www.thelancet.com/respiratory Published online June 6, 2019 http://dx.doi.org/10.1016/S2213-2600(19)30187-0 1 Articles Lancet Respir Med 2019 Published Online June 6, 2019 http://dx.doi.org/10.1016/ S2213-2600(19)30187-0 See Online/Comment http://dx.doi.org/10.1016/ S2213-2600(19)30183-3 *Members listed in the appendix Division of Respiratory Medicine, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON Canada (Prof F Ratjen MD); University of Toronto, Toronto, ON, Canada (Prof F Ratjen, S Stanojevic PhD); Translational Medicine, Research Institute, SickKids, Toronto, ON, Canada (Prof F Ratjen, S Stanojevic); Division of Pediatric Pulmonology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA (Prof S D David MD); Collaborative Health Studies Coordinating Center, Department of Biostatistics, University of Washington, Seattle, WA, USA (Prof R A Kronmal PhD, K D Hinckley Stukovsky MS, N Jorgensen MS); Division of Pulmonary Medicine, Seattle Children’s Hospital, Seattle, WA, USA (Prof M Rosenfeld MD); and Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA (Prof M Rosenfeld) Correspondence to: Prof Felix Ratjen, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada felix.ratjen@sickkids.ca See Online for appendix Introduction The absence of functional CFTR in the airway epithelium of people with cystic fbrosis results in depletion of water from the airway surface and impaired mucociliary clear- ance, leading to chronic infection and infammation. 1–3 Patients aged 6 years or younger with cystic fbrosis can have clinically silent lung disease, which results in abnormal pulmonary function and structural lung damage. 3,4 Thus, interest is growing in early initiation of treatments to prevent or delay lung disease progression. Inhaled hypertonic saline is an attractive early intervention agent because it increases liquid hydration of airway surfaces, thereby improving mucociliary clearance. It is recommended for use in patients with cystic fbrosis older than 6 years, 5–8 but guidance regarding its role in younger patients is lacking. In the randomised controlled ISIS trial, 9 7% hypertonic saline was compared with 0·9% isotonic saline in patients younger than 6 years. The frequency of pulmonary exacerbations, the primary endpoint, did not difer between two groups during the 48-week treatment period, but possible treatment efects of hypertonic saline were noted in two small sub-studies of physiological endpoints. In a predefned subgroup of 45 participants younger than 17 months, the change in forced expiratory volume in 0·5 s (FEV 0·5 ), as measured by infant pulmonary function Inhaled hypertonic saline in preschool children with cystic fibrosis (SHIP): a multicentre, randomised, double-blind, placebo-controlled trial Felix Ratjen, Stephanie D Davis, Sanja Stanojevic, Richard A Kronmal, Karen D Hinckley Stukovsky, Neal Jorgensen, Margaret Rosenfeld, for the SHIP Study Group* Summary Background Inhaled hypertonic saline enhances mucociliary clearance, improves lung function, and reduces pulmonary exacerbations in people with cystic fbrosis older than age 6 years. We aimed to assess the efect of inhaled hypertonic saline on the lung clearance index (LCI 2·5 )—a measure of ventilation inhomogeneity—in children aged 3–6 years with cystic fbrosis. Methods The Saline Hypertonic in Preschoolers (SHIP) Study was a randomised, double-blind, placebo-controlled trial at 25 cystic fbrosis centres in Canada and the USA. Eligible participants were aged 36–72 months; had a confrmed diagnosis of cystic fbrosis; were able to comply with medication use, study visits, and study procedures; and were able to complete at least two technically acceptable trials of multiple breath washout (MBW). Participants were randomly assigned (1:1) via a web-based data entry system that confrmed enrolment eligibility to inhaled 7% hypertonic saline or 0·9% isotonic saline nebulised twice daily (for no more than 15 min per dose) for 48 weeks. Permuted block randomisation was done separately for participants aged 36–54 months and those aged 55–72 months to ensure approximate balance by treatment group in the two age groups. The primary endpoint was the change in the LCI 2·5 measured by nitrogen MBW from baseline to week 48. All study sites were trained and certifed in MBW. Analysis was by intention to treat. This study is registered with Clinicaltrials.gov, number NCT02378467. Findings Between April 21, 2015, and Aug 4, 2017, 150 participants were enrolled and randomly assigned, 76 to the hypertonic saline group and 74 to the isotonic saline group. Overall 89% of the MBW tests produced acceptable data. At 48 weeks, treatment with hypertonic saline was associated with a signifcant decrease (ie, improvement) in LCI 2·5 compared with isotonic saline (mean treatment efect –0·63 LCI 2·5 units [95% CI –1·10 to –0·15]; p=0·010). Six participants in the hypertonic saline group had ten serious adverse events and eight participants in the isotonic saline group had nine serious adverse events. The serious adverse events reported were cough (two patients [3%] in the hypertonic saline group vs three [4%] in the isotonic saline group), gastrostomy tube placement or rupture (two [3%] vs one [1%]), upper gastrointestinal disorders (one [1%] vs two [3%]), distal intestinal obstruction syndrome (one [1%] vs one [1%]), and decreased pulmonary function (none vs one [1%]). None of these serious adverse events was judged to be treatment related. Interpretation Inhaled hypertonic saline improved the LCI 2·5 in children aged 3–6 years, and could be a suitable early intervention in cystic fbrosis. Funding Cystic Fibrosis Foundation. Copyright © 2019 Elsevier Ltd. All rights reserved.