Liver immunosuppression free trial ("LIFT"), version 1

• Register: ISRCTN
• Last refreshed on: 17 October 2022
• Main ID: ISRCTN47808000
• Date of registration: 08/07/2015
• Prospective Registration: Yes
• Primary sponsor: King's College London
• Public title: Liver immunosuppression free trial ("LIFT"), version 1
• Scientific title: Prospective randomised marker-based trial to assess the clinical utility and safety of biomarker-guided immunosuppression withdrawal in liver transplantation ("LIFT" Trial).
• Date of first enrolment: 01/08/2015
• Target sample size: 148
• Recruitment status: Completed
• URL: https://www.isrctn.com/ISRCTN47808000
• Study type: Interventional
• Study design: Randomised; Interventional; Design type: Treatment (Treatment)
• Phase: Not Applicable

Countries of recruitment

England, United Kingdom

Contacts

• Name: Jurate Wall

Key inclusion & exclusion criteria

Inclusion criteria:
Current participant inclusion criteria as of 29/01/2019:
1. At the time of screening: more than 3 years post-transplant if participants are =50 years old, OR = 6 years post-transplant if participant age is =50 years old.
2. Recipient of either deceased or living donor liver transplant.
3. Recipient of single organ transplant only
4. Liver function tests: direct bilirubin =17.1 umol/L and ALT =60 IU/L at the screening visit.
5. On calcineurin inhibitor (CNI) IS with or without one of the following: Low dose mycophenolic acid (= 1080 mg daily), mycophenolate mofetil (MMF = 1500 mg daily), azathioprine (= 150 mg daily), sirolimus/everolimus; or on monotherapy with sirolimus/everolimus or mycophenolate/mycophenolic acid monotherapy (effective contraception must be used
before beginning mycophenolate therapy, during therapy, and for six weeks following discontinuation of therapy, see Appendix 6),
6. Ability to sign informed consent.

Previous participant inclusion criteria:
1. At the time of screening: more than 3 years post-transplant if participants are =50 years old, OR = 6 years post-transplant if participant age is 18-49 years old.
2. Recipient of either deceased or living donor liver transplant
3. Recipient of single organ transplant only
4. Liver function tests: direct bilirubin =17.1 umol/L and ALT =60 IU/L at the screening visit.
5. On calcineurin inhibitor (CNI) based maintenance IS and no more than one of the following: Low dose mycophenolic acid (= 1080 mg daily), mycophenolate mofetil (MMF = 1500 mg daily), or azathioprine (= 150 mg daily); or on mycophenolate/mycophenolic monotherapy (effective contraception must be used before beginning mycophenolate therapy, during therapy, and for six weeks following discontinuation of therapy)
6. Ability to sign informed consent

Exclusion criteria:
Current participant exclusion criteria as of 29/01/2019:
1. Serum positivity for HCV-RNA
2. Serum positivity for HIV-1 infection, HBV surface antigen or HBV-DNA
3. Immune-mediated liver disease in which IS discontinuation is inadvisable (autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis).
4. Acute or chronic rejection within the 52 weeks prior to screening.
5. GFR <30 mL/min (to mitigate the risk of worsening renal failure should rejection occur and high level of CNI be required).
6. The need for chronic anti-coagulation that cannot be safely discontinued to safely perform for a liver biopsy.
7. Baseline (screening) liver biopsy showing any of the following: a) acute rejection according to Banff criteria; b) early or late chronic rejection according to Banff criteria; c) inflammatory activity and/or fibrosis in excess of permissive criteria (Table 1) (25); f) any other findings that might make participation in the trial unsafe. Eligibility will be determined by the central pathologist.
8. Patient age <18 years old at the time of transplant.
9. Pregnant females and females of childbearing age not using effective contraception (See Appendix 6).
10. Current illicit drug or alcohol abuse.
11. Inability to participate in frequent monitoring of liver function (every 3 weeks) and clinical visits during IS withdrawal.
12. Inability to comply with study directed treatment.
13. Any medical condition that in the opinion of the principal investigator would interfere with safe completion of the trial.
14. Participation in another clinical trial during the month prior to enrolment.

Previous participant exclusion criteria:
1. HCV infection (defined by serum positivity for HCV-RNA)
2. Positive serology for HIV-1, hepatitis B surface antigen, or hepatitis B DNA
3. Immune-mediated liver disease in which IS discontinuation is inadvisable (autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis)
4. Acute or chronic rejection within the 52 weeks prior to screening
5. GFR <40 mL/min (to mitigate the risk of worsening renal failure should rejection occur and high level of CNI be required)
6. The need for chronic anti-coagulation that cannot be safely discontinued for a minimum of 1 week to safely perform for a liver biopsy
7. Baseline (screening) liver biopsy showing any of the following:
7.1. Acute rejection according to Banff criteria
7.2. Early or late chronic rejection according to Banff criteria
7.3. Moderate-severe fibrosis (Ishak stage 3 or more)
7.4. Chronic hepatitis (defined as predominantly mononuclear portal inflammation with or without plasma cells) with moderate/marked portal inflammation (Ishak 3 or more) or with mild/moderate interface hepatitis (Ishak 2 or more)
7.5. Perivenular necro-inflammatory activity in a majority of terminal hepatic venules
7.6. Any other findings that might make participation in the trial unsafe. Elligibility will be determined by the central pathologist
8. Pregnant females and females of ch

Age minimum:
Age maximum:
Gender: Both

Health Condition(s) or Problem(s) studied

Topic: Hepatology; Subtopic: Hepatology; Disease: All Hepatology
Digestive System

Intervention(s)

Adult liver transplant recipients will undergo gradual IS withdrawal following randomisation 1:1 to either:
1. Non-Biomarker-based IS weaning (Arm A)
2. Biomarker-based IS weaning (Arm B). Participants allocated to Arm B will be offered IS withdrawal only if they are classified as tolerant on the basis of a biomarker test (Arm B+), while they will remain on maintenance IS if classified as non-tolerant (Arm B-)

Primary Outcome(s)

To determine if the use of a liver tissue transcriptional test of tolerance to stratify liver recipients prior to IS withdrawal accurately identifies operationally tolerant recipients and reduces the incidence of rejection, as compared with a control group in whom IS withdrawal is performed without stratification.

Secondary Outcome(s)

1. To establish the safety of biomarker-guided IS withdrawal
2. To determine the health-economic impact of withdrawing IS in liver transplant recipients and to assess how much this cost is influenced by the use of a diagnostic test of operational tolerance
3. To assess the effect of IS withdrawal on the quality of life of liver transplant recipients
4. To determine the extent to which IS withdrawal improve drug-related co-morbidities
5. To investigate if liver transplant recipients under IS become operationally tolerant over time
6. To determine if the presence of donor-specific anti-HLA antibodies influence the success of IS withdrawal, and whether IS withdrawal promotes the development of anti-HLA antibodies in liver transplant recipients
7. To explore the association between operational liver transplant tolerance, iron metabolism, immunosenescence, and specific gut microbiome profiles

Secondary ID(s)

19194

2014-004557-14

NCT02498977

Source(s) of Monetary Support

National Institute for Health Research

Ethics review

Status:
Approval date:
Contact:

NRES Committee London- South East, 09/02/2015, ref: 14/LO/2172

Results

• Results available: Yes
• Date Completed: 31/03/2021