Title: A PROspective double-blind placebo-controlled multicentre trial of faecal MIcrobiota tranSplantation to improve outcomEs in patients with cirrhosis - PROMISE trial.
Funder: Medical Research Council

Abstract: There is an evolving crisis of chronic liver disease (CLD) in the UK and it is the only major chronic disease which is on the rise. The advanced stages of CLD, known as cirrhosis (a hardening and scarring of the liver), is the third biggest cause of death and loss of working life years behind heart disease and self-harm. People die from cirrhosis young with more than 1 in 10 in their 40s. _x000D_ _x000D_ Patients with cirrhosis are very susceptible to infections, antibiotics become ineffective and patients may become infected with ’super bugs’. There is an urgent need for antibiotic-free approaches. Our body contains trillions of microscopic organisms called bacteria which play an important role in keeping us healthy. Many of these bacteria live within our bowel and help our immune system fight infection. There are increased numbers of ‘unfriendly’ bowel bacteria in patients with cirrhosis which emit substances which are harmful to health and disrupt the immune system. _x000D_ _x000D_ It could be beneficial to replace the unfriendly bowel bacteria in patients with cirrhosis with bacteria donated from a healthy person by performing a type of bowel bacteria transplant (known as faecal microbiota transplantation or FMT). We have recently performed a preliminary trial of FMT which was placed into the bowel with the help of a flexible camera (endoscopy). The study showed FMT was safe with no serious side effects, but patients told us they would prefer to take tablets rather than have an endoscopy. We have therefore made a capsule which contains dried stool from a healthy donor. The patient needs to take 5 of these capsules to have the same dose. _x000D_ _x000D_ We will perform a clinical trial to test whether treating patients with FMT capsules will reduce the likelihood of them getting an infection by measuring the time it takes to develop an infection resulting in hospital admission. This will be compared to a ‘dummy’ capsule that contains no FMT (placebo). Patients will be selected at random to have FMT treatment or placebo and both the study team and the patients will not know which treatment they are taking. The patients will need to take 5 capsules every 3-months. Patients will continue treatment for a total of 21-months or until they develop their first infection leading to hospital admission and will be followed-up for a maximum of 2-years. This study will also examine if having FMT will reduce the side effects of cirrhosis and if it has beneficial effects on the liver and immune system. We will look at whether it reduces hospital admissions, the incidence of ‘super-bug’ infections and death. Laboratory studies will look at whether FMT treatment will help the immune system fight infection._x000D_ _x000D_ The World Health Organisation describes the resistance of bacteria to the effects of antibiotics as one of the biggest threats to global health. The discovery of new antibiotics has not kept pace. The government’s white paper proposes a 5-year plan to tackle resistance to antibiotics. Consultation with our patient co-applicant, patient advisory group, The British Liver Trust and Guts UK Charity have highlighted recurrent hospitalisation, over-use of antibiotics and fear of acquiring a ‘super-bug’ as being important priorities to patients._x000D_ _x000D_ The results and study findings will be published in conjunction with patient support groups, the wider media and the NHS. We will ensure the research impacts on the management of patients with CLD and shapes policy and guideline development

Lay abstract: There is an evolving crisis of chronic liver disease (CLD) in the UK with prevalence and mortality increasing exponentially. End-stage CLD, termed cirrhosis, is the third biggest cause of mortality and loss of working life behind ischaemic heart disease and self-harm. Cirrhosis predisposes to infection resulting in hospitalisation which worsens liver function and precipitates complications with high mortality. With poor outcomes following infection, the propagation of antimicrobial resistance (AMR) and increasing need for liver transplantation, there is an urgent need to reduce infection and the spread of AMR. _x000D_ _x000D_ Patients with cirrhosis have gut dysbiosis and bacterial translocation culminating in systemic inflammation, endotoxemia and innate immune dysfunction. Treatment with the antibiotic rifaximin led to significant reductions in all-cause admissions, length of stay, 30-day readmissions and episodes of bacterial peritonitis driven by bacterial translocation. These data are ‘proof of principle’ that modifying the gut microbiota improve outcomes but long-term antibiotics may drive AMR. We postulated that replacing the gut microbiome in cirrhosis with gut bacteria from a healthy donor using a faecal microbiota transplant (FMT) would offer an antibiotic-free alternative. _x000D_ _x000D_ We performed a safety and feasibility study of FMT endoscopically administered into the jejunum and showed it to be safe and well-tolerated in patients with advanced cirrhosis. It reduced stool Enterococcus faecalis(p=0.000006) and enteropathogenic Escherichia coli (p=0.0033) along with ameliorating systemic inflammation and enhancing innate immune responses but it was not powered to detect differences in clinical outcomes. We learned that not all patients were willing to undergo invasive endoscopy and FMT as a ‘pill’ was preferred. We have thus developed lypholised encapsulated freeze-dried FMT manufactured in our MHRA-licensed facility. _x000D_ _x000D_ A phase 2b multicentre, randomised, double-blinded, placebo-controlled trial will evaluate encapsulated FMT for 2-years in 300 patients with alcohol or non-alcoholic fatty liver disease cirrhosis (MELD score 8-16). Five FMT capsules derived from 80g of stool from a healthy donor or matched placebo capsules will be randomly allocated (1:1) and patients treated every 90-days for up to 2-years. The primary endpoint is time-to-infection resulting in hospitalisation. Secondary endpoints include decompensating cirrhotic events, progression to liver failure, antibiotic usage, the incidence of AMR, all-cause hospitalisation rates, liver disease severity scores and mortality. Mechanistic endpoints include quantification of plasma bacterial DNA, plasma and faecal cytokines/biomarkers, plasma and faecal metabolome, faecal microbiome composition and diversity, monocyte and mucosal-associated T-cell function and genes encoding AMR._x000D_ _x000D_ The trial will commence in May 2021 with a 6-month set-up phase with the first centre opening in Nov 2021. All 10 centres will be open by April 2022. Recruitment will be months 7-30, follow-up months 30-54, and analysis, reporting and dissemination months 55-60. _x000D_ _x000D_ Dissemination will be by conventional academic routes, in high impact journals and international conference presentations, involving patient support groups led by the British Liver Trust, wider media and NHS organisations. We will ensure the research impacts on the management of patients with cirrhosis shaping policy and guideline development.

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL