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

Abstract

Background: 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.

Methods: In 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.

Results: At 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.

Conclusions: Treatment 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 registration: Clinicaltrials.gov NCT01437397.

Figure 1

Study design. ACL400/FOR12 FDC, fixed-dose combination of aclidinium 400 μg and formoterol 12 μg; ACL400/FOR6 FDC, fixed-dose combination of aclidinium 400 μg and formoterol 6 μg; D, day; Wk, week.

Figure 2

Patient disposition. ^*Study terminated by Sponsor; ACL400/FOR12 FDC, fixed-dose combination of aclidinium 400 μg and formoterol 12 μg; ACL400/FOR12 FDC, fixed-dose combination of aclidinium 400 μg and formoterol 6 μg; COPD, chronic obstructive pulmonary disease; ITT, intention-to-treat.

Figure 3

Mean changes from baseline in 1-hour morning postdose FEV ₁ (A) at week 24 (coprimary endpoint) and (B) over time across duration of study. Analyses were based on a mixed-model for repeated measures. All active treatment groups were significant versus placebo (p < 0.0001) at all study visits. ^*p < 0.05 versus placebo; ^§p < 0.05 versus aclidinium, formoterol, and placebo. ACL400/FOR12 FDC, fixed-dose combination of aclidinium 400 μg and formoterol 12 μg; ACL400/FOR6 FDC, fixed-dose combination of aclidinium 400 μg and formoterol 6 μg; D1, day 1; D4, day 4; FEV₁, forced expiratory volume in 1 second; LS, least squares.

Figure 4

Mean changes from baseline in morning predose (trough) FEV ₁ (A) at week 24 (coprimary endpoint) and (B) over time across duration of study. Analyses were based on a mixed-model for repeated measures. ^*p < 0.05 versus placebo; ^‡p < 0.05 versus formoterol and placebo; ^§p < 0.05 versus aclidinium, formoterol, and placebo. ACL400/FOR12 FDC, fixed-dose combination of aclidinium 400 μg and formoterol 12 μg; ACL400/FOR6 FDC, fixed-dose combination of aclidinium 400 μg and formoterol 6 μg; FEV₁, forced expiratory volume in 1 second; LS, least squares.

Figure 5

Mean changes from baseline in FEV ₁ 0–3 hours (A) on day 1 and (B) at week 24. Analyses were based on a mixed-model for repeated measures. ^*p < 0.05 versus placebo; ^†p < 0.05 versus aclidinium and placebo; ^§p < 0.05 versus aclidinium, formoterol, and placebo; ^¥p < 0.05 versus aclidinium/formoterol FDC 400/6 and placebo. No significant differences between the two FDCs at any timepoint. ACL400/FOR12 FDC, fixed-dose combination of aclidinium 400 μg and formoterol 12 μg; ACL400/FOR6 FDC, fixed-dose combination of aclidinium 400 μg and formoterol 6 μg; FEV₁, forced expiratory volume in 1 second; LS, least squares.

Figure 6

Improvements in TDI focal score as assessed by (A) mean changes from baseline at week 24, (B) percentage of patients who responded at week 24, and (C) percentage of patients who responded over time. Mean changes were analyzed using a mixed-model for repeated measures. Responders were defined as patients who had a TDI focal score improvements of ≥1 unit; ORs based on a logistic random effect model for active treatment versus placebo. ^*p < 0.01 versus placebo; ^**p ≤ 0.001 versus placebo; ^†p < 0.05 versus aclidinium and placebo; ^‡p < 0.05 versus formoterol and placebo. ACL400/FOR12 FDC, fixed-dose combination of aclidinium 400 μg and formoterol 12 μg; ACL400/FOR6 FDC, fixed-dose combination of aclidinium 400 μg and formoterol 6 μg; LS, least squares; OR, odds ratio; TDI, Transition Dyspnea Index.

Figure 7

Improvements in SGRQ total score as assessed by (A) mean changes from baseline at week 24, (B) percentage of patients who responded at week 24, and (C) percentage of patients who responded over time. Mean changes were analyzed using a mixed-model for repeated measures. Responders were defined as patients who had a ≥4-point improvement from baseline in SGRQ total score, with ORs based on a logistic random effect model for active treatment versus placebo. ^*p < 0.05 versus placebo; ^**p ≤ 0.001 versus placebo. ACL400/FOR12 FDC, fixed-dose combination of aclidinium 400 μg and formoterol 12 μg; ACL400/FOR6 FDC, fixed-dose combination of aclidinium 400 μg and formoterol 6 μg; LS, least squares; OR, odds ratio; SGRQ, St. George’s Respiratory Questionnaire.

Figure 8

Mean changes from baseline to week 24 in (A) E-RS overall average daily score over the study period, (B) nighttime symptom severity, and (C) early morning symptom severity. Parenthetical values are the percent changes from baseline for the specified group. The E-RS analysis was conducted using the ITT exacerbation population, defined as all randomized patients who received ≥1 dose of double-blind study drug; the analyses of nighttime and early morning symptom severity were conducted using the general ITT population. For all outcomes, mean changes were analyzed using a mixed-model for repeated measures. ^*p < 0.05 versus placebo; ^†p < 0.05 versus aclidinium and placebo; ^§p < 0.05 versus aclidinium, formoterol, and placebo. ACL400/FOR12 FDC, fixed-dose combination of aclidinium 400 μg and formoterol 12 μg; ACL400/FOR6 FDC, fixed-dose combination of aclidinium 400 μg and formoterol 6 μg; EMSCI, early morning symptoms of COPD instrument; E-RS, EXACT respiratory symptoms; ITT, intention-to-treat; LS, least square; NiSCI, nighttime symptoms of COPD instrument.