Emergency Department Probiotic Treatment of Pediatric Gastroenteritis
Condition: Gastroenteritis
MeSH terms: Gastroenteritis; Emergencies
Study type: Interventional
Phase: Phase 3

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      Although probiotic clinical trials have been performed, only one (still unpublished) has been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?
    

Intervention name(s): Placebo; Lacidofil
Intervention type(s): Drug; Drug
Intervention description(s): 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.; 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.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Diarrhea