Dose selection for glycopyrrolate/eFlow® phase III clinical studies: results from GOLDEN (Glycopyrrolate for Obstructive Lung Disease via Electronic Nebulizer) phase II dose-finding studies

Abstract

Background: Long-acting muscarinic antagonists (LAMAs) are recommended for the treatment of chronic obstructive pulmonary disease (COPD). Glycopyrrolate/eFlow® is an investigational drug-device combination of the LAMA glycopyrrolate administered by an eFlow® Closed System (eFlow® CS) nebulizer. The GOLDEN 2 (NCT01706536) and GOLDEN 6 (NCT02038829) Phase II, multicenter studies were conducted to inform dose selection for the GOLDEN Phase III clinical trials. Bronchodilator responses and safety assessments supported dose selection.

Methods: Subjects with moderate-to-severe COPD were randomized into 28-day parallel-group (GOLDEN 2) or 7-day crossover (GOLDEN 6) studies and received placebo, glycopyrrolate (3, 6.25, 12.5, 25, 50 or 100 μg twice daily [BID]) or aclidinium bromide 400 μg BID. The primary endpoint of both studies was change from baseline in trough forced expiratory volume in 1 s (FEV1). Safety assessments included the incidence of treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events, and discontinuation due to TEAE. Lung function data collected in both studies were pooled.

Results: The combined GOLDEN 2 (n = 282) and GOLDEN 6 (n = 96) studies included 378 subjects. On Days 7 and 28 there were dose-ordered, statistically significant and clinically important lung function improvements in glycopyrrolate treatment groups. Specifically, on Day 7, glycopyrrolate produced >0.100 L placebo-adjusted changes from baseline in trough FEV1 (12.5 μg BID: 0.122 L; 25 μg BID: 0.123 L; 50 μg BID: 0.137 L) and FEV1 AUC0-12 (12.5 μg BID: 0.145 L; 25 μg BID: 0.178 L; 50 μg BID: 0.180 L). The improvements in lung function for the glycopyrrolate 25 and 50 μg BID doses were comparable to those with aclidinium bromide 400 μg BID (FEV1: 0.149 L; FEV1 AUC0-12: 0.172 L). Acceptable safety profiles were observed across all groups in both studies.

Conclusions: The efficacy and safety findings supported selection of glycopyrrolate 25 and 50 μg BID doses for the Phase III GOLDEN studies and provided preliminary evidence for the use of nebulized glycopyrrolate as a maintenance therapy for COPD.

Keywords: COPD; GOLDEN; Glycopyrrolate; LAMA; Nebulizer; Phase II; eFlow® CS.

Conflict of interest statement

Ethics approval and consent to participate

Ethics approval was provided by:

GOLDEN 2

Central IRB: Shulman Associates IRB, 4445 Lake Forest Drive, Suite 300, Cincinnati, OH 45242 (Chair: Susan Nelson MSN, RN, CNS).

Local IRB: Dr. Nicola Hanania, Baylor College of Medicine Office of Research, One Baylor Plaza, Suite 600D, Houston, TX 77030 (Chair: Vernon R Sutton, MD, BS).

GOLDEN 6

Central IRB: Quorum Review IRB, 1501 Fourth Ave, Suite 800, Seattle, WA 98101 (Chair: Steven Rosenfeld MD, MBA).

Consent for publication

Not applicable

Competing interests

JFD has served as a consultant to Sunovion, AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Novartis, Theravance, and has served on Drug Safety Monitoring Boards for AstraZeneca, Novartis, Gilead, INSMED and Grifolds. RT and TG are employees of Sunovion. AW was an employee of Sunovion at the time of the study.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

GOLDEN 2 study design. BID, twice daily

Fig. 2

GOLDEN 6 study design. aSafety follow-up was conducted 5–7 days after the Early Termination visit for subjects who discontinued the study prior to completing all scheduled treatment periods. BID, twice daily

Fig. 3

Mean change from baseline in FEV1 over time on Day 7 (pooled population). BID, twice daily. FEV1, forced expiratory volume in 1 second

Fig. 4

Placebo-adjusted change from baseline in FEV1 AUC0-12 on Day 7 (a: GOLDEN 2; b: GOLDEN 6; c: pooled population). AUC, area under the curve. BID, twice daily. CI, confidence interval. FEV1, forced expiratory volume in 1 second. LS, least squares