A clinical trial to test whether treating patients with liver cirrhosis with capsules containing healthy stool bacteria or a dummy capsule (placebo) will reduce the time it takes to develop an infection resulting in hospital admission
| ISRCTN | ISRCTN17863382 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN17863382 |
| EudraCT/CTIS number | 2022-000300-35 |
| IRAS number | 1004822 |
| ClinicalTrials.gov number | NCT06461208 |
- Submission date
- 14/03/2022
- Registration date
- 25/03/2022
- Last edited
- 22/11/2024
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Infections and Infestations
Plain English Summary
Background and study aims
Our body contains trillions of bacteria. Many of these live in our bowels which keeps us healthy and helps our immune system to fight against infections. However, an increased number of ‘unfriendly’ bacteria are found in the bowel of patients with liver cirrhosis (permanent liver damage), which makes them highly susceptible to infections. Antibiotics are becoming less effective as they are used so frequently, and the bowel can become infected with ‘super-bugs’.
Replacing the unfriendly bowel bacteria in patients with cirrhosis with healthy bacteria donated from healthy volunteers (faecal microbiota transplantation) could be highly beneficial and reduce antibiotic usage. Findings from the initial FMT trial (the PROFIT trial) showed that FMT administered during endoscopy was safe with no serious side effects. However, patients said that they would prefer to take tablets rather than have an endoscopy. The researchers have therefore made an FMT capsule from freeze-dried stool and this study will test whether treating patients with these FMT capsules reduces their likelihood of getting an infection.
Who can participate?
Patients aged 18 years and above who have been diagnosed with alcohol-related cirrhosis or non-alcoholic fatty liver disease (sometimes referred to as metabolic-associated fatty liver disease) cirrhosis at any time point
What does the study involve?
Participants will be selected at random to take FMT capsules or 'dummy’ capsules that contain no FMT (placebo) and both the study team and the participants will not know which treatment they are taking. The participants will need to take five capsules every 3 months 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 whether FMT reduces the side effects of cirrhosis and has beneficial effects on the liver and immune system. The researchers will look at whether FMT 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.
What are the possible benefits and risks of participating?
Patients will be taking part in a new and innovative trial to assess the beneficial effects of FMT capsules in patients with cirrhosis. There are no curative treatments available to patients with cirrhosis, aside from liver transplantation. Unfortunately, due to the scarcity of donor organs, even those listed for transplant can wait months or even years for a new liver. Others are too unwell or frail or deemed ineligible to be listed for a liver transplant.
The researchers will also gather information during the trial on how the FMT works in patients with cirrhosis including the impact on the make-up and function of the gut microbiome. They will examine whether FMT can reduce the likelihood of developing an infection and being admitted to the hospital.
There are no risks involved in taking part with regard to the samples being obtained, and the amount of blood taken will not be harmful to the patient. The placebo treatment is not harmful but is not expected to have any benefit as it contains no active drug or treatment. All patients, regardless of whether they receive placebo or FMT have the same rigorous follow-up and support from the trials team. They will be closely monitored after the treatment is given and will be seen at regular intervals afterwards to see if they have experienced any side effects. The researchers do not anticipate any serious problems to occur after the FMT or placebo treatment, but the participants will be given contact numbers should they run into any problems outside of the trial visits.
Where is the study run from?
King's College Hospital NHS Foundation Trust (UK)
When is the study starting and how long is it expected to run for?
November 2021 to June 2028
Who is funding the study?
National Institute for Health Research Efficacy and Mechanism Evaluation (NIHR) (UK)
Who is the main contact?
1. Prof. Debbie Shawcross (Chief Investigator), debbie.shawcross@kcl.ac.uk
2. Ms Sue Cheung, promise@kcl.ac.uk
Contact information
Principal Investigator
Institute of Liver Studies
King’s College Hospital and King’s College London
Denmark Hill
London
SE5 9RS
United Kingdom
| Phone | +44 (0)203 299 3713 |
|---|---|
| debbie.shawcross@kcl.ac.uk |
Public
Research Management and Innovation Directorate
Institute of Psychiatry
16 De Crespigny Park
Denmark Hill
King’s College London
London
SE5 8AF
United Kingdom
| Phone | +44 (0)20 7848 0532 |
|---|---|
| promise@kcl.ac.uk |
Study information
| Study design | Multicentre randomized double-blind parallel-group placebo-controlled multi-centre trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised parallel trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use contact details to request a participant information sheet |
| Scientific title | 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 (PROMISE) |
| Study acronym | PROMISE |
| Study hypothesis | The researchers will perform a clinical trial to test whether treating patients with alcohol-related and metabolic-associated fatty liver cirrhosis with faecal microbiota transplantation (FMT) capsules vs placebo capsules will reduce the likelihood of them getting an infection by measuring the time it takes to develop an infection resulting in hospital admission. |
| Ethics approval(s) |
Approved 16/03/2023, East of England – Cambridge South Research Ethics Committee (Equinox House, City Link, Nottingham, NG2 4LA, United Kingdom; +44 (0)207 104 8084; cambridgesouth.rec@hra.nhs.uk), ref: 22/EE/0247 |
| Condition | Infection in patients with cirrhosis |
| Intervention | Randomisation: Patients will be randomised on a 1:1 basis to either FMT or placebo using the King's Clinical Trial Unit (KCTU) web-based randomisation system. Randomisation will be at the level of the individual using the method of block randomisation with varying block sizes, stratified by site. Intervention: Patients will be randomly allocated to two treatment arms: 1. Active treatment - patients assigned to this group will receive the active drug (FMT capsules) 2. The comparison or ‘control group’: Participants in this group will receive a ‘placebo’ treatment. The placebo will be a dummy capsule and will NOT contain any stool The FMT product contains 0.9% sodium chloride and 5% trehalose (cryoprotectant) as excipients. A minimum of 80 g of faeces from a single donor will be used to manufacture one batch of five capsules. Following lyophilisation, the material will be encapsulated in five size 0 delayed-release methylcellulose capsules (DRcaps™, Capsugel®, Livingston, UK). Placebo capsules will contain microcrystalline cellulose. The capsules for the FMT and placebo will be identical in appearance. The capsules are coloured Swedish orange, resulting in an opaque appearance through which the contents cannot be seen. FMT material will be fully traceable from donor to recipient. Aliquots of donor stool will be kept for 30 years to allow for future testing if required. The patients will need to take five 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 at different timepoints - baseline, 30 days (telephone call), 3, 6, 9, 12, 15, 18, 21 and 24 months. At each clinic visit, patients will receive five capsules of the medicine (either the FMT or the placebo) to be taken by mouth and swallowed with water or cordial. |
| Intervention type | Biological/Vaccine |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Faecal microbiota transplantation (FMT) |
| Primary outcome measure | Time to the first infection resulting in hospital admission i.e., the date the patient is admitted to the hospital due to infection, collected using the King's Clinical Trials Unit Index Hospitalisation (Primary Endpoint) form administered by the research nurse at each clinic visit i.e, 3, 6, 9, 12, 15, 18, 21 and 24 months. When the patients meet the primary endpoint, they do not receive further IMP or attend trial visits, but they will continue to be enrolled in the trial for the purposes of monitoring of other clinical endpoints, e.g. all-cause mortality and liver-related mortality. |
| Secondary outcome measures | 1. Incidence of decompensating events including hepatic encephalopathy, new-onset ascites, variceal bleeding and spontaneous bacterial peritonitis, measured using study-specific laboratory analyses on blood, stool and urine samples at baseline, 3, 6 and 12 months 2. Progression to acute-on-chronic liver failure (ACLF) (the development of one or more organ failures) measured using study-specific laboratory analyses on blood, stool and urine samples at baseline, 3, 6 and 12 months 3. Infection rates and antibiotic usage collected using the concomitant medications log following randomisation 4. Incidence of AMR including skin and nose colonisation with methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), extended-spectrum beta-lactamase-producing bacteria (ESBL), fluoroquinolone-resistant Gram-negative and carbapenem-resistant Enterobacteriales, measured using study-specific laboratory analyses on blood, stool and urine samples at baseline, 3, 6 and 12 months 5. Hospitalisation rates (liver-related and all-cause), including the length of stay and admission to high dependency/intensive care, collected using the King's Clinical Trials Unit Hospitalisation Log and patient medical notes at 3, 6, 9, 12, 15, 18, 21 and 24 months 6. Liver disease severity measured using the Child-Pugh, Model For End-Stage Liver Disease (MELD) and United Kingdom Model for End-Stage Liver Disease (UKELD) scores at baseline, 3, 6, 9, 12, 15, 18, 21 and 24 months 7. Quality of life measured using the EQ-5D-5L questionnaire at baseline, 3, 6, 12 and 24 months 8. All-cause mortality and liver-related mortality collected from patient medical notes and adverse events log at day 30 over the telephone and thereafter at each clinic visit i.e., 3, 6, 9, 12, 15, 18, 21 and 24 months 9. Depression and anxiety measured using the Hospital Anxiety and Depression Scale (HADS) at baseline, 3, 6, 12 and 24 months 10. Alcohol use disorder-related events in patients enrolled with alcohol-related cirrhosis, measured using the alcohol-use disorders identification test (AUDIT questionnaire) at baseline, 3, 6, 12 and 24 months and urinary ethyl glucuronide/ethyl sulphate levels if tested as part of the standard of care 11. Faecal microbiome composition analysed by sequencing and metabolome analysis at baseline, 3, 6 and 12 months 12. Dietary habits measured using a study-specific dietary questionnaire developed by the team at baseline |
| Overall study start date | 01/11/2021 |
| Overall study end date | 30/06/2028 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 300 |
| Participant inclusion criteria | 1. Age 18 years or over 2. Confirmed alcohol-related cirrhosis or metabolic-associated fatty liver (MAFLD) cirrhosis based on clinical, radiological and/or histological criteria 3. Model For End-Stage Liver Disease (MELD) score 8-16 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 consent (if patients lose capacity during the trial a legal representative will be appointed on their behalf) |
| Participant exclusion criteria | 1. Severe or life-threatening food allergy (e.g., peanut allergy) 2. Pregnancy or planned pregnancy. Urine testing will be performed at randomisation to rule out pregnancy in females 3. Breastfeeding 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 g/day (1 unit of alcohol contains 10 ml or 8 g 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 such as 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 foodstuffs containing ‘live bacteria’ such as live yoghurts, kefir, fermented vegetables such as sauerkraut/kombucha or cheese) within 7 days prior to randomisation 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 |
| Recruitment start date | 21/06/2023 |
| Recruitment end date | 30/01/2026 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
- Wales
Study participating centres
Denmark Hill
London
SE5 9RS
United Kingdom
London
SW17 0QT
United Kingdom
Newport
NP20 2UB
United Kingdom
Department of Metabolism, Digestion and Reproduction
Norfolk Place
St Mary’s Campus
London
W2 1PG
United Kingdom
Room 6.1, Level 6 Clinical Sciences Building
University of Leeds
Beckett Street
Leeds
LS9 7TF
United Kingdom
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom
Derby Road
Nottingham
NG7 2UH
United Kingdom
Glasgow
G4 0SF
United Kingdom
Dundee
DD1 9SY
United Kingdom
Gateshead
NE9 6SX
United Kingdom
Derby
DE22 3NE
United Kingdom
Bournemouth
BH7 7DW
United Kingdom
Sponsor information
Hospital/treatment centre
King’s Health Partners Clinical Trials Office
Floor 16, Tower Wing
Guy’s Hospital
Great Maze Pond
London
SE1 9RT
England
United Kingdom
| Phone | +44 (0)20 71885732 |
|---|---|
| rebecca.newton@kcl.ac.uk | |
| Website | http://www.kcl.ac.uk/index.aspx |
"ROR" |
https://ror.org/01n0k5m85 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- NIHR Efficacy and Mechanism Evaluation Programme, EME
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 30/07/2028 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Published as a supplement to the results publication |
| Publication and dissemination plan | The study findings will be disseminated by conventional academic routes, aiming for high impact open access peer-reviewed journal(s), and by the involvement of patient support groups, wider media and NHS organisations to ensure a broad readership. In year 1 the researchers will publish the trial protocol. They intend to publish their results 1 year after the overall trial end date (this is tentative as they have not yet started recruitment to the trial). The results will be published in one or more high impact open access journals and will include presentations at prominent gastroenterology and hepatology national and international conferences including the British Association for the Study of the Liver (BASL), British Society of Gastroenterology (BSG), European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Disease (AASLD) Annual Conferences. The researchers will ensure the research impacts on the management of patients with advanced cirrhosis and shapes policy and guideline development ensuring the data is included in relevant Cochrane reviews and that NICE, BSG and other bodies involved in the development of national/international guidelines are aware when relevant. The British Liver Trust (BLT) will be central in leading the dissemination of the trial results and ensuring that the public and patients will be kept fully informed. They will also disseminate relevant findings through their website, newsletters and using social media platforms. At the end of the trial, the researchers will hold a public webinar in conjunction with the BLT as an opportunity to disseminate the study findings and to bring everyone together to look at what was created and share learnings. Dr Edwards is a scientific advisor to The House of Commons All-Party Parliamentary Group on Liver Health, and Prof Shawcross, Drs Goldenberg, Edwards, Patel and Mullish sit on the Gut Microbiota for Health Expert Panel. They will continue to utilise the links of the Policy Institute at King’s College London who have worked with Prof. Dame Sally Davies (outgoing Chief Medical Officer) for many years (she is a Visiting Professor and the UK Special Envoy on antimicrobial resistance). The researchers will issue joint press releases coordinated between KCL, King’s Health Partners, the NIHR and the British Liver Trust. |
| IPD sharing plan | The datasets generated and/or analysed during the current study will be published as a supplement to the results publication |
Editorial Notes
22/11/2024: The following changes were made to the trial record:
1. The recruitment end date was changed from 30/11/2024 to 30/01/2026.
2. The overall end date was changed from 31/03/2026 to 30/06/2028.
3. The intention to publish date was changed from 30/04/2026 to 30/07/2028.
4. The plain English summary was updated to reflect these changes.
5. The clinicaltrials.gov number was added.
30/01/2024: The following changes were made:
1. The recruitment end date was changed from 30/11/2025 to 30/11/2024.
2. The study participating centre at Royal Liverpool University Hospital was removed.
3. The study participating centre at Royal Bournemouth Hospital was added.
18/07/2023: The following changes have been made:
1. The recruitment start date was changed from 01/02/2023 to 21/06/2023.
2. The public contact was updated.
3. The ethics approval was added.
4. The individual participant data (IPD) sharing plan was added.
07/11/2022: Ethics approval details added, the recruitment start date was changed from 01/11/2022 to 01/02/2023.
05/05/2022: The recruitment start date has been changed from 01/04/2022 to 01/11/2022.
04/04/2022: The intention to publish date has been corrected from 30/04/2022 to 30/04/2026.
24/03/2022: Trial's existence confirmed by the NIHR.
