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

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.