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Probiotics for the Prevention of Antibiotic-Associated Diarrhea (PAID)

Primary Purpose

Acute Diarrhea

Status
Terminated
Phase
Not Applicable
Locations
Canada
Study Type
Interventional
Intervention
Probiotic (BioK+)
Placebo
Sponsored by
The Hospital for Sick Children
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Acute Diarrhea focused on measuring Probiotics, diarrhea, antibiotic, children, hospital

Eligibility Criteria

1 Year - 17 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. 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).
  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.
  3. Parent (if parent-report) or patient (if patient-report) is able to communicate in English (read, write, speak).

Exclusion Criteria:

  1. Parental or patient (e.g. child > 12 years old) report of current diarrhea, diarrhea within the last week.
  2. Lactose intolerance.
  3. Allergies to strawberry, dried citrus pulp, or any other components of the study product.
  4. Immuno-compromised patients or those on immunosuppressive agents (e.g. heart or kidney transplant, complex care, sickle cell disease, chemotherapy agents, oral prednisone).
  5. 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).
  6. Children with serious and/or unstable medical conditions (e.g. diabetes, cardiovascular, renal, lung, psychiatric illness, bleeding disorders, etc.).
  7. Children admitted to a medical or surgical subspecialty unit.
  8. Patients enrolled in another study.
  9. Patients previously randomized to this study.
  10. Patient is pregnant.

Sites / Locations

  • McMaster Children's Hospital
  • The Hospital for Sick Children

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Probiotic (BioK+)

Placebo

Arm Description

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.

Strawberry flavored tub of milk, identical (taste, color, odor) to the active Bio-K+ treatment.

Outcomes

Primary Outcome Measures

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).
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).

Secondary Outcome Measures

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.
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.
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.

Full Information

First Posted
April 12, 2016
Last Updated
April 16, 2018
Sponsor
The Hospital for Sick Children
Collaborators
McMaster University
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1. Study Identification

Unique Protocol Identification Number
NCT02817165
Brief Title
Probiotics for the Prevention of Antibiotic-Associated Diarrhea
Acronym
PAID
Official Title
Probiotics in the Prevention of Antibiotic-Associated Diarrhea in Hospitalized Children: a Randomized Trial
Study Type
Interventional

2. Study Status

Record Verification Date
April 2018
Overall Recruitment Status
Terminated
Why Stopped
Slow recruitment
Study Start Date
November 2016 (undefined)
Primary Completion Date
October 2017 (Actual)
Study Completion Date
January 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
The Hospital for Sick Children
Collaborators
McMaster University

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Diarrhea
Keywords
Probiotics, diarrhea, antibiotic, children, hospital

7. Study Design

Primary Purpose
Prevention
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
16 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Probiotic (BioK+)
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Strawberry flavored tub of milk, identical (taste, color, odor) to the active Bio-K+ treatment.
Intervention Type
Dietary Supplement
Intervention Name(s)
Probiotic (BioK+)
Intervention Description
Probiotic (BioK+) with 3 stains of Lactobacillus
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Strawberry flavored tub of milk, identical (taste, color, odor) to the active Bio-K+ treatment.
Primary Outcome Measure Information:
Title
Incidence of antibiotic-associated diarrhea (AAD)
Description
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).
Time Frame
2 weeks after antibiotic + probiotic completion
Title
Incidence of antibiotic-associated diarrhea (AAD), global impression
Description
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).
Time Frame
2 weeks after antibiotic + probiotic completion
Secondary Outcome Measure Information:
Title
Severity of AAD
Description
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.
Time Frame
2 weeks after antibiotic completion
Title
Adverse events
Description
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.
Time Frame
2 weeks after antibiotic completion
Title
Duration of AAD
Description
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.
Time Frame
2 weeks after antibiotic completion

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Patricia Parkin, MD
Organizational Affiliation
The Hospital for Sick Children
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Gordon Guyatt, MD
Organizational Affiliation
McMaster University
Official's Role
Study Chair
Facility Information:
Facility Name
McMaster Children's Hospital
City
Hamilton
State/Province
Ontario
ZIP/Postal Code
L8N 3Z5
Country
Canada
Facility Name
The Hospital for Sick Children
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X8
Country
Canada

12. IPD Sharing Statement

Plan to Share IPD
Undecided
IPD Sharing Plan Description
To be determined.
Citations:
PubMed Identifier
20566617
Citation
Johnston BC, Shamseer L, da Costa BR, Tsuyuki RT, Vohra S. Measurement issues in trials of pediatric acute diarrheal diseases: a systematic review. Pediatrics. 2010 Jul;126(1):e222-31. doi: 10.1542/peds.2009-3667. Epub 2010 Jun 21.
Results Reference
background
Citation
Johnston B, Pirrello D, Lytvyn L, Mahant S, Sherman P, Ship N, Parkin P. Prospective cohort study of antibiotic-associated diarrhea among hospitalized children. Symposium Probio, Quebec City, Canada. (October 29, 2015).
Results Reference
background
PubMed Identifier
26695080
Citation
Goldenberg JZ, Lytvyn L, Steurich J, Parkin P, Mahant S, Johnston BC. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev. 2015 Dec 22;(12):CD004827. doi: 10.1002/14651858.CD004827.pub4.
Results Reference
background

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Probiotics for the Prevention of Antibiotic-Associated Diarrhea

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