Efficacy and safety of aclidinium bromide compared with placebo and tiotropium in patients with moderate-to-severe chronic obstructive pulmonary disease: results from a 6-week, randomized, controlled Phase IIIb study

Abstract

Background: This randomized, double-blind, Phase IIIb study evaluated the 24-hour bronchodilatory efficacy of aclidinium bromide versus placebo and tiotropium in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD).

Methods: Patients received aclidinium 400 μg twice daily (morning and evening), tiotropium 18 μg once daily (morning), or placebo for 6 weeks. The primary endpoint was change from baseline in forced expiratory volume in 1 second area under the curve for the 24-hour period post-morning dose (FEV1 AUC0-24) at week 6. Secondary and additional endpoints included FEV1 AUC12-24, COPD symptoms (EXAcerbations of chronic pulmonary disease Tool-Respiratory Symptoms [E-RS] total score and additional symptoms questionnaire), and safety.

Results: Overall, 414 patients were randomized and treated (FEV1 1.63 L [55.8% predicted]). Compared with placebo, FEV1 AUC0-24 and FEV1 AUC12-24 were significantly increased from baseline with aclidinium (∆ = 150 mL and 160 mL, respectively; p < 0.0001) and tiotropium (∆ = 140 mL and 123 mL, respectively; p < 0.0001) at week 6. Significant improvements in E-RS total scores over 6 weeks were numerically greater with aclidinium (p < 0.0001) than tiotropium (p < 0.05) versus placebo. Only aclidinium significantly reduced the severity of early-morning cough, wheeze, shortness of breath, and phlegm, and of nighttime symptoms versus placebo (p < 0.05). Adverse-event (AE) incidence (28%) was similar between treatments. Few anticholinergic AEs (<1.5%) or serious AEs (<3%) occurred in any group.

Conclusions: Aclidinium provided significant 24-hour bronchodilation versus placebo from day 1 with comparable efficacy to tiotropium after 6 weeks. Improvements in COPD symptoms were consistently numerically greater with aclidinium versus tiotropium. Aclidinium was generally well tolerated.

Figure 1.

Patient disposition. AE, adverse event; BID, twice daily; QD, once daily.

Figure 2.

Change from baseline in FEV₁ AUC_0–24, FEV₁ AUC_12–24, and FEV₁ AUC_0–12 compared with placebo (A) on day 1 and (B) at week 6 (ITT population). Data reported as LS mean (95% CI) differences from placebo (ANCOVA). ^‡p < 0.001; ^§p < 0.0001 for aclidinium or tiotropium versus placebo. ^¶p < 0.05; ^#p < 0.01 for aclidinium versus tiotropium. ANCOVA, analysis of covariance; AUC, area under the curve; AUC_0–24, AUC over the 24-hour period post-morning treatment; AUC_12–24, AUC over the nighttime period; AUC_0–12, AUC for the 12-hour period post-morning treatment; BID, twice daily; CI, confidence interval; FEV₁, forced expiratory volume in 1 second; ITT, intent-to-treat; LS, least squares; QD, once daily.

Figure 3.

Change from baseline in FEV₁ over 24 hours (A) on day 1 and (B) at week 6. Data reported as LS mean change from baseline (ANCOVA). p < 0.01 for aclidinium and tiotropium versus placebo at each time point. ^¶p < 0.05; ^#p < 0.01; ^∥p < 0.001; ^¶¶p < 0.0001 for aclidinium versus tiotropium. ANCOVA, analysis of covariance; BID, twice daily; FEV₁, forced expiratory volume in 1 second; LS, least squares; QD, once daily.

Figure 4.

Change from baseline in E-RS total and domain scores over 6 weeks. Data reported as LS mean (95% CI) difference from placebo (ANCOVA). *p < 0.05; ^†p < 0.01; ^§p < 0.0001 for aclidinium or tiotropium versus placebo. ANCOVA, analysis of covariance; BID, twice daily; CI, confidence interval; E-RS, EXAcerbations of Chronic pulmonary disease Tool (EXACT)-Respiratory Symptoms; LS, least squares; QD, once daily.

Figure 5.

Difference from placebo in change from baseline in (A) severity of early-morning symptoms, (B) severity of nighttime symptoms and number of nocturnal awakenings due to COPD symptoms, and (C) limitation of activity caused by COPD symptoms (COPD additional symptoms questionnaire) over 6 weeks (ITT population). Data reported as LS mean differences from placebo (ANCOVA). *p < 0.05; ^†p < 0.01; ^‡p < 0.001 for aclidinium or tiotropium versus placebo. ^¶p < 0.05 for aclidinium versus tiotropium. Severity of overall early-morning and nighttime symptoms rated on a 5-point scale from 1 = ‘did not experience any symptoms’ to 5 = ‘very severe’; individual morning symptoms rated on a 5-point scale from 0 = ‘no symptoms’ to 4 = ‘very severe’; limitation of activity rated on a 5-point scale from 1 = ‘not at all’ to 5 = ‘a very good deal’. ANCOVA, analysis of covariance; BID, twice daily; COPD, chronic obstructive pulmonary disease; ITT, intent-to-treat; LS, least squares; QD, once daily.