SHIP 2019.

Study characteristics
Methods	RCT. Design: parallel design. Duration: 48 weeks. Location: multicentre in USA and Canada.
Participants	150 children were enrolled Inclusion criteria: confirmed diagnosis of CF; written informed consent by parent or legal guardian; age ≥ 36 months and ≤72 months at screening visit; able to comply with medication use, trial visits and trial procedures as judged by the site investigator; able to perform technically acceptable multiple breath washout measurements at the screening and enrolment visits. Exclusion criteria: acute intercurrent respiratory infection, defined as an increase in cough, wheezing, or respiratory rate with onset within 3 weeks preceding screening or enrolment visit; acute wheezing at screening or enrolment visit; oxygen saturation < 95% (< 90% in centres located above 4000 feet elevation) at screening or enrolment visit; physical findings that would compromise the safety of the participant or the quality of the trial data as determined by site investigator; investigational drug use within 30 days prior to at screening or enrolment visit; treatment with inhaled HS at any concentration within 30 days prior to screening or enrolment visit; chronic lung disease not related to CF; inability to tolerate first treatment dose at the enrolment visit. Baseline characteristics Age, mean (SD): HS 4.5 (1.0) years; IS 4.4 (0.9) years. Age group 36 to 54 months, n (%): HS 44 (58%); IS 43 (58%). Age group 55 to 72 months, n (%): HS 32 (42%); IS 31 (42%). Sex, n (%): HS 36 male (47%) and 40 female (53%); IS: 33 male (45%) and 41 female (55%). CFTR genotype homozygous delta F508, n (%): HS 38 (50%); IS 40 (54%). CFTR genotype compound heterozygote delta F508, n (%): HS 33 (43%); IS 28 (38%). CFTR genotype other, n (%): HS 5 (7%); IS 6 (8%). LCI2-5 mean (SD): HS 9.3 (2.0); IS 9.4 (2.0). FEV0.75 % predicted mean (SD): HS 90.6 (12.4); IS 95.0 (16.2).
Interventions	Intervention: 4 mL 7% HS via inhalation 2x daily. Control: 4 mL 0.9% HS via inhalation 2x daily. The delivery system for both groups is a PARI Sprint Junior nebulizer with a PARI Baby facemask or mouthpiece driven by a PARI Vios® compressor. (PARI Respiratory Equipment, Midlothian, VA, USA)
Outcomes	Primary outcomes Change from baseline in LCI measured by N2 multiple breath washout Secondary outcomes Change from baseline in FEV0.75 measured by preschool spirometry Protocol‐defined pulmonary exacerbation rate Health‐related QOL measured by the modified parent‐reported CFQ‐R for preschoolers Respiratory signs as measured by the Cystic Fibrosis Respiratory Sign Diary for ages 0 ‐ 6 (CFRSD0‐6) Treatment‐emergent CF respiratory pathogens from clinical respiratory cultures
Notes	Principal investigators: Stephanie Davis, MD Indiana University; Richard A Kronmal, PhD University of Washington; Felix Ratjen, MD, PhD, FRCPC Hospital for Sick Kids, Toronto; Margaret Rosenfeld, MD, MPH Seattle Children's Hospital. Study start date: March 2015. Estimated primary completion date: August 2018. Estimated Study completion date: February 2019.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random permuted block randomisation was done separately for participants aged 36 to 54 months and 55 to 72 months. The code was generated via a web‐based data entry system.
Allocation concealment (selection bias)	Low risk	A web‐based data entry system was used to allocate the random code. Site pharmacists were provided with unique kit numbers for dispensation.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants, care providers, and investigator were blinded to allocation.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessors were blinded to allocation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	10 participants did not complete the study. HS group: 3 withdrew (1 intolerant of study drug, 1 perceived treatment burden to be too great, 1 lost to follow‐up). IS group: 7 withdrew (3 lost to follow‐up, 2 time constraints, 1 perceived treatment burden to be too great, 1 perceived insufficient benefit from study drug). Sample size was calculated assuming ⍺ of 0.05 with 80% power. They estimated that they would need a sample size of 128 but due to the uncertainty of the treatment effect size they increased the sample size to 150.
Selective reporting (reporting bias)	Low risk	All outcomes listed in the trial registration document and in the methods were reported in the results.
Other bias	Unclear risk	Those performing the statistical analysis were not blinded.