Aclidinium bromide and formoterol fumarate as a fixed-dose combination in COPD: pooled analysis of symptoms and exacerbations from two six-month, multicentre, randomised studies (ACLIFORM and AUGMENT)

Abstract

Background: The combination of aclidinium bromide, a long-acting anticholinergic, and formoterol fumarate, a long-acting beta2-agonist (400/12 μg twice daily) achieves improvements in lung function greater than either monotherapy in patients with chronic obstructive pulmonary disease (COPD), and is approved in the European Union as a maintenance treatment. The effect of this combination on symptoms of COPD and exacerbations is less well established. We examined these outcomes in a pre-specified analysis of pooled data from two 24-week, double-blind, parallel-group, active- and placebo-controlled, multicentre, randomised Phase III studies (ACLIFORM and AUGMENT).

Methods: Patients ≥40 years with moderate to severe COPD (post-bronchodilator forced expiratory volume in 1 s [FEV1]/forced vital capacity <70 % and FEV1 ≥30 % but <80 % predicted normal) were randomised (ACLIFORM: 2:2:2:2:1; AUGMENT: 1:1:1:1:1) to twice-daily aclidinium/formoterol 400/12 μg or 400/6 μg, aclidinium 400 μg, formoterol 12 μg or placebo via Genuair™/Pressair®. Dyspnoea (Transition Dyspnoea Index; TDI), daily symptoms (EXAcerbations of Chronic pulmonary disease Tool [EXACT]-Respiratory Symptoms [E-RS] questionnaire), night-time and early-morning symptoms, exacerbations (Healthcare Resource Utilisation [HCRU] and EXACT definitions) and relief-medication use were assessed.

Results: The pooled intent-to-treat population included 3394 patients. Aclidinium/formoterol 400/12 μg significantly improved TDI focal score versus placebo and both monotherapies at Week 24 (all p < 0.05). Over 24 weeks, significant improvements in E-RS total score, overall night-time and early-morning symptom severity and limitation of early-morning activities were observed with aclidinium/formoterol 400/12 μg versus placebo and both monotherapies (all p < 0.05). The rate of moderate or severe HCRU exacerbations was significantly reduced with aclidinium/formoterol 400/12 μg compared with placebo (p < 0.05) but not monotherapies; the rate of EXACT-defined exacerbations was significantly reduced with aclidinium/formoterol 400/12 μg versus placebo (p < 0.01) and aclidinium (p < 0.05). Time to first HCRU or EXACT exacerbation was longer with aclidinium/formoterol 400/12 μg compared with placebo (all p < 0.05) but not the monotherapies. Relief-medication use was reduced with aclidinium/formoterol 400/12 μg versus placebo and aclidinium (p < 0.01).

Conclusions: Aclidinium/formoterol 400/12 μg significantly improves 24-hour symptom control compared with placebo, aclidinium and formoterol in patients with moderate to severe COPD. Furthermore, aclidinium/formoterol 400/12 μg reduces the frequency of exacerbations compared with placebo.

Trial registration: NCT01462942 and NCT01437397 (ClinicalTrials.gov).

Fig. 1

CONSORT diagram of patient flow in the pooled ACLIFORM and AUGMENT studies. Data for the 400/6 μg dose of the FDC are not reported in this paper and can be found elsewhere [23, 24]; AE, adverse event; FDC, aclidinium/formoterol fixed-dose combination

Fig. 2

TDI focal score at Week 24 (a) and over 24 weeks (b). Data are LS means ± SE for the pooled ITT population; ^*** p < 0.001 vs placebo, ^‡ p < 0.05 vs aclidinium ^†† p < 0.01 vs formoterol; FDC, aclidinium/formoterol fixed-dose combination; ITT, intent-to-treat; LS, least squares; MCID, minimum clinically important difference; ns, not significant; SE, standard error; TDI, Transitional Dyspnoea Index

Fig. 3

Difference from placebo in change from baseline in symptom severity over 24 weeks. a Night-time symptoms; b early-morning symptoms; Data are LS means differences from placebo ± 95 % CIs for the pooled ITT population; ^* p < 0.05, ^*** p < 0.001 vs placebo; ^aNocturnal awakenings were the average number of awakenings per night. Other night-time symptoms were measured on a scale from 0 (no symptoms) to 4 (very severe symptoms). Larger negative values indicate greater improvements in symptom severity; CI, confidence interval; FDC, aclidinium/formoterol fixed-dose combination; ITT, intent-to-treat; LS, least squares

Fig. 4

Rate of COPD exacerbations based on HCRU (a) and EXACT (b) definitions. Data are LS means and RR (CI) for the pooled ITT-exacerbations population; ^* p < 0.05, ^** p < 0.01 vs placebo, ^ǂ p < 0.05 vs aclidinium; CI, confidence interval; COPD, chronic obstructive pulmonary disease; EXACT; EXAcerbations of Chronic pulmonary disease Tool; FDC, aclidinium/formoterol fixed-dose combination; HCRU, Healthcare Resource Utilisation; ITT, intent-to-treat; LS, least squares; RR, rate ratio