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

点击翻译按钮获取中文摘要

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.