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）是美国的主要公共卫生问题，其中30-50％死亡 头28天。在过去的几十年中，立体疗法一直是管理患者的标准治疗方法 但是，由于严重的AH，这些患者的生存率并未显着提高。而且， 器官短缺和肝移植成本是患有肝移植的主要障碍 啊。越来越多的证据表明，肠道轴在酒精诱导的组织损伤和肝脏中的作用 饮酒者的失败。晚期酒精肝患者的肠道微生物群落 已知疾病是不良生物的。因此，微生物组指导的疗法可以补充微生物 AH患者的缺乏可能会减少疾病并发症。此外，在过去的几年中， 多项研究表明，粪便微生物组移植（FMT）是一种安全，更有效的方法 治疗肝硬化和复发性脑病。印度调查人员最近的一项研究表明 肠道菌群的调节已显示可改善严重AH患者的生存率。但是， 研究面临一些局限 肝炎，使用鼻四齿管来输送粪便微生物组，缺乏肠道分析的细节 微生物组。在这项拟议的临床试验中，我们假设严重AH患者的FMT是安全的，并且 将改善肠道微生物组的多样性，这可能有助于改善 患者的生化参数，预后评分和临床结果。为了检验这一假设，我们 提案招募12例严重AH患者，使用Simon的两阶段参加一次中心试验 Minimax设计，其中包含胶囊的微生物组悬浮液，称为PRIM-DJ2727 管理。这项试验研究的目的如下：1）探索FMT在改善临床方面的影响 12例严重AH患者的结果。符合条件的患者将获得10次PRIM-DJ2727（每天30克） 一个星期，然后每周一次，持续3周。我们计划根据里尔评分评估FMT响应率 生化参数，预后评分和整体生存的变化。 2）表征肠道微生物组 在FMT和FMT后的几个时间点与严重酒精性肝炎患者有关的多样性；这会 可以通过分析的粪便样品在几周（1＆4）和几个月（3＆ 6）。尽管没有证据支持肝病患者FMT给药的严重不利影响，但 我们的目的是监视研究参与者的治疗安全。这项拟议的研究可能会产生重大影响 在肝病学领域。它将阐明FMT作为安全，有效和负担得起的工具的潜在用途 在管理严重AH的患者中。这项试点研究的结果可能会促使将来大规模进行 在严重AH中使用FMT的随机对照临床试验。这可能以后有助于改造医疗 通过在多种胃肠道疾病中使用FMT的大门，在胃肠病学领域的管理。