Efficacy and Safety of Twice-Daily Glycopyrrolate Versus Placebo in Patients With COPD: The GEM2 Study

Abstract

Long-acting bronchodilators including muscarinic antagonists are central to the management of patients with COPD. The Glycopyrrolate Effect on syMptoms and lung function (GEM2) study assessed the efficacy and safety of twice-daily glycopyrrolate 15.6 μg in patients with moderate-to-severe airflow limitation. This 12-week multicenter, double-blind study randomized (1:1) patients to glycopyrrolate 15.6 μg twice daily (b.i.d.) or placebo both delivered via the NeohalerTM device. The primary objective was superiority of glycopyrrolate compared with placebo for forced expiratory volume in 1 second (FEV1) standardized area under curve (AUC) between 0 and 12 hours post dosing (FEV1 AUC0-12h)at week 12. Other outcomes included additional spirometry parameters, health status using St George's Respiratory Questionnaire (SGRQ), dyspnea via Transition Dyspnea Index (TDI), rescue medication use and COPD symptoms reported by patients via the electronic diary. Safety was also assessed. Of the 432 patients randomized (glycopyrrolate, n=216; placebo, n=216), 96% completed the planned treatment phase. The study met its primary objective (superiority of glycopyrrolate compared with placebo for FEV1 AUC0-12h).Compared with placebo, glycopyrrolate showed significant improvements in lung function parameters (p<0.001). Health status (SGRQ total score and COPD assessment test), rescue medication use and daily total COPD symptom scores were significantly improved with glycopyrrolate versus placebo over 12 weeks. Improvements in dyspnea were observed with glycopyrrolate and placebo although the treatment difference was not statistically significant. Overall, differences in the incidences of adverse events and serious adverse events between the groups were not considered clinically meaningful. No deaths were reported. Twice-daily glycopyrrolate 15.6 μg showed statistically significant and clinically meaningful improvements compared with placebo in lung function, COPD symptoms, health status, and rescue medication usage in COPD patients with moderate-to-severe airflow limitation.

Clinical trial registration: NCT01715298.

Keywords: bronchodilator; chronic obstructive pulmonary disease; glycopyrrolate; glycopyrronium; long-acting muscarinic antaagonist; lung function; twice daily.

Conflict of interest statement

EK has served on speaker panels, advisory boards and as consultant for AstraZeneca (Pearl), Amphastar, Forest Laboratories, Sunovion, Boehringer Ingelheim, Teva Labs, Novartis, Mylan and Theravance. TMS has received research funding from Novartis, GlaxoSmithKline, Boehringer Ingelheim, Forest Research Institute, Astra Zeneca, Sunovion, and Pearl Therapeutics. PK has received research support for studies of COPD from Astra Zeneca, Amphastar, Boehringer Ingelheim, Forrest Laboratory, Novartis, Mylan, Sunovian and Teva. AW has no conflict of interests. JHE, FP and PD are employees of the study sponsor, Novartis. MH is contracted to work for Novartis. All authors participated in the development and writing of the manuscript and take full responsibility for the content of the article. All authors approved the final draft that was submitted. PD, JHE, MH and FP contributed to the design of the study. EK, the principal investigator of the study, has read and commented on the full study report, and had final responsibility for the decision to submit for publication. TMS, PK and AW as investigators of the study, contributed to the writing of each draft of the manuscript. All the investigators were involved in primary data collection. PD, JHE, MH and FP, as employees of the sponsor, contributed to the design and preparation, conduct, analysis and interpretation of the study for the manuscript, and also contributed to the writing of each draft of the manuscript.

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