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）是美国的一个主要公共卫生问题，其中30-50%的人在24小时内死亡。 前28天在过去的几十年里，类固醇治疗一直是管理患者的标准治疗方法 然而，对于严重的AH，它并没有显著提高这些患者的生存率。此外，委员会认为， 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-肝轴在酒精诱导的组织损伤和肝脏损伤中的作用。 酗酒者的失败。晚期酒精性肝病患者肠道菌群的研究 已知疾病是生态失调的。因此，可以补充微生物的微生物组导向疗法 在AH患者中的缺乏可以减少疾病的并发症。此外，在过去的几年里， 多项研究表明，粪便微生物组移植（FMT）是一种安全且更有效的方法， 治疗肝硬化和复发性脑病。印度调查人员最近的一项研究显示， 肠道微生物群的调节已经显示出改善患有严重AH的患者的存活率。但 这项研究面临一些局限性，包括：对酒精中毒患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，以及缺乏肠道微生物分析的细节 微生物组在这项拟议的临床试验中，我们假设FMT在重度AH患者中是安全的， 将导致肠道微生物组多样性的改善，这可能有助于改善 患者的生化参数、预后评分和临床结果。为了验证这个假设，我们 建议招募12名重度AH患者参加单中心试验，采用Simon的两阶段， 最小最大设计，其中将使用含有微生物群悬浮液的胶囊，称为PRIM-DJ 2727， 管理。本研究的目的如下：1）探讨FMT在改善临床症状方面的作用， 12例重度AH患者的结局。合格患者将接受10剂PRIM-DJ 2727（30克/天） 持续一周，然后每周一次持续3周。我们计划根据里尔评分评估FMT应答率， 生化参数、预后评分和总生存率的变化。2)表征肠道微生物组 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 通过使用全基因组测序在第1周（1和4周）和第3个月（3和 6）。尽管没有证据支持FMT给药对肝病患者的严重不良反应， 我们的目的是监测研究参与者的治疗安全性。这项拟议中的研究可能会产生重大影响 在肝病学领域。它将揭示裂变材料条约作为一种安全、有效和负担得起的工具的潜在用途 严重AH患者的治疗。这项试点研究的结果可能会促进未来大规模的 FMT用于重度AH的随机对照临床试验。这以后可能有助于医疗转型 通过为FMT在多种胃肠道疾病中的使用打开大门，促进胃肠病学领域的管理。

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.