Lactobacillus Reuteri DSM 17938 in the Prevention of Antibiotic-associated Diarrhea in Children: Protocol of a Randomized Controlled Trial

Study Overview
=================
Brief Summary
-----------------
The aim of this study is to assess the effect of Lactobacillus reuteri DSM 17938 administration for the prevention of diarrhea and AAD in children.

Detailed Description
-----------------
Introduction: Addition of some probiotics appears to reduce the risk of antibiotic-associated diarrhea (AAD). Effects of probiotics are strain specific, thus the efficacy and safety of each probiotic strain should be established separately. We aim to assess the effect of Lactobacillus reuteri DSM 17938 administration for the prevention of diarrhea and AAD in children. Methods and analysis: A total of 250 children younger than 18 years treated with antibiotics will be enrolled into a double-blind, randomized placebo-controlled trial in which they will additionally receive L reuteri DSM 17938 at a dose 2 x 10^8 colony-forming units or an identically appearing placebo, orally, twice daily, for the entire duration of antibiotic treatment. The primary outcome measures will be the frequency of diarrhea and AAD. Diarrhea will be defined according to one of 3 definitions: (a) ≥3 loose or watery stools per day for a minimum of 48 hours during antibiotic treatment; (b) ≥3 loose or watery stools per day for a minimum of 24 hours during antibiotic treatment; (c) ≥2 loose or watery stools per day for a minimum of 24 hours during antibiotic treatment. AAD will be diagnosed in cases of diarrhea, defined clinically as above, caused by C. difficile or for otherwise unexplained diarrhea (i.e. negative laboratory stool tests for infectious agents).

Official Title
-----------------
Lactobacillus Reuteri DSM 17938 in the Prevention of Antibiotic-associated Diarrhea in Children: Protocol of a Randomized Controlled Trial

Conditions
-----------------
Diarrhea, Antibiotic Associated Diarrhea

Intervention / Treatment
-----------------
* Drug: Lactobacillus reuteri DSM 17938
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: age younger than 18 years; oral or intravenous antibiotic therapy which started within 24 hours of enrollment; signed informed consent. Exclusion Criteria: pre-existing acute or chronic diarrhea, history of chronic gastrointestinal disease (e.g., inflammatory bowel disease, cystic fibrosis, celiac disease, food allergy) or other severe chronic disease (e.g., neoplastic diseases), immunodeficiency, use of probiotics within 2 weeks prior to enrollment, use of antibiotics within 4 weeks prior to enrollment, prematurity, and exclusive breastfeeding.

Ages Eligible for Study
-----------------
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: L reuteri DSM 17938<br>L reuteri DSM 17938 2 x 10^8 twice daily | Drug: Lactobacillus reuteri DSM 17938<br>* Lactobacillus reuteri DSM 17938 twice daily 2 x 10^8<br>|
| Placebo Comparator: Controls<br>Identically appearing placebo twice daily | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| frequencies of diarrhea and antibiotic associated diarrhea | Three different definitions of diarrhea will be used, as the definitions of diarrhea/AAD in published studies vary. These will include diarrhea defined as: (a) ≥3 loose or watery stools per day for a minimum of 48 hours during antibiotic treatment; (b) ≥3 loose or watery stools per day for a minimum of 24 hours during antibiotic treatment, and (c) ≥2 loose or watery stools per day for a minimum of 24 hours during antibiotic treatment. AAD will be diagnosed in cases of diarrhea, defined clinically as above, caused by C. difficile or for otherwise unexplained diarrhea (i.e., negative laboratory stool tests for infectious agents). In all cases, loose or watery stools will correspond to scores of 5 to 7 on the BSF scale or A-consistency on the AISS. | during antibiotic treatment, an average of 10 days and 7 days of follow up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| infectious diarrhea | rotavirus, adenovirus, norovirus, Salmonella, Shigella, Campylobacter, Yersinia and C. difficile | during antibiotic treatment, an average of 10 days and 7 days of follow up | 
| the need for discontinuation of the antibiotic treatment |  | during antibiotic treatment, an average of 10 days | 
| the need for hospitalization to manage the diarrhea (in outpatients) |  | during antibiotic treatment, an average of 10 days and 7 days of follow up | 
| the need for intravenous rehydration in any of the study groups |  | during antibiotic treatment, an average of 10 days and 7 days of follow up | 
| adverse events |  | during antibiotic treatment, an average of 10 days and 7 days of follow up |