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Ethnic sensitivity assessment of fluticasone furoate/vilanterol in East Asian asthma patients from randomized double-blind multicentre Phase IIb/III trials.

ABSTRACT: BACKGROUND:Fluticasone furoate (FF)/vilanterol (VI) is a once daily (OD) inhaled corticosteroid/long-acting ?2-agonist combination asthma therapy approved in Japan and the EU. FF/VI efficacy and safety data from asthma studies including patients in East Asia were evaluated to assess ethnic sensitivity. METHODS:Randomized, double-blind, multicenter Phase IIb/III trials were assessed. Change from baseline relative to placebo or twice-daily fluticasone propionate 500 ?g in trough FEV1 was compared between patients from Japan (N?=?148) and Not-Japan (N?=?3,066; three studies). Adverse events (AEs), laboratory results, and electrocardiograms were compared between patients from Japan?+?Korea (N?=?188) and Not-Japan?+?Korea (N?=?3,840; five studies). RESULTS:For trough FEV1, improvements from baseline (least-squares mean difference [95% confidence interval]) were reported for FF/VI 100/25 ?g OD versus placebo at Week 12 (Japan: 0.323 L [0.104-0.542]; Not-Japan: 0.168 L [0.095-0.241]). Improvements from baseline (least-squares mean change [standard error]) were reported with FF/VI 200/25 ?g OD at Week 24 (Japan: 0.355 L [0.1152]; Not-Japan: 0.396 L [0.0313]). A greater proportion of patients from Japan?+?Korea versus Not-Japan?+?Korea reported AEs in all treatment arms including placebo (FF/VI 100/25 ?g: 79% versus 57%; FF/VI 200/25 ?g: 64% versus 45%; placebo: 41% versus 23%). There were no notable differences in treatment-related or class-related AEs. No clinically significant changes in electrocardiogram assessments or statistically significant differences in 24 h urinary cortisol excretion were observed between the Japan?+?Korea and Not-Japan?+?Korea cohorts. CONCLUSIONS:Good efficacy and an acceptable safety profile were observed for FF/VI 100/25 ?g and 200/25 ?g OD in East Asian asthma patients; these globally recommended doses are appropriate for asthma patients in Japan. TRIAL REGISTRATION:Clinicaltrials.gov registration numbers: NCT01165138 , NCT01134042 , NCT01086384 , NCT00603278 , NCT00603382 .

SUBMITTER: Gross AS

PROVIDER: S-EPMC4690330 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Ethnic sensitivity assessment of fluticasone furoate/vilanterol in East Asian asthma patients from randomized double-blind multicentre Phase IIb/III trials.

Gross Annette S AS Goldfrad Caroline C Hozawa Soichiro S James Mark H MH Clifton Christine S CS Sugiyama Yutaro Y Jacques Loretta L

BMC pulmonary medicine 20151224

<h4>Background</h4>Fluticasone furoate (FF)/vilanterol (VI) is a once daily (OD) inhaled corticosteroid/long-acting β2-agonist combination asthma therapy approved in Japan and the EU. FF/VI efficacy and safety data from asthma studies including patients in East Asia were evaluated to assess ethnic sensitivity.<h4>Methods</h4>Randomized, double-blind, multicenter Phase IIb/III trials were assessed. Change from baseline relative to placebo or twice-daily fluticasone propionate 500 μg in trough FEV ...[more]

PMID: 26704701

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Project description:BACKGROUND:This analysis of the IMPACT study assessed the cardiovascular (CV) safety of single-inhaler triple therapy with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus FF/VI and UMEC/VI dual therapy. METHODS:IMPACT was a 52-week, randomized, double-blind, multicenter Phase III study comparing the efficacy and safety of FF/UMEC/VI 100/62.5/25 mcg with FF/VI 100/25 mcg or UMEC/VI 62.5/25 mcg in patients ?40?years of age with symptomatic chronic obstructive pulmonary disease (COPD) and??1 moderate/severe exacerbation in the previous year. The inclusion criteria for the study were intentionally designed to permit the enrollment of patients with significant concurrent CV disease/risk. CV safety assessments included proportion of patients with and exposure-adjusted rates of on-treatment CV adverse events of special interest (CVAESI) and major adverse cardiac events (MACE), as well as time-to-first (TTF) CVAESI, and TTF CVAESI resulting in hospitalization/prolonged hospitalization or death. RESULTS:Baseline CV risk factors were similar across treatment groups. Overall, 68% of patients (n =?7012) had ?1 CV risk factor and 40% (n =?4127) had ?2. At baseline, 29% of patients reported a current/past cardiac disorder and 58% reported a current/past vascular disorder. The proportion of patients with on-treatment CVAESI was 11% for both FF/UMEC/VI and UMEC/VI, and 10% for FF/VI. There was no statistical difference for FF/UMEC/VI versus FF/VI or UMEC/VI in TTF CVAESI (hazard ratio [HR]: 0.98, 95% confidence interval [CI]: 0.85, 1.11; p =?0.711 and HR: 0.92, 95% CI: 0.78, 1.08; p =?0.317, respectively) nor TTF CVAESI leading to hospitalization/prolonged hospitalization or death (HR: 1.19, 95% CI: 0.93, 1.51; p =?0.167 and HR: 0.96, 95% CI: 0.72, 1.27; p =?0.760, respectively). On-treatment MACE occurred in ?3% of patients across treatment groups, with similar prevalence and rates between treatments. CONCLUSIONS:In a symptomatic COPD population with a history of exacerbations and a high rate of CV disease/risk, the proportion of patients with CVAESI and MACE was 10-11% and 1-3%, respectively, across treatment arms, and the risk of CVAESI was low and similar across treatment arms. There was no statistically significant increased CV risk associated with the use of FF/UMEC/VI versus FF/VI or UMEC/VI, and UMEC/VI versus FF/VI. TRIAL REGISTRATION:NCT02164513 (GSK study number CTT116855).

Project description:BACKGROUND:Single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 ?g has been shown to improve lung function and health status, and reduce exacerbations, versus budesonide/formoterol in patients with chronic obstructive pulmonary disease (COPD). We evaluated the non-inferiority of single-inhaler FF/UMEC/VI versus FF/VI?+?UMEC using two inhalers. METHODS:Eligible patients with COPD (aged ?40 years; ?1 moderate/severe exacerbation in the 12 months before screening) were randomized (1:1; stratified by the number of long-acting bronchodilators [0, 1 or 2] per day during run-in) to receive 24-week FF/UMEC/VI 100/62.5/25 ?g and placebo or FF/VI 100/25 ?g?+?UMEC 62.5 ?g; all treatments/placebo were delivered using the ELLIPTA inhaler once-daily in the morning. Primary endpoint: change from baseline in trough forced expiratory volume in 1 s (FEV1) at Week 24. The non-inferiority margin for the lower 95% confidence limit was set at -?50 mL. RESULTS:A total of 1055 patients (844 [80%] of whom were enrolled on combination maintenance therapy) were randomized to receive FF/UMEC/VI (n?=?527) or FF/VI?+?UMEC (n?=?528). Mean change from baseline in trough FEV1 at Week 24 was 113 mL (95% CI 91, 135) for FF/UMEC/VI and 95 mL (95% CI 72, 117) for FF/VI?+?UMEC; the between-treatment difference of 18 mL (95% CI -13, 50) confirmed FF/UMEC/VI's was considered non-inferior to FF/VI?+?UMEC. At Week 24, the proportion of responders based on St George's Respiratory Questionnaire Total score was 50% (FF/UMEC/VI) and 51% (FF/VI?+?UMEC); the proportion of responders based on the Transitional Dyspnea Index focal score was similar (56% both groups). A similar proportion of patients experienced a moderate/severe exacerbation in the FF/UMEC/VI (24%) and FF/VI?+?UMEC (27%) groups; the hazard ratio for time to first moderate/severe exacerbation with FF/UMEC/VI versus FF/VI?+?UMEC was 0.87 (95% CI 0.68, 1.12). The incidence of adverse events was comparable in both groups (48%); the incidence of serious adverse events was 10% (FF/UMEC/VI) and 11% (FF/VI?+?UMEC). CONCLUSIONS:Single-inhaler triple therapy (FF/UMEC/VI) is non-inferior to two inhalers (FF/VI?+?UMEC) on trough FEV1 change from baseline at 24 weeks. Results were similar on all other measures of efficacy, health-related quality of life, and safety. TRIAL REGISTRATION:GSK study CTT200812; ClinicalTrials.gov NCT02729051 (submitted 31 March 2016).

Project description:Study objectiveTo investigate the pharmacodynamic and pharmacokinetic profiles of fluticasone furoate (FF)/vilanterol (VI) - a fixed-dose combination of an inhaled corticosteroid (ICS) and a long-acting β2 -agonist for the treatment of asthma and chronic obstructive pulmonary disease - after single and repeat administration in healthy Chinese subjects.DesignDouble-blind, placebo-controlled, single-site, randomized, four-way crossover study.SettingThe Clinical Pharmacological Research Centre at Peking Union Medical College Hospital [PUMCH]) in Beijing, China.SubjectsSixteen healthy, nonsmoking Chinese adults.InterventionSubjects were randomized to receive FF/VI 50/25, 100/25, or 200/25 μg, or placebo once/daily in the morning, delivered by the Ellipta dry powder inhaler, for 7 consecutive days. The subjects then received the other three treatments, with each treatment period separated by a 7-day washout period.Measurements and main resultsThe co-primary outcome measures reflected pharmacodynamic responses relating to recognized class effects of the two drug classes: reduced serum cortisol level (ICSs), and increased Fridericia's corrected QT interval (QTcF) and reduced serum potassium level (long-acting β2 -agonists). Co-primary pharmacodynamic endpoints were 0-24-hour weighted mean serum cortisol level on day 7 (cortisol0-24 hr, Day 7 ), and 0-4-hour weighted mean and maximum QTcF and weighted mean and minimum serum potassium level on days 1 and 7. Fluticasone furoate and VI plasma concentrations, derived pharmacokinetic parameters, and safety were also assessed. Of the 16 subjects randomized, 15 completed the study. Reductions in cortisol0-24 hour, Day 7 of 15% and 25% were observed with FF/VI 100/25 and 200/25 μg, respectively, versus placebo. Minor increases (< 10 msec) in maximum QTcF on day 7 were seen with FF/VI 50/25 and 100/25 μg but not with 200/25 μg. Slight decreases in serum potassium level were only observed in subjects receiving FF/VI 50/25 μg on day 1 and FF/VI 50/25 and 200/25 μg on day 7. Fluticasone furoate accumulation (day 7 vs day 1) for FF/VI 50/25-200/25 μg ranged from 38 to 54% for maximum observed concentration and 63-71% for area under the concentration-time curve from 0 to 4 hours. Fluticasone furoate pharmacokinetics were less than dose proportional. The VI pharmacokinetic profiles were similar for all three FF/VI doses. Adverse events were all mild in intensity and were reported by 13 (81%) of the 16 subjects.ConclusionIn healthy Chinese subjects, minimal and non-clinically relevant β-adrenergic pharmacodynamic effects were observed with FF/VI doses ranging from 50/25 to 200/25 μg. FF dose-dependent reductions in serum cortisol levels of 15-25% were seen after administration of FF/VI 100/25 and 200/25 μg. FF/VI was safe and well tolerated in these subjects at doses ranging from 50/25 to 200/25 μg.

Project description:INTRODUCTION:There is a paucity of data describing prescribing patterns and adherence to therapy of inhaled corticosteroids (ICS) in combination with long-acting β2-agonists (LABA) in the Japanese population in clinical practice. METHODS:This was a non-interventional, retrospective, cohort study of patients who were prescribed medication for asthma, using data from the Japan Medical Data Center Claims Database. Data from patients aged ≥ 15 years with a prescription of asthma drugs between December 2014 and October 2015 (Day 0, the index date when asthma medication was initiated) were analysed in 12-month pre-index and post-index periods. Part 1 focused on baseline characteristics and epidemiological outcomes in the pre- and post-index period in the overall asthma population, whereas comparing medication adherence [number of prescribed days per year and proportion of days covered (PDC)] between ICS/LABA-naïve patients treated with once-daily fluticasone furoate/vilanterol (FF/VI) and twice-daily fluticasone propionate/salmeterol (FP/SAL) was the primary endpoint in Part 2. RESULTS:Of the available patient data (N = 2,953,652), 28,699 patients were identified as having asthma. ICS/LABA was the main asthma treatment prescribed; 11,167 (38.9%) patients were continuous ICS/LABA users. In ICS/LABA-naïve asthma patients, treatment with once-daily FF/VI was associated with higher medication adherence compared with twice-daily FP/SAL; mean [standard deviation (SD)] number of prescribed days per year was 97.8 (115.9) for FF/VI versus 80.5 (92.7) for FP/SAL (p = 0.04), mean (SD) PDC was 26.7% (31.5) for FF/VI versus 21.9% (24.8) for FP/SAL (p = 0.04). FF/VI was also associated with a lower rate of treatment discontinuation and no difference in use of short-acting beta2-agonists or oral corticosteroids compared with FP/SAL. CONCLUSIONS:ICS/LABA was the major prescribed asthma treatment in Japan. Medication adherence was greater with FF/VI, which may indicate that patients are more likely to adhere to once-daily FF/VI versus twice-daily FP/SAL. FUNDING:This study was funded by GSK (study sponsor). STUDY REGISTRATION:GSK Study No. 207264, GSK Study Register site: https://www.gsk-clinicalstudyregister.com/search/?search_terms=207264 .

Dataset Information

Ethnic sensitivity assessment of fluticasone furoate/vilanterol in East Asian asthma patients from randomized double-blind multicentre Phase IIb/III trials.

Publications

Ethnic sensitivity assessment of fluticasone furoate/vilanterol in East Asian asthma patients from randomized double-blind multicentre Phase IIb/III trials.

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