Efficacy and Safety of Umeclidinium Added to Fluticasone Propionate/Salmeterol in Patients with COPD: Results of Two Randomized, Double-Blind Studies

Abstract

Combinations of drugs with distinct and complementary mechanisms of action may offer improved efficacy in the treatment of chronic obstructive pulmonary disease (COPD). In two 12-week, double-blind, parallel-group studies, patients with COPD were randomized 1:1:1 to once-daily umeclidinium (UMEC; 62.5 μg and 125 μg) or placebo (PBO), added to twice-daily fluticasone propionate/salmeterol (FP/SAL; 250/50 μg). In both studies, the primary efficacy measure was trough forced expiratory volume in 1 second (FEV1) at Day 85. Secondary endpoints were weighted-mean (WM) FEV1 over 0-6 hours post-dose (Day 84) and rescue albuterol use. Health-related quality of life outcomes (St. George's Respiratory Questionnaire [SGRQ] and COPD assessment test [CAT]) were also examined. Safety was assessed throughout. Both UMEC+FP/SAL doses provided statistically significant improvements in trough FEV1 (Day 85: 0.127-0.148 L) versus PBO+FP/SAL. Similarly, both UMEC+FP/SAL doses provided statistically-significant improvements in 0-6 hours post-dose WM FEV1 versus PBO+FP/SAL (Day 84: 0.144-0.165 L). Rescue use over Weeks 1-12 decreased with UMEC+FP/SAL in both studies versus PBO+FP/SAL (Study 1, 0.3 puffs/day [both doses]; Study 2, 0.5 puffs/day [UMEC 125+FP/SAL]). Decreases from baseline in CAT score were generally larger for both doses of UMEC+FP/SAL versus PBO+FP/SAL (except for Day 84 Study 2). In Study 1, no differences in SGRQ score were observed between UMEC+FP/SAL and PBO+FP/SAL; however, in Study 2, statistically significant improvements were observed with UMEC 62.5+FP/SAL (Day 28) and UMEC 125+FP/SAL (Days 28 and 84) versus PBO+FP/SAL. The incidence of on-treatment adverse events across all treatment groups was 37-41% in Study 1 and 36-38% in Study 2. Overall, these data indicate that the combination of UMEC+FP/SAL can provide additional benefits over FP/SAL alone in patients with COPD.

Keywords: bronchodilation; inhaled corticosteroid; long-acting beta agonist; long-acting muscarinic antagonist.

Figure 1.

Summary of patient disposition in Study 1 (A) and Study 2 (B). 
AE, adverse event; FP/SAL, fluticasone propionate/salmeterol combination; ITT, intent-to-treat; PBO, placebo; PP, per protocol; UMEC, umeclidinium.
*The run-in population included screening failures, run-in failures, and those in the ITT population (i.e., any patient who took at least one dose of open-label FP/SAL during the run-in period). Study 1: Reasons for withdrawal: PBO + FP/SAL: AE (n = 6), withdrew consent (n = 3), lost to follow-up (n = 2), protocol deviation (n = 4), lack of efficacy (n = 11), subject reached protocol-stopping criteria (n = 1); UMEC 62.5 + FP/SAL: PBO + FP/SAL: AE (n = 5), withdrew consent (n = 1), protocol deviation (n = 3), lack of efficacy (n = 5); UMEC 125 + FP/SAL: AE (n = 10), withdrew consent (n = 5), protocol deviation (n = 3), lack of efficacy (n = 3). Study 2: Reasons for withdrawal: PBO + FP/SAL: AE (n = 13), withdrew consent (n = 7), lost to follow-up (n = 1), protocol deviation (n = 2), lack of efficacy (n = 8); UMEC 62.5 + FP/SAL: AE (n = 10), withdrew consent (n = 8), protocol deviation (n = 1), lack of efficacy (n = 6); UMEC 125 + FP/SAL: AE (n = 6), withdrew consent (n = 4), lost to follow-up (n = 1), protocol deviation (n = 1), lack of efficacy (n = 6).

Figure 2.

LS mean (95% CI) change from baseline in trough FEV₁ (L) in Study 1 (A) and Study 2 (B) (ITT). CI, confidence interval; FEV₁, forced expiratory volume in 1 second; FP/SAL, fluticasone propionate/salmeterol combination; ITT, intent-to-treat; LS, least squares; PBO, placebo; UMEC, umeclidinium. Analysis performed using a repeated measures model with covariates of treatment, baseline (mean of the two assessments made 30 minutes and 5 minutes pre-dose on Day 1), smoking status, Day, Day by baseline and Day by treatment interactions.

Figure 3.

LS mean (95% CI) change from baseline in 0–6 hours WM FEV₁ (L) in Study 1 (A) and Study 2 (B) (ITT). CI, confidence interval; FEV₁, forced expiratory volume in 1 second; FP/SAL, fluticasone propionate/salmeterol combination; ITT, intent-to-treat; LS, least squares; PBO, placebo; UMEC, umeclidinium; WM, weighted mean. Analysis performed using a repeated measures model with covariates of treatment, baseline (mean of the two assessments made 30 minutes and 5 minutes pre-dose on Day 1), smoking status, Day, Day by baseline and Day by treatment interactions.

Figure 4.

Serial (24 hours) FEV₁ LS mean (95% CI) change from baseline on Day 1 and Day 84 (ITT population) in Study 1 (A) and Study 2 (B). CI, confidence interval; FEV₁, forced expiratory volume in 1 second; FP/SAL, fluticasone propionate/salmeterol combination; ITT, intent-to-treat; LS, least squares; PBO, placebo; UMEC, umeclidinium. Analyses performed using a separate repeated measures model for each Day with covariates of treatment, baseline (mean of the two assessments made 30 minutes and 5 minutes pre-dose on Day 1), smoking status, time, time by baseline and time by treatment interactions.