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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.