Available inhaled corticosteroid/long-acting β2-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.
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 FF/VI in patients with COPD.
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 FF/VI (50/25 μg, 100/25 μg, and 200/25 μg), 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 FF/VI.
Eighty-seven patients were screened; 54 completed run-in and were randomized to double-blind 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 β2-agonists within the 3 months before screening (63%). All 3 strengths of once-daily FF/VI 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 μg 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.
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.
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Published online: July 12, 2012
Accepted: June 8, 2012
For information regarding institution names, please see the table in Supplemental Appendix C in the online version at http://dx.doi.org/10.1016/j.clinthera.2012.06.005.
© 2012 Elsevier HS Journals, Inc. Published by Elsevier Inc. All rights reserved.