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 - R01HD088428 的行政补充 益生菌是活的微生物，当摄入足够量时，可为健康带来益处 益生菌治疗最常见的适应症之一是预防抗生素相关疾病。 腹泻（AAD），但许多用于 AAD 的益生菌产品的功效并没有得到严格的支持 独立研究，通常会导致无证据的使用。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，以最好的方式推进研究 研究了双歧杆菌菌株，动物双歧杆菌乳亚种（B.lactis）BB-12（BB-12），通过 研究性新药途径作为该途径的一部分，我们之前进行了两项第一期安全性试验。 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其安全性 BB-12在预防AAD方面根据母奖R01HD088428探索可能的机制。 BB-12 负责改善 AAD 的作用，我们还在研究肠道微生物群组成和 通过在 BB-12 给药前后的多个时间点收集粪便样本来发挥作用。 当前的试验“评估 BB-12 在抗生素相关性中的作用的 II 期随机对照试验” 腹泻及其对肠道微生物群的影响”，已成功招募 205 名 3 岁至 12 年前，该研究因 COVID-19 大流行而暂停。 支持因这些延误而产生的意外费用，以实现我们事先确定的 300 名招聘目标 当前试验的具体目标和假设保持不变，包括： · 目标 1：测试高剂量添加 BB-12 的酸奶与普通酸奶相比，在预防 AAD 方面的功效 接受抗生素治疗的儿童饮用不含 BB-12 的酸奶。 假设：接受抗生素治疗的儿童如果接受含有 BB-12 的酸奶，腹泻次数会减少 与那些接受不含 BB-12 的对照酸奶的人相比。 · 目标 2：评估添加 BB-12 的酸奶的安全性。 假设：含有 BB-12 的酸奶在这一较大的儿科人群中是安全的且耐受性良好。 是一项 II 期试验，需要对高剂量 BB-12 进行额外的安全性评估。 · 目标3：开展粪便微生物群落纵向群落结构和基因表达分析，以 评估高剂量 BB-12 对接受抗生素的儿科人群的影响。 假设：（i）抗生素的使用会改变肠道的组成和基因表达谱 儿科患者的微生物群，以及 (ii) 同时摄入酸奶中的 BB-12 将减轻抗生素的作用 使用 16S rRNA 和宏转录组分析确定，它会引起肠道微生物群的紊乱。 我们的长期目标是确定 BB-12 对多种胃肠道疾病状态的影响和 通过高水平的独立研究，行政补充对于延续至关重要。 并完成本次试验，并保持项目的总体影响与其预期相符 原来批准的目标。

项目成果

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

用于定义和估计美国成人和儿童活微生物膳食摄入量的分类系统。

• 发表时间: 2022-07-06
• 作者: Marco, Maria L;Hutkins, Robert;Hill, Colin;Fulgoni, Victor L;Cifelli, Christopher J;Gahche, Jaime;Slavin, Joanne L;Merenstein, Daniel;Tancredi, Daniel J;Sanders, Mary E
• 通讯作者: Sanders, Mary E

Molecular mechanisms of probiotic prevention of antibiotic-associated diarrhea.

益生菌预防抗生素相关性腹泻的分子机制。

• DOI: 10.1016/j.copbio.2020.01.005
• 发表时间: 2020-02-01
• 期刊: Current opinion in biotechnology
• 影响因子: 7.7
• 作者: Solomon A. Mekonnen;D. Merenstein;C. Fraser;M. Marco
• 通讯作者: M. Marco