A randomized controlled trial of glycopyrrolate administered by metered dose inhaler in patients with uncontrolled asthma despite ICS/LABA treatment

Objective To evaluate the efficacy and safety of three doses of glycopyrrolate metered dose inhaler (GP MDI) in patients with uncontrolled asthma despite treatment with inhaled corticosteroid/long-acting beta(2)-agonists (ICS/LABA) with or without tiotropium, to characterize the benefit of triple therapy. Method This phase II/III, double-blind study randomized patients to 24 weeks' treatment with twice-daily GP MDI 36 mu g, 18 mu g, 9 mu g, or placebo MDI (all delivered via Aerosphere inhalers), or once-daily open-label tiotropium 2.5 mu g. Patients continued their own ICS/LABA regimen throughout the study. The primary endpoint was change from baseline in forced expiratory volume in 1 s (FEV1) area under the curve from 0 - 4 h (AUC(0 - 4)) at Week 24. Secondary endpoints included patient questionnaires to measure asthma control or symptoms. Safety was also assessed. Results The primary analysis (modified intent-to-treat) population included 1066 patients. The primary study endpoint was not met (changes from baseline in FEV1 AUC(0 - 4) at Week 24 were 294 mL, 284 mL, 308 mL, 240 mL, and 347 mL for GP MDI 36 mu g, GP MDI 18 mu g, GP MDI 9 mu g, placebo, and open-label tiotropium, respectively). There were no significant differences between treatment and placebo in secondary endpoints at Week 24. Post-hoc analyses using post-bronchodilator FEV1 as the baseline measurement, or averaging values across multiple baseline visits, showed a dose-related response to GP MDI. The incidence of adverse events was low and similar across treatments. Conclusion Although this study did not meet its primary endpoint, post hoc analyses identified a dose-related response to GP MDI when alternative definitions of baseline FEV1 were used in the analyses.