Budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler, formulated using co-suspension delivery technology, improves lung function and exacerbation outcomes in patients with COPD without a recent history of exacerbations: subgroup analysis of KRONOS study

Purpose: In the KRONOS study (NCT02497001; Ferguson et al Lancet Respir Med 2018), the triple fixed-dose combination budesonide/glycopyrrolate/formoterol fumarate metered-dose-inhaler (BGF MDI) improved lung function and exacerbations vs. dual therapies in patients with COPD who were not required to have had prior exacerbations. We conducted a post-hoc subgroup analysis in patients without exacerbations in the previous year.

Methods: Patients with moderate-to-very severe COPD and CAT-score ≥ 10 were randomized 2 : 2 : 1 : 1 to BGF MDI 320/18/9.6 µg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 µg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 µg, or open-label budesonide/formoterol fumarate dihydrate dry-powder-inhaler (BUD/FORM DPI) 400/12 µg (2 inhal. 2 x/d for 24 weeks). Post-hoc-analysis included co-primary endpoints (morning pre-dose trough FEV₁ and FEV₁ AUC_0 – 4), and the annualized moderate/severe (m/s) COPD exacerbations rate. All p-values are nominal.

Results: In total, 74.4% (1411/1896) of patients in the KRONOS modified intent-to-treat population had no recent exacerbation history (mean age 65.5 years; 72.8% male; 69.9% used inhaled corticosteroids at screening). At Week 24, change from baseline in morning pre-dose trough FEV₁ was significantly improved with BGF MDI vs. BFF MDI (LSM difference 83 mL [52 – 115]; p < 0.0001) and BUD/FORM DPI (46 mL [15 – 78]; p = 0.0043) but not vs. GFF MDI (5 mL [− 21 – 31]; p = 0.6876). BGF MDI significantly improved FEV₁ AUC_0 – 4 at Week 24 vs. BFF MDI (LSM difference [95% CI] 133 mL [91 – 175]; p < 0.0001) and BUD/FORM DPI (86 mL [44 – 128]; p < 0.0001) but not vs. GFF MDI (− 2 mL [− 36 – 32]; p = 0.9011). Adjusted annualized rates of m/s exacerbations were 0.41, 0.80, 0.42, and 0.47 for BGF MDI, GFF MDI, BFF MDI and BUD/FORM DPI, respectively. BGF MDI significantly reduced the rate of m/s exacerbations vs. GFF MDI (treatment incidence rate ratio 0.52 [0.37 – 0.72]; p = 0.0001) but not vs. BFF MDI and BUD/FORM DPI.

Conclusion: In this KRONOS subgroup analysis of patients without m/s exacerbations in the previous year, BGF MDI improved lung function vs. BFF MDI and reduced the COPD exacerbation rate vs. GFF MDI. Results were consistent with findings in the overall KRONOS population demonstrating that exacerbation benefits were not driven by patients with a recent exacerbation history.