Clinical trial NCT06461208: A PROspective Faecal MIcrobiota tranSplantation Trial to Improve outcomEs in Patients With Cirrhosis
Official title: PROMISE Trial: A PROspective Randomised Double-blind Parallel Group Placebo-controlled Multicentre Trial of Faecal MIcrobiota tranSplantation to Improve the Primary outcomE (First Hospitalisation Due to Infection) in Patients With Cirrhosis Over 24 Months
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Liver Cirrhosis
Keywords: Fatty Liver Alcoholic
Alcohol-related Liver Disease
Metabolic dysfunction-Associated Steatotic Liver Disease
Liver Cirrhosis
MASLD
MASLD-ALD overlap cirrhosis
ALD
Faecal Microbiota Transplant
Metabolic Fatty Liver Disease
Fatty Liver Disease
Gut Microbiota
Cirrhosis
PROMISE
Lead sponsor: King's College London
Sponsor class: OTHER
Collaborators: name: St George's, University of London
name: Guy's and St Thomas' NHS Foundation Trust
name: Imperial College London
name: King's College Hospital NHS Trust
name: BRITISH LIVER TRUST
First posted: 2024-06-14
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients will be randomised 1:1 to FMT or placebo.
Primary purpose: PREVENTION

Brief summary: A feasibility trial called PROFIT has previously shown that FMT administered endoscopically into the jejunum in patients with cirrhosis is safe and feasible and have identified some potential mechanisms of action that warrant further interrogation. The aim of the PROMISE Trial is to evaluate the efficacy and mechanisms of action of encapsulated FMT (versus placebo) to reduce infection and mortality in patients with alcohol-related and metabolic dysfunction-Associated Steatotic Liver (MASLD) cirrhosis.

Detailed description: 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.

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. The 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 that are harmful to health and disrupt the immune system.

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). The PROFIT trial was recently performed as 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. The chief investigator and her team have therefore made a capsule which contains dried stool from a healthy donor. Participants will need to take 5 of these capsules to achieve the same dose.

The PROMISE clinical trial is 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. Participants will need to take 5 capsules every 3-months. Participants 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. The investigator team will study 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.

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. The results and study findings will be published in conjunction with patient support groups, the wider media and the NHS. The investigator will ensure the research impacts on the management of patients with CLD and shapes policy and guideline development.

Eligibility criteria: Inclusion Criteria:

1. Aged ≥ 18 years
2. Confirmed Alcohol-related (ALD) or Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) or MASLD-ALD Overlap cirrhosis based on clinical, radiological and/or histological criteria.
3. MELD score 8-16 28
4. Patients with alcohol-related cirrhosis must have been abstinent for a minimum of 4 weeks prior to randomisation.
5. Patients must be deemed to have the capacity to provide written informed consent to participate.

Exclusion Criteria:

1. Severe or life-threatening food allergy (e.g., peanut allergy)
2. Pregnancy or planned pregnancy\*. Urine testing will be performed at screening to rule out pregnancy in females.
3. Breast-feeding
4. Patients treated for acute variceal bleeding, infection, overt hepatic encephalopathy, bacterial peritonitis or ACLF within 14 days prior to randomisation.
5. Active alcohol consumption of \>20 grams/day \[1 unit of alcohol contains 10mLs or 8g of alcohol\]
6. Had a previous liver transplant
7. Patients with inflammatory bowel disease.
8. Patients with coeliac disease.
9. Patients with a history of prior gastrointestinal resection or surgery that could change the gut microbiome or result in bacterial overgrowth e.g. gastric bypass
10. Active malignancy including hepatocellular carcinoma
11. Patients with an expected life expectancy \<6 months or listed for liver transplantation
12. Infected with HIV, hepatitis B or C \[patients who have undetectable hepatitis B or C DNA/RNA can be recruited\].
13. Patients who have received antibiotics or probiotics (excluding food stuffs containing 'live bacteria' such as live yoghurts, kefir, fermented vegetables such as sauerkraut/kombucha or cheese) within 7 days prior to randomisation. Protocol Version 3.0 - 03/11/2023 33
14. Swallowing disorder, oral-motor dyscoordination or likely inability/unwillingness to ingest study medication.
15. Patients who have received another investigational drug or device within 4 months prior to randomisation.
16. Patients, who in the opinion of the PI, have a medical condition, or other relevant psychological, familial, or social factor that may jeopardise their health, compliance, or influence the trial integrity in any way.

Primary outcomes:
measure: Defined infection resulting in hospital admission
timeFrame: From date of randomisation until the date of first hospitlisation, assessed up to Month 24.
Secondary outcomes:
measure: Incidence of decompensating events
timeFrame: Screening - End of Visit (Month 24)
measure: Progression to ACLF (Acute on Chronic Liver Failure) i.e. the development of one or more organ failure
timeFrame: Screening - End of Visit (Month 24)
measure: All-cause culture-confirmed infection
timeFrame: Screening - End of Visit (Month 24)
measure: Incidence of antibiotic usage
timeFrame: Screening - End of Visit (Month 24)
measure: Occurrence of AMR (Anti-Microbial Resistance)
timeFrame: Screening - End of Visit (Month 24)
measure: Hospitalisation rates (liver-related and all-cause) (time to event) including the length of stay (time to discharge among hospitalised participants) and admission to high dependency/intensive care.
timeFrame: Screening - End of Visit (Month 24)
measure: Change in liver disease severity scores
timeFrame: Screening - End of Visit (Month 24)
measure: Change in liver disease severity scores
timeFrame: Screening - End of Visit (Month 24)
measure: Change in liver disease severity scores
timeFrame: Screening - End of Visit (Month 24)
measure: Change in quality of life (EQ-5D-5L) scores
timeFrame: Screening - End of Visit (Month 24)
measure: Change in depression and anxiety scores (using HADS)
timeFrame: Screening - End of Visit (Month 24)
measure: All-cause mortality and liver-related mortality.
timeFrame: Screening - End of Visit (Month 24)
measure: Change in alcohol use disorder-related events in patients enrolled with alcohol-related cirrhosis as assessed by the alcohol-use disorders identification test (AUDIT score)
timeFrame: Screening - End of Visit (Month 24)
measure: Change in urinary ethyl glucuronide/ethyl sulphate levels if tested as part of the standard of care.
timeFrame: Screening - End of Visit (Month 24)
Other outcomes:
Locations:
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
city: Bristol
country: United Kingdom
facility: Southmead Hospital
city: Bristol
country: United Kingdom
facility: Bristol Royal Infirmary
city: Derby
country: United Kingdom
facility: Royal Derby Hospital
city: Dundee
country: United Kingdom
facility: Ninewells Hospital
city: Gateshead
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital
city: Hull
country: United Kingdom
facility: Hull Royal Infirmary
city: Leeds
country: United Kingdom
facility: St. James University Hospital
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: St. George's University Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: St. Mary's Hospital
city: Newcastle Upon Tyne
country: United Kingdom
facility: Freeman Hospital
city: Newport
country: United Kingdom
facility: Royal Gwent Hospital
city: Nottingham
country: United Kingdom
facility: Queen's Medical Centre
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
Study officials:
References: