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.

目前治疗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