Single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy versus tiotropium monotherapy in patients with COPD.
ABSTRACT: Chronic obstructive pulmonary disease (COPD) treatment guidelines do not currently include recommendations for escalation directly from monotherapy to triple therapy. This 12-week, double-blind, double-dummy study randomized 800 symptomatic moderate-to-very-severe COPD patients receiving tiotropium (TIO) for ≥3 months to once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 mcg via ELLIPTA (n = 400) or TIO 18 mcg via HandiHaler (n = 400) plus matched placebo. Study endpoints included change from baseline in trough forced expiratory volume in 1 s (FEV1) at Days 85 (primary), 28 and 84 (secondary), health status (St George's Respiratory Questionnaire [SGRQ] and COPD Assessment Test [CAT]) and safety. FF/UMEC/VI significantly improved trough FEV1 at all timepoints (Day 85 treatment difference [95% CI] 95 mL [62-128]; P < 0.001), and significantly improved SGRQ and CAT versus TIO. Treatment safety profiles were similar. Once-daily single-inhaler FF/UMEC/VI significantly improved lung function and health status versus once-daily TIO in symptomatic moderate-to-very-severe COPD patients, with a similar safety profile.
Project description:<h4>Introduction</h4>Dual bronchodilator therapy is reserved as a second-line treatment in patients with chronic obstructive pulmonary disease (COPD) and provides benefits in lung function and health status versus monotherapy. The aim of this study was to determine whether early initiation of a dual bronchodilator versus monotherapy reduced the risk of deterioration in COPD.<h4>Methods</h4>This post hoc pooled analysis investigated the efficacy and safety of umeclidinium/vilanterol (UMEC/VI) 62.5/25 mcg/day compared with tiotropium (TIO) 18 mcg/day in a maintenance-naïve (MN) subgroup of patients relative to the intent-to-treat (ITT) population from three 6-month active comparator studies (n = 1747). Other treatment arms (UMEC/VI 125/25, VI 25 and UMEC 125) comprised 850 patients in total but were not included in this analysis. The primary endpoint was trough forced expiratory volume in 1 s (FEV<sub>1</sub>). St George's Respiratory Questionnaire (SGRQ) score, rescue medication use, and a novel composite endpoint of short-term clinically important deterioration (CID; ≥100 ml decrease in trough FEV<sub>1</sub>, ≥4-unit increase in SGRQ score, or a COPD exacerbation) were also assessed.<h4>Results</h4>UMEC/VI improved trough FEV<sub>1</sub> versus TIO at day 169 [least squares mean (95% confidence interval): MN: 146 ml (102-189) and ITT: 95 ml (71-118); both P < 0.001]. Both UMEC/VI and TIO improved SGRQ and rescue use in the two populations, with greater improvements in rescue use with UMEC/VI versus TIO. UMEC/VI reduced the risk of short-term clinically important deterioration versus TIO [hazard ratio; 95% confidence interval: MN: 0.66 (0.51-0.85); ITT: 0.62 (0.54-0.71), both P ≤ 0.001]. Adverse events were similar across both populations and treatments.<h4>Conclusions</h4>Early use of dual-bronchodilator therapy has superior efficacy on lung function and may reduce the risk of short-term deterioration compared to monotherapy in symptomatic patients with COPD.<h4>Clinical trial registration</h4>GSK analysis 202066 (NCT01316900/DB2113360, NCT01316913/DB2113374, NCT01777334/ZEP117115).<h4>Funding</h4>This study was funded by GSK.
Project description: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.
Project description:<h4>Background</h4>A 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 (FEV<sub>1</sub>) 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.<h4>Methods</h4>This 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 FEV<sub>1</sub> 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.<h4>Results</h4>UMEC/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.<h4>Conclusion</h4>UMEC/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 ?<sub>2</sub>-agonist (LAMA/LABA) treatments can be considered cost effective in Spain.
Project description:<h4>Introduction</h4>Real-world trial data comparing single- with multiple-inhaler triple therapy (MITT) in COPD patients are currently lacking. The effectiveness of once-daily single-inhaler fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) and MITT were compared in usual clinical care.<h4>Methods</h4>INTREPID was a multicentre, randomised, open-label, phase IV effectiveness study comparing FF/UMEC/VI 100/62.5/25 µg <i>via</i> the ELLIPTA inhaler with a clinician's choice of any approved non-ELLIPTA MITT in usual COPD clinical practice in five European countries. Primary end-point was proportion of COPD Assessment Test (CAT) responders (≥2-unit decrease in CAT score from baseline) at week 24. Secondary end-points in a subpopulation included change from baseline in forced expiratory volume in 1 s (FEV<sub>1</sub>) and percentage of patients making at least one critical error in inhalation technique at week 24. Safety was also assessed.<h4>Results</h4>3092 patients were included (FF/UMEC/VI n=1545; MITT n=1547). The proportion of CAT responders at week 24 was significantly greater with FF/UMEC/VI <i>versus</i> non-ELLIPTA MITT (OR 1.31, 95% CI 1.13-1.51; p<0.001) and mean change from baseline in FEV<sub>1</sub> was significantly greater with FF/UMEC/VI (77 mL <i>versus</i> 28 mL; treatment difference 50 mL, 95% CI 26-73 mL; p<0.001). The percentage of patients with at least one critical error in inhalation technique was low in both groups (FF/UMEC/VI 6%; non-ELLIPTA MITT 3%). Safety profiles, including incidence of pneumonia serious adverse events, were similar between treatments.<h4>Conclusions</h4>In a usual clinical care setting, treatment with once-daily single-inhaler FF/UMEC/VI resulted in significantly more patients gaining health status improvement and greater lung function improvement <i>versus</i> non-ELLIPTA MITT.
Project description:<h4>Introduction</h4>We report the results of the first direct comparison of the once-daily fixed-dose long-acting muscarinic antagonist/long-acting β<sub>2</sub>-agonist (LAMA/LABA) combinations umeclidinium/vilanterol (UMEC/VI) and tiotropium/olodaterol (TIO/OLO) in patients with COPD.<h4>Methods</h4>This 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 (FEV<sub>1</sub>) 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 FEV<sub>1</sub> at week 8 with a noninferiority margin of - 50 mL in the per-protocol (PP) population. The incidence of adverse events was also assessed.<h4>Results</h4>In 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 FEV<sub>1</sub> at week 8 [FEV<sub>1</sub> 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 FEV<sub>1</sub> 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.<h4>Conclusion</h4>In this first direct comparison of two once-daily fixed-dose LAMA/LABA combinations, superiority was observed for the primary end point of trough FEV<sub>1</sub> 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.<h4>Trial registration</h4>ClinicalTrials.gov identifier NCT02799784.<h4>Funding</h4>GlaxoSmithKline.
Project description:<h4>Introduction</h4>The phase 3 InforMing the PAthway of COPD (chronic obstructive pulmonary disease) Treatment (IMPACT) trial, single-inhaler therapy with fluticasone furoate (FF) 100 μg, umeclidinium (UMEC) 62.5 μg, and vilanterol (VI) 25 μg demonstrated a reduction in the rate of moderate or severe exacerbations compared with FF/VI or UMEC/VI in patients with symptomatic COPD at risk of exacerbations. This article reports additional evidence of improvements in symptoms and health-related quality of life (HRQoL) with FF/UMEC/VI compared with either FF/VI or UMEC/VI from the IMPACT study.<h4>Methods</h4>Patient-reported HRQoL assessments and symptom measures included as pre-specified IMPACT end points were the St George's Respiratory Questionnaire (SGRQ), COPD Assessment Test (CAT), and Baseline Dyspnea Index (BDI) as the anchor for the Transitional Dyspnea Index (TDI) focal score (BDI/TDI) in a subset of patients enrolled at study sites in North America and Europe. Change from baseline was assessed at weeks 4, 28, and 52.<h4>Results</h4>The intent-to-treat population included 10,355 patients (TDI population: 5058 patients). Clinically meaningful improvements in SGRQ total score between baseline and week 52 favored FF/UMEC/VI over FF/VI (- 1.8 units, p < 0.001) and UMEC/VI (- 1.8 units, p < 0.001). Similar improvements in the CAT and TDI focal score were also observed with FF/UMEC/VI versus FF/VI or UMEC/VI.<h4>Conclusions</h4>This study demonstrates that in patients with symptomatic COPD at risk of exacerbations, once-daily FF/UMEC/VI, compared with FF/VI or UMEC/VI, improves patient-perceived HRQoL and symptoms.<h4>Trial registration number</h4>NCT02164513.
Project description:<h4>Background</h4>The InforMing the Pathway of COPD Treatment (IMPACT) trial demonstrated lower moderate/severe exacerbation rates with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus FF/VI or UMEC/VI in patients with chronic obstructive pulmonary disease (COPD) and a history of exacerbations. Since IMPACT was a global study, post-hoc analyses were conducted by geographic region to investigate potential differences in overall findings.<h4>Methods</h4>IMPACT was a 52-week, randomized, double-blind trial. Patients with symptomatic COPD and ≥1 moderate/severe exacerbation in the prior year were randomized 2:2:1 to once-daily FF/UMEC/VI 100/62.5/25µg, FF/VI 100/25µg, or UMEC/VI 62.5/25µg. Endpoints assessed in the overall, Western Europe and North America populations included on-treatment moderate/severe exacerbation (rates and time-to-first), trough forced expiratory volume in 1 second and St George's Respiratory Questionnaire (SGRQ) total score. Safety was assessed.<h4>Results</h4>Overall, 10,355 patients were enrolled, 3164 from Western Europe, 2639 from North America. FF/UMEC/VI significantly reduced on-treatment moderate/severe exacerbation rates versus FF/VI and UMEC/VI in Western Europe (rate ratios 0.82 [95%CI 0.74-0.91], <i>P</i><.001 and 0.76 [0.67-0.87], <i>P</i><.001) and in North America (0.87 [0.77-0.97], <i>P</i>=.014 and 0.69 [0.60-0.80], <i>P</i><.001). FF/UMEC/VI reduced time-to-first moderate/severe exacerbation and improved lung function versus FF/VI and UMEC/VI in both regions, and improved SGRQ total score in Western Europe, but not North America. Safety profiles were generally similar between treatment groups/regions; the inhaled corticosteroid class effect of increased pneumonia incidence was seen in North America but not Western Europe.<h4>Conclusion</h4>Consistent with intent-to-treat results, FF/UMEC/VI reduced moderate/severe exacerbation rate and risk and improved lung function in Western Europe and North America; however, between-regions differences were seen for SGRQ total score and pneumonia incidence.<h4>Clinical trial registration</h4>NCT02164513.
Project description:<h4>Introduction</h4>Directly recorded patient experience of symptoms and health-related quality of life (HRQoL) can complement lung function and exacerbation rate data in chronic obstructive pulmonary disease (COPD) clinical studies. The FULFIL study recorded daily symptoms and activity limitation together with additional patient-reported outcomes of dyspnea and HRQoL, as part of the prespecified analyses. FULFIL co-primary endpoint data have been previously reported.<h4>Methods</h4>FULFIL was a phase III, 24-week, randomized, double-blind, double-dummy, multicenter study comparing once-daily single inhaler triple therapy [fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI)] 100 µg/62.5 µg/25 µg with twice-daily inhaled corticosteroid/long-acting β<sub>2</sub>-agonist therapy [budesonide/formoterol (BUD/FOR)] 400 µg/12 µg in patients with symptomatic COPD at risk of exacerbations. A subset participated for 52 weeks. Patient-reported assessments were: Evaluating Respiratory Symptoms in COPD™ (E-RS: COPD), St George's Respiratory Questionnaire (SGRQ) for COPD, COPD Assessment Test (CAT), baseline and transitional dyspnea indices (TDI) and daily and global anchor questions for activity limitation.<h4>Results</h4>FF/UMEC/VI showed greater reductions from baseline in 4-weekly mean E-RS: COPD total and all subscale scores compared with BUD/FOR; differences were statistically significant (P < 0.05) at each time period. FF/UMEC/VI also demonstrated greater improvements from baseline at weeks 4 and 24 in SGRQ domain scores and TDI focal score compared with BUD/FOR. At weeks 4 and 24, improvements greater than the minimal clinically important difference from baseline were observed in CAT score with FF/UMEC/VI, but not BUD/FOR; differences were statistically significant (P ≤ 0.003).<h4>Conclusion</h4>These findings demonstrate sustained daily symptom and HRQoL benefits of FF/UMEC/VI versus BUD/FOR. The inclusion of the CAT may provide data that are readily generalizable to everyday clinical practice.<h4>Trial registration</h4>ClinicalTrials.gov number: NCT02345161.<h4>Funding</h4>GSK.
Project description:BACKGROUND:The comparative efficacy of inhaled corticosteroid/long-acting muscarinic antagonist/long-acting ?2-agonist (ICS/LAMA/LABA) triple therapy administered via single or multiple inhalers in patients with chronic obstructive pulmonary disease (COPD) has not been evaluated comprehensively. We conducted two replicate trials comparing single- with multiple-inhaler ICS/LAMA/LABA combination in COPD. METHODS:207608 and 207609 were Phase IV, 12-week, randomized, double-blind, triple-dummy non-inferiority trials comparing once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25??g via Ellipta inhaler, with twice-daily budesonide/formoterol (BUD/FOR) 400/12??g via metered-dose inhaler plus once-daily tiotropium (TIO) 18??g via HandiHaler. Patients had symptomatic COPD and forced expiratory volume in 1?s (FEV1) <?50% predicted, or FEV1 <?80% predicted and???2 moderate or 1?severe exacerbations in the prior year. The primary endpoint in both trials was weighted mean change from baseline (wmCFB) in 0-24-h FEV1 at Week 12. Secondary endpoints included CFB in trough FEV1 at Day 84 and 85. Other endpoints included serial FEV1 and health status outcomes at Week 12. Safety was evaluated descriptively. RESULTS:The modified per-protocol population included 720 and 711 patients in studies 207608 and 207609 (intent-to-treat population: 728 and 732). FF/UMEC/VI was non-inferior to BUD/FOR+TIO for wmCFB in 0-24-h FEV1 at Week 12 (Study 207608 treatment difference [95% confidence interval]: 15?mL [-?13, 43]; Study 207609: 11?mL [-?20, 41]). FF/UMEC/VI improved trough FEV1 CFB versus BUD/FOR+TIO at Day 84 and 85 (Day 85 treatment difference: Study 207608: 38?mL [10, 66]; Study 207609: 51?mL [21, 82]) and FEV1 at 12 and 24?h post-morning dose at Week 12 in both studies. No treatment differences were seen in health status outcomes. Safety profiles were similar between treatments; pneumonia occurred in 7 (<?1%) patients with FF/UMEC/VI and 9 (1%) patients with BUD/FOR+TIO, across both studies. CONCLUSIONS:FF/UMEC/VI was non-inferior to BUD/FOR+TIO for wmCFB in 0-24-h FEV1 at Week 12 in patients with COPD. Greater improvements in trough and serial FEV1 measurements at Week 12 with FF/UMEC/VI versus BUD/FOR+TIO, together with similar health status improvements and safety outcomes including the incidence of pneumonia, suggest that once-daily single-inhaler FF/UMEC/VI triple therapy is a viable option for patients looking to simplify their treatment regimen. TRIAL REGISTRATION:GSK (207608/207609; NCT03478683/NCT03478696).
Project description:Triple inhaled corticosteroid (ICS)/long-acting muscarinic antagonist (LAMA)/long-acting ?2-agonist (LABA) therapy is recommended for symptomatic patients with chronic obstructive pulmonary disease (COPD) and at risk of exacerbations. However, the benefits versus side-effects of triple inhaled therapy for COPD, based on distinct patient clinical profiles, are unclear. FULFIL, a phase III, randomised, double-blind study, compared 24?weeks of once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25?µg using the Ellipta inhaler with twice-daily budesonide/formoterol (BUD/FOR) 400/12?µg using the Turbuhaler. Subgroup analyses of forced expiratory volume in 1?s (FEV1), St George's Respiratory Questionnaire (SGRQ) Total score and exacerbation rates were carried out. Subgroups were defined by COPD medication at screening (ICS+LABA, BUD+FOR, ICS+LABA+LAMA, LAMA alone, tiotropium alone and LAMA+LABA), by disease severity (lung function and exacerbations) and by exacerbation history (exacerbation severity and frequency). In the intent-to-treat population (n=1810) at week 24, FF/UMEC/VI (n=911) versus BUD/FOR (n=899) improved FEV1 and SGRQ Total score and reduced mean annual exacerbation rates in all disease severity and exacerbation history subgroups. FF/UMEC/VI versus BUD/FOR improved FEV1 and SGRQ Total score in all medication subgroups and reduced mean annual exacerbation rates in all medication subgroups, except LAMA+LABA. Adverse events were similar across subgroups. These findings support the benefit of FF/UMEC/VI compared with dual ICS/LABA therapy in patients with symptomatic COPD regardless of disease severity or prior treatment and may help to inform clinical decision making.