A PROspective double-blind placebo-controlled multicentre trial of faecal MIcrobiota tranSplantation to improve outcomEs in patients with cirrhosis - PROMISE trial.

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.

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.

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.

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.

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.

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.