Aclidinium improves exercise endurance, dyspnea, lung hyperinflation, and physical activity in patients with COPD: a randomized, placebo-controlled, crossover trial

Abstract

Background: This study evaluated the effects of aclidinium bromide, a long-acting muscarinic antagonist indicated for maintenance treatment of chronic obstructive pulmonary disease (COPD), on exercise endurance, dyspnea, lung hyperinflation, and physical activity.

Methods: In this randomized, double-blind, crossover study, patients with stable COPD and moderate-to-severe airflow limitation received aclidinium 400 μg twice daily or placebo via Genuair®/Pressair(®a) for 3 weeks (2-week washout between treatment periods). The primary endpoint was change from baseline to Week 3 in endurance time, measured by constant work rate cycle ergometry testing at 75% peak incremental work rate. Changes from baseline in intensity of exertional dyspnea (Borg CR10 Scale®) and trough inspiratory capacity were secondary endpoints. Additional endpoints included changes from baseline in other spirometric, plethysmographic, and physical activity (assessed by objective accelerometer measurement) parameters. Efficacy endpoints were analyzed using an analysis of covariance model.

Results: In total, 112 patients were randomized and treated (mean age 60.3 years; mean post-bronchodilator forced expiratory volume in 1 s 1.7 L [56.7% predicted]; mean endurance time 485.7 s). After 3 weeks, endurance time was significantly increased with aclidinium versus placebo (treatment difference 58.5 s; p < 0.05). At Week 3, aclidinium significantly reduced dyspnea intensity at isotime during exercise (treatment difference -0.63; p < 0.05) and improved trough inspiratory capacity (treatment difference 78 mL; p < 0.05) versus placebo. Significant improvements in spirometric, plethysmographic, and some physical activity parameters were observed with aclidinium versus placebo.

Conclusions: These results suggest that aclidinium significantly improves exercise endurance, exertional dyspnea, hyperinflation, and physical activity in patients with COPD.

Trial registration: ClinicalTrials.gov identifier: NCT01471171; URL: http://www.clinicaltrials.gov.

Figure 1

Study design. Symptom-limited incremental cycle exercise testing was performed at screening to determine maximum work rate. Constant work rate exercise testing at 75% of symptom-limited maximum work rate was conducted pre-dose at Visits 1 and 3 (baseline), and at 3 h post-dose at Visits 2 and 4. Spirometry was performed pre-dose at Visits 1 and 3 (baseline) and at Visits 2 and 4; plethysmography was performed pre-dose at Visits 1 and 3 (baseline), and at 2 h post-dose at Visits 2 and 4. BID, twice daily.

Figure 2

Patient disposition. BID, twice daily; ITT, intent-to-treat.

Figure 3

Change from baseline in exercise endurance time at Week 3. Change from baseline in exercise endurance time during constant work rate cycle ergometry to symptom limitation at 75% of the maximum work rate was assessed at Week 3 (ITT population). Data reported as least squares means change from baseline (analysis of covariance) + standard error; Δ = least squares means difference (95% confidence interval). ^*p < 0.05 versus placebo. BID, twice daily; ITT, intent-to-treat.

Figure 4

Change from baseline in dynamic IC at end of exercise at Week 3. Change from baseline in dynamic IC measured before exercise, at isotime, and at end of exercise was assessed at Week 3 (ITT population). Data reported as least squares means change from baseline (analysis of covariance) + standard error; Δ = least squares means difference (95% confidence intervals). ^***p < 0.001, ^****p < 0.0001 versus placebo. BID, twice daily; IC, inspiratory capacity; ITT, intent-to-treat.

Figure 5

EELV during exercise at baseline and at Week 3. EELV during constant work rate cycle ergometry in patients receiving a) placebo, or b) aclidinium 400 μg BID. EELV was assessed at rest, at isotime, and at end of exercise at baseline and at Week 3 (ITT population). Data are descriptive and reported as mean ± standard deviation. EELV was assessed as IC subtracted from mean TLC 2 h post-dose. Mean isotime was calculated as 386 seconds. BID, twice daily; EELV, end-expiratory lung volumes; IC, inspiratory capacity; ITT, intent-to-treat; TLC, total lung capacity.

Figure 6

Changes from baseline in exercise endurance and physical activity at Week 3, by baseline physical activity. Changes from baseline in a) exercise endurance time during constant work rate cycle ergometry to symptom limitation at 75% of the maximum work rate, b) daily step count, c) duration of moderate activity >3 metabolic equivalents, and d) energy expenditure at Week 3 were assessed according to baseline physical activity levels (inactive, sedentary, or at least moderately active; ITT population). Data reported as least squares means change from baseline (analysis of covariance) + standard error; Δ = least squares means difference (95% confidence intervals). n = number of patients in each subgroup included in the analyses. ^*p < 0.05 versus placebo. BID, twice daily; ITT, intent-to-treat.