title: A randomized, three-period crossover study of umeclidinium as monotherapy in adult patients with asthma.
abstract: BACKGROUND
  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 dose-response, 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 (12-14-day washout). Trough forced expiratory volume in one second (FEV1), 0-24-h weighted mean (WM) FEV1, and safety were assessed. Serial spirometry and pharmacokinetic assessments were performed in a subgroup.
  
  
  RESULTS
  Subjects had a mean baseline pre- and post-bronchodilator FEV1 of 71% and 88% predicted, respectively. Significant improvements in change from baseline trough FEV1 were observed for UMEC 15.6 OD (0.066 L; p = 0.036) and UMEC 125 OD (0.088 L; p = 0.005) versus placebo, but not other OD or BID doses. UMEC increased 0-24-h WM FEV1 versus placebo (0.068-0.121 L [p ≤ 0.017] with no clear dose-response). Treatment differences were similar for corresponding OD and BID doses in serial assessments. UMEC was rapidly absorbed, with evidence of some accumulation. The incidence of on-treatment adverse events was 9-21% for UMEC and 12% for placebo. There were no treatment-related effects on laboratory parameters.
  
  
  CONCLUSIONS
  The modest trough FEV1 improvements did not conclusively support a therapeutic benefit of UMEC in non-ICS treated patients with asthma.
  
  
  BACKGROUND
  NCT01641692.
authors.affiliation: Respiratory Medicines Development Center, GlaxoSmithKline, Research Triangle Park, NC 27709-3398, United States. Electronic address: laurie.a.lee@gsk.com.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Lee
authors.affiliation: R&D Projects, Clinical Platforms & Sciences, GlaxoSmithKline, Uxbridge, Middlesex, UB11 1BT, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Briggs
authors.affiliation: Respiratory Medicines Development Center, GlaxoSmithKline, Research Triangle Park, NC 27709-3398, United States.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Edwards
authors.affiliation: R&D Projects, Clinical Platforms & Sciences, GlaxoSmithKline, Uxbridge, Middlesex, UB11 1BT, UK.
authors.forename: Shuying
authors.initials: S
authors.lastname: Yang
authors.affiliation: Respiratory Medicines Development Center, GlaxoSmithKline, Research Triangle Park, NC 27709-3398, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Pascoe
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D011812:Quinuclidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001993:Bronchodilator Agents; C573971:GSK573719; D018727:Muscarinic Antagonists; D011812:Quinuclidines
keywords: Asthma; Fixed-dose combination; Inhaled corticosteroid; Muscarinic antagonist; Trough FEV(1)