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

Abstract

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 AUC0-12) 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 AUC0-12 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.

Keywords: Bronchodilators; COPD maintenance; Co-Suspension™ Delivery Technology; LAMA; Metered dose inhaler.

Figures

Fig. 1

Study design schematic. Rand Randomization; PFT Pulmonary Function Test; Rx Treatment

Fig. 2

Patient disposition figure. Patients were randomized into 1 of 120 treatment sequences. Each sequence included four out of the eight possible treatments administered for 14-day periods separated by 7- to 21-day washout periods. GP glycopyrrolate; MDI metered dose inhaler

Fig. 3

Primary endpoint: LSM change from baseline in FEV1 AUC0–12 on Day 14 (mITT population). Primary efficacy comparison for superiority to placebo: *p < 0.05; **p < 0.001; ***p < 0.0001. FEV1AUC0–12 forced expiratory volume in 1 s, area under the curve from 0 to 12 h; GP glycopyrrolate; LSM least squares mean; MDI metered dose inhaler; mITT modified intent-to-treat

Fig. 4

Time to onset of action (≥10 % improvement from baseline FEV1) on Day 1 (mITT population). Cumulative data are shown. Adjusted difference versus placebo: *p < 0.05; **p < 0.01; ***p < 0.001; ****p ≤ 0.0001. Adjusted difference versus open-label tiotropium: †p < 0.05; ††p < 0.01; †††p < 0.001; ††††p ≤ 0.0001. Time to onset was defined as the first post-baseline time when a ≥10 % improvement in FEV1 was seen relative to baseline FEV1, where baseline was defined as the mean of evaluable 60- and 30-min pre-dose values across Visits 2, 5, 8, and 11. P-values were obtained using the Murray method to account for correlation between the times to onset observed in the same subject at different periods. FEV1 forced expiratory volume in 1 s; GP glycopyrrolate; MDI metered dose inhaler; mITT modified intent-to-treat

Fig. 5

Proportion of patients achieving ≥12 % improvement in FEV1 on Day 1 (mITT population). Treatment difference versus placebo: *p < 0.05; **p < 0.01; ***p < 0.0001. Treatment difference versus open-label tiotropium: †p < 0.01; ††p < 0.001; †††p < 0.0001. Estimated percentages, differences between percentages, and p-values were based on a logistic regression model with achievement of ≥12 % improvement in FEV1 as binary response and the following factors in the model: baseline FEV1, bronchodilator reversibility at Screening, period, and treatment. Exchangeable correlation between responses of the same subject at different periods was assumed. FEV1 forced expiratory volume in 1 s; GP glycopyrrolate; MDI metered dose inhaler; mITT modified intent-to-treat