Randomized study of the effects of Aerochamber Plus® Flow-Vu® on the efficacy, pharmacokinetics and safety of glycopyrronium/formoterol fumarate dihydrate metered dose inhaler in patients with chronic obstructive pulmonary disease

Objectives: This study compared the efficacy, pharmacokinetics (PK), and safety of GFF MDI (Bevespi Aerosphere (R)), a fixed-dose combination of glycopyrronium and formoterol fumarate dihydrate (14.4/10 mu g) delivered by a metered dose inhaler (MDI) formulated using innovative co-suspension delivery technology, in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) with and without the Aerochamber Plus (R) Flow-Vu (R) valved holding chamber (VHC). Methods: In this multicenter, open-label, crossover, Phase III study (NCT02454959), patients were randomized to receive GFF MDI 14.4/10 mu g (equivalent to glycopyrrolate/formoterol fumarate 18/9.6 mu g) twice daily for 7 days with and without the VHC. The primary endpoint was forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV1 AUC(0-12)) on Day 8. Steady state PK parameters for glycopyrronium and formoterol (AUC(0-12), peak concentration [C-max] and time to peak concentration [t(max)]) were estimated from 12-h plasma concentration time data on Day 8. Safety and tolerability were also assessed throughout. Results: Eighty patients were randomized. On Day 8, the ratio (90% confidence interval [CI]) of least squares mean (LSM) FEV1 AUC(0-12) for GFF MDI with VHC (LSM = 1538 mL; n = 67) versus without VHC (LSM = 1516 mL; n = 68) was 101.4% (100.1, 102.7). PK parameters were comparable overall with a slightly higher exposure to glycopyrronium with the VHC. The AUC(0-12) geometric LSM ratio (90% CI) for GFF MDI with versus without VHC was 115.99% (99.74, 134.89) for glycopyrronium and 96.66% (86.69, 107.78) for formoterol. GFF MDI with and without VHC were well tolerated with a similar adverse event profile. Conclusions: The magnitude of bronchodilatory effect was similar with and without a VHC following GFF MDI treatment. This, together with the PK and safety profiles, supports the use of the VHC with GFF MDI for the maintenance treatment of COPD, which could be particularly useful for patients who have difficulty with the coordination of an MDI.