Safety of Lactobacillus Reuteri in Healthy Children Aged 2-24 Months

Phase I double blinded randomized trial of the safety and tolerability of Lactobacillus reuteri DSM 17938 given for five successive days in healthy children. Sixty children will receive study product at a treatment to placebo ratio of 2:1 and followed for 3 months for safety outcomes.

The study is a single center Phase 1 double blind placebo controlled trial of Lactobacillus reuteri DSM 17938 in children aged 2-24 months. The study population is based in a community with a registered clinical trial center in rural Peru where this protocol can be done in a highly controlled setting. The study is intended to enroll healthy children living in a resource constrained setting where chronic undernutrition and diarrheal disease is common, as this is the population that is most likely to receive benefit from the use of this and or other probiotic products for the treatment of acute infectious diarrhea and environmental enteropathy.

Up to 100 subjects will be enrolled in order to obtain the randomization of 60 subjects, who will receive study product or placebo at a ratio of 2:1. Participants will be enrolled between the ages of 8 weeks and 24 months. There will be no age stratification. Participants will be screened with a baseline history and physical examination and laboratory tests to determine the HIV status of the child, as well baseline laboratory tests to evaluate occult infections, hepatic function, and renal function. Upon randomization subjects will be screened and randomized to a treatment arm. Product will be administered under the direct supervision of study staff daily for 5 days. The primary outcome is the safety and tolerability of the product at this dose and formulation. Safety will be assessed by the monitoring of baseline laboratory tests at 5 and 28 days following the initiation of therapy and by AE monitoring. Tolerability will be evaluated by analyzing 28 day diary cards that are distributed to all randomized subjects on which parents record their child's symptoms (specifically fever, anorexia/oral intake, vomiting, diarrhea, irritability, rash, wheezing, or open fields which allows them to describe any issue their child may experience and grade its severity) . Secondary outcomes include:

1) The assessment of the duration of shedding of Lactobacillus reuteri (Lr) strain DSM 17938 following administration. This will be determined by and endpoint PCR assay for L. reuteri done on stool collected on D3, D5, D12, D15, D18, D24, D28, D36 on all participants.

The planned enrollment period is four months and the participation of individual subjects is for 3 months. The study should be completed in 7 months. Safety monitoring by treatment group, i.e., infants assigned to active or placebo study product will be conducted by NIDDK appointed DSMB under the direction of the NIDDK Program Official.

Eligibility Criteria:
Inclusion Criteria:

* In order to be eligible to participate in this study, a subject must meet all of the following criteria:

  * Have a parental permission form signed by both parents
  * Be between 8 weeks to 24 months of age with no preexisting exclusion criteria
  * Have parents who are willing to comply with all planned study procedures and be available for planned study visits for 3 months.

Exclusion Criteria:

* 1) No enrollment of family members in households where any of the following are present:

  1. Another study participant in the household
  2. Presence of immune suppressed individuals or use of immunosuppressive agents (including but not limited to corticosteroids, methotrexate, etc.) by any household member
  3. Presence of a serious congenital anomaly or chronic medical condition that in the opinion of the investigators would contraindicate participation in any household member, including history of gastrointestinal surgery, chronic gastrointestinal illness, abnormal intestinal anatomy, or abnormal bowel functionality

     The following risk factors are at the level of the individual child:

     2) Allergy to penicillin, cephalosporins, clindamycin or gentamicin 3) History of antibiotic use in the last 30 days 4) Use of probiotic products within the past 30 days, including masato (local product with fermenting bacteria) and yogurt products containing live bacterial cultures.

     5) History of diarrheal illness within the past 30 days (See definition in Protocol Appendix B) 6) Presence of fever or a pre-existing adverse event monitored in the study (See Protocol Appendix B Definitions of AEs for specific adverse events monitored in the study) 7) Positive results on serum diagnostic tests for antibodies to HIV.

     8) Presence of severe anemia, defined as serum hemoglobin \< 7 gm/dL

     9) Out of range laboratory values for total leucocyte count, BUN, Creatinine, AST, ALT, and total bilirubin monitored as potential adverse events, as described in Appendix E.

     10) Pre-enrollment stool sample (collected within 14 days of day 1 of the study) is positive for L. reuteri by PCR.