Dose-response to inhaled glycopyrrolate delivered with a novel Co-Suspension™ Delivery Technology metered dose inhaler (MDI) in patients with moderate-to-severe COPD

Background: This study forms part of the first complete characterization of the dose-response curve for glycopyrrolate (GP) delivered using Co-Suspension™ Delivery Technology via a metered dose inhaler (MDI). We examined the lower GP MDI dose range to determine an optimal dose for patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). Methods: This randomized, double-blind, chronic-dosing, balanced incomplete-block, placebo-controlled, crossover study compared six doses of GP MDI (18, 9, 4.6, 2.4, 1.2, and 0.6 μg, twice daily [BID]) with placebo MDI BID and open-label tiotropium dry powder inhaler (18 μg, once daily [QD]) in patients with moderate-to-severe COPD. Patients were randomized into 1 of 120 treatment sequences. Each sequence included 4 of 8 treatments administered for 14-day periods separated by 7- to 21-day washout periods. The primary efficacy endpoint was change from baseline in forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV₁ AUC_0-12) on Day 14. Secondary efficacy endpoints included peak change from baseline (post-dose) in FEV₁ and inspiratory capacity (IC) on Days 1, 7, and 14; change from baseline in morning pre-dose trough FEV₁ on Days 7 and 14; change from baseline in 12-h post-dose trough FEV₁ on Day 14; time to onset of action (≥10 % improvement in mean FEV₁) and the proportion of patients achieving ≥12 % improvement in FEV₁ on Day 1; and pre-dose trough IC on Days 7 and 14. Safety and tolerability were also assessed. Results: GP MDI 18, 9, 4.6, and 2.4 μg demonstrated statistically significant and clinically relevant increases in FEV₁ AUC_0-12 compared with placebo MDI following 14 days of treatment (modified intent-to-treat population = 120). GP MDI 18 μg was non-inferior to open-label tiotropium for peak change in FEV₁ on Day 1 and morning pre-dose trough FEV₁ on Day 14. All doses of GP MDI were well tolerated with no unexpected safety findings. Conclusions: These efficacy and safety results support GP MDI 18 μg BID as the most appropriate dose for evaluation in Phase III trials in patients with moderate-to-severe COPD. Trial registration: ClinicalTrials.gov NCT01566773. Registered 27 March 2012.