Diarrhea causes a billion illness episodes and 2.5 million deaths/year in children under the age of 5 years in the developing world and China. Oral rehydration therapy has reduced mortality from this disease, but repeated episodes of diarrhea still affect many children in the developing world, contributing to the problem of malnutrition. Probiotic bacteria have been shown to be effective for treatment of pediatric diarrhea in many studies, but variations in study design, probiotic agents used, and causes of diarrhea make it difficult to determine the most appropriate role for probiotics in childhood diarrhea in malnourished populations from developing countries. This proposal is submitted to the R34 NIH Clinical Trial Planning Grant Program to support development of a Phase III clinical trial evaluating the relative efficacy of the most promising probiotic agents for treatment of diarrhea in a population representative of high-risk undernourished children around the world, examining practical issues of cost and distribution, adverse effects, the impact of breast feeding, and pathogen-specific responses. The investigators will build on their extensive experience in community based clinical trials in Peru by supporting the necessary but time consuming work needed to prepare for a successful clinical trial with the current grant. The principal investigator will work with Peru-based consultants to build laboratory and field site capabilities in the community of Santa Clara, Peru, a rural community in the Amazon Basin located 10 km. from the urban center of Iquitos. This community has been the site of an ongoing successful longitudinal surveillance study of Shigella transmission, and it was chosen as a site for the probiotics clinical trial due to high rates of diarrhea and childhood malnutrition. The planning grant will be used to support investigator time, travel expenses, and equipment needed for 1) developing an ongoing mechanism for census data collection to identify potential subjects for the clinical trial, 2) training and infrastructure improvements in the clinical laboratory to optimize capability for diagnostic testing of diarrhea cases, microbiologic methods for quality control, and evaluation of adverse events, 3) discussions with manufacturers of probiotic products to be included in the clinical trial, 4) obtaining agreements for administration and human subjects monitoring from involved institutions, including the establishment of a Data Safety Monitoring Board and Certification Training, 5) establishing Standard Operating Procedures (SOP) and documentation Procedures for the clinical trial phase, along with tools for data collection and procedures for periodic analyses, and 6) development of dialog with the community to build support for the trial and address concerns. Support for these activities during a planning period before the clinical trial will greatly facilitate the implementation of the trial.
