Gastroenteritis Clinical Trial
Official title:
Impact of Emergency Department Probiotic Treatment of Pediatric Gastroenteritis: Randomized Controlled Trial
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.
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Although probiotic clinical trials have been performed, only one (still unpublished) has been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?
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