title: Lung clearance index as an outcome measure for clinical trials in young children with cystic fibrosis. A pilot study using inhaled hypertonic saline.
abstract: BACKGROUND
  Lung clearance index (LCI), measured by multiple breath washout (MBW), is a noninvasive measure of ventilation inhomogeneity that holds promise as an objective physiologic endpoint for clinical trials in infants and preschool children with cystic fibrosis (CF).
  
  
  OBJECTIVE
  To study the feasibility of using LCI to assess treatment effect outcomes in CF trials of infants and preschoolers.
  
  
  METHODS
  The Infant Study of Inhaled Saline trial was a multicenter, randomized, controlled trial of hypertonic (7%) versus isotonic (0.9%) saline inhaled twice daily for 48 weeks in children with CF under 6 years of age. LCI measurements were performed in a single-center pilot substudy at baseline and 48 weeks using a respiratory mass spectrometer and sulfur hexafluoride as the tracer gas. LCI measurements were standardized using published normative data (zLCI) to account for height-related changes in LCI during early childhood. A generalized estimating equation model with an interaction between treatment group and test occasion was used to estimate a treatment effect.
  
  
  RESULTS
  A total of 27 participants were randomized; 25 participants, aged (median [range]) 2.6 (0.34-4.95) years, had acceptable baseline and follow-up LCI measures. On average, LCI decreased in the hypertonic saline group (n = 12) by 1.19 z-scores units (95% confidence interval [CI] = -2.46 to 0.06), and remained stable in the isotonic saline group (n = 13) at 0.81 (95% CI = -0.40 to 2.02). A significant treatment effect was observed for zLCI (2.01; 95% CI = 0.26 to 3.76; P = 0.025).
  
  
  CONCLUSIONS
  MBW testing is feasible in an interventional study in infants and preschool children with CF. These pilot findings support the development of MBW and LCI as an objective outcome measure in interventional trials in young children with CF, and provide estimates for sample size calculations for future studies.
authors.affiliation: Division of Respiratory Medicine, Department of Pediatrics, The Hospital for Sick Children and University of Toronto, 555 University Avenue, Ontario, Canada. padmaja.subbarao@sickkids.ca
authors.forename: Padmaja
authors.initials: P
authors.lastname: Subbarao
authors.forename: Sanja
authors.initials: S
authors.lastname: Stanojevic
authors.forename: Meghan
authors.initials: M
authors.lastname: Brown
authors.forename: Renee
authors.initials: R
authors.lastname: Jensen
authors.forename: Margaret
authors.initials: M
authors.lastname: Rosenfeld
authors.forename: Stephanie
authors.initials: S
authors.lastname: Davis
authors.forename: Lyndia
authors.initials: L
authors.lastname: Brumback
authors.forename: Per
authors.initials: P
authors.lastname: Gustafsson
authors.forename: Felix
authors.initials: F
authors.lastname: Ratjen
mesh_terms: D000280:Administration, Inhalation; D001944:Breath Tests / Q000379:methods*; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D003550:Cystic Fibrosis / Q000175:diagnosis / Q000628:therapy*; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D010865:Pilot Projects; D012462:Saline Solution, Hypertonic / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D012462:Saline Solution, Hypertonic