Probiotics for the Prevention of Antibiotic-Associated Diarrhea

Study Overview
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Brief Summary
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In North America, one of the most common reasons for hospitalization in previously healthy children is for the treatment of infections with antibiotics. This study will determine if, in previously healthy children hospitalized and prescribed intravenous (IV) antibiotics, the co-administration of a probiotic milk product containing good bacteria, is safe and effective for reducing AAD, as compared to a placebo (identical appearing milk product). This will be a two-center, randomized, masked, placebo-controlled clinical trial. The results of this study will help inform clinicians and families on the use of probiotics in the prevention of AAD, a common side effect of antibiotic use among hospitalized children.

Detailed Description
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A two-centred randomized, multi-blind (i.e. patients, caregivers, data collectors, outcome assessors, data managers and analysts), placebo-controlled clinical trial intended to evaluate the efficacy and safety of Bio-K+ (Lactobacillus acidophilus CL1285, Lactobacillus casei LBC80R and Lactobacillus rhamnosus CLR2) in the prevention of AAD in hospitalized children 1 year to 17 years of age administered IV antibiotics.

Official Title
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Probiotics in the Prevention of Antibiotic-Associated Diarrhea in Hospitalized Children: a Randomized Trial

Conditions
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Acute Diarrhea

Intervention / Treatment
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* Dietary Supplement: Probiotic (BioK+)
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants will be children aged 1 year to 17 years admitted to the General Pediatric inpatient unit at The Hospital for Sick Children (Site 1) or McMaster Children's Hospital (Site 2). Participants will be prescribed IV antibiotics with a planned duration of 1 or more days, and a total course of both IV and oral antibiotics, if applicable, of no more than 28 days. Parent (if parent-report) or patient (if patient-report) is able to communicate in English (read, write, speak). Exclusion Criteria: Parental or patient (e.g. child > 12 years old) report of current diarrhea, diarrhea within the last week. Lactose intolerance. Allergies to strawberry, dried citrus pulp, or any other components of the study product. Immuno-compromised patients or those on immunosuppressive agents (e.g. heart or kidney transplant, complex care, sickle cell disease, chemotherapy agents, oral prednisone). Patients with known or potentially compromised gut integrity (e.g. short gut, Inflammatory Bowel Disease, Celiac disease, Irritable Bowel Syndrome, nasogastric, nasojejunal or gastrostomy tube). Children with serious and/or unstable medical conditions (e.g. diabetes, cardiovascular, renal, lung, psychiatric illness, bleeding disorders, etc.). Children admitted to a medical or surgical subspecialty unit. Patients enrolled in another study. Patients previously randomized to this study. Patient is pregnant.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Probiotic (BioK+)<br>Children will receive 10-40 billion CFUs/day of Bio-K+ (Lactobacillus acidophilus CL1285, Lactobacillus casei LBC80R and Lactobacillus rhamnosus CLR2), with dose based on their weight. The product will be administered as a strawberry flavored tub of milk. | Dietary Supplement: Probiotic (BioK+)<br>* Probiotic (BioK+) with 3 stains of Lactobacillus<br>|
| Placebo Comparator: Placebo<br>Strawberry flavored tub of milk, identical (taste, color, odor) to the active Bio-K+ treatment. | Other: Placebo<br>* Strawberry flavored tub of milk, identical (taste, color, odor) to the active Bio-K+ treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of antibiotic-associated diarrhea (AAD) | The investigators will employ a questionnaire addressing Pediatric Acute Diarrhea (qPAD), a measure of diarrhea involving the assessment of stool frequency and consistency for each bowel movement. To measure consistency, the qPAD contains a stool consistency classification system. Our registered sample size is based on pilot data from The Hospital for Sick Children indicating that the incidence of AAD is 33% (95% CI 23% to 43%) according to the qPAD. Given an estimated baseline AAD risk of 32.9% and a 48% relative risk reduction in AAD (Johnston et al, Cochrane Library, 2011), a randomized trial with 80% power and a 2-sided alpha of 0.05 comparing Bio-K+ with placebo would require a total sample size of 118 patients per group (236 total). | 2 weeks after antibiotic + probiotic completion | 
| Incidence of antibiotic-associated diarrhea (AAD), global impression | Given that parents have knowledge of the child's typical bowel movements per day, the investigators will also employ a Global Rating Scale for diarrhea (GRSd), using a 0 to 4 scale (0 = no diarrhea, 1 = mild diarrhea, 2 = moderate diarrhea, 3 = severe diarrhea, 4 = worse imaginable diarrhea). The investigators will ask participants to select values based on diarrhea severity, which is a combination of stool frequency and consistency over 24 hours. Our registered sample size is based on the incidence of AAD (33%; 95% CI 23% to 43%) according to the qPAD. However, the incidence of AAD according to GRSd is 23%, which corresponds to the lower bound of the 95% CI for the qPAD. The investigators are currently applying for additional peer-reviewed funds. If these funds are obtained the investigators will power the trial based GRSd, a more conservative AAD incidence (23%). The investigators will also power the trial for a smaller treatment effect (39% relative risk reduction). | 2 weeks after antibiotic + probiotic completion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severity of AAD | The investigators will assess severity using the qPAD and the investigators will employ definitions for diarrhea from the Canadian Nosocomial Infection Surveillance Program, modified for use in children, defined as: severe: ≥6 loose/unformed/liquid stools; moderate: ≥3 loose/unformed/liquid stools; mild: a change in stooling pattern to 1-2 loose/unformed/liquid stools daily (Gravel 2007). The investigators will classify severity according to the 24-hour period with the highest degree of severity. | 2 weeks after antibiotic completion | 
| Adverse events | Incidence of mild (e.g. self-resolving), moderate (e.g. those that warrant medical evaluation) and serious (e.g. those that warrant continued hospitalization) adverse events based on criteria adopted by the National Institute of Health common terminology criteria for adverse events (NIH severity) will be evaluated. | 2 weeks after antibiotic completion | 
| Duration of AAD | The investigators will measure duration of AAD using a definition of diarrhea resolution (diarrhea offset) developed based on a systematic review of 138 trials of Pediatric Acute Diarrhea, and Delphi consensus with a panel of experts in pediatrics, clinical gastroenterology and measurement (Johnston BC et al. Pediatrics 2010; Jul;126(1):e222-31; Johnston BC et al. Symposium Probio, Quebec City, Canada, 2015). For children up to 17 years of age, acute diarrhea typically lasts less than 7 days and not longer than 14 days and resolution is marked by production of 2 consecutive normal stools (i.e. soft and formed or hard and formed) stool or; production of one normal stool followed by 12 hours with no stool production or; normal stool production (or no stool production) for a period of 24 hours. | 2 weeks after antibiotic completion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Probiotics, diarrhea, antibiotic, children, hospital