AJRCCM Articles in Press. Published on 15-July-2015 as 10.1164/rccm.201505-1048OC
Page 1 of 53
FLIGHT: efficacy and safety of QVA149 (indacaterol/glycopyrrolate) versus its monocomponents and placebo in patients with COPD Donald A Mahler1,2, Edward Kerwin3, Tim Ayers4, Angel FowlerTaylor4, Samopriyo Maitra5, Chau Thach4, Mark Lloyd4, Francesco Patalano6 and Donald Banerji4
1
Geisel School of Medicine at Dartmouth Hanover, NH USA; 2Valley Regional
Hospital, Claremont, NH, USA; 3Clinical Research Institute of Southern Oregon, PC, Medford, OR, USA; 4Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA; 5Novartis Healthcare Pvt. Ltd., Hyderabad, India; 6Novartis Pharma AG, Basel, Switzerland
Authors’ contribution: Supported by Novartis Pharma AG D.M., E.K., T.A., A.FT., S.M., C.T., F.P., M.L. and D.B. participated in study design and concept of the study. Statistical analyses were overseen by S.M., and C.T. All the authors have contributed in acquisition and interpretation of data and also in drafting and revision of the manuscript. Correspondence and requests for reprints should be addressed to Donald A Mahler, MD. Emeritus Professor of Medicine , Geisel School of Medicine at Dartmouth, Director of Respiratory Services, Valley Regional Hospital, Claremont, NH 03743, USA. Phone: +1 603-650-5533; E-mail: [email protected]
This article has an online supplement, which is accessible from this issue's table of content online at www.atsjournals.org Running title: Efficacy and safety of indacaterol/glycopyrrolate in COPD patients 1
Copyright © 2015 by the American Thoracic Society
AJRCCM Articles in Press. Published on 15-July-2015 as 10.1164/rccm.201505-1048OC
Page 2 of 53
Descriptor number: 9.14 COPD: Pharmacological Treatment Total word count for the body of the manuscript: 3416 At a Glance Commentary Scientific Knowledge on the Subject: FLIGHT1 and FLIGHT2 were two identical 12-week US pivotal registration phase III studies designed to evaluate the efficacy and safety of twice-daily QVA149 (indacaterol/glycopyrrolate) 27.5/15.6 µg (a fixeddose combination of a LABA, indacaterol and a LAMA, glycopyrrolate) as maintenance bronchodilation for the relief of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD). In this manuscript, we have discussed the results from the individual studies (FLIGHT1 and FLIGHT2) in addition to the pooled results by combining the individual study data. We believe that the precision of the risk-benefit effect can best be ascertained by pooling the replicate studies. What This Study Adds to the Field: FLIGHT1 and FLIGHT2 were the first 12-week studies to evaluate the efficacy and safety of a fixed-dose combination of a LABA and a LAMA (indacaterol/glycopyrrolate) administered as twice daily. Results of both individual studies were consistent in demonstrating the superiority of indacaterol/glycopyrrolate over its mono-components (indacaterol and glycopyrrolate) and placebo in terms of improvements in lung function and quality of life, and reduced breathlessness and daily rescue albuterol use with a comparable safety profile to its monocomponents. In these studies, indacaterol/glycopyrrolate demonstrated to be an effective treatment option for physicians in the management of symptomatic patients with moderate-to-severe COPD. Key words: COPD; long-acting β2-agonists; long-acting muscarinic antagonist; Clinical trial; fixed-dose combination 2
Copyright © 2015 by the American Thoracic Society
AJRCCM Articles in Press. Published on 15-July-2015 as 10.1164/rccm.201505-1048OC
Page 3 of 53
Abstract Background: Current GOLD strategy recommends the combination of two long-acting bronchodilators of different pharmacological classes for the management of chronic obstructive pulmonary disease (COPD) if symptoms are not adequately controlled by a single bronchodilator. The FLIGHT1 and FLIGHT2 studies evaluated the efficacy and safety of QVA149 (indacaterol/glycopyrrolate, a fixed-dose combination of a long-acting β2-agonist, [LABA], indacaterol, and a long-acting muscarinic antagonist [LAMA], glycopyrrolate)*, compared with its monocomponents and placebo in patients with moderate-to-severe COPD. Methods: FLIGHT1 and FLIGHT2 were 12-week, identical, multi-center, randomized, double-blind, parallel-group, placebo- and active-controlled studies. Patients were randomized (1:1:1:1) to indacaterol/glycopyrrolate (27.5/15.6µg) twice daily (b.i.d.), indacaterol 27.5µg b.i.d., glycopyrrolate 15.6µg b.i.d. or placebo, all delivered via the Neohaler® device. The primary objective was to demonstrate the superiority of indacaterol/glycopyrrolate versus its monocomponents for standardized area under the curve from 0–12 h (AUC0-12h) for FEV1 at Week-12. Secondary objectives included St. George’s Respiratory Questionnaire (SGRQ) total score and Transition Dyspnea Index (TDI) total score and reduction in daily rescue medication use with indacaterol/glycopyrrolate versus placebo. Results: In total, 2038 patients were included in the pooled analysis. indacaterol/glycopyrrolate was statistically superior in terms of FEV1AUC0-12h compared to its monocomponents (P 1 favors the treatment in the numerator of the ratio (higher chance of a clinically important) . NS, not significant, *P
Page 1 of 53
FLIGHT: efficacy and safety of QVA149 (indacaterol/glycopyrrolate) versus its monocomponents and placebo in patients with COPD Donald A Mahler1,2, Edward Kerwin3, Tim Ayers4, Angel FowlerTaylor4, Samopriyo Maitra5, Chau Thach4, Mark Lloyd4, Francesco Patalano6 and Donald Banerji4
1
Geisel School of Medicine at Dartmouth Hanover, NH USA; 2Valley Regional
Hospital, Claremont, NH, USA; 3Clinical Research Institute of Southern Oregon, PC, Medford, OR, USA; 4Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA; 5Novartis Healthcare Pvt. Ltd., Hyderabad, India; 6Novartis Pharma AG, Basel, Switzerland
Authors’ contribution: Supported by Novartis Pharma AG D.M., E.K., T.A., A.FT., S.M., C.T., F.P., M.L. and D.B. participated in study design and concept of the study. Statistical analyses were overseen by S.M., and C.T. All the authors have contributed in acquisition and interpretation of data and also in drafting and revision of the manuscript. Correspondence and requests for reprints should be addressed to Donald A Mahler, MD. Emeritus Professor of Medicine , Geisel School of Medicine at Dartmouth, Director of Respiratory Services, Valley Regional Hospital, Claremont, NH 03743, USA. Phone: +1 603-650-5533; E-mail: [email protected]
This article has an online supplement, which is accessible from this issue's table of content online at www.atsjournals.org Running title: Efficacy and safety of indacaterol/glycopyrrolate in COPD patients 1
Copyright © 2015 by the American Thoracic Society
AJRCCM Articles in Press. Published on 15-July-2015 as 10.1164/rccm.201505-1048OC
Page 2 of 53
Descriptor number: 9.14 COPD: Pharmacological Treatment Total word count for the body of the manuscript: 3416 At a Glance Commentary Scientific Knowledge on the Subject: FLIGHT1 and FLIGHT2 were two identical 12-week US pivotal registration phase III studies designed to evaluate the efficacy and safety of twice-daily QVA149 (indacaterol/glycopyrrolate) 27.5/15.6 µg (a fixeddose combination of a LABA, indacaterol and a LAMA, glycopyrrolate) as maintenance bronchodilation for the relief of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD). In this manuscript, we have discussed the results from the individual studies (FLIGHT1 and FLIGHT2) in addition to the pooled results by combining the individual study data. We believe that the precision of the risk-benefit effect can best be ascertained by pooling the replicate studies. What This Study Adds to the Field: FLIGHT1 and FLIGHT2 were the first 12-week studies to evaluate the efficacy and safety of a fixed-dose combination of a LABA and a LAMA (indacaterol/glycopyrrolate) administered as twice daily. Results of both individual studies were consistent in demonstrating the superiority of indacaterol/glycopyrrolate over its mono-components (indacaterol and glycopyrrolate) and placebo in terms of improvements in lung function and quality of life, and reduced breathlessness and daily rescue albuterol use with a comparable safety profile to its monocomponents. In these studies, indacaterol/glycopyrrolate demonstrated to be an effective treatment option for physicians in the management of symptomatic patients with moderate-to-severe COPD. Key words: COPD; long-acting β2-agonists; long-acting muscarinic antagonist; Clinical trial; fixed-dose combination 2
Copyright © 2015 by the American Thoracic Society
AJRCCM Articles in Press. Published on 15-July-2015 as 10.1164/rccm.201505-1048OC
Page 3 of 53
Abstract Background: Current GOLD strategy recommends the combination of two long-acting bronchodilators of different pharmacological classes for the management of chronic obstructive pulmonary disease (COPD) if symptoms are not adequately controlled by a single bronchodilator. The FLIGHT1 and FLIGHT2 studies evaluated the efficacy and safety of QVA149 (indacaterol/glycopyrrolate, a fixed-dose combination of a long-acting β2-agonist, [LABA], indacaterol, and a long-acting muscarinic antagonist [LAMA], glycopyrrolate)*, compared with its monocomponents and placebo in patients with moderate-to-severe COPD. Methods: FLIGHT1 and FLIGHT2 were 12-week, identical, multi-center, randomized, double-blind, parallel-group, placebo- and active-controlled studies. Patients were randomized (1:1:1:1) to indacaterol/glycopyrrolate (27.5/15.6µg) twice daily (b.i.d.), indacaterol 27.5µg b.i.d., glycopyrrolate 15.6µg b.i.d. or placebo, all delivered via the Neohaler® device. The primary objective was to demonstrate the superiority of indacaterol/glycopyrrolate versus its monocomponents for standardized area under the curve from 0–12 h (AUC0-12h) for FEV1 at Week-12. Secondary objectives included St. George’s Respiratory Questionnaire (SGRQ) total score and Transition Dyspnea Index (TDI) total score and reduction in daily rescue medication use with indacaterol/glycopyrrolate versus placebo. Results: In total, 2038 patients were included in the pooled analysis. indacaterol/glycopyrrolate was statistically superior in terms of FEV1AUC0-12h compared to its monocomponents (P 1 favors the treatment in the numerator of the ratio (higher chance of a clinically important) . NS, not significant, *P
