Evaluation of oral administration of PRIM-DJ2727 capsule containing microbiota suspension in patients with severe alcoholic hepatitis: An Open-Label Study

严重酒精性肝炎患者口服含有微生物悬浮液的 PRIM-DJ2727 胶囊的评价：一项开放标签研究

• 批准号: 10527603
• 负责人: Prasun Kumar Jalal
• 金额: $ 19万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-18 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527603
• 关键词: Adrenal Cortex Hormones; Adverse effects; Adverse event; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcohols; Biochemical; Biological Assay; Blinded; Cessation of life; Cirrhosis; Clinical; Clinical Trials; Clostridium difficile; Complement; Controlled Clinical Trials; Data; Death Certificates; Diagnosis; Disease; Down-Regulation; Effectiveness; Encephalopathies; Endotoxins; Ethanol; Evaluation; Freeze Drying; Funding; Future; Gastroenterology; Gastrointestinal Diseases; Gastrointestinal Motility; Heavy Drinking; Hepatology; Icterus; Immune response; Incidence; Intake; Intestinal permeability; Light; Liver; Liver Cirrhosis; Liver Failure; Liver diseases; Maddrey score; Medical; Medicine; Microbe; Modeling; Monitor; Oral; Oral Administration; Organ; Outcome; Participant; Patient-Focused Outcomes; Patients; Pilot Projects; Play; Public Health; Randomized; Randomized Controlled Clinical Trials; Recurrence; Regimen; Reporting; Research Personnel; Role; Safety; Sampling Studies; Steroid therapy; Steroids; Survival Rate; Suspensions; Syndrome; Testing; Therapeutic; Tight Junctions; Time; Toxic effect; Tube; United States; antimicrobial peptide; base; capsule; chronic alcohol ingestion; college; cost; design; dysbiosis; efficacy evaluation; end stage liver disease; fecal microbiome; fecal transplantation; follow-up; genome sequencing; gut dysbiosis; gut microbiome; gut microbiota; gut-liver axis; improved; indexing; liver function; liver transplantation; microbial; microbiome; microbiota; mortality; open label; prognostic; recruit; response; side effect; standard care; stool sample; tissue injury; tool; treatment response; whole genome

Alcoholic hepatitis (AH) is a major public health problem in the United States, in which 30-50% die within the first 28 days. For the past few decades, steroid therapy has been the standard treatment in managing patients with severe AH, however, it hasn’t significantly improved survival rates among these patients. Moreover, shortage of organs and cost for liver transplantation are major barriers for liver transplantation in patients with AH. There is growing evidence suggesting the role of the gut-liver axis in alcohol-induced tissue injury and liver failure among heavy alcohol drinkers. The gut microbial community of patients with advanced alcoholic liver diseases is known to be dysbiotic. Therefore, microbiome-directed therapy that can complement microbial deficiencies in patients with AH may reduce complications of the diseases. Furthermore, over the last few years, multiple studies have shown that fecal microbiome transplant (FMT) is a safe and more effective approach in treatment of liver cirrhosis and recurrent encephalopathy. A recent study by Indian investigators showed that modulation of intestinal microbiota has shown to improve survival in patients with severe AH. However, the study faced some limitations including: limited longitudinal assessment of the prognostic scores for alcoholic hepatitis, use of nasoduodenal tube to deliver fecal microbiome, and lack of detail in profiling of intestinal microbiome. In this proposed clinical trial, we hypothesize that FMT in patients with severe AH will be safe and will result in improvement of intestinal microbiome diversity which might contribute to improvement of biochemical parameters, prognostic scores, and clinical outcome of the patients. To test this hypothesis, we propose recruiting 12 patients with severe AH to participate in a single center trial using the Simon’s two-stage, minimax design in which microbiome suspension containing capsules, called PRIM-DJ2727 will be administered. The aims of this pilot study are as follows: 1) To explore the impact of FMT in improving the clinical outcome of 12 patients with severe AH. Eligible patients will receive 10 does of PRIM-DJ2727 (30 grams/day) for a week followed by once weekly for 3 weeks. We plan to assess FMT-response rate based on Lille score and changes in biochemical parameters, prognostic scores, and overall survival. 2) To characterize gut microbiome diversity associated with severe alcoholic hepatitis patients at several time points during and post-FMT; this will be done through analyzing stool samples using whole genome sequencing at weeks (1 & 4) and at months (3 & 6). Despite no evidence to support severe adverse effects for FMT administration in patients with liver diseases, we aimed to monitor the study participants for treatment safety. This proposed study may have a major impact on the field of hepatology. It will shed the light on the potential use of FMT as a safe, effective and affordable tool in managing patients with severe AH. Results from this pilot study may prompt future conduct of large scale randomized controlled clinical trials for FMT use in severe AH. This may later assist in transforming medical management in the gastroenterology field by opening doors for use of FMT in multiple gastrointestinal disorders.

酒精性肝炎（AH）在美国是一个主要的公共卫生问题，其中30-50%的人死亡