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Efficacy and Safety of Once-Daily Inhaled Umeclidinium in Asian Patients with COPD: Results from a Randomized, Placebo-Controlled Study.

ABSTRACT: Purpose:Previous studies demonstrating efficacy and safety of once-daily umeclidinium (UMEC) in patients with chronic obstructive pulmonary disease (COPD) have included few Asian patients. This study evaluated efficacy and safety of UMEC 62.5 mcg versus placebo in Asian patients with COPD. Patients and Methods:A Phase III, randomized, double-blind, parallel-group study. Patients (aged ?40 years with COPD, pre-, and post-albuterol forced expiratory volume in 1 s [FEV1]/forced vital capacity ratio <0.70 and low risk of exacerbations) were randomized 2:1 to once-daily UMEC 62.5 mcg or placebo via the ELLIPTA inhaler for 24 weeks. Primary endpoint was change from baseline (CFB) in trough FEV1 on Day 169. Secondary endpoints were weighted mean FEV1 over 0-6 hrs post-dose on Day 1 and CFB in Transition Dyspnea Index (TDI) focal score on Day 168. Results:A total of 306 patients were included in the modified intent-to-treat population (UMEC: 205; placebo: 101). UMEC versus placebo provided a statistically significant improvement in least squares (LS) mean trough FEV1 between baseline and Day 169 (154 mL [95% confidence interval (CI): 113, 194]; p<0.001). A clinically meaningful difference of 125 mL in favor of UMEC (95% CI: 103, 147; p<0.001) was also seen in LS weighted mean FEV1 0-6 hrs post-dose on Day 1. A LS mean treatment difference in TDI focal score of 0.9 units in favor of UMEC was seen on Day 168 (95% CI: 0.3, 1.5; p=0.004). Incidence of on-treatment adverse events (AEs) was lower in the placebo (55%) versus UMEC arm (60%); non-fatal serious AEs, drug-related AEs, and AEs leading to withdrawal were similar with UMEC and placebo. Conclusion:Once-daily UMEC 62.5 mcg resulted in statistically significant and clinically meaningful improvements in lung function and dyspnea, compared with placebo, in Asian patients with COPD, with no new safety concerns observed.

SUBMITTER: Zhong N

PROVIDER: S-EPMC7173840 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Efficacy and Safety of Once-Daily Inhaled Umeclidinium in Asian Patients with COPD: Results from a Randomized, Placebo-Controlled Study.

Zhong Nanshan N Zheng Jinping J Lee Sang Haak SH Lipson David A DA Du Xin X Wu Shunquan S

International journal of chronic obstructive pulmonary disease 20200417

<h4>Purpose</h4>Previous studies demonstrating efficacy and safety of once-daily umeclidinium (UMEC) in patients with chronic obstructive pulmonary disease (COPD) have included few Asian patients. This study evaluated efficacy and safety of UMEC 62.5 mcg versus placebo in Asian patients with COPD.<h4>Patients and methods</h4>A Phase III, randomized, double-blind, parallel-group study. Patients (aged ≥40 years with COPD, pre-, and post-albuterol forced expiratory volume in 1 s [FEV<sub>1</sub>]/f ...[more]

PMID: 32368027

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Project description:BackgroundCombination of the inhaled long-acting muscarinic antagonist umeclidinium (UMEC; GSK573719) with the long-acting β2-agonist vilanterol (VI) is an approved maintenance treatment for COPD in the US and EU. We compared the efficacy and safety of UMEC/VI with placebo in patients with COPD of Asian ancestry.Patients and methodsIn this 24-week, Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, patients were randomized 1:1:1 to UMEC/VI 125/25 μg, UMEC/VI 62.5/25 μg, or placebo. The primary efficacy end point was trough forced expiratory volume in 1 second (FEV1) on day 169; secondary end points were Transition Dyspnea Index (TDI) focal score at week 24 and weighted mean (WM) FEV1 over 0-6 hours postdose on day 1. Additional end points and safety were also assessed.ResultsBoth UMEC/VI 125/25 μg and UMEC/VI 62.5/25 μg statistically significantly improved trough FEV1 at day 169 versus placebo (UMEC/VI 125/25 μg, 0.216 L, [95% confidence interval [CI] 0.175-0.257]; UMEC/VI 62.5/25 μg, 0.151 L, 95% CI 0.110-0.191; both P<0.001). Statistically significant improvements in TDI score were observed for both UMEC/VI groups versus placebo (UMEC/VI 125/25 μg, 0.9, 95% CI 0.3-1.4, P=0.002; UMEC/VI 62.5/25 μg, 0.7, 95% CI 0.1-1.2, P=0.016). On day 1, both UMEC/VI groups improved 0-6-hour WM FEV1 versus placebo (UMEC/VI 125/25 μg, 0.182 L 95% CI 0.161-0.203; UMEC/VI 62.5/25 μg, 0.160 L, 95% CI 0.139-0.181; both P<0.001). Statistically significant improvements for UMEC/VI groups versus placebo were observed for rescue albuterol use at weeks 1-24 (puffs/day, both P<0.001). The incidence of adverse events was similar across groups.ConclusionIn Asian patients with COPD, once-daily UMEC/VI 125/25 μg and UMEC 62.5/25 μg resulted in clinically meaningful and statistically significant improvements in lung-function end points versus placebo. Symptomatic and quality of life measures also improved. The safety profile of UMEC/VI was consistent with previous studies.

Project description:BACKGROUND:Patients with asthma uncontrolled on inhaled corticosteroids may benefit from umeclidinium (UMEC), a long-acting muscarinic antagonist. METHODS:This Phase IIb, double-blind study included patients with reversible, uncontrolled/partially-controlled asthma for ?6?months, receiving ?100 mcg/day fluticasone propionate (or equivalent) for ?12?weeks. Following a 2-week run-in on open-label fluticasone furoate (FF) 100 mcg, patients were randomised (1:1:1) to receive UMEC 31.25 mcg, UMEC 62.5 mcg or placebo on top of FF 100 mcg once-daily for 24?weeks. As-needed salbutamol was provided. Primary and secondary endpoints were change from baseline in clinic trough forced expiratory volume in 1?s (FEV1) and clinic FEV1 3?h post-dose, respectively, at Week 24. Other endpoints included change from baseline in home daily spirometry (trough FEV1, evening FEV1, morning [pre-dose] and evening peak expiratory flow) over 24?weeks. Safety was assessed throughout the study. RESULTS:The intent-to-treat population comprised 421 patients (UMEC 31.25 mcg: n =139, UMEC 62.5 mcg: n =139, placebo: n =143). UMEC 31.25 mcg and 62.5 mcg demonstrated significantly greater improvements from baseline in clinic trough FEV1 at Week 24 (difference [95% CI]: 0.176?L [0.092, 0.260; p<0.001] and 0.184?L [0.101, 0.268; p<0.001], respectively), clinic FEV1 3?h post-dose at Week 24 (0.190?L [0.100, 0.279; p<0.001] and 0.198?L [0.109, 0.287; p<0.001], respectively) and mean change from baseline in daily home spirometry over 24?weeks versus placebo. No new safety signals were identified. CONCLUSIONS:UMEC is a highly effective bronchodilator that leads to improved lung function when administered as a single bronchodilator on top of FF in subjects with fully reversible, uncontrolled/partially-controlled moderate asthma. These data support a favourable benefit/risk profile for UMEC (31.25 mcg and 62.5 mcg). TRIAL REGISTRATION:GSK study ID: 205832; Clinicaltrials.gov ID: NCT03012061.

Project description:BACKGROUND:Umeclidinium bromide (UMEC) is an inhaled long-acting muscarinic antagonist in development for chronic obstructive pulmonary disease (COPD). METHODS:This was a multicentre, randomised, double-blind, placebo-controlled, three-way cross-over, incomplete block study to evaluate UMEC 15.6, 31.25, 62.5, and 125 ?g administered once daily (QD), and UMEC 15.6 ?g and 31.25 ?g administered twice daily (BID), over 7 days in patients with COPD. Tiotropium was included as an open-label treatment arm. The primary efficacy endpoint was trough forced expiratory volume in 1 second (FEV1) on Day 8. Secondary efficacy endpoints included weighted mean FEV1 over 0-24 hours after morning dosing on Day 7, and serial FEV1 at each time point over 24 hours after morning dosing on Day 7. Safety and pharmacokinetics were also examined. RESULTS:One hundred and sixty-three patients (mean age 59.5 years, 52% female) were randomised. Based on the population dose-response model of trough FEV1 data, the geometric mean potency (ED50) of UMEC was 37 ?g (95% confidence interval [CI]: 18, 57) with a predicted maximum intrinsic efficacy (Emax) at trough of 0.185 L (95% CI: 0.153, 0.218) after QD dosing. UMEC 125 ?g QD demonstrated the greatest improvements in measure of lung function compared with doses of 62.5 ?g and below. UMEC 125 ?g QD exhibited more consistent increases in FEV1 from baseline across serial time points over 24 hours compared with other UMEC doses and tiotropium. Increases in FEV1 over 0-12 hours were similar to those observed over 12-24 hours after the second dose of UMEC was administered. UMEC was rapidly absorbed following inhaled dosing and eliminated from plasma. Adverse events, generally mild, were highest with UMEC 125 ?g QD (18%) compared with placebo (8%), tiotropium (4%) and other UMEC doses (5-12%). CONCLUSIONS:UMEC is a potent QD bronchodilator with geometric mean ED50 of 37 ?g. A dose ordering over the range of UMEC 15.6-125 ?g QD doses was observed, with UMEC 125 ?g showing the greatest improvement in trough FEV1.

Project description:NVA237 is a once-daily dry-powder formulation of the long-acting muscarinic antagonist glycopyrronium bromide in development for the treatment of chronic obstructive pulmonary disease (COPD). The glycopyrronium bromide in COPD airways clinical study 1 (GLOW1) evaluated the efficacy, safety and tolerability of NVA237 in patients with moderate-to-severe COPD.Patients with COPD with a smoking history of ? 10 pack-years, post-bronchodilator forced expiratory volume in 1 second (FEV1) < 80% and ? 30% predicted normal and FEV1/forced vital capacity < 0.70 were enrolled. Patients were randomized to double-blind treatment with NVA237 50 ?g once daily or placebo for 26 weeks with inhaled/intranasal corticosteroids or H1 antagonists permitted in patients stabilized on them prior to study entry. The primary outcome measure was trough FEV1 at Week 12.A total of 822 patients were randomized to NVA237 (n = 552) or placebo (n = 270). Least squares mean (± standard error) trough FEV1 at Week 12 was significantly higher in patients receiving NVA237 (1.408 ± 0.0105 L), versus placebo (1.301 ± 0.0137 L; treatment difference 108 ± 14.8 mL, p < 0.001). Significant improvements in trough FEV1 were apparent at the end of Day 1 and sustained through Week 26. FEV1 was significantly improved in the NVA237 group versus placebo throughout the 24-hour periods on Day 1 and at Weeks 12 and 26, and at all other visits and timepoints. Transition dyspnoea index focal scores and St. George's Respiratory Questionnaire scores were significantly improved with NVA237 versus placebo at Week 26, with treatment differences of 1.04 (p < 0.001) and -2.81 (p = 0.004), respectively. NVA237 significantly reduced the risk of first moderate/severe COPD exacerbation by 31% (p = 0.023) and use of rescue medication by 0.46 puffs per day (p = 0.005), versus placebo. NVA237 was well tolerated and had an acceptable safety profile, with a low frequency of cardiac and typical antimuscarinic adverse effects.Once-daily NVA237 was safe and well tolerated and provided rapid, sustained improvements in lung function, improvements in dyspnoea, and health-related quality of life, and reduced the risk of exacerbations and the use of rescue medication.ClinicalTrials.gov: NCT01005901.

Project description:BACKGROUND:Prospective evidence is lacking regarding incremental benefits of long-acting dual- versus mono-bronchodilation in improving symptoms and preventing short-term disease worsening/treatment failure in low exacerbation risk patients with chronic obstructive pulmonary disease (COPD) not receiving inhaled corticosteroids. METHODS:The 24-week, double-blind, double-dummy, parallel-group Early MAXimisation of bronchodilation for improving COPD stability (EMAX) trial randomised patients at low exacerbation risk not receiving inhaled corticosteroids, to umeclidinium/vilanterol 62.5/25??g once-daily, umeclidinium 62.5??g once-daily or salmeterol 50??g twice-daily. The primary endpoint was trough forced expiratory volume in 1?s (FEV1) at Week 24. The study was also powered for the secondary endpoint of Transition Dyspnoea Index at Week 24. Other efficacy assessments included spirometry, symptoms, heath status and short-term disease worsening measured by the composite endpoint of clinically important deterioration using three definitions. RESULTS:Change from baseline in trough FEV1 at Week 24 was 66?mL (95% confidence interval [CI]: 43, 89) and 141?mL (95% CI: 118, 164) greater with umeclidinium/vilanterol versus umeclidinium and salmeterol, respectively (both p?<?0.001). Umeclidinium/vilanterol demonstrated consistent improvements in Transition Dyspnoea Index versus both monotherapies at Week 24 (vs umeclidinium: 0.37 [95% CI: 0.06, 0.68], p?=?0.018; vs salmeterol: 0.45 [95% CI: 0.15, 0.76], p?=?0.004) and all other symptom measures at all time points. Regardless of the clinically important deterioration definition considered, umeclidinium/vilanterol significantly reduced the risk of a first clinically important deterioration compared with umeclidinium (by 16-25% [p?<?0.01]) and salmeterol (by 26-41% [p?<?0.001]). Safety profiles were similar between treatments. CONCLUSIONS:Umeclidinium/vilanterol consistently provides early and sustained improvements in lung function and symptoms and reduces the risk of deterioration/treatment failure versus umeclidinium or salmeterol in symptomatic patients with low exacerbation risk not receiving inhaled corticosteroids. These findings suggest a potential for early use of dual bronchodilators to help optimise therapy in this patient group.

Project description:Background Fluticasone furoate/vilanterol (FF/VI) is a novel once-daily (OD) inhaled corticosteroid/long-acting ?(2) agonist combination in development for chronic obstructive pulmonary disease (COPD) and asthma. Trial design A multicentre, randomised, double-blind, parallel-group, placebo-controlled study. Methods Participants were patients with moderate-to-severe COPD treated with placebo or FF/VI 400/25 ?g OD for 4 weeks. Study objectives were to assess the safety and efficacy of FF/VI 400/25 ?g OD administered for 4 weeks via a novel dry powder inhaler. Co-primary end points were change from baseline in weighted mean (wm) heart rate 0-4 h postdose at day 28 and the incidence of adverse events (AEs). Secondary end points included change from baseline in trough forced expiratory volume in one second (FEV(1)) (23-24 h postdose; day 29) and wm FEV(1) (0-4 h postdose; day 28). Patients were randomised to receive FF/VI 400/25 ?g or placebo in a 2:1 ratio; all patients and investigators were blinded to active or placebo treatment. Results 60 patients (mean age 64 years) were randomised (FF/VI: n=40; placebo: n=20), and all contributed data to the analysis. Mean screening post-bronchodilator FEV(1) per cent predicted was comparable between groups (FF/VI: 58.5%; placebo: 60.1%). The wm heart rate 0-4 h postdose was similar between groups (difference: 0.6 beats per minute; 95% CI -3.9 to 5.1). More on-treatment AEs were reported in the FF/VI group (68%) compared with the placebo group (50%). The most common drug-related AEs in the FF/VI group were oral candidiasis (8%) and dysphonia (5%). There were no clinically relevant effects on laboratory values, including glucose and potassium, or on vital signs or ECGs/Holters. The FF/VI group had statistically greater improvements compared with placebo in trough FEV(1) (mean difference 183 ml) and 0-4 h postdose wm FEV(1) (mean difference 236 ml). Conclusion FF/VI has a good safety and tolerability profile and improves lung function compared with placebo in patients with COPD. Trial registration number clinical trials.gov-NCT00731822.

Dataset Information

Efficacy and Safety of Once-Daily Inhaled Umeclidinium in Asian Patients with COPD: Results from a Randomized, Placebo-Controlled Study.

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Efficacy and Safety of Once-Daily Inhaled Umeclidinium in Asian Patients with COPD: Results from a Randomized, Placebo-Controlled Study.

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