PMID- 22789766 OWN - NLM STAT- MEDLINE DCOM- 20121228 LR - 20220309 IS - 1879-114X (Electronic) IS - 0149-2918 (Linking) VI - 34 IP - 8 DP - 2012 Aug TI - 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. PG - 1655-66.e5 LID - 10.1016/j.clinthera.2012.06.005 [doi] AB - BACKGROUND: Available inhaled corticosteroid/long-acting 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 (FEV(1)) 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 FF/VI 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 FF/VI (50/25 mug, 100/25 mug, and 200/25 mug), 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 FEV(1) (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. RESULTS: 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 beta(2)-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 FEV(1) than placebo: adjusted mean improvements from placebo in FEV(1) for FF/VI were 220 to 236 mL (all, P < 0.001). Improvements versus placebo in change from period baseline serial FEV(1) 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 mug 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. CI - Copyright (c) 2012 Elsevier HS Journals, Inc. All rights reserved. FAU - Boscia, Joseph A AU - Boscia JA AD - CU Pharmaceutical Research, Union, South Carolina 29379, USA. joseph@cupharmresearch.com FAU - Pudi, Krishna K AU - Pudi KK FAU - Zvarich, Michael T AU - Zvarich MT FAU - Sanford, Lisa AU - Sanford L FAU - Siederer, Sarah K AU - Siederer SK FAU - Crim, Courtney AU - Crim C LA - eng SI - ClinicalTrials.gov/NCT01072149 PT - Clinical Trial, Phase III PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20120711 PL - United States TA - Clin Ther JT - Clinical therapeutics JID - 7706726 RN - 0 (Adrenergic beta-2 Receptor Agonists) RN - 0 (Aerosols) RN - 0 (Androstadienes) RN - 0 (Benzyl Alcohols) RN - 0 (Bronchodilator Agents) RN - 0 (Chlorobenzenes) RN - 0 (Drug Combinations) RN - 0 (Glucocorticoids) RN - 0 (Powders) RN - 028LZY775B (vilanterol) RN - JS86977WNV (fluticasone furoate) SB - IM MH - Administration, Inhalation MH - Adrenergic beta-2 Receptor Agonists/*administration & dosage/adverse effects MH - Aerosols MH - Aged MH - Androstadienes/*administration & dosage/adverse effects MH - Benzyl Alcohols/*administration & dosage/adverse effects MH - Bronchodilator Agents/*administration & dosage/adverse effects MH - Chlorobenzenes/*administration & dosage/adverse effects MH - Cross-Over Studies MH - Double-Blind Method MH - Drug Administration Schedule MH - Drug Combinations MH - Female MH - Forced Expiratory Volume MH - Glucocorticoids/*administration & dosage/adverse effects MH - Humans MH - Lung/*drug effects/physiopathology MH - Male MH - Middle Aged MH - Nebulizers and Vaporizers MH - Powders MH - Pulmonary Disease, Chronic Obstructive/diagnosis/*drug therapy/physiopathology MH - Spirometry MH - Time Factors MH - Treatment Outcome MH - United States MH - Vital Capacity EDAT- 2012/07/14 06:00 MHDA- 2012/12/29 06:00 CRDT- 2012/07/14 06:00 PHST- 2012/02/14 00:00 [received] PHST- 2012/05/18 00:00 [revised] PHST- 2012/06/08 00:00 [accepted] PHST- 2012/07/14 06:00 [entrez] PHST- 2012/07/14 06:00 [pubmed] PHST- 2012/12/29 06:00 [medline] AID - S0149-2918(12)00368-2 [pii] AID - 10.1016/j.clinthera.2012.06.005 [doi] PST - ppublish SO - Clin Ther. 2012 Aug;34(8):1655-66.e5. doi: 10.1016/j.clinthera.2012.06.005. Epub 2012 Jul 11.