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，当给予足够的量时，对健康有益 主持人。益生菌治疗最常见的适应症之一是预防抗生素相关的 腹泻(AAD)。不幸的是，许多用于AAD的益生菌产品的疗效没有得到 严格的独立研究，经常导致非循证使用。我们的研究小组已经 与联邦药品管理局(FDA)密切合作，推动对研究最深入的 双歧杆菌菌株、动物双歧杆菌亚种。乳酸杆菌BB-12(BB-12)，通过调查 新的药物途径。我们之前已经进行了两个阶段的第一阶段安全试验，并根据FDA的要求， 现在正在提议一项第二阶段试验，该试验将检查BB-12预防AAD的有效性和安全性。 该研究产品提供稳定的高剂量BB-12，与Cochrane的发现一致 使用在美国以外研究的其他毒株预防AAD的综述。去探索可能的 BB-12改善AAD的作用机制，我们还将研究肠道微生物区系 通过在多个时间点收集所有参与者的五个粪便样本来确定其组成和功能。胆量 微生物区系包括数百种兼性和专性厌氧菌，它的破坏是 被认为是AAD发展的一个重要因素。 目的1：测试大剂量添加BB-12的酸奶预防AAD的效果，并与 不含BB-12的酸奶，用于接受抗生素治疗的儿童。 假设：服用含有BB-12的酸奶的服用抗生素的儿童腹泻症状较少 而不是服用不含BB-12的对照酸奶。 目的2：评价添加BB-12酸奶的安全性。 假设：在这个更大的儿科人群中，含有BB-12的酸奶将是安全和耐受性良好的。这是一个 第二阶段试验，需要对高剂量BB-12进行额外的安全性评估。 目的3：对粪便微生物区系进行纵向群落结构和基因表达分析 目的：评价大剂量BB-12对接受抗生素治疗的儿童人群的影响。 假设：(I)使用抗生素会改变肠道的成分和基因表达谱 (Ii)同时摄入酸奶中的BB-12将减轻抗生素- 引起肠道微生物区系紊乱，通过16S rRNA和变态转录图谱鉴定。 我们的长期目标是确定BB-12对各种胃肠道疾病状态和 年龄，通过高水平的独立研究。在我们继续提高翻译效率之前 这项研究是FDA要求进行的第二阶段儿科疗效和安全性研究。

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.