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: 10703378
• 负责人: Jasmohan S Bajaj
• 金额: $ 54.6万
• 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/10703378
• 关键词: Abstinence; Affect; Alcohol consumption; Alcohol-Induced Disorders; Alcoholic Hepatitis; Alcohols; Aminobutyric Acids; Antibiotics; Antimicrobial Resistance; Behavioral; 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; Good Manufacturing Process; Hepatic Encephalopathy; Infection; Infrastructure; Link; Liquid substance; Liver; Liver Cirrhosis; Liver Dysfunction; Liver diseases; Measures; Mediator; Medicine; Microbe; Minority; Molecular; Monitor; Morbidity - disease rate; Oral; Organ; Outcome; Participant; Patient Outcomes Assessments; Patients; Pattern; Pharmaceutical Preparations; Phase; Placebos; Plasma; Population; Preparation; Probiotics; Prognosis; Psychometrics; Publishing; Randomized; Recurrence; Safety; Serum; Services; Sickness Impact Profile; Socioeconomic Status; Standardization; Structure; Testing; Therapeutic; Underserved Population; Volatile Fatty Acids; alcohol craving; alcohol use disorder; alcohol use initiation; base; 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; manufacture; metabolomics; microbial; microbial community; microbial composition; microbiota; mortality; novel strategies; pharmacologic; 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.

当前的AUD药物选择只有部分成功，并且在肝硬化方面的证据基础低。肠 可以通过酒精引发的营养不良有助于肝硬化的发展。我们的总体目标是 开发针对肠道菌群的潜在治疗性，以减轻AUD和AROD的影响 通过肠肝轴轴。我们以粪便微生物群移植（FMT）为基础，最初是 开发用于复发性梭菌艰难梭菌感染（RCDI）。我们还以随机的安慰剂显示 对照临床试验在肝硬化中不同FMT公式的好处和安全性。此外， 最近对积极饮用cirrhotic患者的随机试验，我们证明了FMT降低了酒精 消费和渴望，改善了认知和社会心理健康相关的生活质量（HRQOL） 与安慰剂。我们还发现了与胶囊与灌肠FMT的类似植入。 FDA调节FMT 作为药物和生物学。我们的小组使用良好的制造实践来制造FMT产品 液体和冷冻干燥的，封装的配方。 我们的假设是使用FMT重组肠道菌群将减少饮酒 与安慰剂和肝硬化患者相比。为了测试这一点，我们将进行1b/2a期 使用标准化口服的双盲，安慰剂对照，随机临床试验 AUD和肝硬化患者在基线和第30天封装FMT制备（FMT）。 目标1：测量FMT对饮酒的影响。主要结果是节制天数 与安慰剂相比，FMT的三个月。我们将使用 患者报告的措施以及客观的尿和等离子体标记。 目标2：确定FMT对安全性和肝功能障碍的影响。我们将监视安全结果和肝脏 整个试验的功能。 AIM 3：确定FMT对微生物组成和功能的影响。粪便的比较分析 在组之间和内部将执行微生物组成和血清代谢组学。目标 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产物，例如 SCFA，γ-氨基丁酸（GABA），谷氨酸，吲哚化合物和胆汁酸。 目标4：确定FMT对使用认知的影响和患者报告的影响的影响 测试和HRQOL测试。我们将使用经过验证的仪器（疾病）评估HRQOL和认知 冲击轮廓，脑静脉曲张，心理测量肝脑病评分）。 我们将在FDA IND下招募80名参与者患有Aud Cirrhosis（随机1：1与安慰剂）。这 团队可以访问患者，微生物专业知识，基础设施和AUD试验经验，以进行试验。