ACTRN12616000797471.

Trial name or title	Probiotics and the EARly Life effects on intestinal bacteria and inflammation in children with Cystic Fibrosis (PEARL‐CF).
Methods	Trial design: RCT. Trial grouping: parallel group. Randomisation method: block randomisation.
Participants	Inclusion criteria Children aged 0 to 6 years. Participants with CF must fulfil the diagnostic criteria for CF (sweat chloride ≥ 60 mmol/L and/or 2 CF‐causing mutations). Healthy controls include healthy full‐term infants (38 ‐ 40 weeks gestation; > 2.5 kg birth weight), and who do not have any major non‐CF disease (e.g. spina bifida) or gut disease (e.g. inflammatory bowel disease). Exclusion criteria Participants with CF who have had previous intestinal surgery (e.g. meconium ileus) and/or have intestinal resection resulting in short gut syndrome. Participants with CF already on probiotics, but who are not willing to stop supplementation for 3 months prior to randomisation. Healthy controls on probiotics who are not willing to stop. Target sample size Probiotic group: n = 32. Placebo group: n = 32. Healthy controls: n = 64.
Interventions	Probiotic Preparation: total of 15 strains ‐ CFU per 1 g: 10.2 Billion; B lactis BI‐04 3 Billion, L rhamnosus GG 2 Billion, L paracasei Lpc‐37 1 Billion, L plantarum Lp‐115 1 Billion, L rhamnosus HN001 500 Million, L rhamnosus Lr32 500 Million, B animalis HN019 500 Million, L salivarius subsp. salivarius Ls‐33 400 Million, S thermophiles St21 400 Million, B breve Bb‐03 200 Million, L gasseri Lg 36 200 Million, B longum BI‐05 180 Million, B infantis Bi‐26 100 Million, L reuteri 1e1 100 Million,L bulgaricus Lb‐64 100 Million. Excipient: Litesse Ultra (Polydextrose) 950 mg. Dose (probiotic): 2x 1010 CFU/day (0 ‐ 3 year olds) and 3x 1010 CFU/day (over 3 years and up to 6 years). Frequency of administration: daily. Duration: 12 months. Placebo Preparation: placebo. Dose (probiotic): 0. Frequency of administration: daily. Duration: 12 months.
Outcomes	Primary outcome measures Intestinal microbial alpha diversity (richness and Shannon Index). Intestinal microbial beta diversity (Bray‐Curtis dissimilarity). Secondary outcome measures Faecal calprotectin (mg/kg). Faecal metabolome. Faecal proteome. Growth (height, weight and BMI) z scores. Number of pulmonary exacerbations (defined using Fuch's criteria). Number of therapeutic antibiotic courses. Number of hospitalisations. (OPTIONAL) lung function testing. HRQoL (PedsQL). Gastrointestinal symptoms (PedsQL). Adverse events including serious adverse reactions, adverse reactions and mortality. Time points for measurements: baseline, 2 months, 4 months, 6 months, 8 months, 10 months, 12 months (end), 15 months (i.e. 3 months post‐intervention), 18 months, 21 months and 24 months (i.e. 12 months post‐intervention). Length of follow‐up: 104 weeks.
Starting date	17 June 2016.
Contact information	Associate Professor (Keith) Chee Y. Ooi Sydney Children's Hospital Randwick High Street, Randwick 2031, New South Wales Australia Phone: +61293821752 Fax: +61293821401 Email: keith.ooi@unsw.edu.au
Notes	Multicentre at 5 sites: Sydney (Randwick and Westmead), Melbourne, Brisbane and Christchurch (New Zealand). This trial is recruiting healthy controls (without CF) to act as a reference for normal (e.g. intestinal microbiota and inflammatory markers): Data from these healthy participants will not be included in the review.