Restoring immune function in liver failure
| ISRCTN | ISRCTN17604912 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN17604912 |
| IRAS number | 313128 |
| Secondary identifying numbers | 22SM7474, CPMS 53156 |
- Submission date
- 14/02/2025
- Registration date
- 19/02/2025
- Last edited
- 04/03/2025
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Digestive System
Plain English summary of protocol
Background and study aims
Liver failure occurs when liver cells are damaged significantly and are no longer able to function. In some patients their liver may suddenly stop working and this is known as acute liver failure. In these patients they may have no evidence of liver disease before being hospitalised. In other patients the liver may already have sustained damage but has managed to keep functioning well then something happens which means that it is no longer able to perform all its functions adequately. This is known as acute decompensation of cirrhosis. Cirrhosis is the result of long-term damage to the liver which causes scarring. Patients with liver failure have increased susceptibility to infection which usually leads to further deterioration in liver function. The purpose of this study is to investigate how we can improve the function of immune cells in patients with liver failure, ultimately helping to reduce infection. There is no expectation that liver function will be restored. The researchers will be collecting samples and data to investigate whether an anti-PD1 drug can be used to help defects in the immune response in patients with liver failure. There is currently no targeted treatment for this.
Who can participate?
Patients aged 18 years and over with acute liver failure (ALF) or acute decompensation of cirrhosis (AD)
What does the study involve?
The study involves a single dose of a drug (nivolumab) by injection. Blood samples will be taken before the injection and then every 5 days for 20 days.
What are the possible benefits and risks of participating?
There is no guarantee of any benefit from participating in this study. There is a small risk that the drug could cause temporary inflammation of the liver.
Where is the study run from?
Imperial College London (UK)
When is the study starting and how long is it expected to run for?
December 2020 to December 2025
Who is funding the study?
Medical Research Council (UK)
Who is the main contact?
Prof. Mark Thursz, m.thursz@imperial.ac.uk
Contact information
Public, Scientific, Principal Investigator
Division of Digestive Diseases
10th Floor QEQM Wing
London
W2 1NY
United Kingdom
 ORCID ID |
0000-0002-8218-192X |
|---|---|
| Phone | +44 (0)7768 783073 |
| m.thursz@imperial.ac.uk |
Study information
| Study design | Non-CTIMP physiological assessment |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Non randomised study |
| Study setting(s) | Hospital, Laboratory, University/medical school/dental school |
| Study type | Other |
| Participant information sheet | Not available in web format |
| Scientific title | Inhibition of PD-1 to restore monocyte/macrophage function in liver failure |
| Study acronym | Normalise |
| Study objectives | Antibodies targeted at the PD1 molecule will restore immune function in patients with liver failure |
| Ethics approval(s) |
Approved 22/11/2022, Harrow Research Ethics Committee (Level 3, Block B, Whitefriars, Bristol Research Ethics Committee Centre, Bristol, BS1 2NT, United Kingdom; +44 (0)207 104 8012; harrow.rec@hra.nhs.uk), ref: 22/LO/0397 |
| Health condition(s) or problem(s) studied | Liver failure (acute liver failure and acute decompensation of cirrhosis) |
| Intervention | Nivolumab (anti-PD1 antibody) Non-CTIMP, physiological assessment in two groups of patients: 1. Patients (n = 19) with acute liver failure (ALF) 2. Patients (n=59) with acute decompensation of cirrhosis (AD) The study will follow patients up for 30 days. Patients should commence treatment within 48 hours of study enrolment. Anti-PD1 antibody (nivolumab or pembrolizumab) will be administered as a single 240 / 200 mg dose (120 / 100 mg dose in the first sentinel cohort patients) diluted in 100 ml of 0.9% saline and administered intravenously over 30 minutes. |
| Intervention type | Biological/Vaccine |
| Pharmaceutical study type(s) | Physiological assessment of response to PD1 inhibition |
| Phase | Phase 0 |
| Drug / device / biological / vaccine name(s) | Nivolumab, pembrolizumab |
| Primary outcome measure | HLA-DR expression on circulating monocytes measured using flow cytometry on day 15 compared to baseline |
| Secondary outcome measures | 1. Monocyte phagocytosis measured using pH-Rodo uptake in flow cytometry on days 5, 10, 15 and 30 compared to baseline 2. HLA-DR expression on circulating monocytes measured using flow cytometry on days 5, 10, 15 and 30 compared to baseline 3. Incidence of clinically diagnosed infection during the 30 days of follow-up 4. Incidence of bacteraemia diagnosed on blood cultures during the 30 days of follow-up 5. Changes in lipopolysaccharide-induced tumour necrosis factor alpha secretion from monocytes measured by ELISA test on days 5 and 15 compared to baseline 6. Changes in circulating bacterial 16S-ribosomal DNA (16S-rDNA) at days 5 and 10 compared to baseline measured using real-time polymerase chain reaction assays |
| Overall study start date | 16/12/2020 |
| Completion date | 31/12/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 78 |
| Key inclusion criteria | Inclusion criteria – Group 1 (ALF): 1. Male and female patients aged 18 years or older at screening 2. Clinical diagnosis of acute liver failure: 2.1. Presence of jaundice (bilirubin > 40 uMol/L) 2.2. INR > 1.5 2.3. Any degree of encephalopathy 2.4. No history of cirrhosis or advanced chronic liver disease 3. Informed consent (provided by a relative or a professional legal representative when the patient lacks capacity) Inclusion criteria – Group 2 (AD): 1. Male and female patients aged 18 years or older at screening 2. Clinical diagnosis of acute decompensation of cirrhosis including acute-on-chronic liver failure characterised by at least one of: 2.1. Ascites 2.2. Spontaneous bacterial peritonitis 2.3. Encephalopathy (any degree) 2.4. Variceal haemorrhage 3. Evidence of cirrhosis based on any of the following: 4. Liver biopsy (at any time) 5. Elastography (at any time) FS >10 KPa 6. Radiological imaging (at any time) 7. Informed consent (provided by the patient or a relative or a professional legal representative when the patient lacks capacity) |
| Key exclusion criteria | 1. Candidates for liver transplantation within 2 months 2. Duration of clinically apparent jaundice >3 months before baseline visit 3. Evidence of acute viral hepatitis 4. Biliary obstruction 5. Hepatocellular carcinoma 6. Any known autoimmune disorder, including autoimmune-mediated liver failure 7. Previous treatment with any checkpoint inhibitor 8. Untreated sepsis 9. Evidence of current malignancy (except non-melanotic skin cancer) 10. Patients with known hypersensitivity or contraindications to anti-PD-L1 antibody (nivolumab or pembrolizumab) 11. Pregnant or lactating women 12. Currently enrolled in a CTIMP 13. Known HIV infection |
| Date of first enrolment | 01/12/2022 |
| Date of final enrolment | 30/11/2025 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centres
St Marys Hospital
South Wharf Road
London
W2 1BL
United Kingdom
London
SE5 9RS
United Kingdom
London
SW17 0QT
United Kingdom
Sponsor information
University/education
Research Governance and Integrity
Room 221
Medical School Building
St Marys Campus
Norfolk Place
London
W2 1PG
England
United Kingdom
| Phone | +44 (0)2075941862 |
|---|---|
| r.nicholson@imperial.ac.uk | |
| Website | https://www.imperial.ac.uk/research-and-innovation/support-for-staff/joint-research-office/hrs/stakeholders/rgit/ |
"ROR" |
https://ror.org/041kmwe10 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
Results and Publications
| Intention to publish date | |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Stored in non-publicly available repository, Available on request |
| Publication and dissemination plan | The study will be published in peer-reviewed journals. The expectation is that a successful study would lead to an application for a Phase II trial to assess efficacy. |
| IPD sharing plan | Individual patient data (de-identified) will be made available to bona fide investigators on request after publication from Mark Thursz (m.thursz@imperial.ac.uk). Data available: 1. Patient demographics 2. Disease classification 3. Underlying aetiology 4. Severity scores 5. Clinical outcomes 6. Primary outcome 7. Secondary outcomes Availability: from December 2026 Patient consent has been obtained Data will be de-identified |
Editorial Notes
04/03/2025: Internal review.
14/02/2025: Study's existence confirmed by the HRA.
