2015. Glycopyrronium Once-daily Significantly Improves

ORIGINAL ARTICLE

Glycopyrronium once-daily signicantly improveslung function and health status when combinedwith salmeterol/uticasone in patients with COPD:the GLISTEN studya randomised controlled trialPeter A Frith,1 Philip J Thompson,2 Rajeev Ratnavadivel,3 Catherina L Chang,4

Peter Bremner,5 Peter Day,6 Christina Frenzel,7 Nicol Kurstjens,7 the GlistenStudy Group

Additional material ispublished online only. To viewplease visit the journal online(http://dx.doi.org/10.1136/thoraxjnl-2014-206670).

For numbered afliations seeend of article.

Correspondence toProfessor Peter Frith,Respiratory Medicine, SouthernAdelaide Local HealthNetwork, Repatriation GeneralHospital, 216 Daws Rd, DawPark, SA 5041, Australia;[email protected]

PAF and PJT contributedequally.

Received 9 December 2014Revised 16 March 2015Accepted 19 March 2015Published Online First4 April 2015

To cite: Frith PA,Thompson PJ,Ratnavadivel R, et al. Thorax2015;70:519527.

ABSTRACTBackground The optimal use of various therapeuticcombinations for moderate/severe chronic obstructivepulmonary disease (COPD) is unclear. The GLISTEN trialcompared the efcacy of two long-acting anti-muscarinicantagonists (LAMA), when combined with an inhaledcorticosteroid (ICS) and a long-acting 2 agonist (LABA).Methods This randomised, blinded, placebo-controlledtrial in moderate/severe COPD patients compared once-daily glycopyrronium (GLY) 50 mg, once-daily tiotropium(TIO) 18 mg or placebo (PLA), when combined withsalmeterol/uticasone propionate (SAL/FP) 50/500 mgtwice daily. The primary objective was to determine thenon-inferiority of GLY+SAL/FP versus TIO+SAL/FP ontrough FEV1 after 12 weeks. An important secondaryobjective was whether addition of GLY to SAL/FP wasbetter than SAL/FP alone.Results 773 patients (mean FEV1 57.2% predicted)were randomised; 84.9% completed the trial. At week12, GLY+SAL/FP demonstrated non-inferiority to TIO+SAL/FP for trough FEV1: least square mean treatmentdifference (LSMdiff ) 7 mL (SE 17.4) with a lower limitfor non-inferiority of 60 mL. There was signicantincrease in week 12 trough FEV1 with GLY+SAL/FP versusPLA+SAL/FP (LSMdiff 101 mL, p

There is limited evidence comparing the efcacy of LAMAversus LABA/ICS,13 and when combined it is unclear if add-itional benets ensue as studies assessing this are very limited.Karner and Cates searched the Cochrane Airways GroupSpecialised Register of trials and cross references for parallelrandomised controlled trials conducted over 3 months or longerin which comparisons were made between tiotropium (TIO)+LABA/ICS, TIO alone or LABA/ICS alone.14 Only threestudies met their criteria. However, of these only one comparedtriple therapy (LAMA/LABA/ICS) with LABA/ICS and it was apilot study of 81 patients.15 They concluded that furtherresearch was necessary in this area.14

Use of 50 g of a once-daily inhaled dry powder formulationof the LAMA glycopyrronium bromide (GLY) via a Breezhalerprovides comparable improvement in lung function, dyspnoea,health status and exacerbations to that of 18 g of a once-dailyinhaled dry powder formulation of TIO via a HandiHaler, thecurrent standard of care for once-daily inhaled LAMA.16 17 GLYalso has a fast onset of bronchodilation on the rst day whencompared to TIO and is highly efcacious in placebo-controlledstudies.4 17 18

The GLISTEN study is a placebo-controlled blinded multicen-tre trial conducted to assess the non-inferiority of GLYcompared to TIO when combined with an LABA/ICS, salme-terol (SAL)/uticasone propionate (FP). The study was designedto support reimbursement and registration of GLY but import-antly was also designed to allow comparison between GLY+SAL/FP and placebo (PLA)+SAL/FP in terms of efcacy andsafety.

METHODSPatientsPatients were recruited if aged 40 years, had a smoking historyof 10 pack years, a diagnosis of moderate to severe stableCOPD (GOLD guidelines 201019), a post-bronchodilator FEV1/FVC ratio

Statistical analysisThe primary analysis was performed on the PPS using a mixedmodel. Treatment was the xed effect with baseline troughFEV1, FEV1 before and after short-acting bronchodilator atrun-in being covariates. This model also included randomisationstratication factors such as baseline smoking status (current/ex-smoker), baseline COPD severity (moderate/severe) and visitand interaction of treatment arms by visit as xed effects andsubjects as a random effect.Non-inferiority of GLY+SAL/FP to TIO+SAL/FP would be

inferred if the lower bound of the two-sided CI (adjusted formultiple assessments via sequential trial techniques) was greaterthan 60 mL.Superiority of GLY+SAL/FP versus PLA+SAL/FP in terms of

trough FEV1 after 12 weeks of treatment was evaluated usingthe FAS using a similar mixed model as specied for theprimary analysis.Secondary trough FEV1 data, SGRQ scores, rescue medica-

tion use and performance of usual daily activities/night-timeawakenings were analysed with the same mixed model on theFAS with baseline SGRQ, rescue medication and performanceof usual daily activities/night-time awakening scores replacingbaseline FEV1 as covariates, respectively.All safety endpoints were summarised by treatment for the

safety set.

Sample size calculationFor detailed information on sample size and non-inferioritymargin calculation, please refer to the online supplement. Inessence, 170 evaluable patients per treatment group wererequired for adequate power to determine non-inferiority forthe primary variable. One pre-specied unblinded interim ana-lysis after 80 evaluable patients were recruited was accountedfor in the statistical planning. Planned study numbers were alsodeemed adequate to make assessments on differences in key ef-cacy outcomes between GLY+SAL/FP and PLA+SAL/FP.

RESULTSPatient disposition and baseline characteristicsStudy recruitment took place between April 2012 andSeptember 2013. A total of 1059 patients were screened, 773randomised (GLY+SAL/FP: 258; TIO+SAL/FP: 258; PLA+SAL/FP: 257) and 656 (84.9%) completed the study(gure 2). Patients were enrolled at 56 primary care sites and 18secondary/tertiary care sites. Baseline characteristics were similarbetween the three treatment arms (table 1). Mean age was68 years, 64.4% were male, 67.7% had moderate COPD, andthe mean time since diagnosis was 7 years. The mean post-bronchodilator FEV1 was 57.2% of predicted and the FEV1/FVC ratio was 47.1%. In the 12 months before enrolment, 35%of patients had experienced an exacerbation. At baseline, ICS

Figure 2 Patient disposition. FP, uticasone propionate; SAL, salmeterol; TIO, tiotropium.

Frith PA, et al. Thorax 2015;70:519527. doi:10.1136/thoraxjnl-2014-206670 521

Chronic obstructive pulmonary disease

group.bmj.com on May 21, 2015 - Published by http://thorax.bmj.com/Downloaded from

were used by 62.6% of patients randomised to the GLY+SAL/FP arm, 66.3% of those randomised to the TIO+SAL/FP armand 68.1% of those randomised to the PLA+SAL/FP arm(table 1).A higher percentage of patients discontinued the study in the

PLA+SAL/FP arm compared to the GLY+SAL/FP and TIO+SAL/FP arms (22%, 11% and 12%, respectively; 2:p

+SAL/FP (24 patients, 9.3%) and PLA+SAL/FP (32 patients,12.5%), and there was no statistical difference between thetreatment arms.

SafetyThere were no signicant differences in the number of AEs orSAEs between treatment groups, ranging from 57.4% to 64%and 5.8% to 8.5%, respectively (table 2). There were fewercardiac-related AEs in the GLY+SAL/FP arm (1.2%) comparedto the other treatment arms (3.9% and 2.7%) (table 3).Pneumonia was not reported in the GLY+SAL/FP arm, but didoccur in two patients in each of the TIO+SAL/FP and PLA+SAL/FP arms.Three deaths were reported during the study, one during

run-in (congestive cardiac failure), one in the PLA+SAL/FP arm(ventricular brillation) and one in the TIO+SAL/FP arm(multi-organ failure, ischaemic hepatitis and pneumonia).

DISCUSSIONCombining inhaler therapies from different classes of drugs forCOPD is commonly recommended (GOLD 2014) and often

pursued.1 22 23 However, it is important to know if there ismerit in doing so; in particular if there is comparable efcacyfor medications from the same therapeutic class and whethertherapy with GLY+LABA/ICS has advantages over therapy withLABA/ICS in patients with moderate to severe disease. TheGLISTEN study demonstrates that TIO and GLY are comparable

Figure 3 Trough forced expiratory volume in 1 s (FEV1) at weeks 4, 8 and 12 (full analysis set). FP, uticasone propionate; SAL, salmeterol.

Figure 4 SGRQ-C total scores at 12 weeks. FP, uticasone propionate;SAL, salmeterol; SGRQ, St Georges Respiratory Questionnaire. Data areleast-squares means; error bars show standard error.

Figure 5 (A) Rescue medication use (puffs per day). (B) Percentageof days without rescue medication use. FP, uticasone propionate; SAL,salmeterol. Data show least-squares means; error bars show standarderror.




when added to a LABA/ICS combination in moderate to severeCOPD patients, but more importantly shows the superiority ofusing GLY+LABA/ICS over using a LABA/ICS alone. This is therst time this has been effectively demonstrated.Results for the pre-specied primary outcome (trough FEV1 at

12 weeks) demonstrated the non-inferiority of GLY to TIO whencombined with SAL/FP. Comparable outcomes for GLY versusTIO were also demonstrated for all other outcomes measures:health status, rescue medication use, nocturnal symptoms andactivity performance. These ndings are consistent with resultsfor GLY versus TIO non-inferiority studies in a monotherapysetting, as demonstrated in both open-label17 and blinded16 ran-domised controlled trials. Although not measured in the currentstudy, GLY has been shown in other studies to be superior to TIOin terms of time to onset and on peak FEV1 results.

16 17

GLY in combination with SAL/FP demonstrated statisticallyand clinically signicant improvements in lung function com-pared to PLA+SAL/FP at 4, 8 and 12 weeks. In addition, over12 weeks GLY+SAL/FP provided statistically signicantimprovements in health status, symptom relief and rescue medi-cation in comparison to SAL/FP alone. Furthermore, there wasno increase in AEs when GLY was used with SAL/FP and specif-ically there was no increase in cardiovascular events or anyother SAEs. This adds to existing clinical trial data concerningGLY safety and tolerability.4 17

There have been many studies comparing LABA/ICS therapywith individual monotherapies (ICS, LABA, LAMA). A systematicreview by Kew et al11 of 71 randomised controlled trials(n=73 062; >6 months duration) comparing LABA, LAMA, ICSor combined LABA/ICS and PLA, showed health status and lungfunction were improved most if taking LABA/ICS. The reviewalso concluded that LAMAs and LABAs had similar efcacy11

although triple therapies were not included in their analysis.At the time of writing there are seven published studies asses-

sing triple therapy.15 2429 These studies were identied by sys-tematic reviews14 30 and our own literature searches. Three ofthe seven compared triple therapy with TIO monotherapy.25 28 29

Of these, two28 29 used SAL/FP as their LABA/ICS and one for-moterol/budesonide;25 they were 36 months in duration andone was open label.29 In these studies triple therapy was betterthan TIO monotherapy. Another study compared triple therapywith the dual bronchodilator combination of TIO+SAL(without ICS).24 Over 12 months there was no reduction inexacerbations, but there was improvement in health status andlung function with triple therapy. However, the authorsacknowledged a large number of patient withdrawals and use ofinappropriate treatments during the study, creating some doubtabout the nal data.We were able to identify only three studies comparing triple

therapy with LABA/ICS therapy.15 26 27 One26 was a 2-week

Table 2 Most frequent adverse events (at least 5 patients in any treatment group), serious adverse events (at least 2 patients in any treatmentgroup), death and discontinuations due to adverse events (safety set)

Glycopyrronium+SAL/FP

Tiotropium+SAL/FP

Placebo+SAL/FP

N=257 N=258 N=257

Patients with AEs 150 (58.4%) 165 (64.0%) 148 (57.6%)Upper respiratory tract infection 17 (6.6%) 13 (5.0%) 11 (4.3%)Oral candidiasis 12 (4.7%) 13 (5.0%) 9 (3.5%)Lower respiratory tract infection 7 (2.7%) 5 (1.9%) 4 (1.6%)Nasopharyngitis 3 (1.2%) 7 (2.7%) 5 (1.9%)Viral upper respiratory tract infection 3 (1.2%) 4 (1.6%) 5 (1.9%)Sinusitis 2 (0.8%) 2 (0.8%) 5 (1.9%)Cough 16 (6.2%) 15 (5.8%) 11 (4.3%)Oropharyngeal pain 9 (3.5%) 10 (3.9%) 8 (3.1%)Dyspnoea 7 (2.7%) 9 (3.5%) 10 (3.9%)Dysphonia 6 (2.3%) 15 (5.8%) 5 (1.9%)Rhinorrhoea 6 (2.3%) 1 (0.4%) 3 (1.2%)COPD 0 4 (1.6%) 6 (2.3%)Diarrhoea 5 (1.9%) 2 (0.8%) 2 (0.8%)Dry mouth 5 (1.9%) 9 (3.5%) 2 (0.8%)Nausea 3 (1.2%) 9 (3.5%) 3 (1.2%)Muscle spasms 11 (4.3%) 9 (3.5%) 5 (1.9%)Back pain 4 (1.6%) 8 (3.1%) 5 (1.9%)Fatigue 0 5 (1.9%) 2 (0.8%)Headache 3 (1.2%) 4 (1.6%) 13 (5.1%)Hypertension 3 (1.2%) 6 (2.3%) 5 (1.9%)

Number of SAE(s) 18 36 18Patients with SAE(s) 15 (5.8%) 22 (8.5%) 15 (5.8%)

Small intestinal obstruction 2 (0.8%) 0 0Chronic obstructive pulmonary disease 0 1 (0.4%) 2 (0.8%)Atrial fibrillation 0 2 (0.8%) 1 (0.4%)Pneumonia 0 2 (0.8%) 2 (0.8%)

Death 0 0 1 (0.4%)Discontinued due to AE(s) 14 (5.4%) 17 (6.6%) 17 (6.6%)

AE, adverse event; COPD, chronic obstructive pulmonary disease; FP, fluticasone propionate; SAL, salmeterol; SAE, serious adverse event.

524 Frith PA, et al. Thorax 2015;70:519527. doi:10.1136/thoraxjnl-2014-206670



treatment period crossover study of 41 patients, in which only66% of patients nished the study. Another15 was a 3-monthpilot study with 2629 patients in each arm and showed nosuperiority of any one treatment, while the third study, pub-lished in Chinese,27 is a 12-month non-blinded study thatshowed no difference between active treatments. Despite theirstudy limitations, all three showed some positive benets fromtriple therapy. Studies currently presented in abstract form atinternational meetings suggest further positive evidence forusing triple therapy may emerge.31 On this background, theGLISTEN study is the rst to provide strong evidence for usinga LAMA with an LABA/ICS combination as it demonstrated sig-nicant benets in lung function, health status and rescue medi-cation when GLY was combined with SAL/FP. The extent towhich these results can be extrapolated to other 2-receptoragonists and corticosteroids will require further studies.Improving daily symptoms, health status and lung function are

important goals in COPD therapy, while reducing exacerbationsis equally important. These outcomes may be independent orinteractive. The data from studies addressing triple therapy,including this one, show less obvious impact on exacerbationsand more on health status and lung function. A recent study32

suggests that removing ICS does little to change exacerbationrates but is associated with an incremental reduction in FEV1,suggesting a complex interplay between drug therapy and clinicaloutcomes that needs more careful evaluation.There are potential limitations in the GLISTEN study. Both

moderate and severe COPD patients were enrolled despite atthe time of the study triple therapy only being recommendedfor patients with severe obstruction and/or frequent exacerba-tions (two or more/year or one requiring hospitalisation).19 Thismeans that some patients with moderate obstruction and infre-quent exacerbations may have been enrolled. This enrolmentdecision allowed the efcacy of the treatments to be assessed in

a broader spectrum of disease severity as these patients are com-monly treated in real world practice with LABA/ICStherapy.22 23 This is reected in the baseline characteristics ofthe study populations (table 1). About 60% of patients weretaking ICS prior to recruitment into the trial, although only halfof these had experienced exacerbations and had FEV1

Author afliations1Respiratory Clinical Research Unit, Repatriation General Hospital, Adelaide, SouthAustralia, Australia2The Lung Health Clinic, Centre for Asthma Allergy and Respiratory Research,University of Western Australia, and the Lung Institute of Western Australia, Perth,Western Australia, Australia3Department of Respiratory Medicine, Gosford Hospital, Gosford, New South Wales,Australia4Department of Respiratory and Sleep Medicine, Waikato Hospital, Hamilton, NewZealand5St John of God Hospital, Murdoch, Western Australia, Australia6Medical Centre, Redcliffe Peninsula 7 Day Medical Centre, Brisbane, Queensland,Australia7Clinical Development and Medical Affairs, Novartis Pharmaceuticals Australia PtyLimited, Sydney, New South Wales, Australia

Acknowledgements The authors thank the patients who participated and thestaff at the participating clinical centres.

Collaborators The Glisten study group principal investigators: Ainslie Waddell,Alexander Daniel, Alireza Khoussousi, Andrew Springeld, Andrew Veale, AnthonyNeil Graham, Brad Gallagher, Braj Raj Pande, Brendan OKane, Christopher Jones,Claudio Baldi, Colin Helm, Conor ODochartaigh, Daniel Chambers, Dean Quinn,Derek Yull, Dhanalakshi Karthigesu, Edward Then, Frank Graham, Fred Faigenbaum,Geetha Geddam, Gillian Cameron, Hans Blom, Hershel Goldman, Hilary Snell,Imagard Chia, James Jeong, James Liew, James Salvaris, Jason Pryke, Jim Reid, JohnKolbe, John OSullivan, John Pak, John Upham, Joseph Feiber, Judith OMalley Ford,Kevin Yong, Kyle Perrin, Lawrence Noonan, Len Atlas, Louise Murdoch, MargaretPearce, Mark Bloch, Mark Holmes, Michael Chia, Michael Epton, Michelle Leadston,MK Tandon, Mohan Chitgopeker, Naomi Liebenberg, Neil Hendry, Olakunle Olaniyi,Omesh Singh, Peter Kendall, Peter Van Niekerk, Rodney Willet, Ronald Tomlins,Salven Pillay, Sammy Sharifeh, Simon Carson, Stephen Bingham, Ted Walford, TersiaErasmus, Trevor Claridge, Zoa Hess.

Contributors PAF was the principal investigator of the study. PAF and PJTcontributed equally to the generation of this manuscript. The following authors werethe main investigators in the collaborating centres and directly involved in patientrecruitment and data collection: PAF, PJT, RR, CLC, PB and PD. CF and NK wereinvolved in the design, coordination and project execution of the study. All authorsreviewed and approved the nal version of the manuscript.

Funding The study was sponsored and funded by Novartis PharmaceuticalsAustralia Pty Limited.

Competing interests In the past 5 years PAF has received honoraria for advisorywork and lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline,MediMark International, Menarini, MundiPharma, Novartis, Remedy Healthcare,Servier and Takeda; and has received travel grants to conferences and othermeetings from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Global Alliancefor Respiratory Disease, Lung Foundation Australia, MediMark International,Menarini and Novartis; no payment was received for preparation of this manuscript.Over the last 5 years, PJT has sat on advisory boards for Novartis and Astra Zenecaand has given public lectures sponsored by Astra Zeneca and Novartis. No personalpayments were received with respect to this study or its production. RR hasparticipated in research projects funded by Bioxyne, Novartis and GlaxoSmithKlinewith grants paid to his employing institution. RR was the recipient of a travel grantfrom Novartis. CLC has participated in research projects funded by Novartis,Boehringer-Ingelheim, Grifols, Bayer and Pearl Therapeutics with grants paid to theinstitution where she is employed. PB has received honoraria from GSK, AZ, Novartisand BI for presenting at medical meetings and symposia, and has contributed toclinical research trials funded by the same and other pharmaceutical companies. PDparticipated in research projects funded by Sano and Novartis. CF and NK arefull-time employees of Novartis Pharmaceuticals Australia.

Ethics approval The Therapeutic Goods Administration (TGA) approved this study.

Provenance and peer review Not commissioned; internally peer reviewed.

Open Access This is an Open Access article distributed in accordance with theCreative Commons Attribution Non Commercial (CC BY-NC 4.0) license, whichpermits others to distribute, remix, adapt, build upon this work non-commercially,and license their derivative works on different terms, provided the original work isproperly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

REFERENCES1 The Global Strategy for the Diagnosis, Management and Prevention of COPD,

Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2014. http://www.goldcopd.org

2 Tashkin DP, Celli B, Senn S, et al. A 4-year trial of tiotropium in chronic obstructivepulmonary disease. N Engl J Med 2008;359:154354.

3 Karner C, Chong J, Poole P. Tiotropium versus placebo for chronic obstructivepulmonary disease. Cochrane Database Syst Rev 2012;7:CD009285.

4 Beeh KM, Singh D, Di Scala L, et al. Once-daily NVA237 improves exercisetolerance from the rst dose in patients with COPD: the GLOW3 trial. Int J ChronObstruct Pulmon Dis 2012;7:50313.

5 Calverley P, Pauwels R, Vestbo J, et al. Combined salmeterol and uticasone in thetreatment of chronic obstructive pulmonary disease: a randomised controlled trial.Lancet 2003;361:44956.

6 Donohue JF, Fogarty C, Lotvall J, et al. Once-daily bronchodilators for chronicobstructive pulmonary disease: indacaterol versus tiotropium. Am J Respir Crit CareMed 2010;182:15562.

7 Dahl R, Chung KF, Buhl R, et al. Efcacy of a new once-daily long-acting inhaledbeta2-agonist indacaterol versus twice-daily formoterol in COPD. Thorax2010;65:4739.

8 Calverley PM, Boonsawat W, Cseke Z, et al. Maintenance therapy with budesonideand formoterol in chronic obstructive pulmonary disease. Eur Respir J2003;22:91219.

9 Mahler DA, Wire P, Horstman D, et al. Effectiveness of uticasone propionate andsalmeterol combination delivered via the Diskus device in the treatment of chronicobstructive pulmonary disease. Am J Respir Crit Care Med 2002;166:108491.

10 Calverley PM, Anderson JA, Celli B, et al. Salmeterol and uticasone propionate andsurvival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:77589.

11 Kew KM, Dias S, Cates CJ. Long-acting inhaled therapy (beta-agonists,anticholinergics and steroids) for COPD: a network meta-analysis. CochraneDatabase Syst Rev 2014;3:CD010844.

12 Nannini LJ, Poole P, Milan SJ, et al. Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease.Cochrane Database Syst Rev 2013;11:CD003794.

13 Wedzicha JA, Calverley PM, Seemungal TA, et al. The prevention of chronicobstructive pulmonary disease exacerbations by salmeterol/uticasone propionate ortiotropium bromide. Am J Respir Crit Care Med 2008;177:1926.

14 Karner C, Cates CJ. Combination inhaled steroid and long-acting beta(2)-agonist inaddition to tiotropium versus tiotropium or combination alone for chronic obstructivepulmonary disease. Cochrane Database Syst Rev 2011;(3):CD008532.

15 Cazzola M, Ando F, Santus P, et al. A pilot study to assess the effects ofcombining uticasone propionate/salmeterol and tiotropium on the airowobstruction of patients with severe-to-very severe COPD. Pulm Pharmacol Ther2007;20:55661.

16 Chapman KR, Beeh KM, Beier J, et al. A blinded evaluation of the efcacy andsafety of glycopyrronium, a once-daily long-acting muscarinic antagonist, versustiotropium, in patients with COPD: the GLOW5 study. BMC Pulm Med 2014;14:4.

17 Kerwin E, Hebert J, Gallagher N, et al. Efcacy and safety of NVA237 versusplacebo and tiotropium in patients with COPD: the GLOW2 study. Eur Respir J2012;40:110614.

18 DUrzo A, Ferguson GT, van Noord JA, et al. Efcacy and safety of once-dailyNVA237 in patients with moderate-to-severe COPD: the GLOW1 trial. Respir Res2011;12:156.

19 Global Initiative for Chronic Obstructive Lung Disease (GOLD): Global strategy fordiagnosis, management and prevention of COPD, 2010. http://www.goldcopd.org/Guidelines/guideline-2010-gold-report.html

20 Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry.Eur Respir J 2005;26:31938.

21 Medical Dictionary of Medical Activities (MedDRA). Version 15.1, 2012.22 Bourbeau J, Sebaldt RJ, Day A, et al. Practice patterns in the management of

chronic obstructive pulmonary disease in primary practice: the CAGE study.Can Respir J 2008;15:1319.

23 White P, Thornton H, Pinnock H, et al. Overtreatment of COPD with inhaledcorticosteroidsimplications for safety and costs: cross-sectional observationalstudy. PLoS One 2013;8:e75221.

24 Aaron SD, Vandemheen KL, Fergusson D, et al. Tiotropium in combination withplacebo, salmeterol, or uticasone-salmeterol for treatment of chronic obstructivepulmonary disease: a randomized trial. Ann Intern Med 2007;146:54555.

25 Welte T, Miravitlles M, Hernandez P, et al. Efcacy and tolerability of budesonide/formoterol added to tiotropium in patients with chronic obstructive pulmonarydisease. Am J Respir Crit Care Med 2009;180:74150.

26 Singh D, Brooks J, Hagan G, et al. Superiority of triple therapy with salmeterol/uticasone propionate and tiotropium bromide versus individual components inmoderate to severe COPD. Thorax 2008;63:5928.

27 Fang LZ, Liang X, Zhang JQ, et al. [Combination of inhaled salmeterol/uticasoneand tiotropium in the treatment of chronic obstructive pulmonary disease:a randomised controlled trial]. Zhonghua Jie He He Hu Xi Za Zhi 2008;31:81114.

28 Hanania NA, Crater GD, Morris AN, et al. Benets of adding uticasonepropionate/salmeterol to tiotropium in moderate to severe COPD. Respir Med2012;106:91101.

29 Jung KS, Park HY, Park SY, et al. Comparison of tiotropium plus uticasonepropionate/salmeterol with tiotropium in COPD: a randomized controlled study.Respir Med 2012;106:3829.

526 Frith PA, et al. Thorax 2015;70:519527. doi:10.1136/thoraxjnl-2014-206670



30 Rodrigo GJ, Plaza V, Castro-Rodriguez JA. Comparison of three combinedpharmacological approaches with tiotropium monotherapy in stable moderate tosevere COPD: a systematic review. Pulm Pharmacol Ther 2012;25:407.

31 Siler T, Kerwin E, Sousa A, et al. Efcacy and safety of once-daily umeclidiniumadded to uticasone furoate/vilanterol in chronic obstructive pulmonary disease:results of two replicate randomized 12-week studies. Chest 2014;146(4_MeetingAbstracts):340A.

32 Magnussen H, Watz H, Kirsten A, et al. Stepwise withdrawal of inhaledcorticosteroids in COPD patients receiving dual bronchodilation: WISDOM studydesign and rationale. Respir Med 2014;108:5939.

33 Bateman ED, Ferguson GT, Barnes N, et al. Dual bronchodilation with QVA149versus single bronchodilator therapy: the SHINE study. Eur Respir J2013;42:148494.

34 Decramer M, Anzueto A, Kerwin E, et al. Efcacy and safety of umeclidinium plusvilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over24 weeks in patients with chronic obstructive pulmonary disease: results from twomulticentre, blinded, randomised controlled trials. Lancet Respir Med2014;2:47286.

35 Jones PW, Beeh KM, Chapman KR, et al. Minimal clinically important differencesin pharmacological trials. Am J Respir Crit Care Med 2014;189:2505.




randomised controlled trialain patients with COPD: the GLISTEN study

when combined with salmeterol/fluticasone improves lung function and health status

Glycopyrronium once-daily significantly

the Glisten Study GroupChang, Peter Bremner, Peter Day, Christina Frenzel, Nicol Kurstjens and Peter A Frith, Philip J Thompson, Rajeev Ratnavadivel, Catherina L

doi: 10.1136/thoraxjnl-2014-2066702015 70: 519-527 originally published online April 3, 2015Thorax

http://thorax.bmj.com/content/70/6/519Updated information and services can be found at:

These include:

MaterialSupplementary

0.DC1.htmlhttp://thorax.bmj.com/content/suppl/2015/04/05/thoraxjnl-2014-20667Supplementary material can be found at:

References #BIBLhttp://thorax.bmj.com/content/70/6/519

This article cites 31 articles, 6 of which you can access for free at:

Open Access

http://creativecommons.org/licenses/by-nc/4.0/non-commercial. See: provided the original work is properly cited and the use isnon-commercially, and license their derivative works on different terms, permits others to distribute, remix, adapt, build upon this workCommons Attribution Non Commercial (CC BY-NC 4.0) license, which This is an Open Access article distributed in accordance with the Creative

serviceEmail alerting

box at the top right corner of the online article. Receive free email alerts when new articles cite this article. Sign up in the

CollectionsTopic Articles on similar topics can be found in the following collections

(492)Drugs: respiratory system (481)Clinical trials (epidemiology)

(139)Open access

Notes

http://group.bmj.com/group/rights-licensing/permissionsTo request permissions go to:

http://journals.bmj.com/cgi/reprintformTo order reprints go to:

http://group.bmj.com/subscribe/To subscribe to BMJ go to:


Glycopyrronium once-daily significantly improves lung function and health status when combined with salmeterol/fluticasone in patients with COPD: the GLISTEN studya randomised controlled trialAbstractIntroductionMethodsPatientsStudy design and treatmentEfficacy assessmentSafety assessmentStatistical analysisSample size calculation

ResultsPatient disposition and baseline characteristicsEfficacySpirometryHealth statusRescue medicationNight-time awakening and performance of daily activitiesExacerbations

Safety

DiscussionConclusionReferences

Documents

2015. Glycopyrronium Once-daily Significantly Improves