Dose-response of an extrafine dry powder inhaler formulation of glycopyrronium bromide: randomized, double-blind, placebo-controlled, dose-ranging study (GlycoNEXT)

Introduction: An extrafine formulation of the long-acting muscarinic antagonist, glycopyrronium bromide (GB), has been developed for delivery via the NEXThaler dry powder inhaler (DPI). This study assessed the bronchodilator efficacy and safety of different doses of this formulation in patients with COPD to identify the optimal dose for further development. Patients and methods: This was a multicenter, randomized, double-blind, placebo-controlled, incomplete block, three-way crossover study, including three 28-day treatment periods, each separated by a 21-day washout period. Eligible patients had a diagnosis of COPD and post-bronchodilator forced expiratory volume in 1 s (FEV1) 40%-70% predicted. Treatments administered were GB 6.25, 12.5, 25 and 50 mu g or matched placebo; all were given twice daily (BID) via DPI, with spirometry assessed on Days 1 and 28 of each treatment period. The primary end point was FEV1 area under the curve from 0 to 12 h (AUC(0-12 h)) on Day 28. Results: A total of 202 patients were randomized (61% male, mean age 62.6 years), with 178 (88%) completing all the three treatment periods. For the primary end point, all the four GB doses were superior to placebo (p<0.001) with mean differences (95% CI) of 114 (74, 154), 125 (85, 166), 143 (104, 183) and 187 (147, 228) mL for GB 6.25, 12.5, 25 and 50 mu g BID, respectively. All four GB doses were also statistically superior to placebo for all secondary efficacy end points, showing clear dose-response relationships for most of the endpoints. Accordingly, GB 25 mu g BID met the criteria for the minimally acceptable dose. Adverse events were reported by 15.5, 16.2, 10.9 and 14.3% of patients receiving GB 6.25, 12.5, 25 and 50 mu g BID, respectively, and 14.8% receiving placebo. Conclusion: This study supports the selection of GB 25 mu g BID as the minimal effective dose for patients with COPD when delivered with this extrafine DPI formulation.