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

BackgroundAclidinium/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.MethodsIn 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.ResultsAt 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.ConclusionsBoth 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 registrationClinicalTrials.gov: NCT01462942.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2466-14-178) contains supplementary material, which is available to authorized users.

A Network Meta-Analysis of Long-Acting Muscarinic Antagonist (LAMA) and Long-Acting β2-Agonist (LABA) Combinations in COPD

“…With non-imputed data, the probabilities of improvement using ACL/FOR were considerably lower versus placebo (70%; mean difference -0.65 units; 95% CrI -3.07 to 1.80), TIO (8%; mean difference 1.78 units; 95% CrI -0.68 to 4.25) and all other combination therapies (\1-6%) than with imputed data. These differences are due to the inclusion of only a single trial reporting outcomes with ACL/FOR versus placebo in the non-imputed data (the ACLIFORM trial [41]) which reported a mean change from baseline in the SGRQ score of -0.65 units; however, the base case analysis also included the AUGMENT trial [42], which reported a considerably larger mean change from baseline of -4.36 units.…”

“…In particular, of the FDCs, only two studies presenting data for ACL/FOR were eligible for inclusion; both of these were 'large' trials (each with[300 patients receiving ACL/FOR [41,42], considerably greater than the previously proposed cut-off for large trials of 100 patients [60]), thereby reducing the likelihood of any distortion of results due to a small study effect [61]. However, the heterogeneity of the studies included in this NMA was not assessed, so the extent of distortion is not known.…”

The clinical relevance of the emphysema-hyperinflated phenotype in COPD

“…These combinations are at least as effective as the simultaneous use of their individual components (possibly via a synergistic effect [137,138]) and significantly improve lung function compared with monotherapy [139][140][141][142][143][144][145]. A positive effect on exercise tolerance has also been demonstrated for indacaterolglycopyrronium and vilanterol-umeclidinium compared with placebo [146,147], although the magnitude of this effect was less when compared to monotherapy with tiotropium.…”

Cardiovascular safety of new inhaled medications for asthma and chronic obstructive pulmonary disease: a critical review from pharmacist perspective

“…103 One clinical study involving subjects with some cardiovascular comorbidities (ACLIFORM-COPD trial) has found no conclusive evidence of significant safety concerns from aclidinium use (in combination with formoterol). 104 The study found that incidences of severe AEs were <5%, and a potential systemic anticholinergic effect of <3%. Although 4 deaths were recorded in the treatment groups, the study did not report any significant change in ECG pattern.…”