title: Variability of sweat chloride concentration in subjects with cystic fibrosis and G551D mutations.
abstract: Sweat chloride concentration, a biomarker of CFTR function, is an appropriate outcome parameter in clinical trials aimed at correcting the basic CF defect. Although there is consensus on a cut-off value to diagnose CF, we have only limited information on the within subject variability of sweat chloride over time. Such information would be useful for sample size calculations in clinical trials. Therefore, we retrospectively analyzed repeated sweat chloride values obtained in patients with G551D mutation(s) assigned to placebo in an ivacaftor interventional trial.
  
  
  
  In subjects with G551D at least 12years of age, a pilocarpine sweat test using Macroduct collector was taken on both arms at 8 time points over 48weeks. We explored 1062 pilocarpine sweat test values obtained in 78 placebo patients of the VX08-770-102 trial.
  
  
  
  Mean overall sweat chloride value (all patients, all tests, n=1062) was 100.8mmol/L (SD 12.7mmol/L). Using a multilevel mixed model, the between-subject standard deviation (SD) for sweat chloride was 8.9mmol/L (95% CI 7.4-10.6) and within-subject SD was 8.1mmol/L (95% CI 7.5-8.7). Limits of repeatability for repeat measurements were -19.7 to +21.6mmol/L using values from one arm, and -13.3 to 11.8mmol/L using mean of values obtained at 4 test occasions. Sample size calculations showed that the minimal treatment effect on sweat chloride concentration that can be demonstrated for a group of 5 patients is around 15mmol/L, using a cross-over design and combinations of 4 tests for each phase of the trial.
  
  
  
  Although the sweat test is considered a robust measure, sweat chloride measurements in patients with CF and a G551D mutation had an inherent biological variability that is higher than commonly considered. Further analyses of placebo group data are crucial to learn more about the natural variability of this outcome parameter.
authors.affiliation: Cystic Fibrosis Reference Centre, University Hospital of Leuven, Leuven, Belgium. Electronic address: francois.vermeulen@uzleuven.be.
authors.forename: F
authors.initials: F
authors.lastname: Vermeulen
authors.affiliation: Vertex Pharmaceuticals Inc., Cambridge, MA, United States.
authors.forename: C
authors.initials: C
authors.lastname: Le Camus
authors.affiliation: Imperial College London, United Kingdom; Paediatric Respiratory Medicine and Department of Cystic Fibrosis , Royal Brompton and Harefield National Health Service Foundation Trust, London, United Kingdom.
authors.forename: J C
authors.initials: JC
authors.lastname: Davies
authors.affiliation: Imperial College London, United Kingdom; London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: D
authors.initials: D
authors.lastname: Bilton
authors.affiliation: London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: D
authors.initials: D
authors.lastname: Milenković
authors.affiliation: Cystic Fibrosis Reference Centre, University Hospital of Leuven, Leuven, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: De Boeck
mesh_terms: D000293:Adolescent; D000328:Adult; D000627:Aminophenols / Q000008:administration & dosage*; D000073537:Biological Variation, Population / Q000235:genetics; D015415:Biomarkers / Q000032:analysis; D002648:Child; D065101:Chloride Channel Agonists / Q000008:administration & dosage; D002712:Chlorides / Q000032:analysis*; D003550:Cystic Fibrosis / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015363:Quinolones / Q000008:administration & dosage*; D012189:Retrospective Studies; D013542:Sweat / Q000737:chemistry*
chemical_list: D000627:Aminophenols; D015415:Biomarkers; D065101:Chloride Channel Agonists; D002712:Chlorides; D015363:Quinolones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor
keywords: Cystic fibrosis; Endpoint; G551D; Sweat chloride; Variability