Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: the 24-week, randomized, placebo-controlled AUGMENT COPD study.

Anthony D D’Urzo,Anne R Leselbaum,Victor Mergel,Edward M Kerwin,Cynthia F Caracta,Stephen I Rennard

doi:10.1186/s12931-014-0123-0

Abstract

BackgroundCombining two long-acting bronchodilators with complementary mechanisms of action may provide treatment benefits to patients with chronic obstructive pulmonary disease (COPD) that are greater than those derived from either treatment alone. The efficacy and safety of a fixed-dose combination (FDC) of aclidinium bromide, a long-acting muscarinic antagonist, and formoterol fumarate, a long-acting β2-agonist, in patients with moderate to severe COPD are presented.MethodsIn this 24-week double-blind study, 1692 patients with stable COPD were equally randomized to twice-daily treatment with FDC aclidinium 400 μg/formoterol 12 μg (ACL400/FOR12 FDC), FDC aclidinium 400 μg/formoterol 6 μg (ACL400/FOR6 FDC), aclidinium 400 μg, formoterol 12 μg, or placebo administered by a multidose dry powder inhaler (Genuair®/Pressair®)*. Coprimary endpoints were change from baseline to week 24 in 1-hour morning postdose FEV1 (FDCs versus aclidinium) and change from baseline to week 24 in morning predose (trough) FEV1 (FDCs versus formoterol). Secondary endpoints were change from baseline in St. George’s Respiratory Questionnaire (SGRQ) total score and improvement in Transition Dyspnea Index (TDI) focal score at week 24. Safety and tolerability were also assessed.ResultsAt study end, improvements from baseline in 1-hour postdose FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC or ACL400/FOR6 FDC compared with aclidinium (108 mL and 87 mL, respectively; p < 0.0001). Improvements in trough FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC versus formoterol (45 mL; p = 0.0102), a numerical improvement of 26 mL in trough FEV1 over formoterol was observed with ACL400/FOR6 FDC. Significant improvements in both SGRQ total and TDI focal scores were observed in the ACL400/FOR12 FDC group at study end (p < 0.0001), with differences over placebo exceeding the minimal clinically important difference of ≥4 points and ≥1 unit, respectively. All treatments were well tolerated, with safety profiles of the FDCs similar to those of the monotherapies.ConclusionsTreatment with twice-daily aclidinium 400 μg/formoterol 12 μg FDC provided rapid and sustained bronchodilation that was greater than either monotherapy; clinically significant improvements in dyspnea and health status were evident compared with placebo. Aclidinium/formoterol FDC may be an effective and well tolerated new treatment option for patients with COPD.Trial registrationClinicaltrials.gov NCT01437397.*Registered trademarks of Almirall S.A., Barcelona, Spain; for use within the US as Pressair® and Genuair® within all other licensed territories.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-014-0123-0) contains supplementary material, which is available to authorized users.

Highlights

Combining two long-acting bronchodilators with complementary mechanisms of action may provide treatment benefits to patients with chronic obstructive pulmonary disease (COPD) that are greater than those derived from either treatment alone
Studies investigating the free combination of Long-acting muscarinic antagonist (LAMA) and Long-acting β2-agonist (LABA) therapies in patients with COPD have shown improved bronchodilation and reduced rescue medication use compared with monotherapy [2,3,5,6]
Though the interaction between LAMAs and LABAs has not been definitively determined, LABAs have been shown to enhance the bronchodilatory effect of LAMAs through a decrease in acetylcholine transmission that leads to a reduction in bronchoconstriction, while LAMAs amplify the effect of LABAs by blocking the muscarinic receptors targeted by acetylcholine, resulting in further bronchodilation [3,21,22]

Summary

Introduction

Combining two long-acting bronchodilators with complementary mechanisms of action may provide treatment benefits to patients with chronic obstructive pulmonary disease (COPD) that are greater than those derived from either treatment alone. The efficacy and safety of a fixed-dose combination (FDC) of aclidinium bromide, a long-acting muscarinic antagonist, and formoterol fumarate, a long-acting β2-agonist, in patients with moderate to severe COPD are presented. In patients with chronic obstructive pulmonary disease (COPD), combining bronchodilators with complementary mechanisms of action has the potential to increase lung function and improve symptom management compared to treatment with a single agent [1]. Studies investigating the free combination of LAMA and LABA therapies (via two separate inhalers) in patients with COPD have shown improved bronchodilation and reduced rescue medication use compared with monotherapy [2,3,5,6]. As treatment with aclidinium has been shown to improve health status, exercise endurance, and nighttime symptoms in patients with COPD [11,13], a fixed-dose combination (FDC) comprising aclidinium bromide/formoterol fumarate (Genuair®/ Pressair®*, approved for delivery of aclidinium monotherapy) may improve lung function, health status, and COPD symptoms while reducing the potential risk for side effects that often occur from increasing doses of monotherapy treatments [1]

Methods

Results

Discussion

Conclusion