A randomized, three-period crossover study of umeclidinium as monotherapy in adult patients with asthma
To our knowledge, no studies in patients with asthma have assessed a long-acting muscarinic antagonist in the absence of inhaled corticosteroids (ICS). Objective: Evaluate the doseeresponse, efficacy, and safety of umeclidinium (UMEC) in patients with asthma not receiving ICS. Methods: In this double-blind, three-period crossover study, 350 subjects were randomized to a sequence of three of eight inhaled treatments: UMEC 15.6, 31.25, 62.5, 125, or 250 mcg once daily (OD), UMEC 15.6 or 31.25 mcg
... twice daily (BID), or placebo, administered for 14 days (12e14-day washout). Trough forced expiratory volume in one second (FEV 1 ), 0e24-h weighted mean (WM) FEV 1 , and safety were assessed. Serial spirometry and pharmacokinetic assessments were performed in a subgroup. Results: Subjects had a mean baseline pre-and post-bronchodilator FEV 1 of 71% and 88% predicted, respectively. Significant improvements in change from baseline trough FEV 1 were observed for UMEC 15.6 OD (0.066 L; p Z 0.036) and UMEC 125 OD (0.088 L; p Z 0.005) versus placebo, but not other OD or BID doses. UMEC increased 0e24-h WM FEV 1 versus placebo (0.068e0.121 L [p 0.017] with no clear doseeresponse). Treatment Abbreviations: Ae, amount of dose excreted unchanged in urine; AE, adverse event; ALT, alanine aminotransferase; AUC, area under the curve; BID, twice daily; bpm, beats per minute; CI, confidence interval; C max , maximum plasma concentration; COPD, chronic obstructive pulmonary disease; ECG, electrocardiogram; Fe, percentage of total dose excreted in urine; FEV 1 , forced expiratory volume in one second; GCP, Good Clinical Practice; HLQ, higher limit of quantification; ICS, inhaled corticosteroid; ICH, International Conference on Harmonisation; INR, international normalized ratio; LAMA, long-acting muscarinic antagonist; LLQ, lower limit of quantification; LS, least squares; NA, not available; NC, non-calculable; ND, not determined; NQ, non-quantifiable; OD, once daily; PEF, peak expiratory flow; PK, pharmacokinetic; PVC, premature ventricular contraction; SAE, serious adverse event; SD, standard deviation; SE, standard error; T last , time of the last point with quantifiable concentration; T max , time to maximum plasma concentration; ULN, upper limit of normal; UMEC, umeclidinium bromide; VPD, ventricular premature depolarization; WM, weighted mean. Respiratory Medicine (2015) 109, 63e73 differences were similar for corresponding OD and BID doses in serial assessments. UMEC was rapidly absorbed, with evidence of some accumulation. The incidence of ontreatment adverse events was 9 e21% for UMEC and 12% for placebo. There were no treatment-related effects on laboratory parameters. Conclusion: The modest trough FEV 1 improvements did not conclusively support a therapeutic benefit of UMEC in non-ICS treated patients with asthma. ClinicalTrials.gov: NCT01641692.