A randomized, blinded study to evaluate the efficacy and safety of umeclidinium 62.5 μg compared with tiotropium 18 μg in patients with COPD

Abstract

Background: The long-acting muscarinic antagonists umeclidinium (UMEC) and tiotropium (TIO) are approved once-daily maintenance therapies for COPD. This study investigated the efficacy and safety of UMEC versus TIO in COPD.

Methods: This was a 12-week, multicenter, randomized, blinded, double-dummy, parallel-group, non-inferiority study. Patients were randomized 1:1 to UMEC 62.5 μg plus placebo or TIO 18 μg plus placebo. The primary end point was trough forced expiratory volume in 1 second (FEV1) at day 85 (non-inferiority margin -50 mL; per-protocol [PP] population). Other end points included weighted mean FEV1 over 0-24 and 12-24 hours post-dose. Patient-reported outcomes comprised Transition Dyspnea Index score, St George's Respiratory Questionnaire total score, and COPD Assessment Test score. Adverse events were also assessed.

Results: In total, 1,017 patients were randomized to treatment. In the PP population, 489 and 487 patients received UMEC and TIO, respectively. In the PP population, change from baseline in trough FEV1 was greater with UMEC versus TIO at day 85, meeting non-inferiority and superiority margins (difference: 59 mL; 95% confidence interval [CI]: 29-88; P<0.001). Similar results were observed in the intent-to-treat analysis of trough FEV1 at day 85 (53 mL, 95% CI: 25-81; P<0.001). Improvements in weighted mean FEV1 over 0-24 hours post-dose at day 84 were similar with UMEC and TIO but significantly greater with UMEC versus TIO over 12-24 hours post-dose (70 mL; P=0.015). Clinically meaningful improvements in Transition Dyspnea Index and St George's Respiratory Questionnaire were observed with both treatments at all time points. No differences were observed between UMEC and TIO in patient-reported outcomes. Overall incidences of adverse events were similar for UMEC and TIO.

Conclusion: UMEC 62.5 μg demonstrated superior efficacy to TIO 18 μg on the primary end point of trough FEV1 at day 85. Safety profiles were similar for both treatments.

Trial registration: ClinicalTrials.gov NCT02207829.

Keywords: COPD; long-acting muscarinic antagonist; non-inferiority; tiotropium; umeclidinium.

Figure 1

Patient disposition. Note: *Lack of efficacy includes patients who withdrew due to COPD exacerbation. Abbreviations: ASE, all subjects enrolled; TIO, tiotropium; UMEC, umeclidinium.

Figure 2

LS mean change from baseline in trough FEV₁ (mL) (PP population). Notes: n₁, number of patients with analyzable data for ≥1 time points. n₂, number of subjects with analyzable data at the current time point. Abbreviations: CI, confidence interval; FEV₁, forced expiratory volume in 1 second; LS, least squares; PP, per-protocol; SE, standard error; TIO, tiotropium; UMEC, umeclidinium.

Figure 3

LS mean change from baseline in serial FEV₁ (mL) on day 1 (A) and on day 84 (B) (both days: TFH population). Abbreviations: CI, confidence interval; FEV₁, forced expiratory volume in 1 second; LS, least squares; TFH, 24-hour; TIO, tiotropium; UMEC, umeclidinium.

Figure 4

Proportion of trough FEV₁ responders. Notes: *P<0.05. Response was defined as an increase of ≥100 mL above baseline FEV₁. Abbreviations: CI, confidence interval; OR, odds ratio; FEV₁, forced expiratory volume in 1 second; TIO, tiotropium; UMEC, umeclidinium.