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

酒精性肝炎(AH)在美国是一个主要的公共卫生问题，30%-50%的人在 头28天。在过去的几十年里，类固醇治疗一直是管理病人的标准治疗方法。 然而，对于严重的急性肝炎，它并没有显著提高这些患者的存活率。此外， 器官短缺和肝移植费用是肝移植患者肝移植的主要障碍 阿。越来越多的证据表明，肠道-肝轴在酒精诱导的组织损伤和肝脏中所起的作用 大量饮酒者的失败。晚期酒精性肝患者肠道微生物区系的研究 众所周知，疾病是一种有害的生物。因此，微生物群定向治疗可以补充微生物 急性胰腺炎患者的营养不良可能会减少该病的并发症。此外，在过去的几年里， 多项研究表明，粪便微生物组移植(FMT)是一种安全有效的治疗方法 治疗肝硬变和复发性脑病。印度调查人员最近的一项研究表明， 肠道微生物区系的调节已被证明能改善重症急性肝炎患者的存活率。然而， 这项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，以及缺乏肠道特征的细节 微生物组。在这项拟议的临床试验中，我们假设FMT用于重症急性呼吸综合征患者将是安全和 将导致肠道微生物多样性的改善，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 建议招募12名重症急性肝炎患者参加单中心试验，采用西蒙氏两阶段试验， MINIMAX设计，其中含有胶囊的微生物组悬浮液，称为Prim-DJ2727 管理。本先导研究的目的如下：1)探讨FMT对改善临床症状的影响 12例重症急性呼吸窘迫综合征的转归。符合条件的患者将接受10剂Prim-DJ2727(30克/天) 一周后每周一次，连续三周。我们计划根据里尔分数和 生化参数、预后评分和总存活率的变化。2)确定肠道微生物群的特征 在FMT期间和FMT后的几个时间点，与重度酒精性肝炎患者相关的多样性；这将 通过在周(1&4)和月(3&4)使用全基因组测序分析粪便样本来完成 6)。尽管没有证据表明FMT对肝病患者有严重的不良反应， 我们的目标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 在肝病领域。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 在重症急性胰腺炎患者的处理中。这项初步研究的结果可能会促使未来进行大规模的研究 FMT治疗重症急性肝炎的随机对照临床试验。这可能会在以后有助于将医疗 在胃肠病领域打开大门，在多发性胃肠道疾病中使用FMT。

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.