Inventi Impact: Advanced Dosaging

Inventi:pad/20883/16

Dose-Response to Inhaled Glycopyrrolate Delivered with a Novel Co-Suspensionâ?¢ Delivery\nTechnology Metered Dose Inhaler (MDI) in Patients with Moderate-to-Severe COPD

Background: This study forms part of the first complete characterization of the doseââ?¬â??response curve for glycopyrrolate\n(GP) delivered using Co-Suspensionââ??¢ Delivery Technology via a metered dose inhaler (MDI). We examined the lower\nGP MDI dose range to determine an optimal dose for patients with moderate-to-severe chronic obstructive pulmonary\ndisease (COPD).\nMethods: This randomized, double-blind, chronic-dosing, balanced incomplete-block, placebo-controlled, crossover\nstudy compared six doses of GP MDI (18, 9, 4.6, 2.4, 1.2, and 0.6 Ã?¼g, twice daily [BID]) with placebo MDI BID and openlabel\ntiotropium dry powder inhaler (18 Ã?¼g, once daily [QD]) in patients with moderate-to-severe COPD. Patients were\nrandomized into 1 of 120 treatment sequences. Each sequence included 4 of 8 treatments administered for 14-day\nperiods separated by 7- to 21-day washout periods.\nThe primary efficacy endpoint was change from baseline in forced expiratory volume in 1 s area under the curve from\n0 to 12 h (FEV1 AUC0ââ?¬â??12) on Day 14. Secondary efficacy endpoints included peak change from baseline (post-dose) in\nFEV1 and inspiratory capacity (IC) on Days 1, 7, and 14; change from baseline in morning pre-dose trough FEV1 on\nDays 7 and 14; change from baseline in 12-h post-dose trough FEV1 on Day 14; time to onset of action (ââ?°Â¥10 %\nimprovement in mean FEV1) and the proportion of patients achieving ââ?°Â¥12 % improvement in FEV1 on Day 1;\nand pre-dose trough IC on Days 7 and 14. Safety and tolerability were also assessed.\nResults: GP MDI 18, 9, 4.6, and 2.4 Ã?¼g demonstrated statistically significant and clinically relevant increases in FEV1 AUC0ââ?¬â??12 compared with placebo MDI following 14 days of treatment (modified intent-to-treat populati\nGP MDI 18 Ã?¼g was non-inferior to open-label tiotropium for peak change in FEV1 on Day 1 and morning pre-dose\ntrough FEV1 on Day 14. All doses of GP MDI were well tolerated with no unexpected safety findings.\nConclusions: These efficacy and safety results support GP MDI 18 Ã?¼g BID as the most appropriate dose for evaluation\nin Phase III trials in patients with moderate-to-severe COPD.