Seasonal Variation in COPD Exacerbations: a Post-Hoc Analysis from the KRONOS Phase III Study of Budesonide/Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler (BGF MDI)

Rationale: In the Phase 3 KRONOS study, budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI), a fixed-dose combination triple therapy, significantly reduced the moderate/severe chronic COPD exacerbation rate vs. glycopyrrolate/formoterol fumarate (GFF) MDI, with numerical improvements vs. budesonide/formoterol fumarate (BFF) MDI. We conducted a post-hoc analysis for seasonal variation of exacerbation rates.

Methods: KRONOS was a randomized, double-blind, multicenter, 24-week study (NCT02497001) including patients with symptomatic moderate-to-very severe COPD (CAT-score ≥ 10) despite ≥ 2 inhaled maintenance therapies. We analyzed data from the modified intent-to-treat population receiving BGF MDI 320/18/9.6 μg (n = 639), GFF MDI 18/9.6 μg (n = 625), BFF MDI 320/9.6 μg (n = 314), or open-label budesonide/formoterol dry powder inhaler 400/12 μg (BUD/FORM DPI; n = 318). Of these patients, 74% had not experienced an exacerbation in the previous year. Annualized rate of moderate/severe COPD exacerbations was analyzed using negative binomial regression, adjusting for baseline post-bronchodilator % predicted FEV1, baseline eosinophil count, treatment, season, treatment by season interaction, baseline COPD exacerbation history, country, and ICS use at screening. Seasons were defined as: winter, December−February; spring, March−May; summer, June−August; fall, September−November.

Results: Adjusted annualized rates of moderate/severe COPD exacerbations were highest in winter (0.83, 1.60, 0.89, 0.94 for BGF MDI, GFF MDI, BFF MDI, and BUD/FORM DPI, respectively) and lowest in summer (0.25, 0.60, 0.38, 0.44). BGF MDI reduced exacerbations rates vs. GFF MDI regardless of season (treatment incidence rate ratios 0.52, 0.51, 0.42, 0.45 for winter, spring, summer, and fall, respectively; all p < 0.01).

Conclusion: In this population of patients with moderate-to-very severe COPD without a requirement for an exacerbation history in the previous year, seasonal variation in exacerbation rates occurred within each treatment group. The significant reduction in annualized exacerbation rates with BGF MDI vs. GFF MDI was consistently observed across all four seasons, indicating that the 6-month study duration provided a robust assessment of COPD exacerbation rates.