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. BACKGROUND NCT01715298.