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Emergency Department Probiotic Treatment of Pediatric Gastroenteritis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01853124
Recruitment Status : Completed
First Posted : May 14, 2013
Last Update Posted : March 2, 2018
Sponsor:
Collaborators:
Canadian Institutes of Health Research (CIHR)
Alberta Children's Hospital
The Hospital for Sick Children
Children's Hospital of Eastern Ontario
St. Justine's Hospital
IWK Health Centre
Institut Rosell Lallemand
London Health Sciences Center, Children's Hospital
Information provided by (Responsible Party):
Dr. Stephen Freedman, University of Calgary

Tracking Information
First Submitted Date  ICMJE May 9, 2013
First Posted Date  ICMJE May 14, 2013
Last Update Posted Date March 2, 2018
Actual Study Start Date  ICMJE November 2013
Actual Primary Completion Date May 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 13, 2013)
Development of moderate to severe disease in the 2 weeks after the index visit [ Time Frame: Measured daily for 14 days ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 13, 2013)
  • Duration of Diarrhea [ Time Frame: Daily for 14 days ]
  • Duration of Vomiting [ Time Frame: Daily for 14 days ]
  • Return visits for unscheduled care to a health care provider related to vomiting, diarrhea, dehydration, fever, or fluid refusal, within two weeks [ Time Frame: Daily for 14 days ]
  • Work and Daycare Absenteeism [ Time Frame: Daily for 14 days ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: April 1, 2016)
  • Side Effect Profile [ Time Frame: Daily for 14 days ]
    Determine if short course probiotic administration to young children with acute gastroenteritis is associated with an increase in minor side effects
  • Mechanism of Action [ Time Frame: 28 Days ]
    Determine if probiotic administration increases fecal secretory IgA levels in children with acute gastroenteritis
  • Pathogen Load Quantification [ Time Frame: Determine if a 5-day probiotic treatment course administered to children with acute gastroenteritis results in pathogen-specific reductions in stool pathogen load ]
    5 Days
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Emergency Department Probiotic Treatment of Pediatric Gastroenteritis
Official Title  ICMJE Impact of Emergency Department Probiotic Treatment of Pediatric Gastroenteritis: Randomized Controlled Trial
Brief Summary The objective of this study is to determine for previously healthy children who present to a Canadian Emergency Department (ED) with acute gastroenteritis (infection or irritation of the digestive tract); if compared with placebo, the administration of a probiotic agent (Lacidofil) will result in a significantly lower proportion of children developing moderate to severe disease over the subsequent 2 weeks and will not be associated with a significantly greater occurrence of side effects.
Detailed Description

The burden of acute gastroenteritis (AGE) on children and their families continues to be enormous. It accounts for 1.7 million pediatric emergency department (ED) visits annually in the United States and nearly 240,000 in Canada. Children often suffer from prolonged and severe illness; amongst hospitalized Canadian children, 19% have clinical sepsis, 7% seizures and 4% require intensive care unit admission.3 In a study that we conducted at 11 Canadian EDs, 51% of children experienced moderate to severe disease. Parents rate such episodes as being equivalent to a 10 day admission (moderate) and persistent moderate hearing loss (severe). The burden is augmented by the 50% household transmission rate2, 6 and 42% prolonged work absenteeism rate. Apart from supportive care, health-care providers have little to offer to relieve suffering.

Probiotics, which are defined as viable microbial preparations that have a beneficial effect on the health of the host, represent a rapidly expanding field. While they are available as over-the-counter products, according to the National Institutes of Health, the Food and Drug Administration has not yet approved a single agent for any health claims. Further, a 2012 meta-analysis concluded that there is limited data to support their indications and no published pediatric gastroenteritis trials reported on side effects. Thus, understanding the benefits and side effects of probiotics is crucial before widespread use can be endorsed. Although probiotic clinical trials have been performed, only one (still unpublished) has been ED based. Most studies to date have been significantly flawed and guidelines do NOT endorse their use stating that well-controlled human trials are needed. Consequently, we and others have found that they are rarely used in clinical practice. Reasons cited include (1) questionable clinical meaning to the outcomes evaluated thus far; (2) absence of studies in the appropriate patient population, and (3) a lack of confidence in the quality of probiotic agents studied.

This study will address (1) the needs of the medical community, which is aware of the widening gap between the number of important pediatric and adult trials and (2) the interest of caregivers in "probiotics" - 71% are aware of the term; 31% believe they may be beneficial in children with diarrhea, and > 90% would administer a probiotic if it could make their child better. Furthermore, our pilot study has provided promising preliminary data and has proven the feasibility of our methods. Thus we are poised to conduct a randomized controlled trial (RCT)that will definitively determine if meaningful benefits are derived from probiotic use and will provide critical information regarding their mechanism of action. This information will impact on practice, the burden of disease, and ensure that children receive the best care possible. The results of our proposed RCT will enable guidelines to either clearly endorse or recommend against the routine use of a probiotic agent in children with Acute Gastroenteritis.

We also hypothesize that the therapeutic benefits of probiotics in children with AGE vary by infecting pathogen. We have assembled a team to bridge the gap between the clinical RCT team, molecular diagnostics, and immunologic to quantify the pathogen-specific effects of probiotics. The latter is likely because there are distinct mechanisms (e.g. invasive, inflammatory, non-inflammatory) by which pathogens cause clinical symptoms. Similarly, probiotic effects are exerted through multiple modes-of-action (e.g. direct antimicrobial activity, competitive exclusion, immune response stimulation, inhibition of virulence gene or protein expression). The simultaneous evaluation of pathogen-specific effects on clinical, microbiological and immunological levels has not previously been performed.

The knowledge gained through this multi-faceted approach will inform understanding of the probiotic-host-pathogen interactions that are responsible for improved clinical outcomes in children with AGE. Our study population, outpatient children, is both the main group of patients who suffer from AGE as well as the main consumer of probiotics. Thus, our findings will be relevant and ready for translation into clinical care while simultaneously opening up avenues for future research.

The principal questions to be addressed are as follows:

Hypotheses: In children aged 3-48 months presenting to an ED with less than 72 hours of AGE like symptoms, compared with placebo, the administration of a probiotic agent:

  1. Will result in a significantly lower proportion of children developing moderate to severe disease over the subsequent 2 weeks.
  2. Will not be associated with a significantly greater occurrence of minor side effects.
  3. Will be associated with a greater increase in secretory IgA (sIgA).
  4. Will have varying effects based on the etiologic pathogen, given the diverse underlying pathophysiologic processes induced by the causative agents and the multiple mechanisms of action of probiotics.

Clinical Efficacy:

Primary Question: For previously healthy children, ages 3-48 months, who present to an ED with less than 72 hours of AGE like symptoms, is the proportion who develop moderate to severe disease [Modified Vesikari Score (MVS) ≥ 9] following ED evaluation, significantly different in those who receive a probiotic agent (Lacidofil) compared to those who receive placebo?

Secondary Questions: In this group of patients, amongst those receiving active treatment versus placebo:

  1. Is there a difference in the (a) duration of diarrhea or (b) duration of vomiting?
  2. Is there a difference in the proportion who require an unscheduled health care provider visit?
  3. Is there a difference in the effectiveness of treatment based on the infecting pathogen?

Side Effect Profile:

Question: In this group of patients, is the proportion that experiences a side effect (e.g. bloating, fever, abdominal distention, rash) significantly different in those who receive Lacidofil compared to placebo?

Mechanism of Action:

Question: In this group of patients, are fecal sIgA levels 5 days and 4 weeks after the initiation of treatment higher in those who receive Lacidofil compared to those who receive placebo?

Microbiologic - Stool Pathogen-Specific Load:

Question: In this group of patients, is there a difference in the pathogen specific reduction in stool pathogen load in those who receive Lacidofil compared to those who receive placebo?

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Gastroenteritis
Intervention  ICMJE
  • Drug: Placebo
    All patients in this arm of the study will take 1 sachet containing inactive ingredients (maltodextrin, magnesium stearate, and ascorbic acid) twice daily for 5 days. Doses should be ideally separated by 12 hours (minimum of 8 hours) and taken within 30 minutes of food/drink. If the child vomits within 15 minutes of medication administration (initial or subsequent dose), the dose will be repeated. Total of 2 sachets per day for 5 days.
  • Drug: Lacidofil
    All patients in this arm of the study will take 1 sachet twice daily for 5 days. Each sachet will contain a minimum of 4 billion colony-forming units (CFU) of Lactobacillus rhamnosus Rosell-11 (95%) and L. helveticus Rosell-52 (5%). The total weight of all ingredients is 1 gm. Doses should be ideally separated by 12 hours (minimum of 8 hours) and taken within 30 minutes of food/drink. If the child vomits within 15 minutes of medication administration (initial or subsequent dose), the dose will be repeated. Total daily dose = 8 billion CFU x 5 days.
Study Arms  ICMJE
  • Experimental: Lacidofil
    Lacidofil sachet containing active ingredients
    Intervention: Drug: Lacidofil
  • Placebo Comparator: Placebo
    Placebo sachet containing inactive ingredients
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 13, 2013)
886
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE May 2017
Actual Primary Completion Date May 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Presence of diarrhea: defined as ≥ 3 watery stools in a 24-hour period
  • Duration of vomiting and/or diarrhea < 72 hours
  • Age 3 to < 48 months

Exclusion Criteria:

  • Presence of an indwelling vascular access line or structural heart disease
  • Taking immunosuppressive therapy, or known history of immunodeficiency
  • Hematochezia in the preceding 72 hours, underlying significant chronic gastrointestinal problem or inflammatory bowel disease
  • Family member with an indwelling vascular access line, on immunosuppressive therapy, or with a known immunodeficiency
  • Bilious vomiting
  • Probiotic use (supplement) in the preceding 2 weeks
  • Previously enrolled in this trial
  • Daily follow-up not possible
  • Allergy to Soy
  • Pre-existing (known) pancreatic dysfunction or insufficiency
  • Oral or Gastrointestinal surgery within preceding 7 days
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 3 Months to 48 Months   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01853124
Other Study ID Numbers  ICMJE REB13-0045
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Dr. Stephen Freedman, University of Calgary
Study Sponsor  ICMJE Dr. Stephen Freedman
Collaborators  ICMJE
  • Canadian Institutes of Health Research (CIHR)
  • Alberta Children's Hospital
  • The Hospital for Sick Children
  • Children's Hospital of Eastern Ontario
  • St. Justine's Hospital
  • IWK Health Centre
  • Institut Rosell Lallemand
  • London Health Sciences Center, Children's Hospital
Investigators  ICMJE
Principal Investigator: Stephen Freedman, MD University of Calgary
PRS Account University of Calgary
Verification Date February 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP