Background: Bronchodilator medications are central to the symptomatic management of chronic obstructive\npulmonary disease (COPD). Metered-dose inhalers (MDIs) are the most commonly used devices to deliver treatment\nto patients with COPD and asthma, comprising approximately 70% of bronchodilator prescriptions. Proprietary\nporous-particle technology permits the formulation of long-acting muscarinic antagonists, long-acting ?2-agonists,\nand a combination of both in hydrofluoroalkane (HFA) MDIs, providing a solution to formulation challenges\ninherent to the development of HFA MDIs, which have contributed to the development of dry-powder inhalers.\nMethods: In this randomized, double-blind, 4-period, 6-treatment, placebo- and active-controlled, multicenter,\ncrossover study, 4 ascending single doses of a proprietary glycopyrronium (GP) MDI were evaluated compared with\nPlacebo MDI and open-label tiotropium (TIO) in study patients with COPD. Thirty-three study patients were enrolled\nand received single-dose administration of 4 of the 6 treatments (Placebo MDI, TIO 18 ?g, or GP MDI at 14.4, 28.8,\n57.6, and 115.2 ?g ex-actuator) with an interval of 1 to 3 weeks between doses. The primary efficacy endpoint was\npeak change in forced expiratory volume in 1 second (FEV1).\nResults: All 4 doses of GP MDI showed statistically superior efficacy compared with Placebo MDI for peak FEV1\n(differences of 146 to 248 mL; P < .001), with a clear dose ordering of the response. Statistically significant\ndifferences compared with Placebo MDI were noted at almost all doses for the secondary FEV1 parameters\n(P ? .049) except 24-hour trough FEV1 at 28.8 ?g. All doses were safe and well tolerated in this study; the most\nfrequently reported adverse event was dry mouth (0ââ?¬â??14.3% across doses; 9.5% for Placebo MDI, and 9.1% for TIO).\nConclusions: This study demonstrated superior bronchodilatory efficacy of GP MDI compared with Placebo MDI at\nall doses tested, and no serious adverse events were reported. This study supports the further evaluation of GP MDI\nin study patients with COPD. In addition, these findings indicate that the correct dosage of glycopyrronium is no\nmore than 115.2 ?g total daily dose, or 57.6 ?g twice daily based on comparisons with the active comparator.
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