title: Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial.
abstract: BACKGROUND
  Ivacaftor has been previously assessed in patients with cystic fibrosis with Gly551Asp-CFTR or other gating mutations. We assessed ivacaftor in patients with Arg117His-CFTR, a residual function mutation.
  
  
  METHODS
  We did a 24-week, placebo-controlled, double-blind, randomised clinical trial, which enrolled 69 patients with cystic fibrosis aged 6 years and older with Arg117His-CFTR and percentage of predicted forced expiratory volume in 1 s (% predicted FEV1) of at least 40. We randomly assigned eligible patients (1:1) to receive placebo or ivacaftor 150 mg every 12 h for 24 weeks. Randomisation was stratified by age (6-11, 12-17, and ≥18 years) and % predicted FEV1 (<70, ≥70 to ≤90, and >90). The primary outcome was the absolute change from baseline in % predicted FEV1 through week 24. Secondary outcomes included safety and changes in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain scores. An open-label extension enrolled 65 of the patients after washout; after 12 weeks, we did an interim analysis.
  
  
  RESULTS
  After 24 weeks, the treatment difference in mean absolute change in % predicted FEV1 between ivacaftor (n=34) and placebo (n=35) was 2·1 percentage points (95% CI -1·13 to 5·35; p=0·20). Ivacaftor treatment resulted in significant treatment differences in sweat chloride (-24·0 mmol/L, 95% CI -28·01 to -19·93; p<0·0001) and CFQ-R respiratory domain (8·4, 2·17 to 14·61; p=0·009). In prespecified subgroup analyses, % predicted FEV1 significantly improved with ivacaftor in patients aged 18 years or older (treatment difference vs placebo: 5·0 percentage points, 95% CI 1·15 to 8·78; p=0·01), but not in patients aged 6-11 years (-6·3 percentage points, -11·96 to -0·71; p=0·03). In the extension study, both placebo-to-ivacaftor and ivacaftor-to-ivacaftor groups showed % predicted FEV1 improvement (absolute change from post-washout baseline at week 12: placebo-to-ivacaftor, 5·0 percentage points [p=0·0005]; ivacaftor-to-ivacaftor, 6·0 percentage points [p=0·006]). We did not identify any new safety concerns. The studies are registered with ClinicalTrials.gov (the randomised, placebo-controlled study, number NCT01614457; the open-label extension study, number NCT01707290).
  
  
  CONCLUSIONS
  Although this study did not show a significant improvement in % predicted FEV1, ivacaftor did significantly improve sweat chloride and CFQ-R respiratory domain scores and lung function in adult patients with Arg117His-CFTR, indicating that ivacaftor might benefit patients with Arg117His-CFTR who have established disease.
  
  
  BACKGROUND
  Vertex Pharmaceuticals Incorporated.
authors.affiliation: Stanford University School of Medicine, Palo Alto, CA, USA. Electronic address: rmoss@stanford.edu.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Moss
authors.affiliation: Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Flume
authors.affiliation: Queens University Belfast, Belfast, Northern Ireland, UK.
authors.forename: J Stuart
authors.initials: JS
authors.lastname: Elborn
authors.affiliation: Vertex Pharmaceuticals (Europe) Ltd, Milton Park, UK.
authors.forename: Jon
authors.initials: J
authors.lastname: Cooke
authors.affiliation: University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Rowe
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Susanna A
authors.initials: SA
authors.lastname: McColley
authors.affiliation: The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Rubenstein
authors.affiliation: Vertex Pharmaceuticals (Europe) Ltd, Milton Park, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Higgins
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000627:Aminophenols / Q000627:therapeutic use*; D002648:Child; D018118:Chloride Channels / Q000187:drug effects; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D015363:Quinolones / Q000627:therapeutic use*; D019141:Respiratory System Agents / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000627:Aminophenols; C505032:CFTR protein, human; D018118:Chloride Channels; D015363:Quinolones; D019141:Respiratory System Agents; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor