Glycopyrronium once-daily significantly improves lung function and health status when combined with salmeterol/fluticasone in patients with COPD: the GLISTEN study, a randomised controlled trial

Peter A Frith, Philip J Thompson, Rajeev Ratnavadivel, Catherina L Chang, Peter Bremner, Peter Day, Christina Frenzel, Nicol Kurstjens, Glisten Study Group, Ainslie Waddell, Alexander Daniel, Alireza Khoussousi, Andrew Springfield, Andrew Veale, Anthony Neil Graham, Brad Gallagher, Braj Raj Pande, Brendan O'Kane, Christopher Jones, Claudio Baldi, Colin Helm, Conor O'Dochartaigh, 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, John Kolbe, John O'Sullivan, John Pak, John Upham, Joseph Feiber, Judith O'Malley Ford, Kevin Yong, Kyle Perrin, Lawrence Noonan, Len Atlas, Louise Murdoch, Margaret Pearce, 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, Tersia Erasmus, Trevor Claridge, Zofia Hess, Peter A Frith, Philip J Thompson, Rajeev Ratnavadivel, Catherina L Chang, Peter Bremner, Peter Day, Christina Frenzel, Nicol Kurstjens, Glisten Study Group, Ainslie Waddell, Alexander Daniel, Alireza Khoussousi, Andrew Springfield, Andrew Veale, Anthony Neil Graham, Brad Gallagher, Braj Raj Pande, Brendan O'Kane, Christopher Jones, Claudio Baldi, Colin Helm, Conor O'Dochartaigh, 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, John Kolbe, John O'Sullivan, John Pak, John Upham, Joseph Feiber, Judith O'Malley Ford, Kevin Yong, Kyle Perrin, Lawrence Noonan, Len Atlas, Louise Murdoch, Margaret Pearce, 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, Tersia Erasmus, Trevor Claridge, Zofia Hess

Abstract

Background: The optimal use of various therapeutic combinations for moderate/severe chronic obstructive pulmonary disease (COPD) is unclear. The GLISTEN trial compared the efficacy of two long-acting anti-muscarinic antagonists (LAMA), when combined with an inhaled corticosteroid (ICS) and a long-acting β2 agonist (LABA).

Methods: This randomised, blinded, placebo-controlled trial in moderate/severe COPD patients compared once-daily glycopyrronium (GLY) 50 µg, once-daily tiotropium (TIO) 18 µg or placebo (PLA), when combined with salmeterol/fluticasone propionate (SAL/FP) 50/500 µg twice daily. The primary objective was to determine the non-inferiority of GLY+SAL/FP versus TIO+SAL/FP on trough FEV1 after 12 weeks. An important secondary objective was whether addition of GLY to SAL/FP was better than SAL/FP alone.

Results: 773 patients (mean FEV1 57.2% predicted) were randomised; 84.9% completed the trial. At week 12, GLY+SAL/FP demonstrated non-inferiority to TIO+SAL/FP for trough FEV1: least square mean treatment difference (LSMdiff) -7 mL (SE 17.4) with a lower limit for non-inferiority of -60 mL. There was significant increase in week 12 trough FEV1 with GLY+SAL/FP versus PLA+SAL/FP (LSMdiff 101 mL, p<0.001). At 12 weeks, GLY+SAL/FP produced significant improvement in St George's Respiratory Questionnaire total score versus PLA+SAL/FP (LSMdiff -2.154, p=0.02). GLY+SAL/FP demonstrated significant rescue medication reduction versus PLA+SAL/FP (LSMdiff -0.72 puffs/day, p<0.001). Serious adverse events were similar for GLY+SAL/FP, TIO+SAL/FP and PLA+SAL/FP with an incidence of 5.8%, 8.5% and 5.8%, respectively.

Conclusions: GLY+SAL/FP showed comparable improvements in lung function, health status and rescue medication to TIO+SAL/FP. Importantly, addition of GLY to SAL/FP demonstrated significant improvements in lung function, health status and rescue medication compared to SAL/FP.

Trial registration number: NCT01513460.

Keywords: COPD Pharmacology.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Figures

Figure 1
Figure 1
Study design. FP, fluticasone propionate; SAL, salmeterol.
Figure 2
Figure 2
Patient disposition. FP, fluticasone propionate; SAL, salmeterol; TIO, tiotropium.
Figure 3
Figure 3
Trough forced expiratory volume in 1 s (FEV1) at weeks 4, 8 and 12 (full analysis set). FP, fluticasone propionate; SAL, salmeterol.
Figure 4
Figure 4
SGRQ-C total scores at 12 weeks. FP, fluticasone propionate; SAL, salmeterol; SGRQ, St George's Respiratory Questionnaire. Data are least-squares means; error bars show standard error.
Figure 5
Figure 5
(A) Rescue medication use (puffs per day). (B) Percentage of days without rescue medication use. FP, fluticasone propionate; SAL, salmeterol. Data show least-squares means; error bars show standard error.

References

    1. The Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2014. .
    1. Tashkin DP, Celli B, Senn S, et al. . A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008;359:1543–54. 10.1056/NEJMoa0805800
    1. Karner C, Chong J, Poole P. Tiotropium versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2012;7:CD009285 10.1002/14651858.CD009285.pub3
    1. Beeh KM, Singh D, Di Scala L, et al. . Once-daily NVA237 improves exercise tolerance from the first dose in patients with COPD: the GLOW3 trial. Int J Chron Obstruct Pulmon Dis 2012;7:503–13. 10.2147/COPD.S32451
    1. Calverley P, Pauwels R, Vestbo J, et al. . Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2003;361:449–56. 10.1016/S0140-6736(03)12459-2
    1. Donohue JF, Fogarty C, Lotvall J, et al. . Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium. Am J Respir Crit Care Med 2010;182:155–62. 10.1164/rccm.200910-1500OC
    1. Dahl R, Chung KF, Buhl R, et al. . Efficacy of a new once-daily long-acting inhaled beta2-agonist indacaterol versus twice-daily formoterol in COPD. Thorax 2010;65:473–9. 10.1136/thx.2009.125435
    1. Calverley PM, Boonsawat W, Cseke Z, et al. . Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J 2003;22:912–19. 10.1183/09031936.03.00027003
    1. Mahler DA, Wire P, Horstman D, et al. . Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;166:1084–91. 10.1164/rccm.2112055
    1. Calverley PM, Anderson JA, Celli B, et al. . Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356: 775–89. 10.1056/NEJMoa063070
    1. Kew KM, Dias S, Cates CJ. Long-acting inhaled therapy (beta-agonists, anticholinergics and steroids) for COPD: a network meta-analysis. Cochrane Database Syst Rev 2014;3:CD010844 10.1002/14651858.CD010844.pub2
    1. 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 10.1002/14651858.CD003794.pub4
    1. Wedzicha JA, Calverley PM, Seemungal TA, et al. . The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med 2008;177:19–26. 10.1164/rccm.200707-973OC
    1. Karner C, Cates CJ. Combination inhaled steroid and long-acting beta(2)-agonist in addition to tiotropium versus tiotropium or combination alone for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2011;(3):CD008532 10.1002/14651858.CD008532.pub2
    1. Cazzola M, Ando F, Santus P, et al. . A pilot study to assess the effects of combining fluticasone propionate/salmeterol and tiotropium on the airflow obstruction of patients with severe-to-very severe COPD. Pulm Pharmacol Ther 2007;20:556–61. 10.1016/j.pupt.2006.06.001
    1. Chapman KR, Beeh KM, Beier J, et al. . A blinded evaluation of the efficacy and safety of glycopyrronium, a once-daily long-acting muscarinic antagonist, versus tiotropium, in patients with COPD: the GLOW5 study. BMC Pulm Med 2014;14:4 10.1186/1471-2466-14-4
    1. Kerwin E, Hebert J, Gallagher N, et al. . Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2 study. Eur Respir J 2012;40:1106–14. 10.1183/09031936.00040712
    1. D'Urzo A, Ferguson GT, van Noord JA, et al. . Efficacy and safety of once-daily NVA237 in patients with moderate-to-severe COPD: the GLOW1 trial. Respir Res 2011;12:156 10.1186/1465-9921-12-156
    1. Global Initiative for Chronic Obstructive Lung Disease (GOLD): Global strategy for diagnosis, management and prevention of COPD, 2010. .
    1. Miller MR, Hankinson J, Brusasco V, et al. . Standardisation of spirometry. Eur Respir J 2005;26:319–38. 10.1183/09031936.05.00034805
    1. Medical Dictionary of Medical Activities (MedDRA). Version 15.1, 2012.
    1. 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;15:13–19.
    1. White P, Thornton H, Pinnock H, et al. . Overtreatment of COPD with inhaled corticosteroids—implications for safety and costs: cross-sectional observational study. PLoS One 2013;8:e75221 10.1371/journal.pone.0075221
    1. Aaron SD, Vandemheen KL, Fergusson D, et al. . Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 2007;146:545–55. 10.7326/0003-4819-146-8-200704170-00152
    1. Welte T, Miravitlles M, Hernandez P, et al. . Efficacy and tolerability of budesonide/formoterol added to tiotropium in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2009;180:741–50. 10.1164/rccm.200904-0492OC
    1. Singh D, Brooks J, Hagan G, et al. . Superiority of “triple” therapy with salmeterol/fluticasone propionate and tiotropium bromide versus individual components in moderate to severe COPD. Thorax 2008;63:592–8. 10.1136/thx.2007.087213
    1. Fang LZ, Liang X, Zhang JQ, et al. . [Combination of inhaled salmeterol/fluticasone and tiotropium in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial]. Zhonghua Jie He He Hu Xi Za Zhi 2008;31:811–14.
    1. Hanania NA, Crater GD, Morris AN, et al. . Benefits of adding fluticasone propionate/salmeterol to tiotropium in moderate to severe COPD. Respir Med 2012;106:91–101. 10.1016/j.rmed.2011.09.002
    1. Jung KS, Park HY, Park SY, et al. . Comparison of tiotropium plus fluticasone propionate/salmeterol with tiotropium in COPD: a randomized controlled study. Respir Med 2012;106:382–9. 10.1016/j.rmed.2011.09.004
    1. Rodrigo GJ, Plaza V, Castro-Rodriguez JA. Comparison of three combined pharmacological approaches with tiotropium monotherapy in stable moderate to severe COPD: a systematic review. Pulm Pharmacol Ther 2012;25:40–7. 10.1016/j.pupt.2011.10.006
    1. Siler T, Kerwin E, Sousa A, et al. . Efficacy and safety of once-daily umeclidinium added to fluticasone furoate/vilanterol in chronic obstructive pulmonary disease: results of two replicate randomized 12-week studies. Chest 2014;146(4_MeetingAbstracts):340A 10.1378/chest.2059234
    1. Magnussen H, Watz H, Kirsten A, et al. . Stepwise withdrawal of inhaled corticosteroids in COPD patients receiving dual bronchodilation: WISDOM study design and rationale. Respir Med 2014;108:593–9. 10.1016/j.rmed.2014.01.002
    1. Bateman ED, Ferguson GT, Barnes N, et al. . Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study. Eur Respir J 2013;42:1484–94. 10.1183/09031936.00200212
    1. Decramer M, Anzueto A, Kerwin E, et al. . Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials. Lancet Respir Med 2014;2:472–86. 10.1016/S2213-2600(14)70065-7
    1. Jones PW, Beeh KM, Chapman KR, et al. . Minimal clinically important differences in pharmacological trials. Am J Respir Crit Care Med 2014;189:250–5. 10.1164/rccm.201310-1863PP

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