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Introduction: Patients with COPD who remain symptomatic on long-acting bronchodilator monotherapy may benefit from step-up therapy to a long-acting bronchodilator combination. This study evaluated the efficacy and safety of umeclidinium (UMEC)/vilanterol (VI) in patients with moderate COPD who remained symptomatic on tiotropium (TIO)., Methods: In this randomized, blinded, double-dummy, parallel-group study (NCT01899742), patients (N=494) who were prescribed TIO for ≥3 months at screening (forced expiratory volume in 1 s [FEV 1 ]: 50%-70% of predicted; modified Medical Research Council [mMRC] score ≥1) and completed a 4-week run-in with TIO were randomized to UMEC/VI 62.5/25 µg or TIO 18 µg for 12 weeks. Efficacy assessments included trough FEV 1 at Day 85 (primary end point), 0-3 h serial FEV 1 , rescue medication use, Transition Dyspnea Index (TDI), St George's Respiratory Questionnaire (SGRQ), and COPD Assessment Test (CAT). Safety evaluations included adverse events (AEs)., Results: Compared with TIO, UMEC/VI produced greater improvements in trough FEV 1 (least squares [LS] mean difference: 88 mL at Day 85 [95% confidence interval {CI}: 45-131]; P <0.001) and FEV 1 after 5 min on Day 1 (50 mL [95% CI: 27-72]; P <0.001). Reductions in rescue medication use over 12 weeks were greater with UMEC/VI versus TIO (LS mean change: -0.1 puffs/d [95% CI: -0.2-0.0]; P ≤0.05). More patients achieved clinically meaningful improvements in TDI score (≥1 unit) with UMEC/VI (63%) versus TIO (49%; odds ratio at Day 84=1.78 [95% CI: 1.21-2.64]; P ≤0.01). Improvements in SGRQ and CAT scores were similar between treatments. The incidence of AEs was similar with UMEC/VI (30%) and TIO (31%)., Conclusion: UMEC/VI step-up therapy provides clinical benefit over TIO monotherapy in patients with moderate COPD who are symptomatic on TIO alone., Competing Interests: Disclosure EMK has served on advisory boards, speaker panels, and received travel reimbursement from Amphastar, AstraZeneca, Boehringer Ingelheim, Forest, Ironwood, Mylan, Novartis, Pearl, Sunovion, Targacept, Teva, and Theravance; has conducted multicenter clinical research trials for ~40 pharmaceutical companies. CJK, DVG, C-QZ, AC, JHR, and WAF are employees of GSK and hold stocks/shares in GSK. The authors report no other conflicts of interest in this work.

Background: Combination long-acting bronchodilator therapy may be more effective than long-acting bronchodilator monotherapy in chronic obstructive pulmonary disease (COPD)., Objectives: To compare the efficacy and safety of once-daily umeclidinium/vilanterol (UMEC/VI) 125/25 mcg with placebo and UMEC or VI monotherapy in COPD., Methods: This was a double-blind, placebo-controlled, parallel-group study. A total of 1493 patients were randomized (3:3:3:2) to 24 weeks of treatment with UMEC/VI 125/25 mcg, UMEC 125 mcg, VI 25 mcg, or placebo once-daily via dry powder inhaler., Results: Primary efficacy endpoint was trough forced expiratory volume in one second (FEV1) on Day 169 (23-24 h post-dose). Additional lung-function, symptomatic and health-related quality of life endpoints were also assessed. Safety evaluations included: adverse events, vital signs, electrocardiography and clinical laboratory measurements. All active treatments significantly improved trough FEV1 vs placebo (0.124-0.238 L, all p<0.001). Improvements with UMEC/VI 125/25 mcg were significantly greater than for UMEC 125 mcg or VI 25 mcg (0.079 L and 0.114 L; both p≤0.001). Improvements for UMEC/VI 125/25 mcg vs placebo were observed for the transition dyspnea index (1.0 unit; p<0.001), rescue albuterol use at Weeks 1-24 (-1.5 puffs/day) and St. George's Respiratory Questionnaire (-3.60 units, p<0.001). No safety signals were observed., Conclusions: Once-daily UMEC/VI 125/25 mcg was well tolerated and provided greater improvements in lung function, health status, and dyspnea scores compared with monotherapy components and placebo over 24 weeks. This study supports the use of UMEC/VI 125/25 mcg for the maintenance treatment of COPD., Clinical Trial Registration: protocol number: DB2113361; ClinicalTrials.gov identifier: NCT01313637.