Long-term safety of glycopyrrolate: A randomized study of COPD patients
Glycopyrrolate bromide is a quick-onset long-acting muscarinic antagonist bronchodilator with FDA approval for use as maintenance treatment of COPD. Seebri Neohaler is approved for use at a dose of 15.6 ug inhaled twice daily.
The glycopyrrolate effect on symptoms and lung function (GEM) trials comprise the phase III clinical program that support the drugs’ approval in the U.S. The GEM 1 and 2 trials studied the safety and efficacy of glycopyrrolate, 15.6 ug twice daily for 12 weeks. GEM 3 was a 52 week, randomized double-blind parallel-group study that reviewed use of glycopyrrolate for treatment of airflow limitation in patients with moderate to severe COPD. It compared the safety and efficacy of glycopyrrolate 15.6 ug twice daily with that of the long acting beta agonist indacterol, 75 ug once daily. Participants were allowed to continue inhaled corticosteroid treatment at a stable dose as well as albuterol for rescue treatment. All other medications for COPD were prohibited.
Rates of adverse events served as the primary endpoint and were used to assess the tolerability and safety of the study drugs. Multiple secondary endpoints assessed safety and efficacy over the 52 weeks. Patients included in the study were current or ex-smokers, at least 40 years of age with a 10 pack-year smoking history, a post-bronchodilator VC ratio less than 0.7, an FEV1 between 30% and 80% of predicted, and a modified Medical Research Council (mMRC) dyspnea scale grade of 2 or greater. Patients with a history of prolonged QT interval, a corrected QT interval greater than 450 ms, a clinically significant ECG abnormality, significant arrhythmia, renal abnormalities, or asthma were excluded. Also excluded were patients with a history of COPD exacerbation requiring antibiotic therapy, systemic corticosteroids, or hospitalization within the six weeks prior to screening through the run-in period.
Overall, 81.6% of the study patients completed the 52 weeks of therapy; 207 received glycopyrrolate and 210 received indacterol. Overall incidence of adverse drug events was comparable: glycopyrrolate, 77.3%, indacterol, 77.0%. The incidence of serious adverse event incidence was also comparable: glycopyrrolate, 13.1% ; indacterol 13.3%. Most adverse events, which included COPD exacerbations, were respiratory-related. Exacerbation, the most common adverse event, was the leading cause of study drug discontinuation: glycopyrrolate, 3.6%; indacterol, 2.0%, The rate of discontinuation was similar between the two groups: glycopyrrolate, 36.3%; indacterol, 37.1%. Rates of major cardiovascular adverse events—a concern relating to the burden of comorbidities among patients with COPD—were low overall and not statistically different between the two groups: glycopyrrolate, 3.2%; indacterol, 3.1%.
Additionally, treatment groups demonstrated comparable changes to measures of efficacy. Glycopyrrolate recipients experienced statistically similar changes in pre-dose trough FEV1(glycopyrrolate, 0.056 L; indacterol 0.060 L; -0.004 L) and FVC from baseline to week 52 of the study relative to indacterol recipients. Both groups demonstrated a decline in pre-dose FEV1 over time. This finding is consistent with the progressive nature of COPD. Rates of exacerbation were low for both groups. Use of rescue inhalers was not statistically different between treatment groups.
Bottom line: This study demonstrates the role of glycopyrrolate, 15.6 ug twice daily, as a treatment option comparable to indacterol, 75 ug daily, for patients with moderate to severe COPD.
Kathryn Wheeler PharmD, BCPS, is an associate clinical professor of pharmacy practice at the University of Connecticut, School of Pharmacy.