A Phase II randomized controlled trial to evaluate the role of BB-12 in antibiotic-associated diarrhea and its effects on the gut microbiome

摘要 益生菌是活的微生物，当以足够的量施用时， 主持人益生菌治疗最常见的适应症之一是预防与益生菌相关的 腹泻（AAD）。不幸的是，许多用于AAD的益生菌产品的功效并不被 严格的独立研究，往往导致非证据为基础的使用。我们的研究小组 与联邦药品管理局（FDA）密切合作，推动研究， 双歧杆菌菌株，动物双歧杆菌亚种（Bifidobacterium animalis subsp. lactis（B.乳酸）BB-12（BB-12），通过研究 新药途径。我们之前已经进行了两项I期安全性试验，并按照FDA的要求， 目前正在提议进行一项II期试验，该试验将检查BB-12预防AAD的有效性并监测其安全性。 研究产品提供稳定的高剂量BB-12，与科克伦研究结果一致。 使用美国以外研究的其他菌株预防AAD的综述。探讨可能 BB-12改善AAD的作用机制，我们还将研究肠道微生物群 通过在多个时间点从所有参与者收集五个粪便样品来分析其组成和功能。肠道 微生物群包括数百种兼性和专性厌氧菌，其破坏是 假设是AAD发展的重要因素。 目的1：测试高剂量、补充BB-12的酸奶预防AAD的功效， 酸奶没有BB-12，在儿童接受抗生素。 假设：接受抗生素的儿童接受含有BB-12的酸奶将减少腹泻 而不含BB-12的对照酸奶。 目的2：评估添加BB-12的酸奶的安全性。 假设：含有BB-12的酸奶在这个较大的儿科人群中是安全的，耐受性良好。这是一 II期试验需要对高剂量BB-12进行额外的安全性评价。 目的3：对粪便微生物群落进行纵向群落结构和基因表达分析 评价高剂量BB-12对接受抗生素的儿科人群的影响。 假设：（i）给予抗生素将改变肠道的组成和基因表达谱 （ii）同时摄入酸奶中的BB-12将减轻抗生素- 诱导肠道微生物群的紊乱，如使用16 S rRNA和元转录组学分析所鉴定的。 我们的长期目标是确定BB-12对各种胃肠道疾病状态的影响， 通过高水平的独立研究。在我们进行更有效的翻译之前 这项II期儿科疗效和安全性研究是FDA要求的。

Abstract Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. One of the most common indications for probiotic treatment is the prevention of antibiotic-associated diarrhea (AAD). Unfortunately, the efficacy of many probiotic products used for AAD is not supported by rigorous independent research, and often results in non-evidence-based usage. Our research group has worked closely with the Federal Drug Administration (FDA) to move research forward for the most well studied Bifidobacterium strain, Bifidobacterium animalis subsp. lactis (B. lactis) BB-12 (BB-12), via an Investigational New Drug pathway. We have previously conducted two Phase I, safety trials and as per FDA requirements, are now proposing a Phase II trial that will examine efficacy and monitor safety of BB-12 in preventing AAD. The investigational product delivers a stable high dosage of BB-12, consistent with the findings of a Cochrane review for preventing AAD using other strains studied outside of the United States. To explore possible mechanisms responsible for BB-12 effects in ameliorating AAD, we will also study the gut microbiota composition and function by collecting five fecal samples at multiple time points from all participants. The gut microbiota includes hundreds of species of facultative and obligate anaerobes, and its disruption is hypothesized to be an important factor in the development of AAD. AIM 1: To test the efficacy of high dose, BB-12-supplemented yogurt in preventing AAD, compared to yogurt without BB-12, in children receiving antibiotics. Hypothesis: Children receiving antibiotics who receive the yogurt with BB-12 will demonstrate less diarrhea than those receiving a control yogurt without BB-12. AIM 2: To assess the safety of yogurt supplemented with BB-12. Hypothesis: Yogurt containing BB-12 will be safe and well-tolerated in this larger pediatric population. This is a Phase II trial that requires additional safety evaluation of high dose BB-12. AIM 3: To carry out longitudinal community structure and gene expression analysis of fecal microbiota to evaluate the impact of high dose BB-12 in a pediatric population receiving antibiotics. Hypotheses: (i) Administration of antibiotics will alter the composition and gene expression profile of the gut microbiota in pediatric patients, and (ii) concomitant ingestion of BB-12 in yogurt will mitigate the antibiotic- induced disturbance in the gut microbiota, as identified using 16S rRNA and metatranscriptomic profiling. Our long-term goal is to determine the impact of BB-12 on a variety of gastrointestinal disease states and ages, through high-level independent research. Before we proceed with more translational effectiveness research, this Phase II, pediatric efficacy and safety study is required by the FDA.