Faecal Transplantation for Alcohol-Related Hepatitis

Background Alcohol-Related Hepatitis (AH) is a florid presentation of alcohol-related liver disease characterized by liver failure (jaundice and coagulopathy) in the context of recent and heavy alcohol consumption. The condition carries a high fatality risk; patients with severe AH have a 30% mortality rate at 90 days after presentation. Currently no treatment has been shown to improve survival to 90 days. The gastrointestinal microbiome has been consistently implicated in the pathogenesis of AH due to 1 Marked deviation of microbial communities in AH compared to healthy controls, 2 Transferability of AH susceptibility to mice administered the microbiome of AH patients 3 Identification of hepatotoxic proteins in the microbiome of some patients with AH and 4 Improved patient survival after microbiome replacement using faecal microbial transplantation (FMT) in pilot clinical studies. The microbiome produces a wide spectrum of metabolites which influence gut epithelial integrity, hepatic metabolism, immune responses and cerebral function. In a trial in patients with ALD cirrhosis FMT was found to reduce alcohol craving, an important outcome which requires validation. Research question This study sets out to establish the efficacy and mechanisms of action of FMT in patients presenting with severe AH Aims and objectives The overall aim is to determine the role of FMT in patients with AH. The primary objective is to evaluate the efficacy of FMT in patients with severe AH in terms of 90 day mortality. Secondary objectives are to assess the safety of FMT in this patient population and to explore whether FMT has any impact on alcohol craving and whether this translates into higher rates of abstinence. Our mechanistic objectives are to determine the degree of FMT engraftment, using metagenomics, to measure the prevalence and eradication of E. faecalis cytolysin, to demonstrate reduction of faecal proteolytic damage to epithelial integrity and to explore the dynamics of antibiotic resistance genes in the microbiome Methods The study will be a multicentre, double-blind, placebo-controlled randomised trial of encapsulated faecal microbial transplantation using a three-stage group-sequential design. As pilot studies indicate the potential of a large treatment effect two pre-planned interim analyses will be conducted to enable early stopping for efficacy or futility. Population: patients admitted to hospital with severe AH Intervention: FMT containing the equivalent of 80g faecal material from healthy donors Comparator: Placebo - Identical capsules containing only microcrystalline cellulose Outcome: mortality at day 90 Setting: 30 secondary care hospitals across the UK Timelines It is proposed to commence the study in April 2024, allowing six months for set up and regulatory approvals. Recruitment will take place over a two year period with an additional 3 months for follow-up and data collection. A final six month period is proposed for analyses, manuscript and report writing and dissemination activities. Impact and dissemination The study outcomes will be presented to our patient partners and participants through workshops and our website. The results will be presented at international meetings and through publications. FMT is widely available as an intervention for C. difficile infection throughout the NHS, it is reasonable to assume that a positive study will lead to immediate uptake of FMT as a therapeutic option for severe AH.