Efficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study

Abstract

Background: Aclidinium/formoterol is a twice-daily (BID) fixed-dose combination (FDC) in development for chronic obstructive pulmonary disease (COPD). The efficacy and safety of aclidinium/formoterol versus monotherapy and placebo in patients with COPD was assessed.

Methods: In this 24-week double-blind, parallel-group, active- and placebo-controlled, multicentre Phase III study, patients (≥40 years, post-bronchodilator forced expiratory volume in 1 second [FEV1]/forced vital capacity <70% and FEV1 ≥30% but <80% predicted normal) were randomised 2:2:2:2:1 to aclidinium/formoterol 400/12 μg (n = 385) or 400/6 μg (n = 381), aclidinium 400 μg (n = 385), formoterol 12 μg (n = 384) or placebo (n = 194) BID via Genuair®/Pressair®a.

Results: At Week 24, aclidinium/formoterol 400/12 μg and 400/6 μg lead to significant improvements from baseline in 1-hour post-dose FEV1 versus aclidinium (125 mL [95% CI: 90, 160; p < 0 · 001] and 69 mL [95% CI: 34, 105; p < 0.001], respectively) and trough FEV1 versus formoterol (85 mL [95% CI: 51, 119; p < 0.001] and 53 mL [95% CI: 19, 87; p < 0.01], respectively; co-primary endpoints). Additionally, aclidinium/formoterol 400/12 μg and 400/6 μg provided significant improvements in Transition Dyspnoea Index (TDI) focal score versus placebo (1.29 units [95% CI: 0.73, 1.86; p < 0.001] and 1.16 units [95% CI: 0.59, 1.73; p < 0.001], respectively; secondary endpoint). All treatments were well tolerated, with safety profiles of the FDCs similar to those of placebo and monotherapy.

Conclusions: Both aclidinium/formoterol BID doses significantly improved bronchodilation versus monotherapy, and dyspnoea versus placebo, with no increase in safety risk. Aclidinium/formoterol may be an effective treatment for patients with COPD.

Trial registration: ClinicalTrials.gov: NCT01462942.

Figure 1

Patient disposition. AE, adverse event; FDC, fixed-dose combination of aclidinium/formoterol; prot, protocol.

Figure 2

Mean treatment differences for change from baseline in 1-hour post-dose FEV ₁ . (a) At Week 24; (b) Over 24 weeks; Data are presented as least squares means (SE) for the ITT population. ***p < 0.001 vs placebo; ^‡p < 0.05; ^‡‡‡p < 0.001 vs aclidinium; ^†††p < 0.001 vs formoterol; ^§p < 0.05; ^§§p < 0.01 vs FDC 400/6 μg. FDC, aclidinium/formoterol fixed-dose combination; FEV₁, forced expiratory volume in 1 second; ITT, intent-to-treat; SE, standard error.

Figure 3

Mean treatment differences for change from baseline in trough FEV ₁ . (a) At Week 24; (b) Over 24 weeks; Data are presented as least squares means (SE) for the ITT population. **p < 0.01; *** p < 0.001 vs placebo; ^‡p < 0.05 vs aclidinium; ^††p < 0.01; ^†††p < 0.001 vs formoterol. FDC, aclidinium/formoterol fixed-dose combination of aclidinium/formoterol; FEV₁, forced expiratory volume in 1 second; ITT, intent-to-treat; SE, standard error.

Figure 4

Improvement in TDI focal score at 24 weeks (ITT population). Data are presented as least squares means (SE). ^***p < 0.001 vs placebo. FDC, aclidinium/formoterol fixed-dose combination; ITT, intent-to-treat; MCID, minimum clinically important difference; SE, standard error; TDI, transition dyspnoea index.

Figure 5

Change from baseline in SGRQ total score at 24 weeks (ITT population). Data are presented as least squares means (SE). FDC, aclidinium/formoterol fixed-dose combination; ITT, intent-to-treat; MCID, minimum clinically important difference; SE, standard error; SGRQ, St George’s Respiratory Questionnaire.