PRESIS 2019.

Study characteristics
Methods	RCT. Design: parallel assignment. Duration: 52 weeks. Location: multicentre trial conducted at 5 CF centres in Germany within the clinical trial network of the German Centre for Lung Research.
Participants	42 infants with CF were enrolled. Inclusion criteria: confirmed diagnosis of CF established in neonatal period either via CF newborn screening or because of symptoms typical for CF (e.g. meconium ileus), positive family history or positive prenatal screening and fulfilling at least 1 of 3 criteria (sweat chloride ≥ 60mEq/L, 2 CF causing mutations of CFTR gene alterations of transepithelial potential difference of nasal or rectal epithelia typical for CF); age at enrolment is 0 to 4 months; participant's and parent's ability to comply with medication use, trial visits, and trial procedures as judged by the investigator (therefore parents have to understand the character of the study and individual consequences); participation is voluntary so only participants, whose parents or legal guardians gave written consent, are included. Exclusion criteria: born < 30 weeks gestation; prolonged mechanical ventilation in the first 3 months of life; a significant medical disease or condition other than CF likely to interfere with the child's ability to complete the entire protocol; previous major surgery except for meconium ileus; other major organ dysfunction, excluding pancreatic or hepatic dysfunction or another condition due to CF; physical findings that would compromise the safety of the participant or the quality of the trial data as determined by investigator; history of adverse reaction to sedation; known hypersensitivity to treatment; participation in other interventional trials at the same time. Criteria, which lead to a displacement of the procedures in sedation until the child has recovered: clinically significant upper airway obstruction as determined by investigator (e.g. severe laryngomalacia, markedly enlarged tonsils, significant snoring, diagnosed obstructive sleep apnoea); acute intercurrent respiratory infection, defined as an increase in cough, wheezing, or respiratory rate with onset in 2 weeks preceding visit; oxygen saturation < 95% before initial pulmonary function test or initial MRI; severe gastroesophageal reflux, defined as persistent frequent emesis despite anti‐reflux therapy. 42 participants enrolled (originally aimed for 40) aged up to 4 months. Baseline characteristics for all randomised participants (n = 42) Age, mean (SD) years: HS 0.26 (0.08); IS 0.26 (0.07). Sex: HS 10 male and 11 female; IS 10 male and 11 female. CFTR genotype F508del/F508del, n (%): HS 11 (52.4); IS 11 (52.4). CFTR genotype F508del/other, n (%): HS 6 (28.6); IS 8 (38.1). CFTR genotype other/other, n (%): HS 4 (19.0); IS 20 (95.2). Pancreatic insufficiency, n (%): HS 17 (81.0); IS 20 (95.2).
Interventions	Intervention group: 4 mL HS 6% (MucoClear® 6%) administered via inhalation 2x daily for 52 weeks. Control group: 4 mL IS 0.9% administered via inhalation 2x daily for 52 weeks. Both interventions delivered using the PARI LC SPRINT® Junior nebulizer with a baby bend, size‐adapted PARI® Baby face mask size 0 ‐ 3, connection tubing (2.2 m) and a PARI JuniorBOY® SX compressor.
Outcomes	Primary outcome Number of participants with adverse events and serious adverse events at end of trial. Secondary outcomes Rate of protocol‐defined pulmonary exacerbations requiring treatment with oral, inhaled or intravenous antibiotics Time to first pulmonary exacerbation Change from baseline in proportion of children with morphological or functional changes, or both, due to CF lung disease according to MRI chest score and CXR Chrispin‐Norman score (at end of trial) Change in extent and severity of bronchial dilatation after MRI and CXR scores at end of trial Proportion of children with impairments in lung function determined via multiple breath washout at baseline, after 3, 6, 9, and 12 months of inhalation Severity of impairment in lung function test at baseline, after 3, 6, 9, and 12 months Health‐related QOL as assessed by scores from the CFQ‐R (German version), administered quarterly Change in anthropometric and basic respiratory parameters (weight, height, BMI, weight‐for‐height, resting respiratory rate, and room air oxygen saturation) at end of trial Proportion of participants with new isolation of CF pathogen from clinically collected respiratory cultures among participants from whom Pseudomonas aeruginosa or other CF pathogens were not isolated from respiratory cultures prior to enrolment Time to first isolation of a CF pathogen
Notes	Principal investigator: Marcus A. Mall, MD, Heidelberg University, Germany. Collaborator: German Center for Lung Research. Start date: June 2012. Final data collection: November 2016. Supported by grants from the German Federal Ministry of Education and Research (82DZL10106, 82DZL10201, 82DZL10401, and 82DZL10501) and the Dietmar Hopp Foundation. Study solutions and inhalation devices were provided by PARI GmbH, Starnberg, Germany.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation process was based on a randomisation list prepared by a biostatistician of the Coordination Center for Clinical Studies (KKS) Heidelberg not involved in the study. The randomisation list contained subsequent randomisation numbers automatically generated by a dedicated randomisation web service (randomizer.at) for the multicentre setting.
Allocation concealment (selection bias)	Low risk	Randomisation and allocation all done by an independent biostatistician via a web generation service.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of participants, care providers, and investigators. HS and IS inhalation solutions were supplied by Pari GmbH, Starnberg, Germany, as identically packaged 4 mL plastic ampullae. Blinding was done by the hospital pharmacy at Heidelberg University Hospital.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessors were blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Only 2 participants withdrew, 1 in each group with reasons given (the participant in the HS group was withdrawn at 30 weeks due to unblinding because of an exacerbation; the participant in the IS group was withdrawn by the parents as they declined further sedation for study procedures).
Selective reporting (reporting bias)	Unclear risk	QOL is listed in the trial registration document but is not reported in the results.
Other bias	Low risk	No other risk of bias identified. Sample size calculation carried out and met.