title: Long-term safety of glycopyrrolate: A randomized study in patients with moderate-to-severe COPD (GEM3).
abstract: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the United States. Long-acting muscarinic antagonists (LAMAs) are a class of medications used as maintenance therapy for COPD. The GEM3 (Glycopyrrolate Effect on syMptoms and lung function) study assessed the long-term safety and efficacy of a LAMA, glycopyrrolate (GLY) 15.6 μg twice daily (b.i.d.), compared with an approved long-acting β2-agonist (LABA), indacaterol (IND) 75 μg once daily (q.d.) in patients with stable, symptomatic COPD with moderate-to-severe airflow limitation.
  
  
  
  This 52-week, multicenter, double-blind, parallel-group study randomized patients (1:1) of the United States to receive GLY 15.6 μg b.i.d. or IND 75 μg q.d. both delivered via the Neohaler(®) device. The primary objective was to assess the safety and tolerability in terms of adverse event (AE) reporting rates over 52 weeks. Safety was also determined by evaluating multiple secondary endpoints, including vital signs, electrocardiograms (ECGs), and time to first moderate or severe exacerbation. Efficacy-related secondary endpoints included pre-dose forced expiratory volume in one second (FEV1) and forced vital capacity (FVC).
  
  
  
  Of the 511 randomized patients (GLY, n = 254; IND, n = 257), 81.6% completed the study. The overall incidences of AEs (GLY, 77.3%; IND, 77.0%) and serious AEs (GLY, 13.1%; IND, 13.3%) were comparable between the groups. The incidence of major adverse cardiovascular events was low and comparable between the groups. No clinically relevant differences for vital signs or ECG parameters were observed between the treatment groups. The three sudden deaths reported within 30 days of the treatment (GLY, n = 2; IND, n = 1) were adjudicated as unrelated to the study medication. In terms of efficacy, GLY 15.6 μg b.i.d. showed improvements in pre-dose FEV1 and FVC from baseline, which was comparable to those with IND 75 μg q.d., with no statistically significant differences. No significant differences were observed between the treatment groups in the time to first moderate or severe COPD exacerbation.
  
  
  
  GLY 15.6 μg b.i.d. showed a long-term safety profile comparable to that of IND 75 μg q.d. and provided rapid and sustained bronchodilation over 52 weeks in patients with COPD with moderate-to-severe airflow limitation.
  
  
  
  NCT01697696.
authors.affiliation: Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Valley Regional Hospital, Claremont, NH 03743, USA. Electronic address: mahlerdonald@gmail.com.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Mahler
authors.affiliation: Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. Electronic address: alex.h.gifford@hitchcock.org.
authors.forename: Alex H
authors.initials: AH
authors.lastname: Gifford
authors.affiliation: Temple University College of Medicine, Philadelphia, PA, USA. Electronic address: aditi.satti@tuhs.temple.edu.
authors.forename: Aditi
authors.initials: A
authors.lastname: Satti
authors.affiliation: Novartis Pharma AG, Basel, Switzerland. Electronic address: nicola.jessop@novartis.com.
authors.forename: Nicola
authors.initials: N
authors.lastname: Jessop
authors.affiliation: Novartis Pharma AG, Basel, Switzerland. Electronic address: joerg.eckert@novartis.com.
authors.forename: Joerg H
authors.initials: JH
authors.lastname: Eckert
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. Electronic address: peter.dandrea@novartis.com.
authors.forename: Peter
authors.initials: P
authors.lastname: D'Andrea
authors.affiliation: Novartis Pharma AG, Basel, Switzerland. Electronic address: fernando.mota@novartis.com.
authors.forename: Fernando
authors.initials: F
authors.lastname: Mota
authors.affiliation: Novartis Healthcare Pvt. Ltd., Hyderabad, India. Electronic address: rudrani-1.banerjee@novartis.com.
authors.forename: Rudrani
authors.initials: R
authors.lastname: Banerjee
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D000368:Aged; D001993:Bronchodilator Agents / Q000627:therapeutic use; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006024:Glycopyrrolate / Q000008:administration & dosage* / Q000009:adverse effects* / Q000494:pharmacology; D006801:Humans; D007189:Indans / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage* / Q000009:adverse effects* / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D015363:Quinolones / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014481:United States / Q000453:epidemiology; D014797:Vital Capacity / Q000187:drug effects; D055986:Vital Signs / Q000187:drug effects
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D007189:Indans; D018727:Muscarinic Antagonists; D015363:Quinolones; C510790:indacaterol; D006024:Glycopyrrolate
keywords: Bronchodilator; Chronic obstructive pulmonary disease; Glycopyrrolate; Indacaterol; Long-acting muscarinic antagonist; Safety