A phase IIb randomized, chronic-dosing, incomplete block, cross-over study of glycopyrronium, delivered via metered dose inhaler, compared with a placebo and an active control in patients with moderate-to-severe COPD

Abstract

Background: Long-acting muscarinic antagonist (LAMA) and long-acting β₂-agonist (LABA) bronchodilators are key to the pharmacologic treatment of chronic obstructive pulmonary disease (COPD). This Phase IIb study investigated the safety and efficacy of four doses of the LAMA glycopyrronium (GP) delivered using co-suspension delivery technology via metered dose inhaler (MDI). The study was part of a wider clinical trial program performed to determine the optimal dose of GP MDI, the LABA formoterol fumarate dihydrate (FF) MDI, and glycopyrronium/formoterol fumarate dihydrate (GFF) MDI fixed-dose combination to be taken forward into Phase III studies.

Methods: In this randomized, double-blind, 7-day chronic-dosing, three-period incomplete block, cross-over study, patients with moderate-to-severe COPD received two of the four doses of GP MDI (28.8 μg, 14.4 μg, 7.2 μg, and 3.6 μg) twice daily (BID), and either placebo MDI BID or open-label ipratropium MDI 34 μg four times daily. The primary efficacy endpoint was forced expiratory volume in 1 s (FEV₁) area under the curve from 0 to 12 h (AUC_0-12) relative to baseline on Day 7. Secondary and exploratory efficacy endpoints were assessed on Days 1 and 7. Safety and tolerability were evaluated throughout the study.

Results: All GP MDI treatments were superior to placebo MDI for the primary efficacy endpoint (all p < 0.0001). However, only GP MDI 28.8 μg and 14.4 μg demonstrated statistical superiority to placebo MDI for all secondary efficacy endpoints analyzed in this study, with the exception of GP MDI 14.4 μg versus placebo MDI for the proportion of patients achieving ≥12% improvement in FEV₁. No nominally significant differences were observed between GP MDI 28.8 μg and GP MDI 14.4 μg for any of the endpoints. All doses of GP MDI were well tolerated, with no unexpected safety findings.

Conclusions: This study indicated that there was no advantage of GP MDI 28.8 μg compared with GP MDI 14.4 μg. It therefore added to the evidence from the Phase I/II clinical trial program, which identified GP MDI 14.4 μg as the most appropriate dose for use in the Phase III clinical studies.

Trial registration: ClinicalTrials.gov (NCT01350128). Registered May 09, 2011.

Keywords: Bronchodilator; Chronic obstructive pulmonary disease; Co-suspension delivery technology; Glycopyrronium; Long-acting muscarinic antagonist; Long-acting β2-agonist; Metered dose inhaler.

Fig. 1

Study design. PFT Pulmonary function test, Rx Treatment

Fig. 2

Patient disposition. BID Twice daily, GP Glycopyrronium, MDI Metered dose inhaler, QID Four times daily

Fig. 3

Mean change from baseline in FEV₁ over time on Day 7 (mITT population). Error bars represent standard errors. BID Twice daily, FEV₁ Forced expiratory volume in 1 s, GP Glycopyrronium, MDI Metered dose inhaler, mITT Modified intent-to-treat, QID Four times daily

Fig. 4

Adjusted difference from placebo in FEV₁ AUC_0–12 on Day 7 (mITT population). Error bars represent 95% confidence intervals. All p < 0.0001 versus placebo MDI. AUC_0–12 Area under the curve from 0 to 12 h, BID Twice daily, FEV₁ Forced expiratory volume in 1 s, GP Glycopyrronium, LSM Least squares mean, MDI Metered dose inhaler, mITT Modified intent-to-treat, QID Four times daily