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Dual Bronchodilator Therapy with Umeclidinium/Vilanterol Versus Tiotropium plus Indacaterol in Chronic Obstructive Pulmonary Disease: A Randomized Controlled Trial.

ABSTRACT: INTRODUCTION:The fixed-dose, long-acting bronchodilator combination of umeclidinium/vilanterol (UMEC/VI) has not previously been compared with a combination of a long-acting muscarinic antagonist and long-acting ?2-agonist in patients with chronic obstructive pulmonary disease (COPD). METHODS:This 12-week, randomized, blinded, triple-dummy, parallel-group, non-inferiority study compared once-daily UMEC/VI 62.5/25 mcg with once-daily tiotropium (TIO) 18 mcg + indacaterol (IND) 150 mcg in patients with moderate-to-very-severe COPD. The primary endpoint was the trough forced expiratory volume in 1 s (FEV1) on day 85 (predefined non-inferiority margin -50 mL), and the secondary endpoint was the 0- to 6-h weighted mean (WM) FEV1 on day 84. Other efficacy endpoints [including rescue medication use, the Transition Dyspnea Index (TDI) focal score, and the St. George's Respiratory Questionnaire (SGRQ) score] and safety endpoints [adverse events (AEs), vital signs, and COPD exacerbations] were also assessed. RESULTS:Trough FEV1 improvements were comparable between treatment groups [least squares (LS) mean changes from baseline to day 85: UMEC/VI 172 mL; TIO + IND 171 mL; treatment difference 1 mL; 95 % confidence interval (CI) -29 to 30 mL], demonstrating non-inferiority between UMEC/VI and TIO + IND. The treatments produced similar improvements in the trough FEV1 at other study visits and the 0- to 6-h WM FEV1 (LS mean changes at day 84: UMEC/VI 235 mL; TIO + IND 258 mL; treatment difference -23 mL; 95 % CI -54 to 8 mL). The results for patient-reported measures (rescue medication use, TDI focal score, and SGRQ score) were comparable; both treatments produced clinically meaningful improvements in TDI and SGRQ scores. The incidence of AEs and COPD exacerbations, and changes in vital signs were similar for the two treatments. CONCLUSION:UMEC/VI and TIO + IND, given once daily, provided similar improvements in lung function and patient-reported outcomes over 12 weeks in patients with COPD, with comparable tolerability and safety profiles. TRIAL NUMBERS:ClinicalTrials.gov study ID NCT02257385; GSK study no. 116961.

SUBMITTER: Kalberg C

PROVIDER: S-EPMC4875926 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Dual Bronchodilator Therapy with Umeclidinium/Vilanterol Versus Tiotropium plus Indacaterol in Chronic Obstructive Pulmonary Disease: A Randomized Controlled Trial.

Kalberg Chris C O'Dell Dianne D Galkin Dmitry D Newlands Amy A Fahy William A WA

Drugs in R&D 20160601 2

<h4>Introduction</h4>The fixed-dose, long-acting bronchodilator combination of umeclidinium/vilanterol (UMEC/VI) has not previously been compared with a combination of a long-acting muscarinic antagonist and long-acting β2-agonist in patients with chronic obstructive pulmonary disease (COPD).<h4>Methods</h4>This 12-week, randomized, blinded, triple-dummy, parallel-group, non-inferiority study compared once-daily UMEC/VI 62.5/25 mcg with once-daily tiotropium (TIO) 18 mcg + indacaterol (IND) 150 ...[more]

PMID: 27028749

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Project description:BackgroundBoth long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs) are widely used in the treatment of chronic obstructive pulmonary disease (COPD). A novel LAMA/LABA combination of umeclidinium/vilanterol (UMEC/VI; 62.5 μg/25 μg) is approved for chronic obstructive pulmonary disease (COPD) treatment.ObjectiveThis study aimed to assess the efficacy and cost-effectiveness of UMEC/VI versus tiotropium (TIO) 18 μg in symptomatic patients with COPD from the perspective of the Chinese National Healthcare System.MethodsA simple analysis included three studies in the meta-analysis that compared UMEC/VI with TIO. A Markov model was developed to estimate the cost-effectiveness of UMEC/VI compared with TIO treatment in symptomatic patients with COPD. First, utilities, clinical efficacy, and adverse events obtained from the literature were utilized as model inputs. Costs were from Chinese average data, including local data. Costs were expressed in dollars based on 2020 prices. Then, the model outputs including drug costs, other medical costs, and total costs, and quality-adjusted life years (QALYs) were estimated. Costs and outcomes were discounted at a 5% annual rate. Furthermore, incremental cost-effective ratios (ICERs) were analyzed. Finally, the influences of changing parameters on the uncertainty of the results were assessed by means of one-way and probabilistic sensitivity analyses.ResultsThis study revealed that UMEC/VI treatment had a higher rate of clinical efficacy in comparison with TIO, and the differences in the rate of adverse events between the two treatments were not significant. The results indicated that UMEC/VI was superior to TIO, which provided an increase in QALYs (0.002) and a total cost savings of $765.67 per patient over 3 years. In the base case, the ICER of UMEC/VI is -$397468.04/QALY compared with TIO, suggesting that UMEC/VI may be considered a dominant option over TIO. According to the Chinese medical system, the probability of UMEC/VI being cost-effective was 61.6% at a willingness-to-pay (WTP) of $31554/QALY. Sensitivity analyses confirmed that the results were robust.ConclusionUMEC/VI could be considered a cost-effective treatment compared with TIO in symptomatic COPD patients from the Chinese National Healthcare System perspective. These results may help decision-makers in China when making judgements on which treatments to administer.

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:IntroductionWe report the results of the first direct comparison of the once-daily fixed-dose long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) combinations umeclidinium/vilanterol (UMEC/VI) and tiotropium/olodaterol (TIO/OLO) in patients with COPD.MethodsThis was a randomized, two-period crossover open-label study in symptomatic patients with COPD [age 40 years or older, postbronchodilator forced expiratory volume in 1 s (FEV1) of 70% or less and 50% or more of predicted normal values, and modified Medical Research Council Dyspnoea Scale score of 2 or greater] not receiving inhaled corticosteroid therapy. Patients were randomized to receive UMEC/VI (62.5/25 µg once daily) via a multidose dry powder inhaler (ELLIPTA) followed by TIO/OLO (5/5 µg once daily) via a soft mist inhaler (Respimat), each for 8 weeks with an interim 3-week washout or vice versa. The primary end point was the change from baseline in trough FEV1 at week 8 with a noninferiority margin of - 50 mL in the per-protocol (PP) population. The incidence of adverse events was also assessed.ResultsIn total, 236 patients (mean age 64.4 years, 60% male) were included in the intent-to-treat population and 227 were included in the PP population. UMEC/VI treatment was noninferior in the PP population and superior in the intent-to-treat population to TIO/OLO treatment with regard to trough FEV1 at week 8 [FEV1 change from baseline 180 mL vs 128 mL; difference 52 mL (95% confidence interval 28-77 mL); p < 0.001]. Patients receiving UMEC/VI had twofold increased odds of experiencing a clinically meaningful increase (100 mL or more) from baseline in trough FEV1 at week 8 compared with patients receiving TIO/OLO (odds ratio 2.05; 95% confidence interval 1.34-3.14). Adverse events occurred in 25% of patients in the UMEC/VI group and in 31% of patients in the TIO/OLO group.ConclusionIn this first direct comparison of two once-daily fixed-dose LAMA/LABA combinations, superiority was observed for the primary end point of trough FEV1 at week 8 with UMEC/VI compared with TIO/OLO in patients with symptomatic COPD. Both treatments had similar safety profiles. These findings confirm the results of previous indirect LAMA/LABA comparisons, and show that an efficacy gradient exists within the LAMA/LABA class.Trial registrationClinicalTrials.gov identifier NCT02799784.FundingGlaxoSmithKline.

Project description:IntroductionPatients hospitalized for chronic obstructive pulmonary disease (COPD) exacerbations are at risk of further readmissions, increased treatment costs, and excess mortality. This study evaluated inpatient admissions and readmissions in patients receiving initial maintenance therapy with umeclidinium/vilanterol (UMEC/VI) versus tiotropium (TIO).MethodsThis retrospective, matched cohort study identified patients with COPD who initiated maintenance therapy with UMEC/VI or TIO from Optum's de-identified Clinformatics Data Mart database between January 1, 2013, and December 31, 2018 (index date defined as earliest dispensing). Eligibility criteria included: ≥ 1 medical claim for COPD pre-index or on the index date; ≥ 12 months of continuous eligibility pre-index; age ≥ 40 years at index; no pre- or post-index asthma diagnosis; and no pre-index claims for medications containing inhaled corticosteroids, long-acting β2-agonists, or long-acting muscarinic antagonists. Outcomes included time to first on-treatment COPD-related inpatient admission, rate of on-treatment COPD-related admissions, and rate of all-cause and COPD-related readmissions within 30 and 90 days. Propensity score matching was used to adjust for potential confounders.ResultsMatched UMEC/VI and TIO cohorts each included 7997 patients and were balanced on baseline characteristics (mean age 70.9 years; female 47.1-47.6%). Over 12 months, patients initiating UMEC/VI had significantly reduced risk (hazard ratio [95% CI]: 0.87 [0.79, 0.96]; p = 0.006) and rates (rate ratio [95% CI]: 0.80 [0.72, 0.92]; p = 0.008) of COPD-related inpatient admissions compared with TIO. While all-cause readmission rates were similar between treatment cohorts, readmission rates among patients with an initial admission length of stay of 1-3 days were numerically lower for UMEC/VI versus TIO (30-day readmissions: 10.5% vs. 12.4%; 90-day readmissions: 15.5% vs. 19.8%). Similar patterns were observed for COPD-related readmissions.ConclusionsThese findings highlight the real-world benefits of dual therapy with UMEC/VI versus TIO in reducing inpatient admissions and readmissions in patients with COPD, which may translate to lower healthcare costs.

Project description:BackgroundA head-to-head study demonstrated the superiority of once-daily umeclidinium bromide/vilanterol (UMEC/VI) 62.5/25 mcg on trough forced expiratory volume in 1 s (FEV1) versus once-daily tiotropium/olodaterol (TIO/OLO) 5/5 mcg in symptomatic patients with chronic obstructive pulmonary disease (COPD). This analysis evaluated the cost effectiveness of UMEC/VI versus TIO/OLO from a Spanish National Healthcare System perspective, using data from this study and Spanish literature.MethodsThis analysis was conducted from the perspective of the Spanish National Healthcare System with a 3-year horizon as base case. A disease progression model using a linked risk equation approach was used to estimate disease progression and associated healthcare costs, and quality-adjusted life years (QALYs). The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study was used to develop the statistical risk equations for clinical endpoints, and costs were calculated using a health state approach (by dyspnea severity). Utilities for QALY calculation were estimated using patient baseline characteristics within a regression fit to Spanish observational data. Treatment effect, expressed as change from baseline in FEV1 was obtained from the head-to-head study and used in the model (UMEC/VI minus TIO/OLO difference: + 52 mL [95% confidence interval: 28, 77]). Baseline patient characteristics were sourced from Spanish literature or the head-to-head study if unavailable. A scenario analysis using only the intent-to-treat (ITT) population from the head-to-head study, and sensitivity analyses (including probabilistic sensitivity analyses), were conducted. Direct healthcare costs (2017 Euro) were obtained from Spanish sources and costs and benefits were discounted at 3% per annum.ResultsUMEC/VI was associated with small improvements in QALYs (+ 0.029) over a 3-year time horizon, compared with TIO/OLO, alongside cost savings of €393/patient. The ITT scenario analysis and sensitivity analyses had similar results. All probabilistic simulations resulted in UMEC/VI being less costly and more effective than TIO/OLO.ConclusionUMEC/VI dominated TIO/OLO (more effective and less expensive). These results may aid payers and decision-makers in Spain when making judgements on which long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) treatments can be considered cost effective in Spain.

Project description:IntroductionFew randomised controlled trials (RCTs) have directly compared long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) dual maintenance therapies for patients with chronic obstructive pulmonary disease (COPD). This systematic literature review and network meta-analysis (NMA) compared the efficacy of umeclidinium/vilanterol (UMEC/VI) versus other dual and mono-bronchodilator therapies in symptomatic patients with COPD.MethodsA systematic literature review (October 2015-November 2020) was performed to identify RCTs ≥ 8 weeks long in adult patients with COPD that compared LAMA/LABA combinations against any long-acting bronchodilator-containing dual therapy or monotherapy. Data extracted on changes from baseline in trough forced expiratory volume in 1 s (FEV1), St George's Respiratory Questionnaire (SGRQ) total score, Transitional Dyspnoea Index (TDI) focal score, rescue medication use and moderate/severe exacerbation rate were analysed using an NMA in a frequentist framework. The primary comparison was at 24 weeks. Fixed effects model results are presented.ResultsThe NMA included 69 full-length publications (including 10 GSK clinical study reports) reporting 49 studies. At 24 weeks, UMEC/VI provided statistically significant greater improvements in FEV1 versus all dual therapy and monotherapy comparators. UMEC/VI provided similar improvements in SGRQ total score compared with all other LAMA/LABAs, and significantly greater improvements versus UMEC 125 μg, glycopyrronium 50 μg, glycopyrronium 18 μg, tiotropium 18 μg and salmeterol 50 μg. UMEC/VI also provided significantly better outcomes versus some comparators for TDI focal score, rescue medication use, annualised moderate/severe exacerbation rate, and time to first moderate/severe exacerbation.ConclusionUMEC/VI provided generally better outcomes compared with LAMA or LABA monotherapies, and consistent improvements in lung function (measured by change from baseline in trough FEV1 at 24 weeks) versus dual therapies. Treatment with UMEC/VI may improve outcomes for symptomatic patients with COPD compared with alternative maintenance treatments.

Dataset Information

Dual Bronchodilator Therapy with Umeclidinium/Vilanterol Versus Tiotropium plus Indacaterol in Chronic Obstructive Pulmonary Disease: A Randomized Controlled Trial.

Publications

Dual Bronchodilator Therapy with Umeclidinium/Vilanterol Versus Tiotropium plus Indacaterol in Chronic Obstructive Pulmonary Disease: A Randomized Controlled Trial.

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