Lung function improvements with twice-daily aclidinium/formoterol fixed-dose combination in two 24-week studies in patients with COPD

Background: Combining bronchodilators with complementary mechanisms of action may improve lung function in patients with COPD. A fixed-dose combination (FDC) of the long-acting muscarinic antagonist aclidinium bromide and the long-acting β 2 agonist formoterol fumarate is in clinical development. Aim: To assess bronchodilation with aclidinium/formoterol FDC in patients with moderate-to-severe COPD. Methods: In two multicentre, randomized Phase III studies (ACLIFORM and AUGMENT) patients were randomized to 24 weeks' double-blind treatment with inhaled aclidinium/formoterol FDC 400 µg/12 µg or 400 µg/6 µg, aclidinium 400 µg, formoterol 12 µg, or placebo, twice-daily. Co-primary endpoints at Week 24 were changes from baseline in 1-hr morning post-dose FEV 1 vs aclidinium and morning pre-dose (trough) FEV 1 vs formoterol. Results: Mean baseline FEV 1 was 1.38 L in ACLIFORM and 1.36 L in AUGMENT (54.2% and 53.5% predicted, respectively). Significant improvements in both co-primary endpoints were observed with both doses of the FDC at the first time-point assessed; these improvements were generally maintained at study end (Table). Additionally, each FDC produced clinically significant improvements in FEV 1 vs placebo from as early as 5 minutes post-dose on Day 1 (range: 100 – 128 mL, both p < 0.0001). Conclusions: Aclidinium/formoterol FDC 400/12 µg and 400/6 µg produced rapid, sustained improvements in bronchodilation compared with the monotherapies and placebo over six months in patients with COPD; the greatest improvements were seen with FDC 400/12 µg vs FDC 400/6 µg. Tab. 1: Improvements in bronchodilation with aclidinium/formoterol FDCs (ACLIFORM and AUGMENT studies; ITT population) *p < 0.05; a ACLIFORM (NCT01462942; aclidinium, n= 383; formoterol, n= 383; placebo, n = 194); bAUGMENT (NCT01437397; aclidinium, n= 337; formoterol, n= 332; placebo, n= 331); 'First time point assessed: ACLIFORM, Day 7; AUGMENT, Day 4; FDC, aclidinium/formoterol fixed-dose combination; FEV 1 , forced expiratory volume in 1 second; ITT, intent-to-treat; LSMD, least square mean difference; SE, standard error FDC 400/12 µg FDC 400/6 µg ACLIFORM AUGMENT ACLIFORM AUGMENT LSMD (SE), mL n = 385 a n = 335 b n = 381 a n = 333 b 1-hr morning post-dose FEV 1 vs aclidinium Day 1 45 (11)* 42 (11)* 26 (11)* 30 (11)* Week 24 125 (18)* 108 (18)* 69 (18)* 87 (18)* 1-hr morning post-dose FEV 1 vs placebo Day 1 210 (14)* 205 (11)* 191 (14)* 193 (11)* Week 24 299 (22)* 284 (19)* 244 (22)* 263 (18)* Morning pre-dose (trough) FEV 1 vs formoterol Week l c 64 (13)* 55 (12)* 52 (13)* 48 (12)* Week 24 85 (17)* 45 (17)* 53 (17)* 26 (17) Morning pre-dose (trough) FEV 1 vs placebo Week l c 147 (16)* 152 (12)* 134 (16)* 145 (12)* Week 24 143 (21)* 130 (18)* 111 (21)* 111 (18)* Funding: This study was supported by Almirall S.A., Barcelona, Spain and Forest Laboratories LLC, a subsidiary of Actavis plc, New York, NY, USA