Clinically Important Deterioration Among Patients with Chronic Obstructive Pulmonary Disease (COPD) Treated with Nebulized Glycopyrrolate: A Post Hoc Analysis of Pooled Data from Two Randomized, Double-Blind, Placebo-Controlled Studies

PURPOSE: Using a composite endpoint, pooled data from two 12-week Phase III placebo-controlled trials (GOLDEN 3, NCT02347761; GOLDEN 4, NCT02347774) were analyzed to determine whether glycopyrrolate inhalation solution (25 mcg and 50 mcg) administered twice daily (BID) via the eFlow(®) Closed System nebulizer (GLY) reduced the risk of clinically important deterioration (CID) in patients with moderate-to-very-severe COPD. METHODS: CID was defined as ≥100-mL decrease from baseline in post-bronchodilator trough forced expiratory volume in one second (FEV(1)), or ≥4-unit increase in baseline St. George’s Respiratory Questionnaire (SGRQ) total score, or moderate/severe exacerbation. The relative treatment effect of GLY versus placebo on the odds of CID (any and by component endpoints) was expressed as the odds ratio (OR) and 95% confidence interval (CI). Subgroups categorized by age (<65/≥65 years), sex, smoking status (current/former), long-acting beta agonist (LABA) use, FEV(1) (<50%/≥50%), and peak inspiratory flow rate (PIFR) (<60 L/min/≥60 L/min) were analyzed. RESULTS: Compared to placebo, GLY 25 mcg and 50 mcg BID over 12 weeks significantly reduced the risk of CID by 50% (OR: 0.50 [0.37–0.68]) and 40% (OR: 0.60 [0.44–0.80]), respectively. Subjects treated with GLY 25 mcg BID were 59% less likely to experience CID in FEV(1) (OR: 0.41 [0.27–0.62]) and 48% less likely to perceive CID in health status (OR: 0.52 [0.37–0.73]). Statistically significant reductions were also observed at the higher dose. The incidence of moderate/severe exacerbations was low and comparable among the cohorts. GLY 25 mcg BID was significantly more effective than placebo (p<0.05) in preventing CID irrespective of age, smoking status, LABA use, COPD severity, or PIFR. Subjects <65 years (OR 0.45 [0.29–0.68]) and those with PIFR <60 L/min (OR 0.36 [0.20–0.67]) exhibited the largest benefit. CONCLUSION: Nebulized GLY over 12 weeks significantly reduced the risk of CID and provided greater short-term stability in patients with moderate-to-very-severe COPD.