Title: PROFIT Trial: A PROspective, randomised placebo controlled feasibility trial of Faecal mIcrobiota Transplantation in cirrhosis
Funder: Department of Health and Social Care

Abstract: Background: Patients with advanced cirrhosis have enteric dysbiosis with small bowel bacterial overgrowth and translocation of bacteria across the gut. This culminates in systemic inflammation and endotoxemia, inducing innate immune dysfunction which predisposes to infection, and development of complications such as bleeding, sepsis and hepatic encephalopathy. It also plays a key role in the natural history of cirrhosis by influencing the rate of progression to advanced liver disease and terminal liver failure. Modulating the gut microbiota with the non-absorbable antibiotic rifaximin has been associated with a reduction in endotoxemia, reduced hospital re-admission rates and improved liver disease severity scores raising the possibility that modulation of gut microbiota may significiantly modify the natural history of chronic liver failure. Faecal microbiota transplantation (FMT) is a well-established treatment to modify the gut microbiome and has been shown to be safe and efficacious. Hypothesis and Aims : We hypothesize that in patients with advanced cirrhosis FMT may reduce the progression to chronic liver failure. Whether FMT is feasible in the setting of cirrhosis remains to be investigated. We propose to conduct a feasibility trial to assess whether stabilising gut dysbiosis with FMT in patients with advanced cirrhosis is both feasible and safe. Objectives, Endpoints and Success Criteria: Primary Endpoints: (i) Assessment of the feasibility of FMT Assess recruitment rates and adherence (including palatability of the intervention) Assess tolerability of FMT e.g reflux rates (ii) Assessment of the safety of FMT Success Criteria of Primary Endpoints: (i) Assessment of the feasibility and tolerability of FMT: >50% consent rate >25% recruitment rate >80% recruited patients treated successfully and completing study up to day 90 Availability of obtaining sufficient stool donors for the study Reflux rates of transplanted material Intolerable (resulting in withdrawal from the study) gastrointestinal side effects of (ii) Assessment of the safety of FMT: Incidence of any transmissable bacterial or viral infection that is deemed to have been acquired from the donor including Clostrium difficile infection. The development of any serious side effects or reactions. Secondary Objectives: The secondary objectives of the study are to provide preliminary evidence of efficacy for a larger randomised trial, with the purpose of: (i) Choosing the optimal primary outcome, and (ii) Estimating the parameters for sample size calculation. (iii) To estimate the costs and resources required to implement this novel therapy in a NHS environment. Mechanistic Outcomes: (i) Plasma endotoxin and bacterial DNA quantification at 7 and 90-days. (ii) Changes in intestinal permeability and faecal biomarkers (calprotectin) at 90-days. (iii) Changes in leucocyte function at 7 and 90-days. Study Intervention: Intervention: FMT derived from a healthy donor (200mls) will be administered via a gastroscope into the duodenum following bowel preparation. Comparison: Placebo solution (200mls 0.9% normal saline and 12.5% glycerol) administered via a gastroscope into the duodenum following bowel preparation. Study Design Single centre, randomized, single-blinded, placebo-controlled study evaluating FMT against placebo performed over 18 months. Patients with advanced but stable cirrhosis with a MELD score between 10-16 will be recruited. Fifteen patients will be randomized to FMT and five patients to placebo in a 3:1 ratio. Patients will be evaluated at baseline and at 7 and 90-days. Number of Participants: 20 Duration of Study: 3-months Potential Benefits to Patients and the NHS: As enteric dysbiosis plays a key role in the natural history of cirrhosis by influencing the rate of progression to terminal liver failure, introducing an intervention which normalises the gut microbiome may reduce the development of the complications including bleeding, infection, encephalopathy, ascites and acute-on-chronic liver failure which will reduce hospitalisation, improve outcomes and may lengthen transplant-free survival.

Lay abstract: Our body contains trillions of microscopic organisms called bacteria which play an important role in keeping us healthy. These bacteria live mainly in our bowel and help our immune system fight infection. Liver disease is becoming more common in the UK and repeated liver damage causes the liver to be shrunken and scarred. This is known as cirrhosis. There are increased numbers of bowel bacteria in patients with cirrhosis with more unfriendly bacteria which emit substances which disrupt the immune system. These patients often develop severe infections which result in them being hospitalised and often dying. Antibiotic treatment is prescribed but sometimes this is ineffective. It could be beneficial to replace the unhealthy bowel bacteria in patients with cirrhosis with bacteria donated from a healthy person by performing a type of bowel bacteria transplant. This is safe but has never been undertaken in patients with cirrhosis. This involves flushing out unfriendly bacteria and replacing them during a gastroscopy with bacteria donated from a healthy person who has been carefully screened similar to blood donors. A gastroscopy involves passing a thin flexible camera through the mouth, down the gullet into the small bowel where the bacteria transplant is placed. This is a safe procedure and serious complications are uncommon. This study will examine whether this is a feasible treatment that is both safe and palatable to patients without any adverse effects. It will also examine whether treatment may improve the health of patients with cirrhosis preventing them developing infections. Twenty four patients will receive a bacteria transplant and eight an identical transplant without bacteria known as a placebo . Patients will have blood and stool samples collected before, and after the transplant, (1 week and 3 months) to assess what impact the transplant has on their bowel bacteria and their immune system.

Research activity codes: 6.4 SURGERY
Health categories: ORAL AND GASTROINTESTINAL