Fecal microbiota transplant for Alcohol-Associated Cirrhosis

粪便微生物群移植治疗酒精相关性肝硬化

基本信息

批准号：
10444624
负责人：
Jasmohan S Bajaj
金额：
$ 54.85万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-12 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10444624
关键词：
Abstinence Affect Alcohol consumption Alcohol-Induced Disorders Alcoholic Hepatitis Alcohols Aminobutyric Acids Antibiotics Antimicrobial Resistance Bile Acids Biological Brain Cirrhosis Clinical Clinical Trials Clostridium difficile Cognition Cognitive Cognitive Therapy Development Disease Double-Blind Method Encapsulated Engraftment Enrollment FDA approved Feces Formulation Freeze Drying Functional disorder Glutamates Goals Hepatic Encephalopathy Infection Infrastructure Link Liquid substance Liver Liver Cirrhosis Liver Dysfunction Liver diseases Measures Mediator of activation protein Medicine Microbe Minority Molecular Monitor Morbidity - disease rate Oral Organ Outcome Participant Patient Outcomes Assessments Patients Pattern Pharmaceutical Preparations Phase Placebo Control Placebos Plasma Population Preparation Probiotics Prognosis Psychometrics Publishing Randomized Randomized Clinical Trials Recurrence Safety Serum Services Sickness Impact Profile Socioeconomic Status Standardization Structure Testing Therapeutic Underserved Population Volatile Fatty Acids alcohol craving alcohol use disorder base behavioral pharmacology brain dysfunction capsule cognitive function cognitive testing comparative craving disorder prevention double-blind placebo controlled trial enema administration evidence base experience fecal transplantation gamma-Aminobutyric Acid gut dysbiosis gut microbes gut microbiota gut-brain axis health related quality of life improved instrument liver function liver injury liver transplantation metabolomics microbial microbial community microbial composition microbiota mortality novel strategies primary outcome psychologic psychosocial randomized placebo-controlled clinical trial randomized trial safety outcomes success therapeutic target trial design urinary

项目摘要

Current medication options for AUD have only partial success and have a low evidence base in cirrhosis. Gut dysbiosis, which may be initiated by alcohol, contributes to cirrhosis development. Our overarching goal is to develop a potent therapeutic targeting the intestinal microbiota to alleviate the impact of AUD and AROD through the gut-liver-brain axis. We base our approach on fecal microbiota transplant (FMT), originally developed for recurrent Clostridioides difficile infection (rCDI). We have also shown in randomized, placebo- controlled clinical trials the benefit and safety of different FMT formulations in cirrhosis. Furthermore, in a recent randomized trial of actively drinking AUD cirrhotic patients, we demonstrated that FMT reduced alcohol consumption and craving, and improved cognition and psychosocial health-related quality of life (HRQOL) versus placebo. We also found similar engraftment with capsule versus enema FMT. The FDA regulates FMT as a drug and a biologic. Our group uses Good Manufacturing Practices to manufacture FMT products in both liquid and freeze-dried, encapsulated formulations. Our hypothesis is that restructuring the gut microbiota using FMT will reduce alcohol consumption compared to placebo in patients with AUD and cirrhosis. To test this, we will conduct a Phase 1b/2a double-blind, placebo-controlled, randomized clinical trial using administration of a standardized oral encapsulated FMT preparation (FMT) at baseline and day 30 in patients with AUD and cirrhosis. Aim 1: Measure the effect of FMT on alcohol consumption. The primary outcome is number of abstinent days at three months in FMT compared to placebo. We will assess daily alcohol consumption and cravings using patient-reported measures and objective urinary and plasma markers. Aim 2: Determine the impact of FMT on safety and liver dysfunction. We will monitor safety outcomes and liver function throughout the trial. Aim 3: Determine the impact of FMT on microbial compositional and function. Comparative analyses of stool microbial composition, and serum metabolomics will be performed between and within groups. Targeted metabolomics will be focused on neuroactive metabolites that are produced or modulated by microbiota, e.g., SCFA, γ-aminobutyric acid (GABA), glutamate, indolic compounds, and bile acids. Aim 4: Determine the impact of FMT on brain dysfunction and patient-reported outcomes using cognitive testing and HRQOL testing. We will evaluate HRQOL and cognition using validated instruments (Sickness Impact Profile, EncephalApp Stroop, Psychometric Hepatic Encephalopathy Score). We will enroll 80 participants with AUD cirrhosis (randomized 1:1 to FMT versus placebo) under FDA IND. The team has access to patients, microbial expertise, infrastructure and AUD trial experience to carry out the trial.

目前 AUD 的药物选择仅取得部分成功，并且在肝硬化方面的证据基础较低。酒精可能引发的菌群失调会导致肝硬化的发展。开发一种针对肠道微生物群的有效治疗方法，以减轻 AUD 和 AROD 的影响我们的方法最初基于粪便微生物群移植（FMT）。开发用于复发性艰难梭菌感染（rCDI）我们还在随机安慰剂中进行了研究。此外，还进行了不同 FMT 制剂治疗肝硬化的益处和安全性的对照临床试验。最近对积极饮酒的 AUD 肝硬化患者进行的随机试验表明，FMT 可以减少酒精摄入消费和渴望，以及改善认知和心理社会健康相关的生活质量（HRQOL）我们还发现 FMT 胶囊植入与灌肠 FMT 类似。作为药物和生物制剂，我们的团队使用良好生产规范来生产 FMT 产品。液体和冻干、胶囊制剂。我们的假设是，使用 FMT 重组肠道微生物群将减少饮酒量为了测试这一点，我们将进行 1b/2a 期试验。使用标准化口服给药的双盲、安慰剂对照、随机临床试验 AUD 和肝硬化患者在基线和第 30 天时使用胶囊化 FMT 制剂 (FMT)。目标 1：衡量 FMT 对饮酒量的影响主要结果是戒酒天数。在 FMT 三个月后，我们将使用安慰剂来评估每日饮酒量和渴望。患者报告的测量值以及客观的尿液和血浆标记物。目标 2：确定 FMT 对安全性和肝功能障碍的影响我们将监测安全性结果和肝功能。在整个试验过程中发挥作用。目标 3：确定 FMT 对粪便微生物组成和功能的影响比较分析。微生物组成和血清代谢组学将在组间和组内进行。代谢组学将重点关注微生物群产生或调节的神经活性代谢物，例如 SCFA、γ-氨基丁酸 (GABA)、谷氨酸、吲哚化合物和胆汁酸。目标 4：利用认知功能确定 FMT 对脑功能障碍和患者报告结果的影响我们将使用经过验证的工具评估 HRQOL 和认知（疾病）。影响概况、EncephalApp Stroop、心理测量肝性脑病评分）。我们将根据 FDA IND 招募 80 名患有 AUD 肝硬化的参与者（按 1:1 随机分配至 FMT 与安慰剂）。团队可以利用患者、微生物专业知识、基础设施和 AUD 试验经验来开展试验。