title: Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials.
abstract: BACKGROUND
  Whether the combination of a once-daily inhaled corticosteroid with a once-daily longacting β(2) agonist is more protective than a once-daily longacting β(2) agonist alone against exacerbations of chronic obstructive pulmonary disease (COPD) is unknown. We hypothesised that fluticasone furoate and vilanterol would prevent more exacerbations than would vilanterol alone.
  
  
  METHODS
  We did two replicate double-blind parallel-group 1 year trials. Both studies began on Sept 25, 2009. Study 1 ended on Oct 31, 2011, and study 2 on Oct 17, 2011. Eligible patients were aged 40 years or older, had a history of COPD, a smoking history of 10 or more pack-years, a ratio of forced expiratory volume in 1 s (FEV(1)) to forced vital capacity of 0·70 or less after bronchodilators (and an FEV(1) of 70% or less of predicted), and a documented history of one or more moderate or severe disease exacerbations in the year before screening. Patients were randomly assigned (1:1:1:1) on the basis of the Registration and Medication Ordering System to 25 μg vilanterol alone or 25 μg vilanterol combined with either 50 μg, 100 μg, or 200 μg fluticasone furoate once daily. Our primary endpoint was the yearly rate of moderate and severe exacerbations. The trials were analysed separately and a pooled analysis was also done. These trials are registered with ClinicalTrials.gov (NCT01009463 and NCT01017952).
  
  
  RESULTS
  1622 patients in study 1 and 1633 patients in study 2 were randomly assigned. In study 1, no significant difference in exacerbation rate was noted between the 200/25 μg fluticasone furoate/vilanterol group and the vilanterol only group (mean 0·90 events vs 1·05 events per year; ratio 0·9 [95% CI 0·7-1·0]). Because of the statistical hierarchy used, we could not infer significance for the 50 μg and 100 μg groups. In study 2, significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group (p=0·0398 for the 50 μg group, 0·0244 for the 100 μg group, and 0·0004 for the 200 μg group). In the pooled analysis, significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group (0·0141 for the 50 μg group, <0·0001 for the 100 μg group, and 0·0003 for the 200 μg group). Nasopharyngitis was the most frequently reported adverse event in both studies. Pneumonia and fractures were reported more frequently with fluticasone furoate and vilanterol than with vilanterol alone. Eight deaths from pneumonia were noted in the fluticasone furoate/vilanterol groups compared with none in the vilanterol only group.
  
  
  CONCLUSIONS
  Addition of fluticasone furoate to vilanterol was associated with a decreased rate of moderate and severe exacerbations of COPD in patients with a history of exacerbation, but was also associated with an increased pneumonia risk.
  
  
  BACKGROUND
  GlaxoSmithKline.
authors.affiliation: Lung Health Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Dransfield
authors.affiliation: McGill University, Montreal, QC, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Bourbeau
authors.affiliation: St George's University of London, London, UK.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Jones
authors.affiliation: Baylor College of Medicine, Houston, TX, USA.
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Hanania
authors.affiliation: Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Mahler
authors.affiliation: Odense University Hospital, Odense, Denmark; University of Southern Denmark, Odense, Denmark; Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Vestbo
authors.affiliation: Southern California Institute for Respiratory Diseases, Los Angeles, CA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wachtel
authors.affiliation: University of Michigan, Ann Arbor, MI, USA.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Martinez
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Barnhart
authors.affiliation: GlaxoSmithKline, Stockley Park, London, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Sanford
authors.affiliation: GlaxoSmithKline, Stockley Park, London, UK.
authors.forename: Sally
authors.initials: S
authors.lastname: Lettis
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Crim
authors.affiliation: University of Liverpool, Liverpool, UK. Electronic address: pmacal@liverpool.ac.uk.
authors.forename: Peter M A
authors.initials: PM
authors.lastname: Calverley
mesh_terms: D000280:Administration, Inhalation; D000368:Aged; D000730:Androstadienes / Q000008:administration & dosage / Q000009:adverse effects; D001592:Benzyl Alcohols / Q000008:administration & dosage / Q000009:adverse effects; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000009:adverse effects; D002722:Chlorobenzenes / Q000008:administration & dosage / Q000009:adverse effects; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004338:Drug Combinations; D016903:Drug Monitoring; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D011014:Pneumonia / Q000453:epidemiology / Q000209:etiology; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D012129:Respiratory Function Tests / Q000379:methods; D012137:Respiratory System / Q000187:drug effects* / Q000503:physiopathology; D018570:Risk Assessment; D016896:Treatment Outcome
chemical_list: D000730:Androstadienes; D001592:Benzyl Alcohols; D001993:Bronchodilator Agents; D002722:Chlorobenzenes; D004338:Drug Combinations; D005938:Glucocorticoids; C550468:vilanterol; C523187:fluticasone furoate