Effect of Once-Daily Fluticasone Furoate/Vilanterol on 24-Hour Pulmonary Function in Patients With Chronic Obstructive Pulmonary Disease: A Randomized, Three-Way, Incomplete Block, Crossover Study

Background: Available inhaled corticosteroid/longacting beta(2)-agonist combinations for chronic obstructive pulmonary disease (COPD) require twice-daily administration. The combination of fluticasone furoate (FF) and vilanterol (VI) FF/VI is being developed in a novel dry powder inhaler for the treatment of COPD and asthma with the potential for once-daily dosing. Results from Phase II studies have shown clinically and statistically significant improvements over placebo in trough (24-hour postdose) forced expiratory volume in 1 second (FEV1) after once-daily dosing with FF or VI (VI concurrently with an inhaled corticosteroid) in asthma and VI in COPD. Objectives: This Phase III, multicenter, randomized, double-blind, placebo-controlled study was designed based on guidance from drug regulators with the goal of evaluating the 24-hour spirometric effect of once-daily FFNI in patients with COPD. Methods: Patients (aged >= 40 years) who completed a 2-week placebo run-in period were randomized to 1 of 18 three-course sequences of placebo and 2 of 3 dose combinations of FFNI (50/25 mu g, 100/25 mu g, and 200/25 mu g), dosed once daily in the morning. Each 28-day treatment period was separated by a 2-week, single-blind, placebo washout period. The primary end point was time-adjusted (weighted mean) 0 to 24-hour FEV1 (AUC) at the end of each 28-day treatment period (period days 28-29). Safety profile assessments included incidence of adverse events (AEs) (defined according to the Medical Dictionary for Regulatory Activities), 12-lead ECG outputs, vital signs (pulse rate, diastolic and systolic blood pressure) and clinical laboratory assessments (including fasting serum glucose and potassium) and 24-hour serum cortisol. The pharmacokinetics of FF and VI were assessed at the end of each 28-day treatment period with FFNI. Results: Eighty-seven patients were screened; 54 completed run-in and were randomized to doubleblind treatment. The mean patient age was 57.9 years, and 46% were male. The majority of patients were current smokers (83%) and were receiving short-acting beta(2)-agonists within the 3 months before screening (63%). All 3 strengths of once-daily FFNI demonstrated significantly higher 0 to 24-hour (period days 28-29) change from period baseline weighted mean FEV1 than placebo: adjusted mean improvements from placebo in FEV1 for FF/VI were 220 to 236 mL (all, P < 0.001). Improvements versus placebo in change from period baseline serial FEV1 measures were observed at each time-point and with each strength of FF/VI over the 0 to 25-hour period (period days 28-29), indicating sustained bronchodilation. The overall incidence of on-treatment AEs was low (10%-12% with FF/VI; 4% with placebo); 2 serious AEs were reported during washout periods (1 AE after FF/VI 50/25 mu g and 1 AE after placebo) but neither was considered treatment related. No serious AEs were reported during the treatment periods or during the follow-up period. No clinically or statistically significant differences from placebo were reported for serum glucose or potassium. No significant effects on vital signs, ECG, or 24-hour serial serum cortisol were reported. The extent of systemic exposure to FF and VI at steady state was low for all strengths of FF/VI. Conclusions: FF/VI inhaled once daily in the morning for 28 days produced significant improvements in pulmonary function with a prolonged (>24 hours') duration of action in this population of patients with COPD. The combination was well tolerated. ClinicalTrials.gov identifier: NCT01072149. (Clin Ther. 2012;34:1655-1666) (C) 2012 Elsevier HS Journals, Inc. All rights reserved.