pros

tol w

as e

stim

ated

to

beC

an$4

101

(95%

CI:

–220

to

18,1

46)

The

aut

hors

con

clud

edth

at p

resc

ribin

gm

isopr

osto

l for

all

patie

nts

with

RA

at

leas

t 52

yea

rs o

f age

cost

s $9

5,76

6 fo

r ea

chad

ditio

nal G

I eve

ntav

erte

d. W

hen

patie

nts

are

at a

hig

her

risk

the

cost

per

GI e

vent

aver

ted

is m

arke

dly

redu

ced.

The

aut

hors

sugg

est

that

the

sere

sults

pro

vide

a b

ette

res

timat

e of

the

tru

eco

st-e

ffect

iven

ess

ofm

isopr

osto

l bas

ed o

nen

dosc

opic

dat

a an

dm

odel

ling

of r

esou

rce

use

cont

inue

d

Appendix 12

370

Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

Kris

tians

en, 1

99912

Nor

way

(soc

ieta

l)

To c

ompa

re t

heco

st-e

ffect

iven

ess

ofa

fixed

com

bina

tion

of d

iclo

fena

c an

dm

isopr

osto

l aga

inst

dicl

ofen

ac in

the

trea

tmen

t of

pat

ient

sw

ith R

A

A d

eter

min

istic

deci

sion-

anal

ytic

(dec

ision

-tre

e) m

odel

was

use

d to

der

ive

the

cost

-effe

ctiv

enes

s of

the

trea

tmen

t op

tions

.T

his

was

cal

cula

ted

inte

rms

of t

he c

ost

per

LYG

and

cos

t pe

rQ

ALY

gai

n

Clin

ical

: syn

thes

is of

prev

ious

ly p

ublis

hed

clin

ical

stud

ies.

Dire

ct c

osts

= in

clud

ed:

sour

ce =

inpa

tient

car

e =

diag

nosis

-rel

ated

gro

upch

arge

s (D

RG)

Dru

gs =

mar

ket

pric

es

Indi

rect

cos

ts =

not

incl

uded

(alth

ough

the

aut

hors

rep

ort

that

the

stu

dy w

asun

dert

aken

from

a s

ocie

tal

pers

pect

ive)

Reso

urce

use

=no

t re

port

ed

(US

dolla

rs, 1

996)

6 m

onth

sA

vera

ge c

ost

per

patie

nt fo

rfe

mal

es w

ith a

risk

of

com

plic

atio

ns s

imila

r to

tha

t in

the

MU

CO

SA s

tudy

(som

epa

tient

s ha

ving

risk

fact

ors,

som

e no

t):

Dic

lofe

nac–

miso

pros

tol

com

bina

tion

= $

327

Dic

lofe

nac

= $

298

The

aut

hors

rep

orte

d th

ein

crem

enta

l cos

t pe

r LY

G a

ndth

e co

st p

er Q

ALY

gai

ned

ofre

plac

ing

dicl

ofen

ac w

ith a

dicl

ofen

ac–m

isopr

osto

lco

mbi

natio

n ac

ross

a r

ange

of

risk

fact

ors

for

RA:

RA –

no

risk

fact

ors:

cost

per

QA

LY, m

ales

=$9

5,90

0, fe

mal

es =

$72

,700

RA +

hist

ory

of G

I ble

edin

g,m

ales

= $

4900

, fem

ales

=$4

100

RA +

2 r

isk fa

ctor

s, m

ales

=co

st s

avin

g, fe

mal

es =

cos

tsa

ving

The

aut

hors

con

clud

eth

at r

epla

cing

dic

lofe

nac

with

fixe

ddi

clof

enac

–miso

pros

tol

in t

he t

reat

men

t of

patie

nts

with

RA

isco

st-e

ffect

ive

whe

nre

stric

ted

to R

Apa

tient

s at

incr

ease

dris

k of

ser

ious

GI e

vent

s

cont

inue

d


371


Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

Dav

ey, 2

00015

8

Aus

tral

ia(h

ealth

care

sys

tem

pers

pect

ive)

To c

ompa

re t

heco

st-e

ffect

iven

ess

ofm

isopr

osto

l for

NSA

ID-in

duce

d G

Ida

mag

e ag

ains

t no

miso

pros

tol

(pla

cebo

)

The

tw

o tr

eatm

ent

optio

ns w

ere

com

pare

d in

thr

eepo

pula

tions

: (i)

the

popu

latio

n in

the

MU

CO

SA t

rial (

8843

patie

nts)

;88

(ii) p

atie

nts

with

ahi

stor

y of

pep

ticul

cer

dise

ase;

(ii

i) pa

tient

s>

65ye

ars

of a

ge

A d

ecisi

on-a

naly

ticm

odel

was

use

d to

deriv

e th

e co

st-

effe

ctiv

enes

s of

the

two

trea

tmen

top

tions

. Thi

s w

asca

lcul

ated

in t

erm

s of

the

cost

per

life

-yea

rsa

ved

and

the

cost

per

defin

ite s

erio

us G

Iev

ent

aver

ted

One

-way

SA

was

use

dto

tes

t fo

r un

cert

aint

y

Clin

ical

: MU

CO

SA t

rial a

ndsy

nthe

sis o

f pre

viou

slypu

blish

ed s

tudi

es

Dire

ct c

osts

= in

clud

ed:

sour

ce =

miso

pros

tol =

pric

e fo

r a

90-t

able

t pa

cket

;in

patie

nt a

nd o

utpa

tient

=ch

arge

dat

a (h

ospi

tal,

GP)

Indi

rect

cos

ts =

not

incl

uded

Reso

urce

use

= e

xper

top

inio

n

(Aus

tral

ian

dolla

rs, 1

996/

97)

1 ye

arC

ost-

effe

ctiv

enes

s:

(i) C

ost

per

life-

year

sav

ed:

Tota

l tria

l pop

ulat

ion

(MU

CO

SA):

miso

pros

tol =

$181

(117

), no

miso

pros

tol =

$33

(22)

,Pa

tient

s w

ith a

hist

ory

of p

eptic

ulce

r: m

isopr

osto

l = $

192

(125

), no

miso

pros

tol =

$90

(58)

Patie

nts

>65

year

s of

age

:m

isopr

osto

l = $

186

(121

), no

miso

pros

tol =

$40

(26)

,in

crem

enta

l cos

t =

$40

,322

(26,

208)

(ii) C

ost

per

defin

ite s

erio

us G

Iev

ent

aver

ted:

Tota

l tria

l pop

ulat

ion

(MU

CO

SA):

miso

pros

tol =

$181

(117

), no

miso

pros

tol =

$33

(22)

Patie

nts

with

a h

istor

y of

pep

ticul

cer:

miso

pros

tol =

$19

2(1

25),

no m

isopr

osto

l = $

90(5

8)Pa

tient

s >

65 y

ears

of a

ge:

miso

pros

tol =

$18

6 (1

21),

no m

isopr

osto

l = $

40 (2

6)

The

aut

hors

con

clud

eth

at m

isopr

osto

lre

pres

ents

a c

ost-

effe

ctiv

e tr

eatm

ent

optio

n in

the

ir se

ttin

g

cont

inue

d

Appendix 12

372

Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

Rahm

e, 2

00115

9

Can

ada

(Pro

vinc

ial

Gov

ernm

ent

ofQ

uebe

c, C

anad

a)

To c

ompa

re t

he G

Ihe

alth

care

res

ourc

eus

e (H

CRU

) and

asso

ciat

ed c

osts

for

inpa

tient

s ta

king

afix

ed c

ombi

natio

n of

dicl

ofen

ac a

ndm

isopr

osto

l aga

inst

othe

r N

SAID

s

The

stu

dy p

opul

atio

nco

mpr

ised

a co

hort

of 1

2,08

7 pa

tient

sag

ed 6

6ye

ars

and

over

sel

ecte

d fr

omth

e G

over

nmen

t of

Que

bec

and

Hea

lthIn

sura

nce

Age

ncy

Dat

abas

e

The

aut

hors

use

d a

3-st

age

mod

el t

ode

term

ine

the

fact

ors

that

influ

ence

d th

edi

rect

med

ical

cos

ts o

fG

I HC

RU: (

i) a

logi

stic

regr

essio

n m

odel

to

estim

ate

the

risk

of G

IH

CRU

; (ii)

a li

near

regr

essio

n m

odel

to

estim

ate

the

dire

ctco

sts

of G

I HC

RU fo

rth

ose

who

had

suc

hev

ents

; (iii

)m

ultip

licat

ion

of t

hees

timat

ed r

isks

from

mod

el 1

by

the

cost

sfr

om m

odel

2 t

o gi

veth

e es

timat

ed d

irect

cost

s of

GI H

CRU

for

all p

atie

nts

Clin

ical

: coh

ort

stud

y fr

omRA

MQ

dat

a

Dire

ct c

osts

= in

clud

ed:

sour

ce =

rei

mbu

rsem

ent

cost

s fr

om R

AM

Q;

Can

adia

n In

stitu

te fo

r H

ealth

Info

rmat

ion

Indi

rect

cos

ts =

not

incl

uded

Reso

urce

use

= c

ohor

t st

udy

(Can

adia

n do

llars

, 199

7)

2 ye

ars

Ave

rage

dire

ct m

edic

al c

osts

of

the

GI H

CRU

per

pat

ient

dur

ing

the

2-ye

ar fo

llow

-up:

Dic

lofe

nac–

miso

pros

tol G

roup

= $

310.

52N

SAID

gro

up =

$23

1.19

The

aut

hors

con

clud

eth

at t

heir

resu

ltssh

owed

no

signi

fican

tdi

ffere

nces

in G

I HC

RUin

pat

ient

s ta

king

dicl

ofen

ac–m

isopr

osto

lco

mpa

red

with

tho

seta

king

NSA

IDs

AC

CES

, art

hriti

s co

st c

onse

quen

ce e

valu

atio

n sy

stem

; b.d

., tw

ice

daily

; BEF

, Bel

gian

fran

cs; B

NF,

Briti

sh N

atio

nal F

orm

ular

y; C

EAC

, cos

t-ef

fect

iven

ess

acce

ptab

ility

cur

ve;

DRG

, dia

gnos

is-re

late

d gr

oups

; EC

R, e

xtra

-con

trac

tual

ref

erra

ls; €

, eur

os; F

DC

, fix

ed d

ose

com

bina

tion;

GI,

gast

roin

test

inal

; HA

A, h

ealth

act

ivity

ana

lysis

; Hb,

hae

mog

lobi

n;

HC

RU, h

ealth

care

res

ourc

e us

e; H

K$,

Hon

g Ko

ng d

olla

rs; I

CF,

iatr

ogen

ic c

ost

fact

or; M

EMO

: Med

icin

es M

onito

ring

Uni

t; M

IMS,

Mon

thly

Inde

x of

Med

ical

Spe

cial

ities

; MPC

I,m

inim

um p

erce

ptib

le c

linic

al im

prov

emen

t; M

UC

OSA

, Miso

pros

tol U

lcer

Com

plic

atio

ns O

utco

me

Safe

ty A

sses

smen

t; N

LG, D

utch

gui

lder

s; N

OK

, Nor

weg

ian

kron

e;

NSA

ID, n

on-s

tero

idal

ant

i-inf

lam

mat

ory

drug

; OA

, ost

eoar

thrit

is; O

CC

P, O

ntar

io C

ase

Cos

t Pr

ojec

t; PU

B, p

eptic

ulc

er b

leed

; QA

LY, q

ualit

y-ad

just

ed li

fe-y

ear;

RA

, rhe

umat

oid

arth

ritis;

RA

MQ

, Rég

ie d

’Ass

uran

ce M

alad

ie d

u Q

uébe

c; S

EK: S

wed

ish k

rone

r; S

MR,

Sco

ttish

mor

bidi

ty r

ecor

ds; S

wF,

Swiss

fran

cs; t

.d.s

., th

ree

times

dai

ly.


373


(b)

Econ

omic

eva

luat

ions

of C

ox-1

NSA

IDS

vers

us C

ox-2

Cox

ibs

or C

ox-2

pre

fere

ntia

ls

Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

Jans

en, 1

99616

0

UK

(UK

NH

S)

To c

ompa

re t

heec

onom

ic im

pact

of

mel

oxic

am 7

.5m

gag

ains

t di

clof

enac

100

mg

reta

rd in

the

trea

tmen

t of

pat

ient

sw

ith O

A in

the

UK

A d

ecisi

on-a

naly

tic(d

ecisi

on-t

ree)

mod

elw

as u

sed

to c

ompa

reth

e ex

pect

ed c

ost

ofm

elox

icam

7.5

mg

agai

nst

dicl

ofen

ac10

0m

g re

tard

in O

Apa

tient

s

One

-way

SA

was

use

dto

tes

t fo

r un

cert

aint

y

Clin

ical

: dou

ble-

blin

dra

ndom

ised

clin

ical

tria

ls.

Dire

ct c

osts

= in

clud

ed:

sour

ce =

BN

F, Be

nefit

Cos

ting

data

base

, Med

icin

esM

onito

ring

Uni

t da

taba

se(M

EMO

) dat

abas

e

Indi

rect

cos

ts =

not

incl

uded

Reso

urce

use

= T

ayes

ide

MEM

O d

atab

ase,

exp

ert

opin

ion

(UK

pou

nds

ster

ling,

199

5)

30 d

ays

Cos

t pe

r pa

tient

(dire

ct m

edic

alco

sts)

:M

elox

icam

7.5

mg

= £

28.1

8D

iclo

fena

c 10

0 m

g re

tard

=£3

7.14

Cos

t sa

ving

of m

elox

icam

7.5

mg

com

pare

d w

ithdi

clof

enac

100

mg

reta

rd =

£8.9

6 pe

r pa

tient

The

aut

hors

con

clud

eth

at t

he c

ost

anal

yses

show

ed a

sav

ing

of£8

.96

per

patie

nt(£

28.1

8 vs

£37

.14)

infa

vour

of m

elox

icam

for

a 30

-day

tre

atm

ent

perio

d of

OA

whe

nco

mpa

red

with

dicl

ofen

ac r

etar

d cont

inue

d

Appendix 12

374

Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

Jans

en, 1

99716

1

Fran

ce, I

taly

and

the

UK

.(F

ranc

e =

Fre

nch

Stat

utor

y H

ealth

Insu

ranc

e;Ita

ly =

Ital

ian

NH

S;U

K =

UK

NH

S)

To c

ompa

re t

heec

onom

ic im

pact

of

mel

oxic

am (7

.5 m

g)ag

ains

t su

stai

ned-

rele

ase

dicl

ofen

ac(1

00 m

g) in

the

trea

tmen

t of

pat

ient

sw

ith O

A in

Fra

nce,

Italy

and

the

UK

A d

ecisi

on-a

naly

tic(d

ecisi

on-t

ree)

mod

elw

as u

sed

to c

ompa

reth

e co

sts

ofm

elox

icam

aga

inst

sust

aine

d-re

leas

edi

clof

enac

in F

ranc

e,Ita

ly a

nd t

he U

K

One

-way

SA

was

use

dto

tes

t fo

r un

cert

aint

y

Clin

ical

: dou

ble-

blin

d RC

Ts

Dire

ct c

osts

= in

clud

ed:

sour

ce =

Fra

nce

= O

ffici

alFr

ench

Tar

iffs

Italy

= It

alia

n D

RGs,

Nat

iona

l Tar

iffs,

Ital

ian

Nat

iona

l For

mul

ator

yU

K =

City

Uni

vers

ity c

ost

data

base

, ben

efit

cost

ing

data

base

, BN

F.

Indi

rect

cos

ts =

not

incl

uded

Reso

urce

use

: exp

ert

opin

ion

(Fre

nch

fran

cs, I

talia

n lir

a,U

K p

ound

s st

erlin

g,

US

dolla

rs, 1

995)

30 d

ays

Ave

rage

cos

t pe

r pa

tient

:

Fran

ce:

Mel

oxic

am =

$37

.99

Dic

lofe

nac

= $

56.1

5In

crem

enta

l cos

t =

$18

.16

(Cos

t sa

ving

of m

elox

icam

=32

%)

Italy

:M

elox

icam

= $

86.8

0D

iclo

fena

c =

$91

.14

Incr

emen

tal c

ost

= $

4.34

(Cos

t sa

ving

of m

elox

icam

=5%

)

UK

:M

elox

icam

= $

43.6

9D

iclo

fena

c =

$57

.58

Incr

emen

tal c

ost

= $

13.8

9(C

ost

savi

ng o

f mel

oxic

am =

24%

)

The

aut

hors

con

clud

eth

at c

ompa

red

with

sust

aine

d di

clof

enac

,m

elox

icam

res

ulte

d in

cost

sav

ings

in F

ranc

e($

18.1

6 =

32%

), Ita

ly($

4.34

= 5

%) a

nd t

heU

K ($

13.8

9 =

24%

)

cont

inue

d


375


Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

McC

abe,

199

813,1

61

UK

(NH

S)

To c

ompa

re t

heco

sts

and

outc

omes

of p

resc

ribin

gal

tern

ativ

e N

SAID

sfo

r th

e tr

eatm

ent

ofRA

and

OA

, and

mor

e sp

ecifi

cally

to

test

the

hyp

othe

sisth

at N

SAID

s w

ithlo

wer

risk

s of

maj

orad

vers

e ev

ents

are

cost

sav

ing

and

mor

eef

fect

ive

The

5 N

SAID

s w

ere

nabu

met

one,

dicl

ofen

ac,

ibup

rofe

n, p

iroxi

cam

and

napr

oxen

(N.B

. Onl

y re

sults

for

nabu

met

one

and

ibup

rofe

n w

ere

repo

rted

)

Two

diffe

rent

deci

sion-

anal

ytic

(dec

ision

-tre

e) m

odel

sw

ere

used

to

com

pare

the

rela

tive

cost

s an

dou

tcom

es a

ssoc

iate

dw

ith t

he 5

alte

rnat

ive

NSA

IDs.

The

cos

t-ef

fect

iven

ess

of t

heal

tern

ativ

e N

SAID

sw

as c

alcu

late

d in

term

s of

the

cos

t pe

rLY

G

The

tw

o se

para

tem

odel

s(C

opre

scrip

tion

and

Switc

hing

) ref

lect

eddi

ffere

nt a

ppro

ache

sto

the

man

agem

ent

ofm

inor

adv

erse

eve

nts

One

-way

SA

use

d to

test

for

unce

rtai

nty

Clin

ical

: dat

a fr

om a

mul

ti-ce

ntre

d RC

T (E

vers

mey

eret

al.19

)

Dire

ct c

osts

= in

clud

ed:

sour

ce: N

SAID

tre

atm

ent

=D

rug

Tarif

f, C

hem

ist,

Dru

ggist

Mon

thly

Pric

e Li

stA

dver

se e

ffect

s =

EC

Rpr

ices

– T

rent

Reg

ion

of U

KN

HS

Indi

rect

cos

ts =

not

incl

uded

Reso

urce

use

= E

CRs

(UK

pou

nds

ster

ling,

199

5)

3 m

onth

sC

ost

per

patie

nt o

f 3 m

onth

s’pr

escr

iptio

n fo

r N

SAID

s:N

abum

eton

e =

£68

.45

Piro

xica

m =

£13

.70

Nap

roxe

n =

£14

.95

Ibup

rofe

n =

£12

.78

Dic

lofe

nac

= £

37.7

7

Cos

t of

car

e fo

r a

hypo

thet

ical

coho

rt o

f 100

,000

pat

ient

sre

ceiv

ing

nabu

met

one

orib

upro

fen

(in p

aren

thes

es: p

erpa

tient

cos

t):

1. C

opre

scrip

tion

mod

el:

Nab

umet

one

– al

l pat

ient

s =

£7,5

97,9

08 (7

5.99

)Ib

upro

fen

– A

ll pa

tient

s =

£3,5

17,0

32 (3

5.17

)2)

. Sw

itchi

ng m

odel

:N

abum

eton

e –

all p

atie

nts

=£6

,314

,234

(64.

20)

Ibup

rofe

n –

all p

atie

nts

=£3

,754

,295

(41.

67)

Cos

t pe

r LY

G u

sing

nabu

met

one

rath

er t

he Ib

upro

fen:

Cop

resc

riptio

n m

odel

= £

2517

Sw

itchi

ng m

odel

= £

1880

The

aut

hors

con

clud

eth

at p

resc

ribin

g ne

wer

,m

ore

expe

nsiv

eN

SAID

s w

ill n

otne

cess

arily

res

ult

inco

st s

avin

gs. T

hem

anag

emen

t of

adv

erse

even

ts c

an h

ave

asig

nific

ant

impa

ct o

nco

sts

whi

ch m

ay b

eju

stifi

able

in r

elat

ion

tom

orta

lity

and

mor

bidi

tyga

ins

asso

ciat

ed w

ithne

w, l

ower

risk

NSA

IDs

cont

inue

d

Appendix 12

376

Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

Liar

opou

los,

199

9162

Gre

ece

(soc

ial s

ecur

ity s

yste

mpe

rspe

ctiv

e)

To c

ompa

re t

he t

otal

cost

s of

15

days

’tr

eatm

ent

with

nim

esul

ide

agai

nst

dicl

ofen

ac in

the

trea

tmen

t of

pat

ient

sw

ith O

A

(Cos

t-m

inim

isatio

nan

alys

is)

The

aut

hors

did

not

expl

icitl

y re

port

the

use

of a

mod

el.

How

ever

, the

aut

hors

do s

tate

tha

t a

mod

elw

as u

sed

to a

sses

s th

em

anag

emen

t of

GI

adve

rse

even

ts t

reat

edon

an

ambu

lato

ry b

asis

and

for

the

calc

ulat

ion

of t

he a

ctua

l cos

t of

thes

e ad

vers

e ev

ents

for

the

two

drug

s

One

-way

SA

was

use

dto

tes

t fo

r un

cert

aint

y

Clin

ical

: MA

of p

revi

ously

publ

ished

stu

dies

(RC

Ts)

Dire

ct c

osts

= in

clud

ed:

sour

ce =

Soc

ial S

ecur

ityFu

nds

– m

inist

ry o

f Hea

lth(G

reec

e)

Indi

rect

cos

ts =

not

incl

uded

Reso

urce

use

= e

xper

top

inio

n (p

anel

of p

hysic

ians

)

(US

dolla

rs, p

rice

year

not

repo

rted

)

15 d

ays

Tota

l cos

t pe

r pa

tient

of 1

5da

ys’

trea

tmen

t:N

imes

ulid

e =

$37

.44

Dic

lofe

nac

= $

58.4

2

(nim

esul

ide

resu

lts in

a c

ost

savi

ng o

f $20

.98

per

patie

ntco

mpa

red

with

dic

lofe

nac)

The

aut

hors

con

clud

eth

at t

heir

cost

-m

inim

isatio

n an

alys

issh

owed

tha

t th

ein

crem

enta

l cos

t of

15da

ys’ t

reat

men

t w

ithni

mes

ulid

e is

$20.

98lo

wer

per

pat

ient

tha

ntr

eatm

ent

with

dicl

ofen

ac

cont

inue

d

Svar

var,

2000

163

Nor

way

(soc

ieta

l)

To c

ompa

re t

heco

st-e

ffect

iven

ess

ofce

leco

xib

agai

nst

NSA

ID m

onot

hera

pyan

d ba

se-c

ase

scen

ario

s fo

r O

A a

ndRA

The

Art

hriti

s C

ost

Con

sequ

ence

Eval

uatio

n Sy

stem

(AC

CES

) mod

el w

asus

ed t

o de

rive

the

cost

-effe

ctiv

enes

s of

the

alte

rnat

ive

trea

tmen

t op

tions

.T

his

was

cal

cula

ted

inte

rms

of t

hein

crem

enta

l cos

t pe

rG

I eve

nt a

vert

ed a

ndth

e in

crem

enta

l cos

tpe

r LY

G

One

-way

SA

was

use

dto

tes

t fo

r un

cert

aint

y

Clin

ical

: syn

thes

is of

dat

afr

om p

revi

ously

pub

lishe

dst

udie

s

Dire

ct c

osts

= in

clud

ed:

sour

ce =

Nor

weg

ian

auth

oriti

es

Indi

rect

cos

ts =

not

incl

uded

Reso

urce

use

= e

xper

top

inio

n (c

linic

ians

inN

orw

ay)

(Nor

weg

ian

kron

e, 1

999)

1 ye

arTo

tal c

osts

per

yea

r pe

r pa

tient

(NO

K):

NSA

ID m

onot

hera

py:

OA

= 2

705,

RA

= 4

243

Cel

ecox

ib: O

A =

212

5,

RA =

372

9Ba

se-c

ase:

OA

= 3

223,

RA

= 5

191

In r

elat

ion

to t

he in

crem

enta

lco

st-e

ffect

iven

ess

of c

elec

oxib

agai

nst

(i) N

SAID

alo

ne, a

nd

(ii) b

ase

case

, the

res

ults

wer

eas

follo

ws:

incr

emen

tal c

ost-

effe

ctiv

enes

s:G

I eve

nts

aver

ted:

NSA

ID a

lone

:O

A =

dom

inan

t, RA

=do

min

ant

Base

cas

e: O

A =

dom

inan

t, RA

= d

omin

ant

LYG

: NSA

ID a

lone

: OA

=do

min

ant,

RA =

dom

inan

t.Ba

se c

ase:

OA

= d

omin

ant,

RA=

dom

inan

t

The

aut

hors

con

clud

eth

at t

he in

trod

uctio

n of

cele

coxi

b in

to t

heN

orw

egia

n N

SAID

mar

ket

and

its u

se a

s a

first

-line

age

nt w

illre

sult

in im

prov

edhe

alth

care

at

a re

duce

dco

st in

pat

ient

s w

ithO

A a

nd R

A


377


Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

Mar

shal

l, 20

0116

4

Can

ada

(Ont

ario

Min

istry

of

Hea

lth)

To c

ompa

re t

hein

crem

enta

l cos

t-ef

fect

iven

ess

ofro

feco

xib

agai

nst

non-

sele

ctiv

eN

SAID

s in

the

trea

tmen

t of

pat

ient

sw

ith o

steo

arth

ritis

aged

>65

yea

rs in

Ont

ario

, Can

ada

A d

ecisi

on-a

naly

tic(d

ecisi

on-t

ree)

mod

elw

as u

sed

to d

eriv

e th

eco

st-e

ffect

iven

ess

ofth

e tw

o dr

ugs.

Thi

sw

as c

alcu

late

d in

term

s of

the

cos

t pe

rad

ditio

nal P

UB

avoi

ded

One

- an

d tw

o-w

ay S

Aw

as u

sed

to t

est

for

unce

rtai

nty

Clin

ical

= p

oole

d an

alys

isfr

om 8

clin

ical

tria

ls

Dire

ct c

osts

= in

clud

ed:

sour

ce =

dru

g co

sts

=O

ntar

io P

ublic

Cla

ims

Dat

aH

ospi

tal =

Ont

ario

cas

eco

stin

g Pr

ojec

t an

d O

ntar

ioSc

hedu

le o

f Ben

efits

Indi

rect

cos

ts =

not

incl

uded

Reso

urce

use

= O

ntar

ioM

inist

ry o

f Hea

lth

(Can

adia

n do

llars

, 199

9)

1 ye

arA

vera

ge a

nnua

l dire

ct m

edic

alco

st p

er p

atie

nt:

Non

-sel

ectiv

e N

SAID

=$5

84.9

1Ro

feco

xib

= $

609.

36(In

crem

enta

l cos

t =

$24

.25)

The

incr

emen

tal c

ost

to a

void

1ad

ditio

nal P

UB

by s

ubst

itutin

gro

feco

xib

for

non-

sele

ctiv

eN

SAID

s =

$22

47

The

aut

hors

con

clud

eth

at t

he r

epla

cem

ent

ofno

n-se

lect

ive

NSA

IDs

with

rof

ecox

ib fo

rtr

eatm

ent

of O

A w

ould

redu

ce t

he in

cide

nce

ofse

rious

GI e

vent

s at

am

odes

t in

crem

enta

lco

st t

o C

anad

ian

prov

inci

al g

over

nmen

ts

cont

inue

d

Appendix 12

378

Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

Moo

re, 2

00116

7

UK

(NH

S)To

exa

min

e th

eec

onom

icim

plic

atio

ns o

fsw

itchi

ng a

ll O

Apa

tient

s cu

rren

tlytr

eate

d w

ithco

nven

tiona

l NSA

IDs

to r

ofec

oxib

The

tre

atm

ent

regi

men

s w

ere

(1) r

ofec

oxib

and

(2)

conv

entio

nal N

SAID

s(r

epre

sent

ed b

y a

com

posit

e of

NSA

IDon

the

UK

mar

ket)

A d

ecisi

on t

ree

was

deve

lope

d to

mod

elth

e ex

pect

ed G

Ihe

alth

care

-rel

ated

reso

urce

use

asso

ciat

ed w

ithpa

tient

s ta

king

rofe

coxi

b or

NSA

ID.

The

inci

denc

e ra

tes

ofG

I eve

nts

was

dete

rmin

ed u

sing

Kapl

an–M

eier

estim

atio

n

Thr

ee b

asel

ine

anal

yses

and

ext

ensiv

ese

nsiti

vity

ana

lyse

s(c

ost

of N

SAID

and

mod

el h

ealth

sta

tes)

wer

e pr

esen

ted

The

stu

dy p

opul

atio

nco

mpr

ised

patie

nts

with

OA

tak

ing

on o

fth

e tw

o tr

eatm

ents

cont

inuo

usly

for

up t

o1

year

. Coh

ort

of10

,000

pat

ient

s

Clin

ical

: syn

thes

is of

prev

ious

ly p

ublis

hed

stud

ies

Dire

ct c

osts

= d

rug

trea

tmen

t, ph

ysic

ian

enco

unte

rs (p

rimar

y ca

rean

d sp

ecia

lists

), la

bora

tory

and

test

s, e

ndos

copy

, Hb

test

ing,

hos

pita

l, su

rger

y

Sour

ce: f

inan

ce s

taff

at N

HS

trus

ts (3

) and

the

lite

ratu

rean

d M

edip

lus

(IMS,

UK

)da

taba

se

Indi

rect

cos

ts =

not

incl

uded

Reso

urce

use

= e

xper

top

inio

n an

d pu

blish

edso

urce

s

(UK

pou

nds

ster

ling,

199

9)

1 ye

arT

he c

osts

for

6 m

odel

hea

lthst

ates

wer

e es

timat

ed: m

inor

GI

prob

lem

lead

ing

to t

reat

men

t =

£39;

out

patie

nt in

vest

igat

ion

for

PUB

and

trea

tmen

t =

£37

6;in

patie

nt in

vest

igat

ion

for

PUB

and

trea

tmen

t =

£81

8;ou

tpat

ient

tre

atm

ent

for

PUB

=£6

75; s

urge

ry fo

r PU

B =

£38

38

The

exp

ecte

d co

sts

per

day

base

d on

obs

erve

d PU

B w

ere

£0.9

1 fo

r ro

feco

xib

and

£0.5

9fo

r co

nven

tiona

l NSA

ID

The

exp

ecte

d co

sts

per

day

base

d on

end

osco

pic

data

with

an 8

5% s

ilent

ulc

er a

djus

tmen

tw

ere

£1.0

3 fo

r ro

feco

xib

and

£1.1

3 fo

r co

nven

tiona

l NSA

ID

The

exp

ecte

d co

sts

per

day

base

d on

end

osco

pic

ulce

r da

taw

ith a

40%

sile

nt u

lcer

adju

stm

ent

wer

e £1

.36

for

rofe

coxi

b an

d £2

.52

for

conv

entio

nal N

SAID

The

aut

hors

con

clud

edth

at t

he in

trod

uctio

n of

rofe

coxi

b re

pres

ents

an

impo

rtan

t th

erap

eutic

adva

ntag

e fo

r pa

tient

s,an

d a

subs

tant

ial

redu

ctio

n in

the

risk

of

GI c

ompl

icat

ions

com

pare

d w

ith p

atie

nts

on c

onve

ntio

nal N

SAID

com

es a

t on

ly a

mod

est

addi

tiona

l cos

t to

the

NH

S

cont

inue

d


379


Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

Pelli

ssie

r, 20

0116

8

USA

(thi

rd-p

arty

pay

er)

To a

sses

s th

e co

st-

effe

ctiv

enes

s of

rofe

coxi

b ag

ains

tno

n-se

lect

ive

NSA

IDs

in t

hetr

eatm

ent

of p

atie

nts

with

OA

A d

ecisi

on-a

naly

tic(d

ecisi

on-t

ree)

mod

elw

as u

sed

to d

eriv

e th

eco

st-e

ffect

iven

ess

ofth

e tw

o he

alth

tech

nolo

gies

. Thi

s w

asca

lcul

ated

in t

erm

s of

the

cost

per

yea

r of

life

save

d an

d th

e co

stpe

r PU

B av

oide

d

One

-way

SA

was

use

dto

tes

t fo

r un

cert

aint

y

Clin

ical

: dat

a sy

nthe

sised

from

8 d

oubl

e-bl

ind

RCTs

tria

ls

Dire

ct c

osts

= in

clud

ed:

sour

ce =

dru

g co

sts

=av

erag

e w

hole

sale

pric

es

Indi

rect

cos

ts =

not

incl

uded

Reso

urce

use

= p

ublis

hed

repo

rts

and

expe

rt o

pini

on

(US

dolla

rs, 1

998)

1 ye

arBa

se-c

ase

anal

ysis:

exp

ecte

dco

st p

er d

ay:

Rofe

coxi

b =

$2.

86N

SAID

s =

$2.

73

Rofe

coxi

b ve

rsus

NSA

IDs:

expe

cted

cos

t pe

r ye

ar o

f life

save

d =

$18

,614

The

aut

hors

con

clud

eth

at t

he s

tudy

sho

wed

that

dru

g co

stdi

ffere

nces

bet

wee

nro

feco

xib

and

NSA

IDs

wer

e m

arke

dly

offs

etby

exp

ecte

d co

stsa

ving

s in

GI p

robl

ems

aver

ted

with

rof

ecox

ib.

The

exp

ecte

d co

st p

erye

ar o

f life

sav

ed,

$18,

614,

was

wel

lw

ithin

the

rep

orte

dth

resh

old

of $

50,0

0 pe

rye

ar

cont

inue

d

Appendix 12

380

Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

Peris

, 200

1166

Spai

n(h

ealth

care

sys

tem

)

To u

nder

take

am

odel

led

econ

omic

com

paris

on o

fac

eclo

fena

c ag

ains

tal

tern

ativ

e N

SAID

sus

ed in

the

trea

tmen

t of

com

mon

art

hriti

cdi

sord

ers

incl

udin

gRA

and

OA

The

alte

rnat

ive

NSA

IDs

wer

edi

clof

enac

, nap

roxe

n,pi

roxi

cam

,ke

topr

ofen

,te

noxi

cam

, and

indo

met

haci

n

A d

ecisi

on-a

naly

tic(d

ecisi

on-t

ree)

mod

elw

as u

sed

to c

ompa

reth

e co

sts

and

effe

ctiv

enes

s of

the

alte

rnat

ive

trea

tmen

tst

rate

gies

Fold

back

ana

lysis

and

boot

stra

p m

etho

dsw

ere

unde

rtak

en t

ote

st t

he r

obus

tnes

s of

the

resu

lts

Clin

ical

: 12

rand

omise

ddo

uble

-blin

ded

clin

ical

tria

ls

Dire

ct c

osts

= in

clud

ed:

sour

ce =

loca

l uni

t co

st d

ata,

hosp

ital a

ccou

ntin

g da

tase

ts,

mar

ket

pric

es (S

pain

)

Indi

rect

cos

ts =

not

incl

uded

Reso

urce

use

= e

xper

t pa

nel

of r

heum

atol

ogist

s

(US

dolla

rs, 1

996)

3 m

onth

sTo

tal c

ost

per

patie

nt (N

SAID

cost

+ ia

trog

enic

cos

t) b

y st

udy,

mea

n va

lue:

1. D

iclo

fena

c =

$10

6.5;

acec

lofe

nac

= $

108.

62.

Indo

met

haci

n =

$87

.9;

acec

lofe

nac

= $

110.

53.

Nap

roxe

n =

$78

.2;

acec

lofe

nac

= $

100.

34.

Ten

oxic

am =

$86

.7;

acec

lofe

nac

= $

87.9

5. K

etop

rofe

n =

$94

.8;

acec

lofe

nac

= $

108.

76.

Piro

xica

m =

$63

.4;

acec

lofe

nac

= $

87.4

Iatr

ogen

ic c

ost

fact

or (I

CF)

:1.

Dic

lofe

nac

= 1

.88;

acec

lofe

nac

= 1

.53

2. In

dom

etha

cin

= 2

.23;

acec

lofe

nac

= 1

.52

3. N

apro

xen

= 1

.55;

acec

lofe

nac

= 1

.38;

4. T

enox

icam

= 1

.63;

acec

lofe

nac

= 1

.38

5. K

etop

rofe

n =

2.2

6;ac

eclo

fena

c =

1.3

06.

Piro

xica

m =

1.1

7;ac

eclo

fena

c =

1.3

2

The

aut

hors

con

clud

eth

at t

he r

esul

ts s

how

edth

at a

cecl

ofen

ac h

ad a

bett

er IC

F th

an t

heot

her

NSA

IDs

used

inth

e an

alys

is, w

hich

intu

rn r

esul

ted

in v

ery

simila

r ov

eral

l cos

ts,

desp

ite t

he h

ighe

rov

eral

l acq

uisit

ion

cost

of a

cecl

ofen

ac

cont

inue

d


381


Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

Tarr

icon

e, 2

00116

5

Fran

ce, I

taly,

Spa

in(h

ealth

care

pro

vide

rs)

To c

ompa

re t

he c

ost

of 1

5 da

ys’

trea

tmen

t w

ithni

mes

ulid

e ag

ains

tdi

clof

enac

in t

hetr

eatm

ent

of p

atie

nts

with

OA

in F

ranc

e,Ita

ly a

nd S

pain

(Cos

t-m

inim

isatio

nan

alys

is)

A d

ecisi

on-a

naly

tic(d

ecisi

on-t

ree)

was

used

to

com

pare

the

tota

l cos

ts (d

irect

) of

nim

esul

ide

agai

nst

dicl

ofen

ac

Two-

way

SA

was

unde

rtak

en t

o te

st fo

run

cert

aint

y

Clin

ical

: MA

of t

hree

RC

Ts.

Dire

ct c

osts

= in

clud

ed:

sour

ce =

Nat

iona

l Tar

iffs;

expe

rt p

anel

Indi

rect

cos

ts =

not

incl

uded

Reso

urce

use

= e

xper

t pa

nel

of G

Ps in

Fra

nce,

Spa

in a

ndIta

ly.

(Eur

os, 1

999)

15 d

ays

15-d

ay c

ost

of t

reat

men

t pe

rca

se:

Nim

esul

ide:

Fra

nce

= €

7,

Italy

= €

10, S

pain

= €

17

Dic

lofe

nac:

Fra

nce

= €

8,

Italy

= €

12, S

pain

= €

21

The

aut

hors

con

clud

eth

at t

heir

cost

-m

inim

isatio

n an

alys

issh

owed

nim

esul

ide

tobe

cos

t sa

ving

com

pare

d w

ithdi

clof

enac

in a

ll th

ree

coun

trie

s co

nsid

ered

.T

he a

utho

rs r

epor

t th

atpr

ojec

ting

thei

r re

sults

to t

he e

stim

ated

OA

prev

alen

ce in

the

ent

irepo

pula

tion

of t

he t

hree

coun

trie

s w

ould

res

ult

in c

ost

savi

ngs

to t

heN

HS

rang

ing

from

am

inim

um o

f€

17,5

00,0

00 in

Fra

nce

to a

max

imum

of

€30

,000

,000

in S

pain

cont

inue

d

Appendix 12

382

Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

Fend

rick,

200

2169

USA

(pay

er p

ersp

ectiv

e)

To c

ompa

re t

heec

onom

ic a

nd c

linic

alef

fect

s of

tw

odi

ffere

nt N

SAID

trea

tmen

t st

rate

gies

in t

he p

reve

ntio

n of

NSA

ID g

astr

opat

hy

Stra

tegy

1: g

ener

icN

SAID

use

d in

itial

ly,w

ith s

afer

, mor

eex

pens

ive

NSA

IDre

serv

ed fo

r pa

tient

sex

perie

ncin

g a

GI

adve

rse

even

ts o

r fo

rpa

tient

s in

tole

rant

of

the

gene

ric N

SAID

Stra

tegy

2: s

afer

,m

ore

expe

nsiv

eN

SAID

use

d in

all

patie

nts

A M

arko

v de

cisio

nan

alys

is w

as u

sed

tode

rive

the

cost

-ef

fect

iven

ess

of t

hetw

o tr

eatm

ent

stra

tegi

es. T

his

was

calc

ulat

ed in

ter

ms

ofth

e in

crem

enta

l cos

tpe

r sy

mpt

omat

ic a

ndco

mpl

icat

ed u

lcer

avoi

ded

SA w

as u

sed

to t

est

for

unce

rtai

nty

Clin

ical

: syn

thes

is of

prev

ious

ly p

ublis

hed

stud

ies

Dire

ct c

osts

= in

clud

ed:

sour

ce =

pay

men

ts m

ade

bym

edic

al s

ervi

ces

by la

rge

priv

ate

Insu

rer

Indi

rect

cos

ts =

not

incl

uded

Reso

urce

use

=no

t re

port

ed

(US

dolla

rs, p

rice

year

no

repo

rted

)

1 ye

arC

ost

per

patie

nt t

reat

ed p

erye

ar:

Stra

tegy

1 =

$23

9St

rate

gy 2

= $

831

Stra

tegy

2 p

reve

nted

an

addi

tiona

l sym

ptom

atic

ulc

er a

tan

incr

emen

tal c

ost

of $

31,9

00an

d a

com

plic

ated

ulc

er a

t a

cost

of $

56,7

00

The

aut

hors

con

clud

eth

at t

he u

nres

tric

ted

use

of s

afer

NSA

IDs

that

red

uce

the

risk

ofsy

mpt

omat

ic u

lcer

has

the

pote

ntia

l to

prod

uce

clin

ical

ben

efits

at in

crem

enta

l cos

t

For

abbr

evia

tions

, see

the

foot

note

to

Ape

ndix

12a

.

Spie

gel,

2003

170

USA

(thi

rd-p

arty

pay

er)

To c

ompa

re t

heco

sts

and

outc

omes

of a

cox

ib (o

nce

daily

) aga

inst

napr

oxen

(tw

ice

daily

) in

the

trea

tmen

t of

patie

nts’

chr

onic

arth

ritis,

in o

rder

to

dete

rmin

e if

the

degr

ee o

f risk

redu

ctio

n in

GI

com

plic

atio

ns b

yco

xibs

offs

ets

thei

rin

crea

sed

cost

A d

ecisi

on-a

naly

tic(d

ecisi

on-t

ree)

mod

elw

as u

sed

to e

stim

ate

the

cost

-effe

ctiv

enes

sof

the

alte

rnat

ive

trea

tmen

t st

rate

gies

.T

his

was

cal

cula

ted

inte

rms

of t

hein

crem

enta

l cos

t pe

rQ

ALY

gai

ned

One

-way

and

mul

tivar

iate

SA

was

unde

rtak

en t

o te

st fo

run

cert

aint

y

Clin

ical

: sys

tem

atic

rev

iew

of

MED

LIN

Ean

d pu

blish

edab

stra

cts

Dire

ct c

osts

= in

clud

ed:

sour

ce =

200

2 A

mer

ican

Med

ical

Ass

ocia

tion

Cur

rent

Proc

edur

al T

erm

inol

ogy

Cod

eboo

k, 2

002

Med

icar

eFr

ee S

ched

ule,

Red

Boo

k

Indi

rect

cos

ts =

not

incl

uded

Reso

urce

use

= n

otre

port

ed

(US

dolla

rs, p

rice

year

not

repo

rted

)

Life

time

Cos

t pe

r pa

tient

(bas

e ca

sean

alys

is –

3% d

iscou

nt r

ate)

:N

apro

xen

= $

4859

Cox

ib =

$16

,433

The

use

of a

cox

ib in

stea

d of

napr

oxen

res

ulte

d in

an

incr

emen

tal c

ost

of $

275,

809

per

QA

LY g

aine

d

The

aut

hors

con

clud

eth

at t

he r

isk r

educ

tion

asso

ciat

ed w

ith c

oxib

sdo

es n

ot o

ffset

the

irin

crea

sed

cost

com

pare

d w

ith n

on-

sele

ctiv

e N

SAID

s su

chas

nap

roxe

n in

the

man

agem

ent

ofav

erag

e-ris

k pa

tient

sw

ith c

hron

ic R

A


383


(c)

Econ

omic

eva

luat

ions

of h

ead-

to-h

ead

com

pari

sons

of C

ox-1

NSA

ID p

lus

GPA

ver

sus

Cox

-2in

hibi

tor

or C

ox-2

pre

fere

ntia

l

Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

Bent

kove

r, 19

9417

1

USA

(hea

lthca

re p

ayer

)

To c

ompa

re t

hedi

rect

med

ical

cos

tsof

thr

ee N

SAID

trea

tmen

t re

gim

ens

in a

pop

ulat

ion

ofel

derly

pat

ient

s(≥

60ye

ars

old)

with

OA

The

thr

ee t

reat

men

tre

gim

ens

com

pare

dw

ere

(i) n

abum

eton

e(1

g/da

y),

(ii) i

bupr

ofen

alo

ne(2

.4g/

day)

, and

(iii)

ibup

rofe

n(2

.4g/

day)

plu

sm

isopr

osto

l(8

00µg

/day

)

A d

ecisi

on-a

naly

ticm

odel

was

use

d to

estim

ate

the

dire

ctm

edic

al c

osts

per

patie

nt t

reat

ed fo

rea

ch o

f the

thr

eetr

eatm

ent

regi

men

s

One

-way

SA

was

use

dto

tes

t fo

r un

cert

aint

y

Clin

ical

: dat

a fr

om a

sin

gle-

blin

d cl

inic

al t

rial

Dire

ct c

osts

= in

clud

ed:

sour

ce =

pre

scrip

tion

drug

s=

who

lesa

le d

rug

cost

s;no

n-pr

escr

iptio

n dr

ugs

=Re

d Bo

ok (1

992)

; dire

ctm

edic

al r

esou

rce

cost

s =

DRG

rei

mbu

rsem

ent

amou

nts

(199

2)

Reso

urce

use

= s

ingl

e-bl

ind

clin

ical

tria

l (Ro

th e

t al

.19

93)78

Indi

rect

cos

ts =

not

Incl

uded

(US

dolla

rs, 1

992)

3 m

onth

sTo

tal d

irect

med

ical

cos

ts p

erpa

tient

tre

ated

:N

abum

eton

e =

$18

3Ib

upro

fen

= $

252

Ibup

rofe

n +

miso

pros

tol =

$270

The

aut

hors

con

clud

eth

at n

abum

eton

e is

cost

savi

ng w

hen

com

pare

dw

ith ib

upro

fen

only

and

ibup

rofe

n +

miso

pros

tol.

Diff

eren

ces

in c

osts

resu

lted

from

hig

her

cost

s of

the

tre

atm

ent

of d

rug-

rela

ted

adve

rse

even

ts w

ith ib

upro

fen

and

high

er d

rug

acqu

isitio

n co

sts

with

ibup

rofe

n +

miso

pros

tol

cont

inue

d

Brix

ner,

1994

172

USA

(hea

lthca

re p

rovi

der)

To c

ompa

re t

heec

onom

ic e

ffect

s(d

irect

med

ical

cost

s) o

fna

bum

eton

e ag

ains

tN

SAID

s al

one

and

NSA

ID/a

nti-u

lcer

ther

apy

in t

hetr

eatm

ent

of p

atie

nts

with

OA

and

RA

A d

ecisi

on-a

naly

ticm

odel

was

use

d to

com

pare

the

dire

ctm

edic

al c

osts

of t

heth

ree

trea

tmen

top

tions

Clin

ical

: syn

thes

is of

prev

ious

ly p

ublis

hed

stud

ies.

Dire

ct c

osts

= d

rugs

=w

hole

sale

acq

uisit

ion

cost

;av

erag

e w

eigh

ted

cost

s;M

edic

are

clai

ms

Indi

rect

cos

ts =

not

incl

uded

Reso

urce

use

= c

linic

al s

tudy

(US

dolla

rs, p

rice

year

not

repo

rted

)

3 m

onth

sD

irect

med

ical

cos

ts (3

mon

ths’

trea

tmen

t)N

abum

eton

e =

$18

6.08

NSA

IDs

alon

e =

$25

9.89

NSA

ID/a

nti-u

lcer

the

rapy

=$2

30.2

4

The

aut

hors

con

clud

eth

at in

eld

erly

pat

ient

sw

ith O

A o

r RA

trea

tmen

t w

ithna

bum

eton

e w

ould

resu

lt in

cos

t sa

ving

sco

mpa

red

with

NSA

IDs

alon

e an

d N

SAID

/ant

i-ul

cer

ther

apy

Appendix 12

384

Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

Gol

dste

in, 1

99717

3

USA

(hea

lthca

re p

rovi

der)

To c

ompa

re t

heco

sts

and

cons

eque

nces

of f

ive

diffe

rent

tre

atm

ent

regi

men

s fo

r th

epr

even

tion

and

man

agem

ent

NSA

ID-in

duce

dga

stro

path

y

The

tre

atm

ent

regi

men

s w

ere:

(i) N

SAID

alo

ne(ii

) NSA

ID w

ithH

2RA

(ii

i) N

SAID

with

miso

pros

tol

(iv) d

iclo

fena

c 50

mg

b.d

–m

isopr

osto

l20

0µg

t.d

.s.

(v) d

iclo

fena

c 75

mg

b.d.

–m

isopr

osto

l20

0µg

b.d

.

A d

ecisi

on-a

naly

ticm

odel

was

use

d to

com

pare

the

dire

ctm

edic

al c

osts

of t

hefiv

e tr

eatm

ent

optio

ns

Clin

ical

: syn

thes

is of

prev

ious

ly p

ublis

hed

stud

ies

Dire

ct c

osts

= in

clud

ed:

sour

ce =

dru

gs, a

vera

gew

hole

sale

cha

rges

;ho

spita

lisat

ion,

mea

n ho

spita

lch

arge

s

Indi

rect

cos

ts =

not

incl

uded

Reso

urce

use

= e

xper

top

inio

n

(US

dolla

rs, 1

996)

6 m

onth

sTr

eatm

ent

cost

s pe

r pa

tient

(6

mon

ths)

:O

vera

ll:N

SAID

reg

imen

s =

$11

53.0

0D

iclo

fena

c –

miso

pros

tol =

$939

.00

(Cos

t re

duct

ion

of $

214.

00)

By in

divi

dual

reg

imen

:N

SAID

alo

ne =

$10

17.0

0 N

SAID

with

H2R

A =

$15

83N

SAID

with

miso

pros

tol =

$135

3.00

Dic

lofe

nac

(50

mg

b.d.

) –m

isopr

osto

l (20

0µg

/t.d

.s.)

$921

.00

Dic

lofe

nac

(75

mg

b.d.

) –m

isopr

osto

l (20

0µg

b.d

.) =

$957

.00

The

aut

hors

con

clud

eth

at in

the

bas

e ca

seth

e di

clof

enac

–m

isopr

osto

l reg

imen

sre

pres

ente

d th

e le

ast

cost

ly t

reat

men

top

tions

, res

ultin

g in

cost

s pe

r pa

tient

of

$214

whe

n co

mpa

red

with

the

NSA

IDre

gim

ens

over

the

6-

mon

th t

reat

men

tpe

riod

cont

inue

d


385


Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

Ko, 2

00017

4

USA

(thi

rd-p

arty

pay

er)

To c

ompa

re t

here

lativ

e co

st-

effe

ctiv

enes

s of

6pr

ophy

lact

icst

rate

gies

aga

inst

no

prop

hyla

xis

in t

hepr

imar

y pr

even

tion

of N

SAID

-indu

ced

ulce

rs in

pat

ient

sag

ed 6

5ye

ars

com

men

cing

NSA

IDtr

eatm

ent

The

pro

phyl

actic

stra

tegi

es c

ompa

red

wer

e:(i)

H. p

ylor

i tes

ting

and

sele

ctiv

etr

eatm

ent

(ii) t

reat

all

empi

rical

ly fo

rH

.pyl

ori

(iii)

conv

entio

nal

dose

H2R

A(iv

) hig

h-do

se H

2RA

(v) m

isopr

osto

l(v

i) om

epra

zole

A d

ecisi

on-a

naly

tic(d

ecisi

on-t

ree)

mod

elw

as u

sed

to c

ompa

reth

e co

st-e

ffect

iven

ess

of t

he a

ltern

ativ

etr

eatm

ent

stra

tegi

es.

Thi

s w

as c

alcu

late

d in

term

s of

the

cos

t pe

rye

ar o

f life

sav

ed

One

and

tw

o-w

ay S

Aw

as u

nder

take

n to

test

for

unce

rtai

nty

Clin

ical

: syn

thes

is of

prev

ious

ly p

ublis

hed

stud

ies

(MED

LIN

E19

66–8

8)

Dire

ct c

osts

= in

clud

ed:

sour

ce =

Med

icar

e Fe

eSc

hedu

le, 1

997,

Dru

g To

pics

Red

Book

, Am

eric

an M

edic

alA

ssoc

iatio

n C

urre

ntPr

oced

ural

Ter

min

olog

yC

ode

Book

Indi

rect

cos

ts =

not

incl

uded

Reso

urce

Use

= M

edic

are

(US

dolla

rs, 1

997)

3 m

onth

sC

ost

per

year

of l

ife s

aved

:(i)

H. p

ylor

i tes

ting

and

sele

ctiv

e tr

eatm

ent

=$2

3,80

0(ii

) Tre

at a

ll em

piric

ally

for

H.p

ylor

i= c

ost

savi

ng(ii

i) co

nven

tiona

l/low

-dos

e H

2RA

= $

78,8

00(iv

) hig

h-do

se H

2RA

= $

78,7

00(v

) miso

pros

tol =

$46

,100

(vi)

omep

razo

le =

$34

,400

The

aut

hors

con

clud

eth

at in

the

bas

elin

ean

alys

is th

e co

st-

effe

ctiv

enes

s of

eac

h of

the

prop

hyla

ctic

stra

tegi

es fo

r th

epr

imar

y pr

even

tion

ofN

SAID

-indu

ced

ulce

rsw

as le

ss t

han

$78,

800

per

year

of l

ife s

aved

,an

d th

at e

mpi

rical

lytr

eatin

g al

l pat

ient

s fo

rH

. pyl

oriw

as c

ost

savi

ng

cont

inue

d

Appendix 12

386

Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

Zab

insk

i, 20

0117

5

Can

ada

(Pro

vinc

ial M

inist

ry o

fH

ealth

)

To c

ompa

re t

heco

sts

and

cons

eque

nces

of

trea

ting

patie

nts

with

six d

iffer

ent

trea

tmen

t re

gim

ens

for

the

man

agem

ent

of O

A a

nd R

A

The

tre

atm

ent

regi

men

s w

ere:

(i) c

elec

oxib

(ii) N

SAID

alo

ne(ii

i) di

clof

enac

–m

isopr

osto

l(iv

) NSA

ID +

PPI

(v) N

SAID

+ H

2RA

(vi)

NSA

ID +

miso

pros

tol

A d

ecisi

on-a

naly

tic(d

ecisi

on-t

ree)

mod

elw

as u

sed

to c

ompa

reth

e co

sts

and

clin

ical

cons

eque

nces

of t

hesix

diff

eren

t tr

eatm

ent

regi

men

s

One

-way

SA

was

use

dto

tes

t fo

r un

cert

aint

y

Clin

ical

: poo

led

anal

ysis

of 8

clin

ical

tria

ls.

Dire

ct c

osts

= in

clud

ed:

sour

ce =

phy

sicia

n fe

es a

ndpr

oced

ures

= O

ntar

ioSc

hedu

le o

f Ben

efits

;H

ospi

talis

atio

n =

acu

te c

are

in O

ntar

io; d

rug

= O

ntar

ioD

rug

Bene

fit D

ata

from

Brog

an In

c.

Indi

rect

cos

ts =

not

incl

uded

Reso

urce

use

= e

xper

top

inio

n (p

hysic

ians

pra

ctisi

ngin

Can

ada)

(Can

adia

n do

llars

, 199

8)

6 m

onth

sW

eigh

ted

aver

age

cost

per

patie

nt p

er 6

mon

ths:

Cel

ecox

ib =

Can

$273

NSA

ID a

lone

= C

an$2

62N

SAID

+ H

2RA

= C

an$4

23D

iclo

fena

c –

miso

pros

tol =

$365

NSA

ID +

miso

pros

tol =

Can

$421

NSA

ID +

PPI

= C

an$7

31

The

aut

hors

con

clud

eth

at t

he r

esul

ts o

f the

stud

y sh

ow t

hat

the

use

of c

elec

oxib

cou

ldre

sult

in t

he a

void

ance

of a

sig

nific

ant

num

ber

of G

I adv

erse

eve

nts.

The

y al

so s

tate

tha

t th

ein

crem

enta

l cos

t of

usin

g ce

leco

xib

in p

lace

of c

urre

nt t

reat

men

tal

tern

ativ

es in

Can

ada

wou

ld n

ot im

pose

an

exce

ssiv

e in

crem

enta

lco

st o

n th

e C

anad

ian

heal

thca

re b

udge

t

cont

inue

d


387


Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

Cha

ncel

lor,

2001

176

Switz

erla

nd(p

ublic

hea

lth in

sure

rs)

To e

stim

ate

the

cost

-ef

fect

iven

ess

ofce

leco

xib

in t

hetr

eatm

ent

of O

A

The

cos

ts a

ndco

nseq

uenc

es in

the

trea

tmen

t of

OA

with

cel

ecox

ib w

ere

com

pare

d ag

ains

tfiv

e tr

eatm

ent

optio

ns:

(i) N

SAID

s al

one

(ii) N

SAID

+ P

PI(ii

i) N

SAID

+ H

2RA

(iv

) NSA

ID +

miso

pros

tol

(v) d

iclo

fena

c–m

isopr

osto

l

A d

ecisi

on-a

naly

ticm

odel

with

Mon

teC

arlo

sim

ulat

ion

was

used

to

com

pare

the

cost

s an

dco

nseq

uenc

es o

f the

six t

reat

men

t op

tions

The

aut

hors

cal

cula

ted

the

cost

-effe

ctiv

enes

sof

cel

ecox

ib c

ompa

red

with

NSA

IDs

alon

e in

term

s of

the

cos

t pe

rad

vers

e ev

ent

avoi

ded.

Thi

s w

ases

timat

ed in

ast

ocha

stic

ver

sion

ofth

e de

cisio

n-an

alyt

icm

odel

usin

g M

onte

Car

lo s

imul

atio

n

One

-way

SA

was

use

dto

tes

t fo

r un

cert

aint

y

Clin

ical

= p

oole

d an

alys

isfr

om c

linic

al t

rials;

MA

of

publ

ished

lite

ratu

re

Dire

ct c

osts

= in

clud

ed:

sour

ce =

hos

pita

l = o

ffici

alpr

ice

list

publ

ished

by

Hea

lthIn

sura

nce

Age

ncy;

dru

g co

sts

= H

ealth

Insu

ranc

e O

ffice

Indi

rect

cos

ts =

not

incl

uded

Reso

urce

use

= e

xper

top

inio

n (C

linic

ians

inSw

itzer

land

)

(Sw

iss fr

ancs

, pric

e ye

ar –

not

repo

rted

)

6 m

onth

sPe

r pa

tient

cos

ts o

f 6m

onth

s’tr

eatm

ent

(Sw

F) (f

igur

es in

pare

nthe

ses

= in

crem

enta

l cos

tto

cel

ecox

ib)

Cel

ecox

ib =

435

NSA

ID a

lone

= 5

09.9

4(7

4.88

) D

iclo

fena

c –

miso

pros

tol =

521.

95 (8

6.89

), N

SAID

+ m

isopr

osto

l =10

33.6

3 (5

98.5

7)N

SAID

+ H

2RA

= 1

201.

09(7

66.0

3)N

SAID

+ P

PI =

141

4.72

(979

.66)

In r

elat

ion

to t

he c

ost-

effe

ctiv

enes

s an

alys

is us

ing

Mon

te C

arlo

sim

ulat

ion,

the

auth

ors

repo

rt t

hat

in 9

5% o

f50

0 ite

ratio

ns, c

elec

oxib

was

pred

icte

d to

sav

e bo

th c

osts

and

adve

rse

even

ts, t

hus

dom

inat

ing

NSA

IDs

alon

e; t

he m

axim

umco

st p

er a

dver

se e

vent

avo

ided

was

Sw

F440

0

The

aut

hors

con

clud

eth

at c

elec

oxib

is t

hem

ost

cost

-effe

ctiv

e of

the

optio

ns c

onsid

ered

for

the

trea

tmen

t of

arth

ritis

patie

nts

inSw

itzer

land

. The

estim

ate

that

cel

ecox

ibw

ill r

esul

t in

cos

tsa

ving

s fo

r he

alth

care

budg

ets

if pa

tient

s ar

esw

itche

d fr

om N

SAID

-ba

sed

regi

men

s cont

inue

d

Appendix 12

388

Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

You,

200

2177

Hon

g Ko

ng(p

ublic

hea

lthor

gani

satio

n)

To a

naly

se t

he c

ost

of c

elec

oxib

and

conv

entio

nal N

SAID

regi

men

s fo

r th

etr

eatm

ent

of O

A a

ndRA T

he t

reat

men

tre

gim

ens

wer

e:1.

cel

ecox

ib2.

NSA

ID o

nly

(nap

roxe

n,di

clof

enac

,ib

upro

fen)

3. N

SAID

plu

s H

2RA

(150

mg

rani

tidin

etw

ice

daily

, 20

mg

fam

otid

ine

twic

eda

ily, n

izat

idin

e15

0m

g tw

ice

daily

or c

imet

idin

e40

0m

g tw

ice

daily

)4.

NSA

ID p

lus

miso

pros

tol

(200

µg t

wo

tofo

ur t

imes

dai

ly)

5. N

SAID

plu

s PP

I(2

0–40

mg

omep

razo

le d

aily

or 1

5–30

mg

lans

opra

zole

dai

ly)

A d

ecisi

on t

ree

was

used

to

simul

ate

the

clin

ical

out

com

es a

ndco

st o

f 5 t

reat

men

tre

gim

ens

One

-way

SA

was

incl

uded

on

patie

nts’

GI r

isk s

core

s an

d al

lcl

inic

al p

roba

bilit

ies

and

cost

s

The

stu

dy p

opul

atio

nw

as a

hyp

othe

tical

coho

rt o

f pat

ient

sw

ith O

A a

nd R

A

Clin

ical

: syn

thes

is of

prev

ious

ly p

ublis

hed

stud

ies

Dire

ct c

osts

: dru

gs, G

PAs

and

med

icin

es in

volv

ed w

ithm

anag

emen

t of

GI e

vent

s,ho

spita

lisat

ion,

clin

ic v

isits

,la

bora

tory

tes

ts, o

esop

hago

-ga

stro

-duo

deno

scop

y an

dsu

rger

y

Sour

ce: d

rugs

– fr

omho

spita

l aut

horit

y. O

ther

cost

s: c

harg

es fo

r ite

mise

dhe

alth

care

ser

vice

s po

sted

inth

e H

ong

Kong

Gaz

ette

.In

dire

ct c

osts

: not

incl

uded

Reso

urce

use

: med

ical

reco

rds

of 1

44 p

atie

nts

adm

itted

to

a pu

blic

tea

chin

gho

spita

l in

Hon

g Ko

ng

(HK

$, w

here

US$

1 =

HK

$7.8

, pric

e ye

ar n

otre

port

ed)

6 m

onth

sT

he e

xpec

ted

cost

s fo

r th

eba

se-c

ase

anal

ysis

wer

e:1.

Cel

ecox

ib =

HK

$154

52.

NSA

ID o

nly

= H

K$1

610

3. N

SAID

plu

s H

2RA

=H

K$1

404

4. N

SAID

plu

s m

isopr

osto

l =H

K$2

213

5. N

SAID

plu

s PP

I = H

K$2

857

The

aut

hors

con

clud

edth

at c

elec

oxib

app

eare

dto

be

the

leas

t co

stly

alte

rnat

ive

in p

atie

nts

with

inte

rmed

iate

to

high

GI r

isk fo

r th

etr

eatm

ent

of O

A a

ndRA

in H

ong

Kong co

ntin

ued


389


Stud

y (p

ersp

ecti

ve)

Stud

y ai

mM

odel

ling

met

hods

Sour

ces

of d

ata

Tim

e ho

rizo

nR

esul

ts

Con

clus

ion

El-S

erag

, 200

2178

USA

(thi

rd-p

arty

paye

r)

To d

eter

min

e th

em

ost

cost

-effe

ctiv

est

rate

gy fo

r re

duci

ngth

e ris

k of

clin

ical

UG

Iev

ents

(sym

ptom

atic

ulce

r, pe

rfor

atio

n,bl

eedi

ng a

ndob

stru

ctio

n) in

NSA

IDus

ers.

The

res

ults

wer

e pr

esen

ted

usin

ga

nom

ogra

m

The

tre

atm

ent

regi

men

s w

ere:

1.

con

vent

iona

lN

SAID

(800

mg

ibup

rofe

n t.d

.s.)

2. c

onve

ntio

nal

NSA

ID p

lus

a sin

gle

dose

of r

egul

ar-

stre

ngth

PPI

(30

mg

lans

opra

zole

dai

ly)

3. c

onve

ntio

nal

NSA

ID p

lus

200

µgm

isopr

osto

l dai

ly4.

cox

ib (1

00m

gce

leco

xib

twic

eda

ily)

5–8.

bism

uth

subs

alic

ylat

e –

met

roni

dazo

le –

tetr

acyc

line

com

bina

tion

and

PPI t

reat

men

t fo

rH

. pyl

orit

wic

e da

ilyfo

r 2

wee

ksfo

llow

ed b

y ea

ch o

fth

e fir

st 4

trea

tmen

tst

rate

gies

A d

ecisi

on-a

naly

tic(d

ecisi

on-t

ree)

mod

elw

as u

sed

to e

valu

ate

the

cost

-effe

ctiv

enes

sof

8 s

trat

egie

s fo

rre

duci

ng t

he r

isk o

f GI

even

ts

The

SA

incl

uded

3va

riabl

es: b

asel

ine

risk

of G

I eve

nts

with

conv

entio

nal N

SAID

alon

e, r

isk o

f GI

even

ts w

ith o

ther

stra

tegi

es o

f NSA

IDan

d co

st o

f the

dru

gs.

One

-, tw

o- a

nd t

hree

-w

ay S

As

wer

eco

nduc

ted

The

mod

el w

asap

plie

d as

sum

ing

that

the

patie

nt w

as a

55

-yea

r-ol

d pe

rson

with

OA

who

req

uire

sN

SAID

the

rapy

for

1ye

ar

Clin

ical

: syn

thes

is of

prev

ious

ly p

ublis

hed

stud

ies

Dire

ct c

osts

: cos

ts o

f dru

gsal

one

and

cost

s of

dru

gs p

lus

cost

of c

linic

al G

I eve

nts

Sour

ce: n

ot r

epor

ted

for

the

unit

cost

s of

dru

gs

The

ass

umed

cos

t of

a U

GI

even

t w

as fi

xed

at $

28,0

00

Indi

rect

cos

ts: n

ot in

clud

ed

Reso

urce

use

: not

rep

orte

d

(US

dolla

rs, p

rice

year

not

repo

rted

)

1 ye

arC

ost

of d

rugs

per

pat

ient

per

year

(US$

):St

rate

gy 1

= $

239;

str

ateg

y 2

=$1

632;

str

ateg

y 3

= $

1209

;st

rate

gy 4

= $

1029

; str

ateg

y 5

= $

423;

str

ateg

y 6

= $

1816

;st

rate

gy 7

= $

1393

; str

ateg

y 8

= $

1213

Cos

t of

str

ateg

y pe

r pa

tient

per

year

(cos

t of

dru

gs p

lus

cost

of

clin

ical

GI e

vent

) ass

umin

gba

selin

e ris

k of

6.5

% fo

r G

Iev

ent

with

con

vent

iona

l NSA

ID:

stra

tegy

1 =

$20

59; s

trat

egy

2=

$24

45; s

trat

egy

3 =

$23

01;

stra

tegy

4 =

$19

39; s

trat

egy

5=

$20

61; s

trat

egy

6 =

$25

38;

stra

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trat

egy

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= $

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$16

,112

; str

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10,5

95; s

trat

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dom

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aut

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con

clud

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at it

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ost-

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rel

ativ

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nsiv

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regi

men

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rpa

tient

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kfo

r G

I eve

nts

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inue

d

Appendix 12

390

Stud

y (p

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mM

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of d

ata

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) $47

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556,

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b

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ted

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2) d

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) dom

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$61

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r O

A p

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rage

risk

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etam

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ntav

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opt

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abbr

evia

tions

, see

the

foot

note

to

App

endi

x 12

a.


391


Appendix 13

Defined daily doses (DDDs) and average dailyquantity (ADQ) for non-steroidal anti-inflammatory

drugs (BNF sub-section 10.1.1)

Administration BNF name DDD ADQ Unit Notesroute

Oral Aceclofenaca,b,c 200 200 mgOral Acemetacina 120 mg New July 2000Oral Azapropazonec 750 900 mgOral Benorylatea 3 3 g =Oral Celecoxiba,b 200 200 mg New July 2000Oral Dexketoprofend 75 50 mg New November 1999Oral, rectal Diclofenac sodiuma 100 100 mgOral Diclofenac sodium and misoprostol 100 mg 4 Tablets New July 2000; DDD

50 mg/200 µg corresponds to diclofenac;ADQ is 2 tablets of each drug

Oral Diclofenac sodium and misoprostol; 100 mg 4 Tablets New July 200075 mg/200 µg 2 tablets of each drug

Oral Diflunisala,d 750 750 mgOral Etodolaca,b 400 600 mgOral Fenbufena 600 900 mgOral Fenoprofena 1.2 1.2 gOral Flurbiprofena,d 200 200 mgOral, rectal Ibuprofena,d 1.2 1.2 gOral Ibuprofen and codeine 300 mg/20 mg 4 Tablets New July 2000Oral, rectal Indomethacina,b 100 100 mg Rectal ADQ; new July 2000Oral, rectal Ketoprofena,d 150 150 mgOral Mefenamic Acida,b,d 1 1 gOral Meloxicama,b,c 15 7.5 mg New November 1999Rectal Meloxicama,b,c 15 15 mg New November 1999Oral Nabumetonea,b 1 1 gOral, rectal Naproxena,d 500 750 mgOral Naproxen and misoprostol 4 Tablets New July 2000

500 mg/200 µg 2 tablets of each drugOral, rectal Piroxicama 20 20 mgOral Rofecoxibb 25 mg New November 1999Oral Sodium Salicylatea 3 3 gOral Sulindaca 400 400 mgOral Tenoxicama 20 20 mgOral Tiaprofenic Acida 600 600 mgOral Tolmetina,b,c 700 800 mg

Indications:a Pain and inflammation in rheumatic disease and other musculoskeletal disorders.b Osteoarthritis.c Ankylosing spondylitis.d Mild to moderate pain including dysmenorrhoea.


393


Appendix 14

References to excluded studies

Study reference Reason forexclusion codea

Multicenter study with nimesulide in rheumatology. [Portuguese]. Arq Bras Med 1992;66:363–7. B

Aabakken L, Larsen S, Osnes M. Cimetidine tablets or suspension for the prevention of Bgastrointestinal mucosal lesions caused by non-steroidal, anti-inflammatory drugs. Scand J Rheumatol 1989;18:369–75.

Aenishanslin W, Barlocher C, Bernoulli R. Misoprostol and cimetidine in treatment of duodenal Culcer. [German]. Schweiz Med Wochenschr 1985;115:1225–31.

Agrawal N, Roth S, Graham D, White R, Germain B, Brown J, et al. Misoprostol compared with Gsucralfate in the prevention of nonsteroidal anti-inflammatory drug induced gastric ulcer: a randomised, controlled trial. Ann Intern Med 1991;115:195–200.

Agrawal NM, Campbell DR, Safdi MA, Lukasik NL, Huang B, Haber MM. Superiority of F (healing, no lansoprazole vs ranitidine in healing nonsteroidal anti-inflammatory drug-associated gastric ulcers: non-GI outcomes)results of a double-blind, randomized, multicenter study. Arch Intern Med 2000;160:1455–61.

Agrifoglio E, Bartolozzi P, Campailla P, Cherubino P, Di Leo P, Fusilli DCF et al. Multicentric study Aon efficacy and tolerance of misoprostol in gastropathy due to NSAIDs. [Italian]. Ortop Traumatol Oggi 1993;13:147–55.

Agus GB, De Angelis R, Mondani P, Moia R. Double-blind comparison of nimesulide and diclofenac Bin the treatment of superficial thrombophlebitis with telethermographic assessment. Drugs 1993;46:200–3.

Ahmed WU, Kirmani SR, Qureshi H, Alam SE, Zuberi SJ. Misoprostol in the treatment of FNSAID-induced gastroduodenal lesions. Indian J Gastroenterol 1991;10:135–6.

Alberdi FJ, Guemes DF, Perez MA. A double-blind study of trithiozine in peptic ulcers. Clinical C (healing, not on Ther 1978;1:251–9. NSAIDs)

Bach GL, Stock K-P, Hudepohl M. Treatment of NSAID-induced gastrointestinal lesions with Fmisoprostol. [German]. Z Rheumatol 1991;50:175–80.

Barbier JP, Haccoun P, Bergmann JF, Arnould B, Hamelin B. Prognostic factors influencing healing Cof reflux esophagitis. A controlled trial of omeprazole versus ranitidine. Study group Omega [French]. Ann Gastroenterol Hepatol 1993;29:213–18.

Berkowitz JM, Rogenes PR, Sharp JT, Warner CW. Ranitidine protects against gastroduodenal Gmucosal damage associated with chronic aspirin therapy. Arch Intern Med 1987;147:2137–9.

Bianchi Porro G, Caruso I, Petrillo M, Montrone F, Ardizzone S . A double-blind gastroscopic Eevaluation of the effects of etodolac and naproxen on the gastrointestinal mucosa of rheumatic patients. J Intern Med 1991;229:5–8.

Bijlsma JW. Treatment of endoscopy-negative NSAID-induced upper gastrointestinal symptoms with Acimetidine: an international multicentre collaborative study. Aliment Pharmacol Ther 1988;2:Suppl: 83.

Blardi P, Gatti F, Auteri A, Di Perri T. Effectiveness and tolerability of nimesulide in the treatment of Costeoarthritic elderly patients. Int J Tissue React 1992;14:263–8.

Bocca M, Giordano M, Del Pizzo M, Nelken A, Ghiggia M, Pomatto E. The use of misoprostol in Bprevention of gastric disease from nonsteroidal anti-inflammatory drugs in oral–maxillofacial surgery. [Italian]. Minerva Ortognatodontica 1990;8:139–41.

Boers M, Dijkmans BAC, Breedveld FC, Camps JAJ, Chang PC, Van Brummelen P, et al. No effect Bof Misoprostol on renal function of rheumatoid patients treated with diclofenac. Br J Rheumatol 1991;30:56–9.

Bolten W, Lemmel EM, Distel M, Bluhmki E, Hanft G, Degner FL. Treatment of rheumatoid Barthritis (RA) with meloxicam: controlled double-blind clinical test with placebo. Z Rheumatol. 1996;55 Suppl 1:112.

continued

Appendix 14

394


Bontoux D. Lumbo-radiculalgia: efficacy, safety and therapeutic benefit of etodolac (600 mg daily) Bversus diclofenac (150 mg daily and placebo). Rhumatologie 1990;42:201–6.

Briancon D, Peterschmitt J, Laviec G. Double-blind parallel-group evaluation of the safety and Eefficacy of etodolac capsules compared with piroxicam capsules in patients with rheumatoid arthritis. Acta Therapeutica 1991;17:35–47.

Cantarelli A, Giannunzio D, Ligorio L, Mapelli A, Veca G, Gallucci M, et al. Comparison of Bnimesulide and naproxen sodium in the control of cancer pain. [Italian]. Minerva Anestesiol1991;57:1103–4.

Carabba M, Galanti A, Paresce E, Angelini M, Re K, Torchiana E, et al. Gastrointestinal effects of Bmeloxicam versus piroxicam by means of gastroduodenoscopy in patients with rheumatoid arthritis. Scand J Rheumatol Suppl 1996;106:55.

Chikanza IC, Clarke B, Hopkins R, MacFarlane DG, Bird H, Grahame R. A comparative study of Dthe efficacy and toxicity of etodolac and naproxen in the treatment of osteoarthritis. Br J Clin Prac1994;48:67–9.

Cohen de Lara A, Gompel H, Baranes C, Bornstein U, Brajer S, Cambray S, et al. Two comparative Cstudies of dosmalfate vs. misoprostol in the prevention of NSAID-induced gastric ulcers in rheumatic patients. Drugs Today 2000;36:73–8.

Copley-Merriman C, Egbuonu-Davis L, Kotsanos JG, Conforti P, Franson T, Gordon G. Clinical Beconomics: a method for prospective health resource data collection. Pharmacoeconomics1992;1:370–6.

Czarnobilski Z, Bem S, Czarnobilski K, Konturek SJ. Carprofen and the therapy of gastroduodenal Culcerations by ranitidine. Hepato-Gastroenterology 1985;32:20–3.

Dammann HG, Simon-Schultz J, Dreyer M, Simon B, Muller P. Effective prophylaxis of Bpiroxicam-induced gastroduodenal lesions with nizatidine. [German]. Z Gastroenterol 1990;28:94–6.

Davies J, Collins AJ, Dixon SA. The influence of cimetidine on peptic ulcer in patients with arthritis F (healing, no taking anti-inflammatory drugs. Br J Rheumatol 1986;25:54–8. non-GI outcomes)

De Oliveira D. The treatment of upper respiratory tract and ear inflammatory non-infectious Bconditions with NSAID. A comparative randomized trial with nimesulide and potassium diclofenac. [Portuguese]. Folha Med 1991;102:87–91.

de Queiros MF. Double-blind comparison of etodolac and naproxen in the treatment of rheumatoid Earthritis. Clin Ther 1991;13:38–46.

Delcambre B. Rheumatoid arthritis: efficacy, safety and therapeutic benefit of etodolac (600 mg daily) Dversus indomethacin (100 mg daily). Rhumatologie 1990;42:213–18.

Di Leo S, Meli MT, Scaricabarozzi I, Bedoschi D. Sicilian multicenter study of the efficacy and Atolerability of nimesulide in gyneacological inflammatory diseases. [Italian]. Minerva Ginecol1990;42:277–81.

Dick WC, Franchimont P, Veys E. Double-blind comparison of etodolac and piroxicam in the Etreatment of rheumatoid arthritis. Clin Ther 1993;15:148–59.

Durakovic Z, Vrhovac B, Falisevac V, Gjurasin M. Therapeutic trial of cimetidine in erosive gastritis. A[Serbocroatian]. Lijecnicki Vjesnik 1979;101:289–93.

Edworthy SM, Devins GM. Improving medication adherence through patient education Cdistinguishing between appropriate and inappropriate utilization. Patient Education Study Group. J Rheumatol 1999;26:1793–801.

Elta GH, Appelman HD, Behler EM, Wilson JA, Nostrant TJ. A study of the correlation between Cendoscopic and histological diagnoses in gastroduodenitis. Am J Gastroenterol 1987;82:749–53.

Famaey JP, Bruhwyler J, Geczy J, Vandekerckhove K, Appelboom T. Open controlled randomized Dmulticenter comparison of nimesulide and diclofenac in the treatment of subacute and chronic low back pain. J Clin Res 1998;1:219–38.

Farini R, Di Mario F, Scalabrin G. Cimetidine vs. trithiozine in the treatment of benign gastric ulcer. CItal J Gastroenterol 1982;14:55.

continued


395



Ferrari E, Pratesi C, Scaricabarozzi I, Trezzani R. A clinical study of efficacy and tolerability of Bnimesulide compared with diclofenac sodium in the treatment of acute superficial thrombophlebitis. [Italian]. Minerva Cardioangiol 1992;40:455–60.

Ferrari E, Pratesi C, Scaricabarozzi I. A comparison of nimesulide and diclofenac in the treatment B of acute superficial thrombophlebitis. Drugs 1993;46:197–9.

Frank WO, Wallin BA, Berkowitz JM, Kimmey MB, Palmer RH, Rockhold F, et al. Reduction of Bindomethacin induced gastroduodenal mucosal injury and gastrointestinal symptoms with cimetidine in normal subjects. J Rheumatol 1989;16:1249–52.

Gabryelewicz S, et al. Preventive effect of ranitidine against gastrointestinal disorders in rheumatic Apatients treated with non-steroidal anti-inflammatory drugs (NSAID). Gastroenterology 1987;92:1398.

Gallucci M, Toscani F, Mapelli A, Cantarelli A, Veca G, Scaricabarozzi I. Nimesulide in the treatment Bof advanced cancer pain. Double-blind comparison with naproxen. Arzneim-Forsch 1992;42:1028–30.

Georg KJ, Mertens D, and Mons GV. Lansoprazole versus misoprostol in the prevention of Dindomethacin-induced gastro-duodenal lesions. A prospective randomized single-blind study in women undergoing hip joint endoprostesis [abstract]. Gut 1997;41 (Suppl 3):A7.

Gottesdiener K, Mehlisch DR, Huntington M, Yuan W-Y, Brown P, Gertz B, et al. Efficacy and Btolerability of the specific cyclooxygenase-2 inhibitor DFP compared with naproxen sodium in patients with postoperative dental pain. Clin Ther 1999;21:1301–12.

Habibullah CM, Singh SP, Phaterpekar SJ. Misoprostol (Cytotec) in NSAID gastropathy. J Assoc APhysicians India 1993;41:770.

Hannequin J-R. Efficacy of Arthrotec(TM) in the treatment of rheumatoid arthritis. Scand J Rheumat DSuppl 1992;21:7–14.

Hunt RH, Bowen B, Mortensen ER, Simon TJ, James C, Cagliola A, et al. A randomized trial F (healthy adults)measuring fecal blood loss after treatment with rofecoxib, ibuprofen, or placebo in healthy subjects. Am J Med 2000;109:201–6.

Huskisson EC, Narjes H, Bluhmki E. Efficacy and tolerance of meloxicam, a new NSAID, in daily Doral doses of 15, 30 and 60 mg in comparison to 20 mg piroxicam in patients with rheumatoid arthritis. Scand J Rheumatol Suppl 1994;98:115.

Jallad NS, Sanda M, Salom IL, Perdomo CS, Garg DC, Mullane JF, et al. Gastrointestinal blood loss in Darthritic patients receiving chronic dosing with etodolac and piroxicam. Am J Med Sci 1986;292:272–6.

Jaszewski R, Graham DY, Stromatt SC. Treatment of nonsteroidal antiinflammatory drug-induced Bgastric ulcers with misoprostol: a double-blind multicenter study. Dig Dise Sci1992;37:1820–4.

Jenoure P, Gorschewsky O, Ryf C, Steigbugel M, Wetzel C, Frey W, et al. Randomised, Bdouble-blind, multicentre study of nimesulide vs. diclofenac in adults with acute sport injuries. J Drug Assess 1998;1 (Part 3):495–508.

Jensen DM, Ho S, Hamamah S, Frankl H, Faigel D, DeMarco D, et al. A randomised study of E (unclear what Omeprazole compared to misoprostol for prevention of recurrent ulcers and ulcer hemorrhage proportion on in high risk patients injesting aspirin or NSAIDs. Gastroenterol 2000;118 (4, Suppl 2):AS92. aspirin rather than

NSAIDs)

Jones AC, Coulson L, Muir K, Tolley K, Lophatananon A, Everitt L, et al. A nurse-delivered advice Cintervention can reduce chronic non-steroidal anti-inflammatory drug use in general practice: a randomized controlled trial. Rheumatology 2002;41:14–21.

Karateev AE, Murav’ev I, Nasonova VA. The endoscopic assessment of the effect of ranitidine Cand pirenzepine on the manifestations of the gastropathy induced by nonsteroidal anti-inflammatory preparations. [Russian]. Terapevticheskii Arkhiv 1997;69:67–9.

Klumb EM, Pinheiro GRC, Ferrari A, Albuquerque EMN. The treatment of acute gout arthritis. BDouble-blind randomized comparative study between nimesulid and indomethacin. [Portuguese]. Rev Bras Med 1996;53:540–6.

continued

Appendix 14

396


Laine L, Cominelli F, Sloane R, Casini-Raggi V, Marin-Sorensen M, Weinstein WM. Interaction of F (healthy NSAIDs and Helicobacter pylori on gastrointestinal injury and prostaglandin production: a volunteers)controlled double-blind trial. Aliment Pharmacol Ther 1995;9:127–35.

Laine L, Sloane R, Ferretti M, Cominelli F. A randomized double-blind comparison of placebo, Fetodolac, and naproxen on gastrointestinal injury and prostaglandin production. Gastrointest Endosc1995;42:428–33.

Lanza FL, Royer GL. NSAID-induced gastric ulceration is dose-related by weight: an endoscopic Bstudy with flurbiprofen. Am.J Gastroenterol 1993;88:683–6.

Lauritsen K, Rutgersson K, Bolling E, Brunner G, Eriksson S, Galmiche JP, et al. Omeprazole and Cranitidine in the prevention of relapse in patients with duodenal ulcer disease. Can J Gastroenterol 1999;13:806–13.

Lei-Munhoz MS, Malavasi GM, Munhoz MLGS, Gananca HHC, Gananca FF. Comparative study Bwith nimesulide vs potassium diclofenac in ent disease. Rev Bras Med 1990;47:591–4.

Lemmel EM, Bolten W, Vargas R, Platt PN, NissilS M, and SD. A double-blind placebo controlled Bstudy of 7.5 mg and 15 mg of meloxicam in patients with rheumatoid arthritis (RA). Scand J Rheumatol Suppl 1994;98:111

Lipscomb GR, Wallis N, Armstrong G, Rees WDW. Gastrointestinal tolerability of meloxicam and F (healthy piroxicam: A double-blind placebo-controlled study. Br J Clin Pharmacol 1998;46:133–7. volunteers)

Lonauer G, Tisscher JR, Lim HG, Bijlsma JW. Double-blind comparison of etodolac and diclofenac Ein patients with rheumatoid arthritis. Curr Med Res Opin 1993;13:70–7.

Lucker PW, Pawlowski C, Friederich I, Faiella F, Magni E. Double-blind, randomised, multi-centre Cclinical study evaluating the efficacy and tolerability of nimesulide in comparison with etodalac in patients suffering from osteoarthritis of the knee. Eur J Rheumatol Inflamm 1994;14:29–38.

Macciocchi A. Results of a Swiss phase IV study. Nimesulide in the daily practice. [German]. ATher Schweiz 1997;13:270–5.

Maeda A. Clinical efficacy of lansoprazole in treatment of gastric ulcer induced by NSAIDs. F (Healing, no [Japanese]. Jpn Pharmacol Ther 1998;26:225–30. non-GI outcomes)

Malavasi GM, Lei Munhoz MS, Caovilla HH, Munhoz ML, Freitas GF. Comparative study of Bnimesulide versus potassium diclofenac in acute otitis media. [Portuguese]. Rev Bra Medi1990;47:373–6.

Manniche C, Malchow-Moller A . The influence of non-steroid anti-inflammatory drugs (NSAID) Con the treatment of peptic ulceration. A prospective randomized investigation. [Danish]. Ugeskr Laeger 1987;149:2143–4.

Marcon V, Cannizeuro R, Valentini M, Cressani B, Costan BF, Angonese C, et al. Sucralfate, Cranitidine and no treatment in gastric ulcer management – a multicenter, prospective, randomized, 24-month follow-up with a study of risk factors of relapse. Digestion 1992;53:72–8.

Marques Neto JF, Samara AM. Double-blind crossover study. Cimetidine/placebo in patients with Drheumatoid arthritis treated with indomethacin. [Portuguese]. Folha Medica 1982;85:885–6.

Martinez RO, Casas H, Mazure PA, Leczycki H, Cosen JN, Canievsky L, et al. Gastroduodenal Flesions in rheumatoid arthritis. Evaluation and treatment. [Spanish]. Acta GastroenterolLatinoam 1988;18:87–96.

McKenna F. Efficacy of diclofenac/misoprostol vs diclofenac in the treatment of ankylosing Dspondylitis. Drugs 1993;45:24–30.

McKenna F, Weaver A, Fiechtner JJ, Bello AE, Fort JG. COX-2 specific inhibitors in the Cmanagement of osteoarthritis of the knee: a placebo-controlled, randomized, double-blind study. JCR J Clin Rheumatol 2001;7:151–9.

Medina Santillan R, Reyes GG, Mateos GE. Prevention of gastroduodenal injury induced by BNSAIDs with low-dose Misoprostol. Proc West Pharmacol Soc 1999;42:33–4.

Menkes CJ. Scapulo-humeral periarthritis: efficacy, safety and therapeutic benefit of etodolac B(600 mg daily) versus piroxicam (40/20 mg daily). Rhumatologie 1990;42:195–200.

continued


397



Metzenroth H, Publig W, Knahr K, Zandl C, Kuchner G, Carda C. Indomethacin as a prophylactic Bagainst ossification following total hip-joint replacement and its effect on the gastric mucosa. [German]. Z Orthop Ihre Grenzgeb 1991;129:178–82.

Milvio C, Borellini P, Milvio E. Tolerability of nimesulide. A long-term clinical trial. Arch Med Interna A1983;35:127–36.

Miniti AM. Comparative study of nimesulide versus naproxen in patients with pharyngo-tonsillitis. BArq Brasde Med 1991;65:511–14.

Monette J, Mogun H, Bohn RL, Avorn J. Concurrent use of antiulcerative agents. J Clin Gastroenterol A1997;24:207–13.

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continued

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continued


399



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a A, not an RCT; B, not of at least 3 weeks duration; C, not a relevant comparison; D, no usable outcome data; E, not at least minimum dose of NSAIDs or gastroprotectors; F, other (e.g. participants were healthy volunteers, or thiswas a healing study that did not report non-GI outcomes or more than 20% of participants were on aspirin rather thanNSAIDs); G, Rostom reference not appropriate to this review.


401


Appendix 15

References to studies awaiting translation

Study reference Original language

Shiokawa Y, Nobunaga M, Saito T, Sakita T, Miwa T, Nakamura K, et al. [Evaluation of Japanesemisoprostol’s clinical utility for gastric/duodenal ulcers seen under long-term use of non-steroidal anti-inflammatory drugs (NSAID) – I. Evaluation of mucosal prophylactic effects by a placebo-controlled double blind comparative study]. Ryumachi 1991;31:554–71.

Shiokawa Y, Nobunaga M, Saito T, Sakita T, Miwa T, Nakamura K, et al. [Evaluation of Japanesemisoprostol’s clinical utility for gastric/duodenal ulcers seen under long-term use of non-steroidal anti-inflammatory drugs (NSAID) – II. Evaluation of therapeutic effects on ulcers under continuous use of NSAID]. Ryumachi 1991;31:572–82.

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Tests for the diagnosis and investigation of urinary tract infection in children

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APPENDIX - The prevention of non-steroidal anti