12-Hour Lung Function Assessment of Budesonide/Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler (BGF MDI) Delivered by Co-suspension Delivery Technology in Patients with COPD

Rationale: In the Phase 3 KRONOS study (NCT02497001; Ferguson et al., Lancet Respir Med 2018) BGF MDI, formulated using co-suspension delivery technology, improved lung function and symptoms and reduced exacerbations versus the corresponding dual therapies in symptomatic patients with moderate-to-very severe COPD. Here we report the KRONOS12-hour pulmonary function test (PFT) sub-study, which assessed lung function over the entire 12-hour dosing interval for BGF MDI, budesonide/formoterol fumarate (BFF) MDI, glycopyrrolate/formoterol fumarate (GFF) MDI, and budesonide/formoterol fumarate dry powder inhaler (DPI).

Methods: KRONOS was a randomized, double-blind, parallel-group study with patients receiving BGF MDI 320/18/9.6 µg, GFF MDI 18/9.6 µg, BFF MDI 320/9.6 µg, or open-label budesonide/formoterol DPI 400/12 µg 2 ×/d for 24 weeks. Only patients from a subset of US sites participated in the 12-hour PFT sub-study. The primary endpoint of the PFT sub-study was FEV₁ area under the curve between 0 – 12 hours (FEV₁ AUC_0 – 12) at Week 24.

Results: A subset of 687 patients (mean age 63.4 years; 51.4% male) was included in the 12-hour PFT sub-study. Adjusted mean changes from baseline in FEV₁ at Week 24 rapidly improved in all treatment groups, peaked at 2 hours post dose, and gradually declined from 2 to 12 hours post dose. BGF MDI improved FEV₁ AUC_0 – 12 versus BFF MDI and budesonide/formoterol fumarate DPI (least squares mean [LSM] differences 95 mL [p = 0.0006] and 65 mL [p = 0.0150], respectively), and had a similar effect to GFF MDI (LSM difference = − 23 mL; p = 0.2920). GFF MDI improved FEV₁ AUC_0 – 12 versus BFF MDI (LSM difference 119 mL; p < 0.0001) and budesonide/formoterol DPI (LSM difference 88 mL; p = 0.0011). Improvements in the change from baseline in FEV₁ AUC with all treatments were sustained throughout the 12-hour dosing period, with greater improvements in the first 6 hours post dose (FEV₁ AUC_0 – 6) than in the second 6 hours (FEV₁ AUC_6 – 12). FEV₁ AUC_0 – 4 results for patients in this sub-study were consistent with the results for the overall KRONOS population.

Conclusion: In patients with moderate-to-very severe COPD, lung function benefits of BGF MDI relative to BFF MDI and budesonide/formoterol DPI were maintained over the whole 12-hour dosing interval, with similar improvements observed for BGF MDI and GFF MDI.