Multicenter Randomized Trial of a Combined Probiotic (Lactobacillus Reuteri LMG P-27481 and Lactobacillus Rhamnosus GG (ATCC 53103) for the Prevention of Antibiotic-Associated Diarrhea and Gastrointestinal Symptoms in Children

Eligible children will be randomly assigned to receive the combined probiotic study product (Noos, Roma, Italia)(BCCMTM Bacterial Collection of Ghent, Belgium, Italian Patent: 102016000011071, International Patent Request : PCT/IB 2017/053856), or placebo as additional treatment to the antibiotic therapy. Kind, dose and duration of antibiotic treatment will be decided by the local clinicians according to good medical practice and current recommendations. The first dose of probiotic will be started the same day of starting the antibiotic treatment, immediately after enrollment. Then, each oral stick will be administered orally once daily, in the morning, before breakfast, during the antibiotic treatment and prolonged for 30 days since starting.

Study product The combined probiotic is made by Lactobacillus reuteri LMG P-27481 and Lactobacillus rhamnosus GG (ATCC 53103), sucralose and isomalt as an oral stick formulation of 1.6 g with a concentration of probiotic of 2x1010 colony forming unit (CFU) per stick, launched in the Italian market with the name of Reuterin®GG (Noos, Roma, Italia).

The probiotic and placebo will be prepared centrally by the probiotic producer as identically appearing oral stick. The placebo will contain only sucralose and isomalt, 1.6 g per stick.

Randomization The allocation sequences and randomization lists has been generated by a online computer system. The probiotic -placebo allocation ratio will be of 1:1. To ensure allocation concealment, an independent subject prepared the randomization schedule and sealed envelopes to be sent to the participant centers. Each investigator will control the packaging and labels of trial treatments sent by the producer with a numerical code with no possible identification of the probiotic product compared to the placebo. The allocation will be consecutively assigned for all enrolled subjects. All investigators, participants, and statisticians will be blinded to the assigned treatment throughout the study and during the data analysis. After completing the analysis of the data or in case of sever adverse event the randomization code will be broken and information about the content of the product (probiotic or placebo) will be revealed by the producer, upon the investigator's request.

Monitoring and collection of data At enrollment a standardized form will record age, gender, anthropometric parameters, vital signs, refilling time, site of infection, laboratory tests, kind, dose and route of administration of antibiotic, diet, previous AAD or other gastrointestinal symptoms, comorbidity and associated treatment. Vesikary scale, anthropometric measures, vital signs, refilling time will be also recorded in each patient at enrollment and in case of occurrence of diarrhea. Bristol stool chart will be used to grade the consistency of stools.