Dose response of umeclidinium administered once or twice daily in patients with COPD: a randomised cross-over study

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 μg administered once daily (QD), and UMEC 15.6 μg and 31.25 μg 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 (FEV(1)) on Day 8. Secondary efficacy endpoints included weighted mean FEV(1) over 0–24 hours after morning dosing on Day 7, and serial FEV(1) 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 FEV(1) data, the geometric mean potency (ED(50)) of UMEC was 37 μg (95% confidence interval [CI]: 18, 57) with a predicted maximum intrinsic efficacy (E(max)) at trough of 0.185 L (95% CI: 0.153, 0.218) after QD dosing. UMEC 125 μg QD demonstrated the greatest improvements in measure of lung function compared with doses of 62.5 μg and below. UMEC 125 μg QD exhibited more consistent increases in FEV(1) from baseline across serial time points over 24 hours compared with other UMEC doses and tiotropium. Increases in FEV(1) 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 μg QD (18%) compared with placebo (8%), tiotropium (4%) and other UMEC doses (5–12%). CONCLUSIONS: UMEC is a potent QD bronchodilator with geometric mean ED(50) of 37 μg. A dose ordering over the range of UMEC 15.6–125 μg QD doses was observed, with UMEC 125 μg showing the greatest improvement in trough FEV(1). TRIAL REGISTRATION: GlaxoSmithKline funded (clinicaltrials.gov NCT01372410; GlaxoSmithKline study number AC4115321).