Randomized study of the safety, pharmacokinetics, and bronchodilatory efficacy of a proprietary glycopyrronium metered-dose inhaler in study patients with chronic obstructive pulmonary disease

Abstract

Background: Bronchodilator medications are central to the symptomatic management of chronic obstructive pulmonary disease (COPD). Metered-dose inhalers (MDIs) are the most commonly used devices to deliver treatment to patients with COPD and asthma, comprising approximately 70% of bronchodilator prescriptions. Proprietary porous-particle technology permits the formulation of long-acting muscarinic antagonists, long-acting β2-agonists, and a combination of both in hydrofluoroalkane (HFA) MDIs, providing a solution to formulation challenges inherent to the development of HFA MDIs, which have contributed to the development of dry-powder inhalers.

Methods: In this randomized, double-blind, 4-period, 6-treatment, placebo- and active-controlled, multicenter, crossover study, 4 ascending single doses of a proprietary glycopyrronium (GP) MDI were evaluated compared with Placebo MDI and open-label tiotropium (TIO) in study patients with COPD. Thirty-three study patients were enrolled and received single-dose administration of 4 of the 6 treatments (Placebo MDI, TIO 18 μg, or GP MDI at 14.4, 28.8, 57.6, and 115.2 μg ex-actuator) with an interval of 1 to 3 weeks between doses. The primary efficacy endpoint was peak change in forced expiratory volume in 1 second (FEV1).

Results: All 4 doses of GP MDI showed statistically superior efficacy compared with Placebo MDI for peak FEV1 (differences of 146 to 248 mL; P<.001), with a clear dose ordering of the response. Statistically significant differences compared with Placebo MDI were noted at almost all doses for the secondary FEV1 parameters (P ≤ .049) except 24-hour trough FEV1 at 28.8 μg. All doses were safe and well tolerated in this study; the most frequently reported adverse event was dry mouth (0-14.3% across doses; 9.5% for Placebo MDI, and 9.1% for TIO).

Conclusions: This study demonstrated superior bronchodilatory efficacy of GP MDI compared with Placebo MDI at all doses tested, and no serious adverse events were reported. This study supports the further evaluation of GP MDI in study patients with COPD. In addition, these findings indicate that the correct dosage of glycopyrronium is no more than 115.2 μg total daily dose, or 57.6 μg twice daily based on comparisons with the active comparator.

Trial registration: This clinical trial was registered on ClinicalTrials.gov, Identifier: NCT00871182.

Figures

Figure 1

Study patient disposition; reports the overall enrollment, allocation, and follow-up for study patients. Two patients were excluded for both failed FEV1 reversibility and a failed ECG, making the total number of patients who failed screening 40.

Figure 2

Mean (±standard error) change from baseline in FEV1 over 24 hours by treatment; represents the results for the peak change in FEV1 (the primary efficacy endpoint) as well as the change in FEV1 from test-day baseline over time.

Figure 3

Adjusted Mean (±standard error) change from baseline in FEV1parameters relative to placebo; provides a concise depiction of the mean change from baseline in peak FEV1, 12-hour FEV1, FEV1AUC0–12, 24 hour FEV1, FEV1AUC0–24, FEV1AUC12–24.

Figure 4

Mean plasma glycopyrronium concentrations over time.