ASSESSMENT OF DRUGS OUT-PATIENTS RHEUMATOID ARTHRITIS

Ann. rheum. Dis. (1967), 26, 373

ASSESSMENT OF DRUGS IN OUT-PATIENTS WITHRHEUMATOID ARTHRITIS

EVALUATION OF METHODS AND A COMPARISON OFMEFENAMIC AND FLUFENAMIC ACIDS WITH PHENYLBUTAZONE

AND ASPIRINBY

R. M. MASON, D. E. BARNARDO*, W. R. FOXt, AND M. WEATHERALL+From the Department ofPhysical Medicine and Rheumatology, the London Hospital, and the Department

ofPharmacology, the London Hospital Medical College

Relief of symptoms in patients with chronicrheumatoid arthritis is difficult. Conventionalanalgesics such as aspirin, paracetamol, and phenyl-butazone have limited efficacy and are not free fromtoxic effects. Any alternative which was moreeffective, safer, or both would be welcome, but mostnew remedies owe such success as they achieve totherapeutic optimism which is a powerful buttransient potentiator of pharmacological effects.The accurate assessment of new drugs by properlycontrolled trials is indispensable. Two drugs whichhave shown promise in laboratory studies and earlyclinical trials are mefenamic and flufenamic acids(Winder, Wax, Scotti, Scherrer, Jones, and Short,1962; Goodley, 1963; Young, 1962), derivatives ofxylylanthranilic acid with actions broadly resemblingthose of aspirin. We have submitted these drugsto a controlled trial, which has already been brieflyreported (Barnardo, Currey, Mason, Fox, andWeatherall, 1966). Since our trial began, severalother trials have been reported. Flufenamic acid(600 mg./day) has been found to be less effectivethan prednisone (Fearnley and Masheter, 1966), andcomparable in effect to aspirin (2,700 mg./day) overperiods up to 6 months (Simpson, Simpson, andMasheter, 1966) and also comparable with phenyl-butazone (300 mg./day) over shorter periods(Rajan, Hill, Barr, and Whitwell, 1967). Mefenamicacid (1,500 mg./day) has been found effective also inosteo-arthritis (Cahill, Hill, Jessop, and HumeKendall, 1965).

The methods of clinical trials are still capable ofmuch improvement. Particularly in trials on out-patients, the opportunities for undetected errors arevery great. Problems of measurement are alsoconsiderable, at least in rheumatoid arthritis, inwhich all of the many measurements which can bemade appear to vary somewhat independently ofeach other (American Rheumatism Association,1965), so that confidence in any one is limited.One cannot decide which is the best of a number ofalternative procedures without testing all of them inparallel. The present trial has been extendedconsiderably beyond the needs of a simple compari-son of drugs in order also to be informative aboutproblems of method.

Methods(1) Patients

All were females over 18 years of age and were selectedby the six participating physicians from the attendersat the Department of Physical Medicine and Rheuma-tology of the London Hospital between October, 1964,and September, 1965. Each had "definite" or "classical"rheumatoid arthritis (Ropes, Bennett, Cobb, Jacox, andJessar, 1959) for more than one year, was not pregnantnor expected to become so during the trial, and had nohistory of cardiac failure, hepatic disease, or provenpeptic ulceration. Patients sensitive, or reacting un-favourably to, either phenylbutazone or aspirin wereadmitted and a provision was made as described below toavoid their receiving the drug to which they were sensitive.Patients receiving other well-stabilized treatment such assteroids or antimalarial drugs were not excluded and theirtreatment with these drugs was continued while they tookpart in the trial. The purpose of the trial was explained toeach patient and anyone who did not wish to take part orwho would have had practical difficulties in co-operatingwas excluded.

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* Present address: Gastro-intestinal Research Unit, Mayo Clinic,Rochester, Minn.t Present address: Research Dzpt., Potato Marketing Board,London, S.W.1.+ Present address: Wellcome Research Laboratories, Beckenham,Kent.

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ANNALS OF THE RHEUMATIC DISEASES

(2) Design and Procedure

Patients differ considerably from one another. Varia-tion in the severity of any given patient's arthritis islikely to be less than the variation between patients.The trial was therefore designed so that drugs werecompared within patients. Each patient was to receiveboth new drugs and an appropriate standard treatment.The choice of a standard presented some difficulty.Many drugs have been shown to be more effective thana placebo in rheumatoid arthritis, so the use of a dummywould have raised ethical problems. Besides, one objectof the trial was to compare the new remedies withstandard treatments, of which aspirin and phenylbuta-zone seemed most appropriate. Some patients are, orbelieve themselves to be, sensitive to one or other of thesedrugs. It is for such patients that a new alternativeanalgesic is particularly needed. The trial therefore hadto be arranged so that such patients could be included,without risk of being exposed to the drug to which theywere perhaps sensitive. This objective was achievedby designing the trial so that aspirin served as the standardtreatment for half the patients and phenylbutazone forthe other half. Ordinarily the choice depended on thestatistical design, but if a patient was believed to reactunfavourably to either drug the physician requestedinstead a sequence omitting the drug in question. Thisrequest was made on four occasions, but the allottedsequence was, in fact, inappropriate and had to bealtered only once.During three consecutive periods, each of 4 weeks'

duration, all patients were supposed to receive mefenamicacid, flufenamic acid, and either phenylbutazone oraspirin in capsules of a different colour. Three kindsof coloured capsule were used (blue, blue and white,and red and yellow) and each drug was dispensed equallyoften in one kind of capsule as another. It was thereforeevident to patients that they were receiving differentremedies in successive periods, but communicationbetween patients or staff about the efficacy of different-looking remedies (Asher, 1948) would not lead tocollective judgements related to a particular drug. Eachof the twelve possible orders of treatment was allocatedto three patients and the three capsule colours werearranged in a Latin square design over each such group.A complete replicate of the design thus required 36patients. When a physician admitted a patient to thetrial, the pharmacist took note of any specific request toavoid a sequence containing either aspirin or phenyl-butazone and then gave the patient the next availablesuitable trial number. Thereafter the pharmacistdispensed the appropriate capsules, leaving both thepatient and the physician unaware of the identity of thetreatment.When patients failed to complete three periods,

additional patients were admitted as replacements, whofollowed the same drug sequence and colour code tomaintain the balanced design. Finally, most patientscontinued in the trial for a fourth period, receiving asecond treatment with whichever drug they had con-sidered most effective in the first three periods. This

replication was achieved by an appropriate instruction tothe pharmacist and did not involve the physician inbreaking the code.The trial proper was preceded by a short pilot study in

which the trial procedure was tested and practised andthe physicians obtained experience in the completion ofthe forms designed for keeping records in the trial.Seven patients were admitted to the pilot study, whichrevealed no appreciable faults of planning. A further36 patients were admitted; four among these failed tocomplete three periods of treatment and a correspondingadditional number were admitted to make a completebalanced set as designed. While the results from thisset were being analysed, further patients were admittedwith a view to completing a second complete set of 36.The results on the first 36 indicated that no substantialdifference was appearing between treatments, and thesecond set was therefore not completed. In all 68patients were admitted, including the seven in the pilotstudy and eight who completed less than three periods.Analyses of comparison between drugs are mostly basedon the balanced set of 36 patients. Other analyses werebased on all the patients studied.Many clinical trials are conducted with fixed dosage of

drugs. The conclusions which can be drawn from singlefixed-dose studies are very limited. If one drug producesbetter results than another, the difference may be dueentirely to the doses chosen, and an otherwise identicaltrial with different doses might produce exactly theopposite result. If each drug is administered at two ormore levels of dosage, and if the larger dose has largeraverage effects than the smaller, a reasonable basis ofcomparison is possible between the dose-response linesfor each drug. But it is seldom possible in practice toachieve a graded response, because the range between theapparently ineffective dose and the evidently toxic doseis usually too small.To avoid this difficulty, doses in the present trial were

selected not by an arbitrary weight of drug but by theresponse of the patient to treatment. Initially the dosesprescribed were 720 mg. aspirin, 100 mg. phenylbutazone,500 mg. mefenamic acid, or 200 mg. flufenamic acid,each given three times daily. In order to adjust the doseto each individual patient, all patients were seen at theend of the first week in each period; their progress wasbriefly reviewed and the physician had the option ofdecreasing or increasing the daily dose by one third (byaltering the frequency of medication to twice or fourtimes daily) if it seemed desirable on grounds of thera-peutic response and toxic manifestations. Provisionwas also made for discontinuation of a drug if worseningof symptoms or toxic effects were severe. In such a casethe patient proceeded immediately to the drug plannedfor the next period. Occasionally a short period withouttreatment was adopted before resuming the trial sequence.The rigidity of design necessary for unbiased comparisonand accurate analysis was therefore combined withappreciable freedom of manoeuvre for the physician inthe treatment of patients.

In addition, at the beginning of each period, eachpatient was given 200 tablets of paracetamol (500 mg.)

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METHODS OF DRUG ASSESSMENT

with instructions to take one or two tablets as necessaryevery four hours if additional pain relief was required.Any established treatment with antimalarials or steroidswas continued in unchanged dosage. Self medicationwith any other drug was discouraged, and the generalpractitioners attending the patients were requested not toprescribe any additional remedies.

Three methods of monitoring the consumption ofdrugs given in the trial were used:

(i) Containers were returned at each attendance andthe number of unused capsules and tablets recorded.

(ii) Patients themselves recorded the number ofcapsules and tablets they had taken in the morning andafternoon each day on progress charts (which aredescribed in section 3c below).

(iii) At each visit to hospital a specimen of urine wascollected for analysis.

(3) Measurements and RecordsRecords were made by the physicians, the physio-

therapists, and the patients themselves, and informationwas compiled also from records of laboratory investi-gations.

(a) Physician's Assessments.-Each physician com-pleted one or other of two standard forms designed forthe trial each time a patient was seen. At the first visitsome relatively stable individual characteristics wererecorded (age, functional capacity on a four-point scale,duration of disease also on a four-point scale, presenceof positive criteria of disease according to the criteria ofthe American Rheumatism Association (Ropes and others,1959)), together with a note of drugs prescribed in theprevious week. These details were not repeated atsubsequent visits. Otherwise the forms were largelysimilar. The version used at return visits is shown, withslight rearrangement for purposes of reproduction, inFig. 1 (overleaf).At the first visit, and at subsequent visits at which

treatment was changed, the physician recorded thepatient's reported duration of morning stiffness (15minutes to greater than 2 hours on a scale 1-5), thefrequency of waking at night (nil to more than four timeson scale 0-5), and the presence or otherwise of spon-taneous pain and pain on movement in the past week (as"absent", "intermittent", or "constant"). These aretogether referred to as the "rheumatoid" group ofsymptoms. The occurrence of certain symptoms whichmight be attributed to the drugs given was noted on athree-point scale. These symptoms were anorexia,nausea, vomiting, dyspepsia, diarrhoea, stomatitis, sorethroat, rash, oedema, headache, vertigo, and eye symp-toms. These are later referred to as "symptomssuggesting toxicity". A similarly scaled recording wasmade of the presence or absence of joint pain as thephysician observed the patient move the following jointsin turn through their full range-neck, hands, wrists,elbows, shoulders, hips, knees, ankles, and feet. Lastly,at the end of the second and third periods, the physicianrecorded the period containing the drug which the

patient felt had benefited her most. The drug given inperiod d was according to the overall preference of thepatient after periods a, b, and c. Sometimes the drugremembered as having given most pain relief was notpreferred overall because of the presence of unwantedsymptoms during its administration. No detailedrecords were made at visits when dosage was reviewedunless the drug was discarded altogether and a new periodof treatment was started.

(b) Physiotherapist's Assessments.-These were madeinitially and at the end of each period of treatment witha given drug. They consisted of:

(i) recording the patient's weight,(ii) measuring the proximal interphalangeal joint

sizes by means of jewellers' rings (Hart and Clark1951),

(iii) measuring the maximum grip generated by eachhand (using a sphygmomanometer cuff inflated to30 mm.Hg and recording the average of three readings),

(iv) measuring the time taken to perform a simpledexterity test with each hand in turn (in which marbleswere taken from a tray alongside and placed in the holesof a solitaire board situated in front of the patient),

(v) measuring the angle of maximum active shoulderabduction,

(vi) measuring the time taken to walk a standarddistance (47 feet) using whatever aid was necessary (andthe same aid on each subsequent occasion).

(c) Patient's Assessments of their Day-to-Day Well-being.-These were recorded on a weekly progress chart.Four charts were supplied at the beginning of a periodtogether with reply-paid envelopes so that each could bereturned by post as soon as it was completed. Entrieswere made by marking appropriate squares in answer tothe questions "Do you feel better?", ". . . much thesame?", or ". . . worse?" Patients were asked to maketheir entries in the morning and at the end of the day, andto state in the appropriate squares the number of capsulesand tablets they had taken during the morning andafternoon of the day.

(d) Laboratory Investigations.-On entry to the trialand at the end of each period, the erythrocyte sedimenta-tion rate, haemoglobin, and white cell count withdifferential were performed. In addition, the latex andsheep-cell agglutination titres were estimated on thefirst attendance if these had not been done during thepreceding 3 months. On entry to the trial and at both theone-week and four-week (end of period) visits, a specimenof urine was analysed "blind" for glucose and proteinand for the presence of paracetamol, aspirin, and themetabolic products of phenylbutazone and bothmefenamic and flufenamic acids. Paracetamol andaspirin could be recognized by the addition of ferricchloride to the urine. Metabolites of the fenamic acidsfluoresced in ultraviolet light but could not accuratelybe distinguished from each other.

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Protocol No: H.220L.55.3

THE LONDON HOSPITALDEPARTMENT OF PHYSICAL MEDICINE & RHEUMATOLOGY

Clinical Evaluation (on admission to trial use form L.55.2)1. Name 2. No. of weeks completed in this period

Trial Number

Date

Current Trial Period a b c d

3. Complete this section one week after startingDrug satisfactory ILower dose needed 2Higher dose needed 3Drug must be changed 4

1 2

new treatment4. Comment:

Complete sections 5-11 when treatment is changed, i.e. normally at 4-weekly visits,but after I week if treatment is unacceptable

5. Duration of morning stiffness 1515-

(Minutes) 30-60-120+

2345

6. Nu mber of times waking at night0 1 2 3 4 5+

7. Symptoms suggesting toxicity

10 ? +

anorexia 1 2 3nausea 1 2 3vomiting 1 2 3dyspepsia 1 2 3d iarrhoea 1 2 3stomatitis 1 2 3sore throat 1 2 3rash 1 2 3oedema 1 2 3headache 1 2 3vertigo 1 2 3eye symptoms* 1 2 3other* 1 2 3

* specify

12. At end of periods b and c, encircle patient'schoice of treatment which has relievedsymptoms most effectively.

after period b a bafter period c a b c

8. Spontaneous pain absent Iintermittent 2constant 3

9. Pain on movement absentintermittentconstant

10. Joint pain nowmovement r

23

on full range of active

right0 ? +

left0 ? +

I __

neck 1 2 3hand 1 2 3 1 2 3wrist 1 2 3 1 2 3elbow 1 2 3 1 2 3shoulder 1 2 3 1 2 3hip 1 2 3 1 2 3knee 1 2 3 1 2 3ankle 1 2 3 1 2 3foot 1 2 3 1 2 3

1~~~~~~~~~~~~~I I. Physician

Dr. TegnerDr. MasonDr. CurreyDr. Duggal

I Dr. Pritchard 52 Dr. Glick 63 Dr. Barnardo 74 Other (specify)

13. Treatment prescribed at this visit:

Further Comment:

Fig. l.-Form used by physicans to record progress of each patient

I 0

-1

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(4) Analysis of Findings

(a) Rating SystemThe various items reported by the physicians (see

Fig. 1) were later summarized as three ratings or scorescomputed as follows:

(i) Rheumatoid symptom rating100

2-1(2a + b + 2c + 2d -6)

where a = duration of morning stiffness (1-5)b = times waking each night (0-5)c = spontaneous pain (1-3)d = pain on movement (1-3)

(The constants in the equation ensure that the ratingtakes values from 0 to 100 only and determine therelative weights attributed to different symptoms. Theweighting was arbitrary, based on clinical judgement:moderate changes in the weighting factors have noappreciable influence on the results of the trial).

(ii) Joint pain on movement rating = 100 f(iii) Symptoms suggesting toxicity rating = 100 e

a, b, c, and d, are the actual ratings for the items so

lettered, and e and f are the means of the individualratings respectively for painful joints and symptomssuggesting toxicity (rating present as 1, doubtful as 0-5,and absent as zero). Each rating lies between zero and100 per cent., representing the range between completeabsence and maximal intensity respectively of all items.

(b) Use of ComputerData from every form completed by a physician,

physiotherapist, or patient (2,312 forms comprising in allabout 10,000 items) were punched on paper tape suitablefor use with an Elliott 803 computing system. Thetape was then read into the computer, and the datachecked for errors and inconsistencies before being storedin a more permanent form on magnetic tape.

Calculation of the scores (Section 4a), listing ofspecific items of information, and much of the analysis

were then obtained from this store by means of computerprogrammes either written by two of the authors (M.W.and W.F.), or taken from the Elliott programme library.A further account of the principles followed in analysisby computer has been published elsewhere (Weatherall,1967).

Results(1) Patients admitted to the Trial

Details are shown in Table I of the principalmeasurements made on all patients at the beginningof the trial. These observations represent the stateat one moment in the course of a chronic disease ineach of 68 patients: moreover, nearly all the patientswere receiving analgesic drugs and sometimessteroids or antimalarial drugs. Consequently, therange of scores for rheumatoid symptoms and forjoints painful on movement extended to zero,although other criteria observed in the patients withzero scores left no doubt about the diagnosis andgave opportunity for therapeutic improvement toappear. As the ranges show, most of the measure-ments follow a positively skewed distribution, andappropriate caution has been adopted in laterstatistical analysis.

(2) Variation between Assessors in the TrialPart of the apparent variation between patients

is probably due to the assessors rather than thepatients themselves. In Table II (overleaf) some ofthe observations shown in Table I are analysedaccording to the physician who admitted the patientto the trial. Two physicianseachsawvery fewpatientsand their results are combined as one doctor,"E".Three of the rows of the Table refer to assessmentsderived from observations of the physicians them-selves; that is, the rheumatoid symptom score, the

TABLE IPATIENTS ON ADMISSION TO TRIAL

Mean of 68 Mean of 8 Range in Standard deviationClinical Particulars Patients Patients 68 of single

Admitted who Withdrew Patients observation

Age (yrs) .. .54 60 19-76 11*2Rheumatoid Symptoms Score (per cent.) .. 57 49 0-100 15-9Pain on Joint Movement Score (per cent.) .. 41 31 0-100 22-9Symptoms Suggesting Toxicity Score (per cent.) 11 20 0-53 13-6Weight (lb.) . .135 135 85-221 26-2Mean Ring Size (mm. diameter)...19 20 11-29 4-1Grip Strength (mm. Hg) .. . 146 145 44-300 67-0Dexterity test time (sec.) .. .27 29 16-55 9 0Abduction Angle .. .281 258 79-360 64-8Walking Time (47ft) (sec.)* . .21 38 9-55 14-3ESR (mm./hr) .. .40 45 6-90 21Haemoglobin (g./100mi.). ..12 12 9-16 1-7White Blood Cells (per c. mm.) .. . 7,600 8,600 4,000-20,500 2,600

*Excluding one patient with a walking timc of 172 seconds.

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TABLE IIPROPERTIES ON ADMISSION IN RELATION TO PHYSICIAN

Physician ...A B C D E*

No. of Patients...8 20 22 12 6

tRheumatoid Symptoms Score (per cent.)...59±6 53±3 63±3 51±6 57 i10

tPain on Joint Movement Score (per cent.)...37±7 29±4 61 ±4 31±6 34±6

tSymptoms Suggesting Toxicity Score (per cent.) 27±5 16±4 4±1 5±2 15±6

tGrip Strength (mm. Hg) .. .149±21 180±18 132±14 125±19 119±19

tDexterity TestTime (sec.)...29±6 25 1 26 1 29±3 35 5

tESR (mm./hr) .. .38 ± 10 30 ± 5 44 4 48 ± 6 42±11

$Latex Titre 1: 40-1 160...2 (25) 2 (10) 3 (14) 1 (8) 3 (50)>1: 160 3 (37) I1 (55) 16 (73) 6 (50) 1 (17)

'SCAT Titre 1: 32-1: 64.2 (25) 1 (5) 4 (18) 0 (0) 0 (0)>1:64 2 (25) 4 (20) 8 (36) 2 (17) 1 (17)

*E refers to the combined results of two physicians each of whom saw too few patients to warrant separate reporting.tMean ± S.E.$No. of patients, with percentage of each physician's patients in parentheses.

painful joint score, and the toxic symptom score.The next three rows refer to assessments made byphysiotherapists (grip strength and dexterity) orlaboratory procedures (ESR). Several physio-therapists were concerned, but any associationbetween a particular physician's patients and a parti-cular physiotherapist was fortuitous. Also there isno reason to expect bias of the ESR associated withthe particular physician. These three criteria cantherefore be used to examine whether all the physi-cians had the same standard of severity of disease inadmitting patients to the trial. It appears thatPhysician B in fact accepted a larger proportion ofless severely ill patients, because the mean gripstrength is greater, dexterity test time shorter, andESR lower in his patients than any other group(P<0 05 on rank order). Physician A possiblyfollowed a similar practice, though with only eightpatients admitted the evidence is scantier, but thereis little difference between the groups seen by C, D,and E in the measurements not made by thephysicians themselves.When the physicians' own assessments are

examined, other differences appear. The rheuma-toid symptom scores do not differ significantly, butthe pain on joint movement was rated very signifi-cantly more severely by Physician C (P<0-001).As there is little reason to suppose that C's patientsdiffered greatly from those admitted by D or E, itappears probable that the high scores represent thereaction of the physician rather than a real differencein the patients. Physician C differed from the otherphysicians in at least two notable ways: she was theonly female physician and herself suffered fromrheumatoid arthritis. The opportunities for per-forming trials in which the sex of the physician and

the illness of the physician can be included in theexperimental design are very limited, but this isolatedobservation suggests that neither variable can safelybe ignored in any investigation of responses totreatment. Other differences appeared betweenphysicians. Physician A, and to some extent B andE, reported a much higher mean number of certainsymptoms (such as nausea, anorexia, or sore throat)in the patients they admitted than did C and D.Indeed, symptoms not obviously related to thepatient's disease were recorded exceptionally rarelyby C, who found no such symptoms in 65 per cent.of patients. The corresponding figure for all otherdoctors is 18 per cent (x2= 11 02; P<0-001).Differences in assessment between different physi-cians are well known (Cochrane, Chapman, andOldham, 1951; Joyce, 1962b), but they are notalways explicitly considered in reports of clinicaltrials. Any systematic transfer of patients fromone physician to another could produce significantchanges in scores which might wrongly be attributedto treatment given; as for instance, if the patientswere all admitted by a consultant and subsequentlyreviewed by a registrar. In this trial patients wereseen by the same physician throughout except whenabsence from the clinic made this impossible.In all, seventeen patients were seen at least once by aphysician other than the one who had admittedthem to the trial, but twelve of these changesoccurred at the end of the fourth period and havelittle influence on the main assessment of the drugs.Most of the remaining five changes involved physi-cians whose ratings did not show evident differences,and in any case the number is such a small fractionof the total that any influence of the change of ratescan safely be ignored in the subsequent analysis.

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It is also evident that some differences in ratingoccurred between physiotherapists, but these werenot of sufficient magnitude nor so systematic as tocause serious errors of interpretation.

(3) Previous and Concurrent TreatmentsAll but three of the 68 patients had been taking

analgesics regularly, mostly acetylsalicylic acid orphenylbutazone alone or in compound tablets(Table III). Seven patients had already receivedmefenamic acid from their hospital doctor or generalpractitioner. In 21 patients another drug orphysiotherapy was continued unchanged for theduration of the trial (Table IV). Prednisone wasused in eleven subjects in a daily dose between 2-5and 7-5 mg. each. Chloroquine (200 mg. daily)was used in three subjects.

TABLE IIIANALGESIC IN REGULAR USE IMMEDIATELY BEFORE

TRIAL

Analgesic No. of Patients

Acetylsalicylic acid alone or in combination 45Phenylbutazone alone or in combination 27Paracetamol alone or in combination 8Mefenamic Acid alone or in combination 7Indomethacin ..5None reported ..3

TABLE IVTREATMENT MAINTAINED CONSTANT DURING TRIAL

Treatment No. of Patients

Prednisone (2 5 to 7 - 5 mg. daily) 11Physiotherapy... 7Chloroquine (200 mg. daily) 3Gold .. 0No concurrent therapy...47

Total 68

(4) Attendance during the Trial and WithdrawalsTable V sets out the actual duration of the 244

treatment periods. Of these 189 (77 per cent.) werewithin 3 days of the intended 4-week duration.

Nearly always these periods were consecutive for

TABLE VDURATION OF TRIAL PERIODS

No. of Days No. of Periods

<25 2628±3 18935 3 17>38 12

Total .. .. .. .. 244

a given patient but on five occasions a period (ofaverage duration 19 days) intervened between theuse of a drug which had been prematurely dis-continued and the start of the next treatment.

Eight patients did not complete three periods andwere considered as "withdrawals" (Table VI).Four withdrew for ostensibly social or personalreasons; two of these were receiving aspirin and oneeach phenylbutazone and flufenamic acid at thetime of withdrawal from the trial. Four withdrewfor apparent medical reasons: one who was receivingphenylbutazone suffered an exacerbation of herarthritis; one who was receiving aspirin developedsymptoms related to hypertension; one who wasreceiving steroids as well as mefenamic acid de-veloped symptoms of an acute gastric ulcer whichwas radiologically confirmed; and the fourth, alsoreceiving mefenamic acid, was taken to anotherhospital than our own after gastro-intestinalbleeding* at home. These two patients withgastric ulcers recovered with conservative treatmentand withdrawal of mefenamic acid. The eightpatients who withdrew included a higher proportionover the age of 60 than the rest of the patients, anda higher proportion (6/8) graded in functionalcapacity 3 than the patients who remained in thetrial (9/60): the latter difference, which is highlysignificant (x2 = 11-5; d.f. = 1; P<0-001), wassupported also by the several independent measuresof functional capacity.

TABLE VINUMBERS OF PATIENTS ADMITTED AND WITHDRAWN

Total admitted 68

Completed 3 periods.60

Treatment ineffective .. . . IIntercurrent illness.Withdrew Unwanted reactions attributed to treatment 2 8Unwilling to continue I

Social reasons 2Not known.

Completed fourth (optional) period 52

(5) Physicians' Anticipation of ProgressWhen admitting a patient to the trial, the physician

indicated in completing his form whether he thoughtthe patient would improve, remain unchanged, ordeteriorate during the trial. No qualification of thisstatement was asked for. Only two patients fellinto the last category; 33 were expected to improveand 33 to remain unchanged.

* It was initially reported that this patient was admitted to hospitalafter an haematemesis (Barnardo and others, 1966). Furtherenquiries did not confirm this report and it now appears that thepatient was admitted with melaena and a haemoglobin of 7-4 g./100ml. No ulcer was reported at a barium meal about 2 weeks later.

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No consistent pattern distinguished the propertiesof patients expected to improve from those notexpected to change. No mean values ofany variablediffered significantly between these two groups.The greatest contrast was shown in the reports ofsymptoms suggesting toxicity (lower in thoseexpected to improve) and pain on movement (loweramong those not expected to change). Onephysician (A) anticipated improvement in all butone of his eight patients, while two physicians(listed jointly as E) put none of their six patients inthis category.

Fig. 2 illustrates the behaviour during the trial offour measurements according to the two mainpredictive groups. After one 4-week period in thetrial, the painful joint score and the grip strengthimproved slightly more among patients expected toimprove than among those not expected to change.After three trial periods, however, this anticipationwas no longer borne out.

Rheuma toidsymptomrating(percent.)

Jointspainfulon movement(percent.)

Grip (mm.H9)

Symptomssuggestingtoxicityrating(percent.)

Fig. 2.-Prol--Mean vs---- Mean va

trial.

(6) ProgrWhen

the mean,the first I

periods c

Rheumatoid 60symptom

(percent.) 50

Joints 4]painful onmovement(percent.) 30

Grip (mm.Hg) 150 ]

16030

Dexteritytest time(sec.) 25 -

E.S.R. 1(mm.Hg) ]

35 -

2 3 4 S.E.PERIOD

Fig. 3.-Progress of all patients during trial.Initial observations based on 68 patients.Final observations based on 50 patients.

65 - large compared with the random variation, but the

consistent occurrence of a trend in the same direction55 ". in most measures suggests that the effect was real.

In some measures, for instance of dexterity, the45 improvement is probably due to practice in per-4 5 forming the test. In others, such as the rheumatoid

symptom score, therapeutic optimism engendered3 5-- ] by the use of new remedies may have contributed.

___________ It will be noted that the improvement was not sharedby the ESR, which increased (insignificantly)throughout the first two periods. The means of

1 measurements after the third and fourth period are-s not precisely comparable with earlier means,

150 - "__________-~~~ _ because some patients had withdrawn. Thesepatients usually had unfavourable scores and their

160 - / absence resulted in apparent improvement of the_________________________ means, including that of the ESR. Even if the

20 eight patients who withdrew before completing threeperiods are excluded, the remaining sixty do not

] constitute a balanced set in that some treatments10 - occurred more commonly in one period than

another. In view of the improvement in successive0- i

E.periods, comparisons on the sixty introduce some

PERIOD undesirable bias.The most satisfactory assessment of the effect of

gress according to physician's prognosis. drugs is therefore based on the results of the 36alues for 33 patients expected to improve during trial. g ebsdo h eut fte3alues for 33 patients expected not to improve during patients who received three periods of treatment

according to the original trial design (Table VII,opposite).

ess in Trial and Response to Treatment The initial improvement generally observed in thethe results of all patients are combined, first or first two periods of the trial is distributeds of most measures improved, at least over over all the treatments, and no one stands out asperiod and often also over the remaining clearly better than any or all of the others. Analyses)f the trial (Fig. 3). The gain was not of variance shows no significant differences in the

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METHODS OF DRUG ASSESSMENTTABLE VII

MEAN VALUES AT ENDS OF PERIODS OF TREATMENTPATIENTS 1-36, PERIODS a, b, and c

Periods of TreatmentValues Tested On Admission

(mean ± S.E.) Aspirin Phenylbutazone Flufenamic MefenamicAcid Acid

No. of Patients 36 18 18 36 36

Rheumatoid Symptoms Score (per cent.).55 *0±2 7 49 3 49*5 51*3 50*3

Pain on Joint Movement Score (per cent.) 44-9±4-2 38-6 33 9 37-6 35-2

Symptoms Suggesting Toxicity Score (per cent.).. 4-5± 1 8 *9 7*5 8 *4 9*9

Mean Ring Size (mm.) .19-9±0-7 18 1 18-6 18-7 18-7

Grip Strength (mm.Hg). 143±11 138 154 157 147

Dexterity Test Time (sec.).26*2±12 24-8 25 *2 24*0 24* 3

Abduction Angle.278±12 289 285 293 280

Walking Time (sec.)* 18-6±1 8 15 3 17-8 16-4 18-7

ESR (mm./hr.) 44-7±3 3 35 3 49.7 43 5 47-4

Haemoglobin (g./100 ml.).12-1±0-2 12-0 11 3 11-6 11*7

White Blood Cells (per cu. mm.).7,800±500 8,400 7,300 7,500 7,700

*Excluding one patient with walking time on admission 172 seconds.

Table, and it is clear that any superiority which onedrug may have over another is too slight to beapparent against the residual variation which hasnot been excluded by the trial design.As the trial was conducted so that the dose of

each drug was adjusted according to the response ofthe patient, it is not surprising that little differenceshould emerge. The fact that all measurementsfollow a similar trend is important: it shows that thevarious drugs are probably acting by a commonmechanism and gives no ground for distinguishing,for instance, an "anti-inflammatory" action ofphenylbutazone or flufenamic acid from an "anal-gesic" action of aspirin or mefenamic acid.

There is, however, one disconcerting aspect of thisevaluation. When records of drug consumptionare taken into account, it appears that only eighteenof the 36 patients considered here were on allcounts evidently taking their intended medicationthroughout the three periods, and in at least sevenof the 108 patient-periods the intended medicationwas undoubtedly not being consumed, becauseexcessive numbers of unused capsules of the drugissued were returned to the pharmacy. When thesepatients are considered separately, no obviousdifference in their progress is apparent. Thisproblem will be discussed more fully elsewhere(Barnardo and Greenwood, in preparation), but itappears that at least three explanations are possible.The simplest is that the drugs are entirely ineffective:this is most unlikely in view of the evidence already

cited that all these drugs are more effective thandummy medication. The second is that, whateverthe physician may direct, the patient adjusts herdosage according to the state of the disease, andconsequently reduces dosage as improvement occurs.The third, which is supported by some evidence fromanalyses of urine, is that some patients obtain orcontinue to consume already available drugs fromother sources, and so diminish their requirementfor the medication supplied in the trial. Whateverthe explanation, much more research into thebehaviour of patients is clearly necessary before anyaccurate appraisal of drugs is possible in out-patient trials of this sort.

(7) Adjustment of Dosage during TreatmentWhatever patients may have done about dosage

without reference to their physician, the quantity ofdrug prescribed to be taken was quite commonlyaltered after the first week of treatment. When achange was made, it was usually to a higher dosage;changes were not appreciably commoner with onedrug than another (Table VIII, overleaf). On thesupposition that the revised doses were all close to theoptimal, the mean doses so obtained for the fourdrugs can be taken as equipotent (Table VIII, lastline). On this basis, the potencies of the new drugsrelative to phenylbutazone are 0 5 (flufenamic acid)and 0 * 2 (mefenamic acid): on the same basis, aspirinis about one-seventh as potent as phenylbutazone.

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382 ANNALS OF THE RHEUMATIC DISEASESTABLE VIII

PREFERENCES AND DOSE ADJUSTMENTS

Treatment

No. of Patient Periods ..

No. in which Dose was UnalteredIncreasedReducedAbandoned ..

Preferences in Fourth Period ..

Mean Dose finally Adopted (g./day)..

Treatment was abandoned with particular drugsbecause of unwanted effects on thirteen occasions.Most of these occurred with the newer drugs. Thedifference might be fortuitous (P- 024), but thenumbers involved are small and it would be unjusti-fied to conclude that there is no difference in toxicitybetween the various drugs in the doses used. Theincidence of individual symptoms is shown in TableIX. Any apparent differences between drugs in theincidence of a symptom are insignificant, except thatseven of the nine reported rashes occurred while thepatients were receiving mefenamic acid. Thisgreater incidence is significant (by Fisher's exacttest; P = 0 02), but among so many comparisons asingle significant finding might well appear at thislevel by chance. However, mefenamic acid alsoappears in Table IX as a cause of vomiting, stoma-titis, and diarrhoea, and it must be recalled that twosubjects who withdrew, one with proven and onewith presumed peptic ulceration, both did so afterreceiving mefenamic acid. It seems probable thatthis drug is least satisfactory in its gastro-intestinaleffects. It is important also not to dismiss differ-ences as non-existent because they do not reachconventional levels of significance with the relativelysmall numbers observed here.

TABLE IXUNWANTED EFFECTS tN 68 PATIENTS IN 192 PERIODS

per cent. IncidenceSide-Effects _ Drug with Highest

On Entry During Incidence* (per cent.)to Trial Trial

Anorexia 4 1 3 Aspirin (17)Nausea .. 6 9 Aspirin (14%)Vomiting .. 0 3 Mefenamic Acid (5 %)Dyspepsia .. 12 29 Flufenamic Acid (34 %)Diarrhoea .. 3 9 Mefenamic Acid (12%)Stomatitis .. 7 9 Mefenamic Acid (12%)Sore throat 4 7 Aspirin (9 %)Rash 2 5 Mefenamic acid (11Oedema .. 22 26 Aspirin (43 Y.)Headache .. 10 17 Aspirin (26%)Vertigo .. 4 10 Phenylbutazone (133)Eye symptoms 4 15 Phenylbutazone (23 %)Other .. 9 16 Flufenamic Acid (21 %)

*The differences between drugs do not reach conventional levels ofstatistical significance. See text for discussion.

(8) Paracetamol ConsumptionIn addition to a prescribed quantity of trial drug,

sometimes consumed faithfully and sometimes not,patients were provided also with tablets containing500 mg. paracetamol as a supplementary or reservemedication. Consumption of these tablets, asjudged by the numbers not returned, varied greatlyfrom patient to patient and usually varied lessbetween periods for a given patient than it variedbetween patients. Interpretation was complicated,as expected, by some failures to return boxes oftablets at the end of periods. Such failures werenot associated with any particular trial drug. Themean quantity of paracetamol apparently consumeddid not differ significantly in relation to the trialdrug taken at the same time.

(9) The Fourth Period of Treatment56 patients remained in the trial for a fourth

period. During this period, the treatment prescribedwas a repetition of whichever drug had appearedmost satisfactory in the first three periods. Therepetition served two purposes. It allowed anobjective display of the patients' preferences, and ifany one drug had been particularly popular, itwould appear as the most frequent choice in thisperiod. Also it provided duplication of theresponses of each patient to one treatment, and sohad special significance in evaluation. If thattreatment was consistently more (or less) effectivethan the other treatments, the fourth period resultswould agree more closely with the previous resultson the same treatment than with the results on othertreatments.

Neither of these criteria indicated any differencebetween the drugs. The frequency of preference isshown in the penultimate line of Table VIII. Thepreferred treatment was not necessarily the same asthe one in which objective measures showed mostimprovement. Phenylbutazone was preferred onthe highest proportion of possible occasions and

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flufenamic acid on the lowest, but the differences aresmall and might readily arise by chance. Thedifferences between ratings in the fourth and earlierperiods showed no consistent pattern, and there isno reason to suppose that repetition of the preferredtreatment achieved any better objective results thanwere obtained with different drugs earlier in thecourse of the trial.

(10) One Year Later13 months after the first patient had completed

the trial, a survey was begun of the progress of allpatients who had left the trial. No exact timing ofthis survey was arranged, but all patients werereported on at some point between 1 and 2 yearsafter they had completed or withdrawn from thetrial. Re-examination by physician and physio-therapist was intended, but changes of staff in theintervening year resulted in a large proportion ofassessments not being made by the original observers.Several patients were not specifically re-assessedbecause they were seen by new staff who were notfamiliar with the requirements of the trial. Eightpatients were not seen at the clinic, but reports fromdoctors elsewhere were obtained about seven ofthese. One, aged 68, had died of congestive heartfailure after a myocardial infarct 23 weeks afterleaving the trial. The remainder were in varyinghealth. None had more disability than expectedfrom their state during the trial, and some hadimproved modestly. None had recognizable persis-ting ill-effects which might be attributed to the drugsthey had received. The final missing patient had notseen her own doctor and could not be found at home,but was reported by neighbours to be very active andat work most of the day and evening. The recordedchanges in the patients seen at our clinic are notpresented in detail because they are influenced by

uncontrolled variation between observers and con-tain only a potentially biased selection of all thepatients (Table X).

(11) Use of Multiple MeasurementsTreatment in rheumatoid arthritis can be assessed

in many ways. In this trial at least fourteen criteriahave been used without exhausting the possibilities.Different measurements have different significance.For instance, the number of joints painful on move-ment, the duration of morning stiffness, or theerythrocyte sedimentation rate might each be takenalone as measures of the patient's illness. If so, itwould be desirable to show that changes in any of themeasurements were significantly correlated withchanges in the rest. Otherwise the concept of anysingle measurable process implicit in the words "thepatient's illness" would become nebulous and itwould be desirable to think again about what wasbeing achieved by treatment.Apart from the measurements which are closely

related to arthritis, others (such as the haemoglobinconcentration or the white cell count) have morediffuse significance, and some (such as the specialcollection of symptoms suggesting toxicity) aremainly evidence of undesirable effects of treatment.If a drug consistently produced unwanted effects atthe same time as it reduced rheumatoid symptoms,the "toxic" score would be correlated with the directcriteria of the rheumatoid disease. Consequentlythe absence of such correlation would be moreencouraging than its presence.

It can also be argued that so many sources ofinaccuracy have been disclosed that the data collectedwere not worth formal analysis. However, differentkinds of data are vulnerable in different ways. Ifthe errors were of such magnitude as to make aparticular kind of measurement useless, correlation

TABLE XPROGRESS OF NINETEEN PATIENTS SEEN AFTER ONE YEAR*

Mean Values of Eight Measurementsat Each Stage

S.E.Measurements At After Period After of Each

Entry 1 year Mean1 2 3 4

1. Rheumatoid Symptoms Score (per cent.).53 49 51 51 45 50 ± 3-62. Pain on Joint Movement Score (per cent.).42 37 34 40 31 31 ± 5*33. Mean Ring Size(mm.).. 20 19 18 17 18 19 ± 0 94. Grip Strength(mm. Hg) 144 143 151 147 144 123 ±17-95. Dexterity Test Time (sec.).27 26 25 25 26 291 ± 2-16. Abduction Angle 286 294 280 293 292 2972' ±15-27. Weight (lb.).128 129 129 129 130 130 ± 6-08. Walking Time (sec.).19 20 18 18 18 233 ± 6-4

*These patients were all from the complete replicate 1-36 (1) excluding one patient value 61 sec.(2) excluding one patient value 20'(3) excluding one patient value 100 sec.

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would disappear between that and other measures.Some sort of overall analysis was therefore justifiableand was in fact reassuring that the trial measure-ments had not been overwhelmed by random events.

Initially it seemed desirable to see how all themeasurements behaved collectively. Correlation co-efficients were therefore calculated between allpossible pairs of fourteen measurements made at thebeginning of the trial, both on the 36 patients whocompleted the formal design and on the 32 others.Each analysis yielded 91 correlation coefficients.With so large a number of coefficients, a few wouldbe expected by chance to exceed conventional levelsof significance. To minimize the influence of suchrandom associations, only those correlations whichwere significant (at the 10 per cent. level) in both setsof patients were taken as important. The choice of10 per cent. rather than the conventional 5 or 1 percent. level followed from the double-testing process,and gives a final probability of a fortuitous correla-tion of at most 1 per cent. These correlations areshown in Fig. 4. They involved particularly thewalking time, the abduction angle, the dexterity testtime, the grip strength, and the ESR. The signs ofthe correlation coefficients depend on whether alow (e.g. grip) or high value (e.g. ESR) meantgreater severity, and they were consistent.

Fig. 4.-Significant correlations between principal measurements.The figure shows pairs of variables between which the coefficients ofcorrelation were significantly different from zero at beyond the 10per cent. level in two independent sets of data (viz. patients 1-36 and37-72). The sign of the coefficient is also shown. Note that a neg-ative sign indicates numerical decrease in one measurement as theother increases, and is as indicative of correlation as a positive sign.

It therefore appeared likely that all these corre-lated measurements were contributing information

about some common process, and a series of fulleranalyses was performed to express the measure-ments in terms of as few components as possible.The method adopted (Harmer, 1961; Seal, 1964)extracted principal components from a correlationmatrix based on most of the variables of Fig. 4,but excluding age, functional capacity, and durationof disease, and including the score for symptomssuggesting toxicity. The twelve variables used wereall measured at five stages in the trial (initially, andafter each 4-weekly period). All except the threelaboratory tests were also analysed in measurementsfrom 44 patients at the follow-up visit from 12 to18 months after entering the trial.

The purpose of such an analysis was to find anumber of weighted combinations, called compo-nents, of all twelve variables. The weights in thefirst component are calculated so that the componentaccounts for as much as possible of all the variabilityin the data; the weights in the second so that itaccounts for as much as possible of the remainingvariation after the first component has been allowedfor, and so that it is not correlated with the firstcomponent, and so on. If the number of compo-nents which account for a significant amount of thevariation is small, say one or two, then the problemis reduced from one of twelve correlated variables toa single component or to two uncorrelated com-ponents.

In these analyses, only one component was con-sistently statistically significant, though the secondand third components had sufficiently clear originsto be given some tentative meaning. The variablesmost highly weighted in the first component includethe grip strength, walking time, rheumatoid symptomscore, abduction angle, and painful joint score. Allthese variables are clearly associatedwith the patient'sdisease, and so the rating for a particular patient onthis component gives a single numerical measure-ment of the severity of that patient's illness relativeto the other patients included in the same analysis.This component accounted in several analyses forabout 29 per cent. of the total variation in all themeasurements, so its isolation, though valuable, stillleaves much to be accounted for. (If all thetwelve variables had been entirely uncorrelated,and twelve factors had been extracted, each factorwould have accounted for one variable, i.e. about8 per cent, of the total). In fact, the second compo-nent accounted for about 16 per cent., and wasassociated particularly with the patient's weight andalso with mean ring size. These two variables aresignificantly (and not surprisingly) correlated witheach other and not much with the remainingmeasurements. The third component was related

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particularly to the white cell count, and negligiblyto any other measurement.

This method of analysis was applied once again,on this occasion to the changes in each kind ofmeasurement during a period of treatment, insteadof to the measurements themselves. Two informa-tive findings might be obtained in this way. First, ifthe variation in scores from period to periodrepresented a real change in severity of the rheuma-toid process, the changes should be correlated inmuch the same way as the measurements themselves.If, on the other hand, the variation was due to anassortment of unrelated influences, no such correla-tion would be expected. Secondly, given realchanges (in the sense just outlined), the componentsobtained by this analysis would give the best singlemeasure of the magnitude of the change and soprovide a basis for determining the effects ofdifferent drugs.

In fact, the changes in different measurementswere not appreciably correlated. Correlation co-efficients between pairs of differences exceeded+ 0 4 or were less than-0- 4 on only eight of 220possible occasions, and did not recur consistentlyin consecutive periods. Evidently, therefore, thevariation in particular measurements within theframework of this trial had little or no generalsignificance about the progress of the disease, andno additional information about the efficacy ofdrugs was obtained by this unifying analyticalprocedure.

(12) Serological Tests and Severity of DiseaseIf the component isolated by the foregoing analysis

is meaningful, it would be expected to relate toother measures of disease which had not been includ-ed in its calculation. Two such measures availablewere the titres obtained in the latex test and the sheepcell agglutination test (Table XI). These titres arerelated to each other, in that sera which agglutinated

TABLE XlRELATION OF LATEX TEST SENSITIVITY TO SHEEP CELLAGGLUTINATION TITRES ON ADMISSION TO TRIAL

Latex Titre ISCAT - _ TotalTitre >1 :40 1 :40-1:160 <1:160 Not

recorded

>1 :8 10 5 12 2 291:8-1:16 2 2 4 - 81:32-1 :64 1 1 7 1 10<1:64 - - 7 - 7

Not 1 3 7 3 14recorded

Total 14 11 37 6 68

sheep cells at a high dilution always also gave apositive latex test at high dilution; but the reversewas not true. The association is significant atabout the 5 per cent. level of probability. When thetitres were compared with individual weightings onthe principal component analysis using the Wilcoxon2-sample rank test, the association with the latextitre was significant (P< 0 05) but not that with theSCAT. The association is not strong but in theexpected direction.

DiscussionFrom the point of view of therapeutic benefit, the

results of this trial are straightforward. No appreci-able difference has been found between aspirin,phenylbutazone, mefenamic acid, and flufenamicacid used for 4 weeks at a time, in doses adjusted tosuit the individual patient. Indeed, the results witheach drug are so similar that approximately equi-potent doses can be specified: these are 2,400 mg.aspirin, 330 mg. phenylbutazone, 1,700 mg.mefenamic acid, and 670 mg. flufenamic acid perday. The ratio of doses for aspirin and flufenamicacid (3 6: 1) agrees reasonably well with the4-5 : 1 estimated by Simpson and others (1966),and the ratio for mefenamic acid and phenylbuta-zone (5-1 :1) is practically identical with theestimate (5 1) given by Cahill and others (1965) inosteo-arthritis. Other trials, reported after thiswork was completed, have reached similar conclu-sions (Rajan and others, 1967; Symposium, 1967).To these findings may be added two impressions,neither carrying the weight of statistical significancebut both open to confirmation or the reverse as moreevidence accumulates. One is that phenylbutazoneseemed marginally more popular with patients andseemed repeatedly to appear in various analyses asperhaps a little more often effective than any of theother three drugs. The same modest preferenceover aspirin and over flufenamic acid is clearlyshown in the sequential diagrams of Rajan and others(1967). The other finding is that mefenamic acidmore often caused gastro intestinal disturbance thanthe remainder.The lack of discrimination between the drugs may

mean that there is really no important differencebetween them, apart from dosage. It may alsomean that all our methods of measurement are soinsensitive that they fail to detect real differences.From this point of view, the absence of a dummy orplacebo treatment from the trial is regrettable. Butdifferences between phenylbutazone and dummyhave been demonstrated clearly with less detailedand no more sensitive measures than those used

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here (Joyce and Mason, 1961; Mason, 1962) andrepetition of such a test of validity would not havebeen in the patients' interests. The use of a singleadjustable dose of each drug also prevents anyestimation of the slope of the dose-response curve.But it is unlikely that the very poorly controlledconditions of dosage in a trial of this kind wouldallow any such curve to be constructed.The uniformity in the patients' responses regard-

less of treatment ought to have been foreseen as alikely outcome which would interfere with thecomparative assessment of different methods ofmeasurement. The correlation and componentanalysis is useful in showing how much differentmeasurements contribute to the overall assessmentof patients at the particular stage here considered,but a similar analysis applied, say, to comparablepatients treated with corticosteroids, or to thepresent patients when their disease had progressedfor a further 5 years, might give quite differentweights to different measurements. For this reason,no attempt has been made to develop a "rheumatoidindex" based on appropriately-weighted combi-nations of scores. More ground work is necessarybefore such a development would be generallyuseful. But the methods of analysis used here arevery simple to apply, given adequate computingfacilities, and provided that basic work of obtainingclinical data has been done with rigorous thorough-ness.Most clinical trials depend to some extent on the

assessment of patients by physicians. The observa-tions reported above (p. 378) are a reminder thatvariation between assessors may be one of the largestsources of error in a trial. Without objectivemeasurements to put alongside physicians' assess-ments, the magnitude of such errror is easily over-looked. Also, if patients are allocated to physiciansby the ordinary processes of some clinics, the varia-tion due to differences between physicians canbecome confused with differences between patientsselected for the physicians. Such selection doesnot appear to have had demonstrable effects in thepresent trial, but in other circumstances has turnedout to be the largest single source of variation in anentire trial (Reynolds, Joyce, Swift, Tooley, andWeatherall, 1965).Anyone who may still wish to find evidence of the

worthlessness of ill-designed, uncontrolled, orinadequately controlled trials will discover plentyin the preceding pages. Particularly, one may notethe subjective improvement observed regardless oftreatment in most of the patients, the entirely spuriousappearance of improvement created by the fallingout of some patients, who happened to be among themore severely-ill participants in the trial, and the

contribution of the physician to assessments. Allthese sources of bias are well known. In at least tworecent trials of treatments in rheumatoid arthritis(Currey, 1965; Donnelly, Lloyd, and Campbell,1967), substantial improvement was achieved bothby the active treatment and by the dummy medica-tion. Failure of patients to take drugs as directedis another major source of error, particularly intrials with out-patients (Dixon, Stradling, andWootton, 1957; Joyce, 1962a; Willcox, Gillan, andHare, 1965). The error appears more likely toaffect interpretations of the trial than health of thepatients, as the present results suggest that non-taking of drugs may be a sign of spontaneousimprovement rather than of delinquency. Evidentlythere is a large field for study of the reasons whypatients reject prescribed treatment. Many influencescan be suggested, and until they are examined andunderstood the value of this kind of trial as evidenceabout the therapeutic efficacy of drugs is limited.On the other hand, it is ultimately the only relevant

way of establishing whether drugs in fact are effec-tive in out-patient conditions, and further improve-ments in methodology are urgently needed.

SummaryFlufenamic acid and mefenamic acid have been

compared with aspirin and phenylbutazone overperiods of 4 weeks in women with rheumatoidarthritis.

Evaluation was based on records made by physi-cians, measurements made by physiotherapists,laboratory estimations, and records kept by patientsthemselves.The trial was conducted so that patients and

physicians were not aware which treatment wasbeing prescribed at any time. Consumption ofprescribed treatments was verified by counts ofreturned drugs, tests of urine, and patient's ownrecords.The doses used were adjusted for each drug in each

patient to find a suitable daily amount.The mean daily doses used after adjustment were

aspirin 2 4 g., phenylbutazone 0 33 g., mefenamicacid 1 * 7 g., and flufenamic acid 0 67 g.No differences were detected in the effectiveness of

the four drugs, so that these doses can be regardedas equipotent.

Differences in toxicity were not statistically con-vincing, but suggested that mefenamic acid wasparticularly liable to cause gastro-intestinal distur-bances.The relative value of different measurements was

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assessed and methods of combining them into asingle criterion of progress were examined. Thesestatistical analyses indicated that much of thevariation in the measurements could be accountedfor by a single underlying cause, but that trials atother stages of rheumatoid arthritis were necessaryto develop a generally applicable system of measure-ment.Major sources of variation include differences in

the assessment of patients by different physicians,subjective improvement of patients during the earlypart of a trial regardless of treatment, and failure ofpatients to consume drugs as prescribed. Failureto control these variables does not make a trialworthless, but reduces its sensitivity and is likely toobscure the modest but possibly useful therapeutic

benefits of particular drugs.This trial would not have been possible without help

from many people. We should like to thank particularlyDr. P. V. Piggott, of Parke, Davis and Company, andDr. P. Fowler, of Geigy (U.K.) Limited, for arrangingfor supplies of drugs to our exacting requirements, andfor much other help and continued interest; to Mr. W.Abbot and the staff of the London Hospital ComputerUnit; to Dr. R. M. Greenwood for supervising the testingof urines for drugs, and for help in analysis of data; tothe physicians and physiotherapists in the Departmentsof Physical Medicine and Rheumatology; to Mrs. I.Howard for extensive clerical assistance; and to thepatients themselves who undertook numerous additionaltests and visits to hospital for the purposes of the trial.The work was supported by a grant (to M.W.) from theMedical Research Council.

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of 499 patients with peripheral rheumatoid arthritis).Asher, R. (1948). Lancet, 2, 771 (A method of testing analgesics).Barnardo, D. E., Currey, H. L. F., Mason, R. M., Fox, W. R., and Weatherall, M. (1966). Brit.

med. J., 2, 342 (Mefenamic acid and flufenamic acid compared with aspirin and phenyl-butazone in rheumatoid arthritis).

Cahill, W. J., Hill, R. D., Jessop, J., and Kendall, P. Hume (1965). Ann. phys. Med., 8, 26 (Trial ofmefenamic acid).

Cochrane, A. L., Chapman, P. J., and Oldham, P. D. (1951). Lancet, 1, 1007 (Observers' errors intaking medical histories).

Coodley, E. L. (1963). West. Med., 4, 228 (Evaluation of drug therapy in rheumatoid arthritis-astudy of flufenamic acid).

Currey, H. L. F. (1965). Ann. rheum. Dis., 24, 382 (Intra-articular thiotepa in rheumatoid arthritis).Dixon, W. M., Stradling, P., and Wootton, I. D. P. (1957). Lancet, 2, 871 (Outpatient P.A.S.

therapy).Donnelly, P., Lloyd, K., and Campbell, H. (1967). Brit. med. J., 1, 69 (Indomethacin in rheu-

matoid arthritis: an evaluation of its anti-inflammatory and side effects).Feamley, M. E., and Masheter, H. C. (1966). Ann.phys. Med., 8,204 (A controlled trial of flufenamic

acid therapy in rheumatoid arthritis).Harmer (1961). Quoted in National-Elliott 803 Library Programme LS 9.Hart, F. Dudley, and Clark, C. J. M. (1951). Lancet, 1, 775 (Measurement of digital swelling in

rheumatoid arthritis).Joyce, C. R. B. (1962a). J. chron. Dis., 15, 1025 (Patient co-operation and the sensitivity of clinica I

trials).- (1962b). Proc. roy. Soc. Med., 55, 776 (Differences between physicians as revealed by clinical

trials).and Mason, R. M. (1961). "Atti Lega int. contro il Reumatismo". X Congr., 2, 1255.

Mason, R. M. (1962). Proc. roy. Soc. Med., 55,512 (Clinical trials).Rajan, K. T., Hill, A. G. S., Barr, A., and Whitwell, E. (1967). Ann. rheum. Dis., 26,43 (Flufenamic

acid in rheumatoid arthritis).Reynolds, E., Joyce, C. R. B., Swift, J. L., Tooley, P. H., and Weatherall, M. (1965). Brit. J. Psy-

chiat., 111, 84 (Psychological and clinical investigation of the treatment of anxious out-patients with three barbiturates and placebo).

Ropes, M. W., Bennett, G. A., Cobb, S., Jacox, R., and Jessar, R. A. (1959). Ann. rheum. Dis., 18,49 (Diagnostic criteria for rheumatoid arthritis, 1958 revision).

Seal, H. (1964). "Multivariate Statistical Analysis for Biologists". Methuen, London.Simpson, M. R., Simpson, N. R. W., and Masheter, H. C. (1966). Ann. phys. Med., 8, 208 (Flu-

fenamic acid in rheumatoid arthritis. Comparison with aspirin and the results of extendedtreatment).

Symposium (1967). "Fenamates in Medicine". Ann.phys. Med., 9, Suppl.Weatherall, M. (1967). Ibid., p. 27 (The value of computers in analysing clinical trials).

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Willcox, D. R. C., Gillan, R., and Hare, E. H. (1965). Brit. med. J., 2, 790 (Do psychiatric out-patients take their drugs?)

Winder, C. V., Wax, J., Scotti, L., Scherrer, R. A., Jones, E. M., and Short, F. W. (1962). J. Pharma-col. exp. Ther., 138, 405 (Anti-inflammatory, antipyretic and antinociceptive properties of

N-(2,3-xylyl) anthranilic acid (Mefenamic acid)).Young, P. (1962). Arthr. and Rheum., 6, 307 (A double blind cross-over comparison of mefenamic

acid (C1-473, Ponstan) with oxyphenbutazone followed by an open comparison with flufenamicacid (C1-440, Arlef)).

L'evaluation des m6dicaments chez des malades externesatteints d'arthrite rhumatismale

REsuME

On compara l'acide flufenamique et l'acide mefen-amique a I'aspirine et a la phenylbutazone pendant desperiodes de quatre semaines chez des femmes atteintesd'arthrite rhumatismale.On basa l'evaluation sur des notes prises par les

medecins, des mesures prises par les physiotherapeutes,des tests de laboratoire et des notes des malades.

L'essai fut arrange en sorte que ni les malades ni lesmedecins puissent identifier le medicament ordonne.Pour verifier la consommation medicamenteuse oncompta les medicaments retournes, analysa l'urine etexamina les notes des malades.Pour arriver a la dose quotidienne appropriee on ajusta

individuellement la dose de chaque medicament.La dose quotidienne moyenne apres l'ajustement fut

de 2,4 g.d'aspirine, 0,33 g. de phenylbutazone, 1,7 g.d'acide mefenamique et 0,67 g. d'acide fluf6namique.On ne trouva pas de difference en ce qui concerne

l'efficacite des quatre medicaments, de mani&re qu'auxdoses indiquees leur puissance peut etre consideree egale.En ce qui concerne la toxicite, du point de vu statistique

les differences furent peu convaincantes, mais on penseque l'acide mefenamique aurait particulierement unetendence a produire des desordres gastro-intestinaux.On evalua la valeur relative de differentes mensurations

et on examina les methodes pour les combiner en un seulcritere du progr&s. Ces analyses statistiques indiquerentque beaucoup de variations des mensurations pourraients'expliquer par une seule cause, mais qu'on aurait besoind'autres essais a d'autres stades de l'arthrite rhumatismalepour developper un syst&me de mensuration d'applicationgenerale.Parmi les sources majeures des variations on trouve

des differences en l'evaluation du malade selon lemedecin, I'amelioration subjective des malades au debutde l'essai independamment de la medication et le fait queles malades ne prennent pas leurs medicaments de lamaniere prescrite. Le defaut de controler ces variablesn'annule pas la valeur de l'essai, mais reduit sa precisionet peut masquer des avantages therapeutiques modesteset possiblement utiles d'un medicament particulier.

La valoraci6n de medicamentos en pacientes ambulantescon artritis reumatoide

SUMARIOSe compararon el acido flufenamico y el acido mefe-

namico con la aspirina y la fenilbutazona duranteperiodos de cuatro semanas en enfermas con artritisreumatoide.La valoraci6n fue basada sobre notas de los medicos,

medidas de los fisioterapeutas, investigaciones delaboratorio y apuntes de los enfermos.La investigaci6n fue conducida de manera que ni los

enfermos ni los medicos conocieron el medicamentorecetado. Para averiguar la toma de los productosrecetados se contaron los medicamentos devueltos, laorina fue analizada y se examinaron los apuntes de losenfermos.

Para Ilegar a la dosis diaria apropiada se ajust6individualmente la dosis de cada medicamento.La dosis diaria media despues de ajuste fue de 2,4 g.

de aspirina, 0,33 g. de fenilbutazona, 1,7 g. de acidomefenamico y 0,67 g. de acido flufenamico.Ne se encontraron diferencias respecto a la eficacidad

de los cuatro medicamentos, de modo que, a dosisindicadas, su poder puede considerarse igual.

Respecto a la toxicidad, las diferencias fueron estadi-sticamente poco convincentes, se sospecha sin embargoque el acido mefenamico en particular puede ocasionardisturbios gastointestinales.

Se consider6 el valor relativo de diferentes modos devaloraci6n y se examinaron metodos para incorporarestos modos en un solo criterio. Analisis estadisticosindican que muchas variaciones de las mediciones puedenposiblemente explicarse por una sola causa, pero senecesitan otras investigaciones de otras etapas de laartritis reumatoide para elaborar un sistema devaloraci6n generalmente aplicable.

Otras fuentes de variaciones incluyen diferencias en lavaloraci6n de los enfermos por diferentes medicos,mejoria subjetiva de los enfermos al principio de lainvestigaci6n independiente de la medicacion y el hechode que los enfermos dejan de tomar los medicamentosde la manera ordenada. El hecho de que estas variablesno se pueden controlar no anula"el valor de la investiga-ci6n pero reduce su precisi6n y puede obscurecer losbeneficios terapeuticos modestos pero posiblementeutiles de un medicamento particular.

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ASSESSMENT OF DRUGS OUT-PATIENTS RHEUMATOID ARTHRITIS