title: Magnitude of umeclidinium/vilanterol lung function effect depends on monotherapy responses: Results from two randomised controlled trials.
abstract: OBJECTIVE
  Dual therapy with bronchodilators of different pharmacological classes may produce greater lung function improvements than either drug alone. However, the relationship between a patient's response to monotherapy and response to dual bronchodilator therapy is currently unknown. We aimed to investigate whether dual therapy with umeclidinium/vilanterol provides additional benefit over umeclidinium or vilanterol monotherapy in patients with chronic obstructive pulmonary disease (COPD) identified as responsive (increase from baseline in forced expiratory volume in 1s [FEV1] of ≥ 12% and ≥ 200 mL, Day 1) or non-responsive to monotherapy.
  
  
  METHODS
  In two randomised, double-blind, three-way complete-block, cross-over studies (DB2116132 n = 207; DB2116133 n = 182; intent-to-treat), all patients (moderate-to-very severe COPD) were randomised to 1 of 6 sequences and received once-daily umeclidinium 62.5 mcg, vilanterol 25 mcg, and umeclidinium/vilanterol 62.5/25 mcg (one treatment/14-day period; 10-14-day washout). Key endpoints were 0-6 h weighted mean FEV1 (Day 14) and trough FEV1 (Day 15). Adverse events, vital signs and COPD exacerbations were assessed. Pooled data are presented.
  
  
  RESULTS
  Umeclidinium/vilanterol significantly (p ≤ 0.001, unless stated otherwise) increased 0-6 h weighted mean FEV1 versus umeclidinium in umeclidinium-responders (+114 mL), versus vilanterol in vilanterol-responders (+92 mL) and versus umeclidinium (+70 mL) and vilanterol (+62 mL) in non-responders. Improvements in trough FEV1 occurred with umeclidinium/vilanterol versus umeclidinium in umeclidinium-responders (+77 mL), versus vilanterol in vilanterol-responders (+86 mL), and versus umeclidinium (+42 mL [p = 0.020]) and vilanterol (+58 mL) in non-responders. All treatments were well tolerated.
  
  
  CONCLUSIONS
  Once-daily umeclidinium/vilanterol significantly improved lung function in patients with COPD, with quantitatively greater improvements in patients identified as responders to umeclidinium and vilanterol monotherapy than non-responders.
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, NC, USA. Electronic address: james_donohue@med.unc.edu.
authors.forename: James F
authors.initials: JF
authors.lastname: Donohue
authors.affiliation: University of Manchester, Medicines Evaluation Unit, University Hospital of South Manchester Foundations Trust, Manchester, UK. Electronic address: DSingh@meu.org.UK.
authors.forename: Dave
authors.initials: D
authors.lastname: Singh
authors.affiliation: Respiratory Medicines Development Centre, GSK, London, UK. Electronic address: clara.x.munzu@gsk.com.
authors.forename: Clara
authors.initials: C
authors.lastname: Munzu
authors.affiliation: Quantitative Sciences Division, GSK, London, UK. Electronic address: sally.5.kilbride@gsk.com.
authors.forename: Sally
authors.initials: S
authors.lastname: Kilbride
authors.affiliation: Respiratory Medicines Development Center, GSK, Research Triangle Park, NC, USA. Electronic address: alison.x.church@gsk.com.
authors.forename: Alison
authors.initials: A
authors.lastname: Church
mesh_terms: D000280:Administration, Inhalation; D000318:Adrenergic beta-Agonists / Q000627:therapeutic use*; D000368:Aged; D001592:Benzyl Alcohols / Q000627:therapeutic use*; D001993:Bronchodilator Agents / Q000627:therapeutic use*; D002722:Chlorobenzenes / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000627:therapeutic use*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000503:physiopathology; D011812:Quinuclidines / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000318:Adrenergic beta-Agonists; D001592:Benzyl Alcohols; D001993:Bronchodilator Agents; D002722:Chlorobenzenes; C573971:GSK573719; D018727:Muscarinic Antagonists; D011812:Quinuclidines; C550468:vilanterol
keywords: Bronchodilators; COPD pharmacology; Chronic obstructive pulmonary disease