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-R 01 HD 088428的管理补充 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），但许多用于AAD的益生菌产品的疗效并不支持严格的 独立研究，往往导致非证据为基础的使用。我们的研究小组一直在研究 与美国食品和药物管理局密切合作， 研究了双歧杆菌动物双歧杆菌亚种Bifidobacterium animalis subsp. lactis（B.乳酸）BB-12（BB-12），通过 研究性新药途径。作为这一途径的一部分，我们之前进行了两项I期安全性试验， 目前正在进行一项II期临床试验，以检查疗效并进一步监测安全性。 BB-12在预防AAD中的作用，根据母公司裁决R 01 HD 088428。探索可能的机制 负责BB-12在改善AAD中的作用，我们也在研究肠道微生物群组成， 通过在BB-12给药前和给药后的多个时间点收集粪便样品来发挥作用。 目前的试验，“一项II期随机对照试验，以评估BB-12在肿瘤相关性 腹泻及其对肠道微生物组的影响”，成功招募了205名3- 12年前，该研究因COVID-19大流行而暂停。我们要求这一补充 以支持由于这些延误而产生的意外费用，以实现我们300人的先验招聘目标 参与者本试验的具体目标和假设保持不变，即： ·目的1：测试高剂量的补充BB-12的酸奶在预防AAD中的功效，与补充BB-12的酸奶相比。 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：评估补充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 是一项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：进行粪便微生物群的纵向群落结构和基因表达分析， 评估高剂量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。行政补充将是至关重要的， 和完成这项试验，并保存该项目的整体影响符合其 最初的目标。

ABSTRACT - Administrative Supplement to R01HD088428 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), but the efficacy of many probiotic products used for AAD is not supported by rigorous independent research, often resulting in non-evidence-based usage. Our research group has been working closely with the United States Food and Drug Administration 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. As part of this pathway, we previously conducted two Phase I, safety trials and are currently conducting a Phase II clinical trial that examines efficacy and further monitors the safety of BB-12 in preventing AAD under the parent award R01HD088428. To explore possible mechanisms responsible for BB-12 effects in ameliorating AAD, we are also studying gut microbiota composition and function by collecting fecal samples at multiple time points pre- and post- BB-12 administration. The current trial, “A Phase II randomized controlled trial to evaluate the role of BB-12 in antibiotic-associated diarrhea and its effects on the gut microbiome”, had successfully enrolled 205 children between the ages of 3- 12 years before the study was suspended due to the COVID-19 pandemic. We are requesting this supplement to support unanticipated expenses due to these delays in order to reach our a priori recruitment goal of 300 participants. The specific aims and hypotheses of the current trial, which remain unchanged, are: · 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. An administrative supplement will be critical to the continuation and completion of this trial, and to the preservation of the overall impact of the project consistent with its originally approved objectives.