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）是美国的一个主要公共卫生问题，30-50%的人死于酒精性肝炎 在过去的几十年里，类固醇疗法一直是治疗患者的标准疗法。 然而，对于严重的 AH，它并没有显着提高这些患者的生存率。 器官短缺和肝移植费用是肝移植患者的主要障碍 啊，越来越多的证据表明肠-肝轴在酒精引起的组织损伤和肝脏中的作用。 重度饮酒者的肠道微生物群落。 已知疾病是生态失调的，因此，可以补充微生物的微生物组定向疗法。 AH 患者的缺乏症可能会减少疾病的并发症。 多项研究表明，粪便微生物移植（FMT）是一种安全且更有效的方法 印度研究人员最近的一项研究表明，肝硬化和复发性脑病的治疗。 肠道微生物群的调节已被证明可以提高严重 AH 患者的生存率。 研究面临一些局限性，包括： 对酗酒者预后评分的纵向评估有限 肝炎、使用鼻十二指肠管输送粪便微生物组以及缺乏肠道分析细节 在这项拟议的临床试验中，我们追求对严重 AH 患者进行 FMT 是安全且有效的。 将导致肠道微生物组多样性的改善，这可能有助于改善 为了检验这一假设，我们对患者的生化参数、预后评分和临床结果进行了检验。 招募 12 名严重 AH 患者参加使用 Simon 两阶段的单中心试验， minimax 设计，其中包含称为 PRIM-DJ2727 的微生物组悬浮液 本试点研究的目的如下： 1) 探讨 FMT 对改善临床的影响。 12 名严重 AH 患者的结果符合条件的患者将接受 10 剂 PRIM-DJ2727（30 克/天）。 一周，然后每周一次，持续 3 周。我们计划根据里尔评分和评估 FMT 反应率。 生化参数、预后评分和总体生存率的变化 2) 表征肠道微生物组。 FMT期间和之后的几个时间点与严重酒精性肝炎患者相关的多样性； 通过在周（1 和 4）和月（3 和 4）使用全基因组测序分析粪便样本来完成 6) 尽管没有证据支持肝病患者服用 FMT 会产生严重不良反应， 我们的目的是监测研究参与者的治疗安全性。这项拟议的研究可能会产生重大影响。 它将揭示 FMT 作为一种安全、有效和负担得起的工具的潜在用途。 这项试点研究的结果可能会促进未来大规模的开展。 FMT 在严重 AH 中的应用的随机对照临床试验这可能有助于改变医学。 通过为 FMT 治疗多种胃肠道疾病打开大门，推动胃肠病学领域的管理。