PROBIOTICS IN PEDIATRIC DIARRHEA IN PERU: PLANNING GRANT

描述（由申请人提供）：在发展中国家和中国，腹泻每年导致10亿例疾病发作和250万例5岁以下儿童死亡。口服补液疗法降低了这种疾病的死亡率，但发展中国家的许多儿童仍然反复腹泻，造成营养不良问题。在许多研究中，益生菌已被证明对治疗儿童腹泻有效，但由于研究设计、使用的益生菌制剂和腹泻原因的差异，很难确定益生菌在发展中国家营养不良人群中儿童腹泻中最合适的作用。该提案已提交给R34 NIH临床试验计划拨款项目，以支持开展一项III期临床试验，评估最有希望的益生菌制剂在治疗腹泻方面的相对功效，研究成本和分配、不良反应、母乳喂养的影响和病原体特异性反应等实际问题。这些研究人员将利用他们在秘鲁社区临床试验方面的丰富经验，支持为成功的临床试验做准备所需的必要但耗时的工作。首席研究员将与秘鲁顾问合作，在距离伊基托斯市中心10公里的亚马逊盆地农村社区圣克拉拉社区建立实验室和现场能力。该社区一直是一项正在进行的志贺氏菌传播纵向监测研究的成功地点，由于腹泻和儿童营养不良的高发率，它被选为益生菌临床试验的地点。计划拨款将用于支持研究者所需的时间、差旅费和设备：1)建立一种持续的普查数据收集机制，以确定临床试验的潜在受试者；2)培训和改善临床实验室的基础设施，以优化腹泻病例诊断测试的能力，质量控制的微生物学方法，以及不良事件评估。3)与拟纳入临床试验的益生菌产品制造商进行讨论；4)从相关机构获得管理和人体受试者监测协议，包括建立数据安全监测委员会和认证培训；5)建立临床试验阶段的标准操作程序（SOP）和文件程序，以及数据收集工具和定期分析程序；6)发展与社区的对话，以建立对试验的支持并解决问题。在临床试验前的规划期间对这些活动的支持将大大促进试验的实施。

DESCRIPTION (provided by applicant): 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.