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

• 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
• 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

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的药物选择仅部分成功，并且在肝硬化中的证据基础较低。肠道 可能由酒精引发的生态失调有助于肝硬化的发展。我们的首要目标是 开发针对肠道微生物群的有效治疗药物，以减轻AUD和AROD的影响 穿过肠-肝-脑轴我们的方法基于粪便微生物群移植（FMT），最初 开发用于复发性艰难梭菌感染（rCDI）。我们还在随机的安慰剂中显示- 对照临床试验的好处和安全性不同FMT配方在肝硬化。此外，在A 最近对主动饮酒的AUD糖尿病患者进行的随机试验表明，FMT可以减少酒精 消费和渴望，改善认知和心理健康相关的生活质量（HRQOL） 对比安慰剂。我们还发现胶囊与灌肠FMT的植入相似。FDA监管FMT 作为药物和生物制剂。我们集团采用良好的生产规范，在两个生产基地生产FMT产品。 液体和冷冻干燥的包封制剂。 我们的假设是，使用FMT重组肠道微生物群将减少酒精消费 在AUD和肝硬化患者中与安慰剂相比。为了测试这一点，我们将进行第1b/2a阶段 一项使用标准化口服给药的双盲、安慰剂对照、随机临床试验 在患有AUD和肝硬化的患者中在基线和第30天的封装的FMT制剂（FMT）。 目的1：测量FMT对酒精消耗的影响。主要结果是禁欲天数 与安慰剂组相比，FMT组三个月时。我们将评估每日饮酒量和渴望使用 患者报告的测量值和客观的尿液和血浆标记物。 目的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脏 在整个审判过程中发挥作用。 目的3：确定FMT对微生物组成和功能的影响。粪便比较分析 微生物组成和血清代谢组学将在组间和组内进行。针对性 代谢组学将集中于由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。 目的4：确定FMT对脑功能障碍和患者报告的结果的影响， 测试和HRQOL测试。我们将使用经过验证的工具（疾病）评估HRQOL和认知 影响特征，脑卒中Stroop评分，心理测量学肝性脑病评分）。 我们将在FDA IND下招募80名患有AUD肝硬化的参与者（1：1随机分配至FMT组与安慰剂组）。 团队可以接触患者、微生物专业知识、基础设施和AUD试验经验来进行试验。