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

一项 II 期随机对照试验，旨在评估 BB-12 在抗生素相关性腹泻中的作用及其对肠道微生物组的影响

• 批准号: 10425501
• 负责人: DANIEL J MERENSTEIN
• 金额: $ 32.7万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425501
• 关键词: Acute; Address; Administrative Supplement; Affect; Age; Antibiotics; Appointment; Area; Authorization documentation; Award; Baltimore; Bifidobacterium; COVID-19; COVID-19 pandemic; Cephalosporins; Child; Childhood; Choices and Control; Clinical; Clinical Trials; Collection; Communities; Data; Diarrhea; Disease Outbreaks; Dose; Drops; Employee; Enrollment; Ethics; Evaluation; Exposure to; Food; Funding; Gastrointestinal Diseases; Gene Expression Profile; Gene Expression Profiling; Genomics; Goals; Guidelines; Health; Health Benefit; Healthcare; Home; Human; Human Resources; Infection; Informed Consent; Ingestion; Institutes; Institutional Review Boards; Intention; Intervention; Intervention Studies; Investigational Drugs; Laboratories; Maryland; Measures; Monitor; Otitis Media; Parents; Participant; Pathway interactions; Penicillins; Pennsylvania; Persons; Pharmacologic Substance; Pharyngitis; Phase; Phase II Clinical Trials; Population; Prevention; Primary Care Physician; Primary Health Care; Probiotics; Procedures; Process; Production; Provider; Public Health; Randomized Controlled Trials; Reporting; Reproducibility; Research; Research Assistant; Research Personnel; Research Support; Resources; Respiratory Tract Infections; Ribosomal RNA; Role; Safety; Sample Size; Sampling; Schedule; Schools; Scientist; Services; Social Distance; Sports; Streptococcus; Structure; Telemedicine; Time; Training; United States Food and Drug Administration; United States National Institutes of Health; Universities; Work; Yogurt; acute rhinosinusitis; antibiotic-associated diarrhea; design; efficacy evaluation; efficacy testing; experience; falls; fecal microbiota; gastrointestinal; genome sciences; gut microbiome; gut microbiota; high risk; improved; metatranscriptomics; microbiome; microbiome research; microorganism; pandemic disease; pediatric patients; personal protective equipment; phase II trial; preservation; prevent; public health emergency; recruit; remote consent; respiratory; virtual

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.

摘要-对R01HD088428的行政补充 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)，但许多用于AAD的益生菌产品的疗效没有得到严格的支持 独立研究，通常导致非循证使用。我们的研究小组一直在努力 与美国食品和药物管理局密切合作，推动研究取得最好的进展 对动物双歧杆菌亚种双歧杆菌进行了研究。乳酸杆菌(B.lactis)BB-12(BB-12) 研究中的新药物途径。作为这一途径的一部分，我们之前进行了两个阶段I，安全性试验 目前正在进行二期临床试验，检查疗效并进一步监测 BB-12在防止AAD的家长奖励下R01HD088428。探索可能的机制 除了BB-12对改善AAD的作用外，我们还在研究肠道微生物区系组成和 通过在使用BB-12之前和之后的多个时间点收集粪便样本来发挥作用。 目前的试验是“评估BB-12在抗生素相关疾病中的作用的第二阶段随机对照试验” 腹泻及其对肠道微生物群的影响“，已经成功地招募了205名3岁以下的儿童- 12年前，这项研究因新冠肺炎疫情而暂停。我们要求提供这份补充材料 支持由于这些延误而产生的意外开支，以实现我们300人的先期招聘目标 参与者。目前试验的具体目标和假设保持不变，包括： ·目标1：测试大剂量添加BB-12的酸奶预防AAD的效果，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。 ·目标2：评估添加BB-12的酸奶的安全性。 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 是一项第二阶段试验，需要对高剂量BB-12进行额外的安全性评估。 ·目标3：开展粪便微生物区系纵向群落结构和基因表达分析 评估大剂量BB-12在接受抗生素治疗的儿童人群中的影响。 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。行政补充将是延续的关键 并完成这一试验，以保持项目的整体影响与其一致 最初批准的目标。

项目成果

A Classification System for Defining and Estimating Dietary Intake of Live Microbes in US Adults and Children.

• DOI: 10.1093/jn/nxac074
• 发表时间: 2022-07-06
• 期刊: The Journal of nutrition