Randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of three doses of co-suspension delivery technology glycopyrronium MDI in Japanese patients with moderate-to-severe COPD

Abstract

Purpose: Due to the burden of COPD in Japan, new pharmacologic treatments are needed to meet patient requirements. This study assessed the efficacy and safety of glycopyrronium (GP) delivered via metered dose inhaler (MDI) in Japanese patients with moderate-to-severe COPD.

Methods: This Phase IIb, multicenter, randomized, double-blind, 7-day, crossover study compared GP MDI 28.8, 14.4, and 7.2 μg with placebo MDI (all administered as two inhalations, twice daily). The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 second (FEV1) on Day 8. Secondary endpoints included FEV1 area under the curve from 0 to 2 hours (AUC0-2) and peak change from baseline in FEV1 on Days 1 and 8 and forced vital capacity AUC0-2 on Day 8. Safety was also assessed. ClinicalTrials.gov Identifier: NCT03256552; http://www.ClinicalTrials.gov.

Results: Sixty-six patients were randomized and 62 were included in the modified intent-to-treat population (mean age 67.5 years). All three GP MDI doses significantly improved change from baseline in morning pre-dose trough FEV1 on Day 8 compared with placebo MDI (least squares mean differences 108-131 mL; all p<0.0001). Significant improvements in secondary efficacy endpoints were also observed for all three GP MDI doses compared with placebo MDI (all p<0.0001). Dose-response plateaued at GP MDI 14.4 μg. No significant safety findings were observed with any GP MDI dose or placebo MDI.

Conclusions: The results of this study suggest that GP MDI 14.4 μg (7.2 μg per inhalation) is the most appropriate dose for use in Phase III studies in Japanese patients with moderate-to-severe COPD.

Keywords: COPD; bronchodilator agents; dose–response relationship; forced expiratory volume; metered dose inhalers.

Conflict of interest statement

Disclosure ESR and AM are employees of Pearl – a member of the AstraZeneca Group. SS is an employee of AstraZeneca. CR is an employee of Pearl – a member of the AstraZeneca Group and an employee of AstraZeneca. The other authors report no conflicts of interest in this work.

Figures

Figure 1

Study design. Notes:aAt Visit 2, study site personnel randomized patients in a 1:1:1:1 ratio with an interactive web-based response system into one of the four pre-defined treatment sequences using a four-treatment, four-sequence Williams design. The patient, study site personnel, and the study sponsor were blinded to the treatment sequence assigned to a patient. bPatients underwent a washout period of at least 7 days, but not >28 days’ duration prior to returning to the clinic for Visit 2. cDay 1 of each treatment period: in-clinic protocol-defined assessments up to and including the 2-hour post-dose time point. On Day 1 of each treatment period, patients were required to withhold from using short-acting bronchodilators for ≥6 hours prior to administration of the first dose of study drug. dDay 8 of each treatment period: in-clinic protocol-defined assessments up to and including the 2-hour post-dose time point. Abbreviation: R, randomization.

Figure 2

Patient disposition. Notes:aThree patients withdrew following treatment with placebo MDI and two withdrew following treatment with GP MDI 14.4 μg. bConsidered by the investigator or designee. Abbreviations: GP, glycopyrronium; MDI, metered dose inhaler.