title: The effect of fluticasone furoate/umeclidinium in adult patients with asthma: a randomized, dose-ranging study.
abstract: BACKGROUND
  We evaluated the dose-response of umeclidinium (UMEC; a long-acting muscarinic antagonist) combined with fluticasone furoate (FF; an inhaled corticosteroid [ICS]) in patients with asthma.
  
  
  METHODS
  In a double-blind, three-period crossover study, 421 subjects (symptomatic on ICS), were randomized to a sequence of three of seven treatments: FF 100 mcg alone, FF 100 mcg combined with UMEC (15.6, 31.25, 62.5, 125, or 250 mcg), or vilanterol 25 mcg (a long-acting β-agonist), inhaled once-daily for 14 days (12-14-day washout). Trough forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), and safety were assessed.
  
  
  RESULTS
  Period baseline was a significant covariate, indicating a potential carryover effect between treatment periods. Across all treatment periods, trough FEV1 improved with FF/UMEC 125 and 250 versus FF (treatment difference 0.055 L [both doses]; p = 0.018). FF/UMEC increased morning (15.9-22.9 L/min) and evening (16.2-28.8 L/min) PEF versus FF. As intended assessments were confounded, post hoc Period 1 data analyses were performed, demonstrating significant increases in trough FEV1 with FF/UMEC 31.25, 62.5, and 250 versus FF. Trough FEV1 improvements with FF/UMEC were greater in subjects with fixed (0.095-0.304 L) versus non-fixed (-0.084 to 0.041 L) obstruction. The incidence of on-treatment adverse events was 13-25% across groups. No treatment-related effects on laboratory parameters were reported.
  
  
  CONCLUSIONS
  FF/UMEC may be a viable treatment for patients with asthma symptomatic on ICS; benefit may be most prominent in those with fixed obstruction. The carryover effect suggests future UMEC studies should use an alternative design. ClinicalTrials.gov: NCT01573624.
authors.affiliation: Respiratory Medicines Development Center, GlaxoSmithKline, Research Triangle Park, NC, 27709-3398, USA. Electronic address: laurie.a.lee@gsk.com.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Lee
authors.affiliation: Clinical Pharmacology Modelling and Simulation, RD Projects Clinical Platforms & Sciences, GlaxoSmithKline, Uxbridge, Middlesex, UB11 1BT, UK.
authors.forename: Shuying
authors.initials: S
authors.lastname: Yang
authors.affiliation: Clinical Research Institute of Southern Oregon, PC, Medford, OR, 97504, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Kerwin
authors.affiliation: Respiratory Medicines Development Center, GlaxoSmithKline, Research Triangle Park, NC, 27709-3398, USA.
authors.forename: Roopa
authors.initials: R
authors.lastname: Trivedi
authors.affiliation: Respiratory Medicines Development Center, GlaxoSmithKline, Research Triangle Park, NC, 27709-3398, USA.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Edwards
authors.affiliation: Respiratory Medicines Development Center, GlaxoSmithKline, Research Triangle Park, NC, 27709-3398, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Pascoe
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000730:Androstadienes / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000730:Androstadienes; D001993:Bronchodilator Agents; D004338:Drug Combinations; D005938:Glucocorticoids; D018727:Muscarinic Antagonists; C523187:fluticasone furoate
keywords: Asthma; Fixed-dose combination; Inhaled corticosteroid; Muscarinic antagonist; Trough FEV(1)