Condition category
Digestive System
Date applied
Date assigned
Last edited
Prospectively registered
Overall trial status
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
Following liver transplantation patients need to be given powerful drugs (known as immunosuppressive medication), to prevent organ rejection. These drugs are usually given for the rest of the patients life, which can result in important side effects. This the main reason why in the long run transplanted patients die more frequently than non-transplanted healthy individuals. Not all liver transplant patients, however, require lifelong immunosuppressive medication. Some of them develop a phenomenon known as operational tolerance and can discontinue this medication without rejecting the transplanted liver. In tolerant patients the withdrawal of anti-rejection medication could increase their survival and improve their quality of life. However, until now there have been no tests to identify tolerant patients before immunosuppression medication is stopped. Our research group recently identified a genetic test of tolerance in liver biopsies that can predict the outcome of immunosuppressive drug withdrawal. This test could radically change the long-term care of liver transplant patients.

Who can participate?
Liver transplant patients that received their new liver more than 3 years ago or more than six years ago if aged 18-49 or at least 50 years old respectively.

What does the study involve?
Participants first have a liver biopsy for the genetic test of tolerance. They are then randomly allocated to one of two groups. Patients randomized to group 1 are offered drug withdrawal regardless of the result of the genetic test. Patients randomized to group 2 undergo drug withdrawal if the genetic test is positive, and continue the immunosuppressive medication if the test is negative. By comparing the outcome of the 2 groups we will determine how much the test can benefit transplanted patients.

What are the possible benefits and risks of participating?
Chronic immuno-suppression (IS) is associated with a variety of life threatening side effects following liver transplantation, including infection, malignancy, hypertension, diabetes, nephrotoxicity and cardiovascular diseases. Calcineurin inhibitor induced nephrotoxicity, in particular, is responsible for a significant rate of chronic renal failure, need for renal replacement therapy and increased mortality. Elimination of calcineurin inhibitors may preserve waning renal function and avoid the associated morbidity and mortality risk.Identification of a reproducible and reliable tolerance signature will allow tailoring of IS to individual patient characteristics. It may also identify critical pathways responsible for the tolerant state that can be therapeutically exploited to induce tolerance in those who do not achieve it spontaneously. While there is abundant information in the literature suggesting that in carefully selected liver recipients IS withdrawal is feasible and safe, the procedure is not without risk, as it can induce immunologically-mediated allograft rejection. In this regard, the main risks of IS withdrawal are acute and/or chronic rejection, silent development of allograft fibrosis, potential complications associated with the need to increase IS to treat rejection episodes; and graft loss or patient mortality.

Where is the study run from?
King's College London (UK)

When is the study starting and how long is it expected to run for?
August 2015 to October 2017

Who is funding the study?
National Institute for Health Research (UK)

Who is the main contact?
Ms Jurate Wall

Trial website

Contact information



Primary contact

Ms Jurate Wall


Contact details

King's College London
Denmark Hill
United Kingdom

Additional identifiers

EudraCT number

2014-004557-14 number

Protocol/serial number


Study information

Scientific title

Prospective randomised marker-based trial to assess the clinical utility and safety of biomarker-guided immunosuppression withdrawal in liver transplantation ("LIFT" Trial).



Study hypothesis

The objective of this study is to determine if a genetic test of tolerance in liver biopsies can be employed to optimize immunosuppression withdrawal, so that withdrawal is only performed in patients who have developed tolerance.

Ethics approval

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

Study design

Randomised; Interventional; Design type: Treatment

Primary study design


Secondary study design

Randomised controlled trial

Trial setting


Trial type


Patient information sheet

Not available in web format, please use contact details to request a participant information sheet


Topic: Hepatology; Subtopic: Hepatology; Disease: All Hepatology


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-)

Intervention type



Drug names

Primary outcome measure

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 measures

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

Overall trial start date


Overall trial end date


Reason abandoned (if study stopped)


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

Participant type


Age group




Target number of participants

Planned Sample Size: 148; UK Sample Size: 98

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 childbearing age not using effective contraception
9. Current illicit drug or alcohol abuse
10. Inability to participate in frequent monitoring of liver function (every 3 weeks) and clinical visits during IS withdrawal
11. Inability to comply with study directed treatment
12. Any medical condition that in the opinion of the principal investigator would interfere with safe completion of the trial

Recruitment start date


Recruitment end date



Countries of recruitment

United Kingdom

Trial participating centre

King's College Hospital (lead)
United Kingdom

Sponsor information


King's College London

Sponsor details

Division of Applied Biomedical Research
United Kingdom

Sponsor type




Funder type


Funder name

National Institute for Health Research

Alternative name(s)


Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government


United Kingdom

Results and Publications

Publication and dissemination plan

In order to disseminate the results of the research we will:
1. Engage with the communication officers at King's College London, MRC Centre for Transplantation and NIHR BRC at Guy´s and St Thomas Trust to highlight our achievements within their websites and newsletters
2. Submit the results to national and international scientific meetings and to high impact factor publications (NEJM, Lancet or similar)
3. Engage with liver transplant recipients through patient groups that promote the interests of patients receiving liver transplants such as LISTEN (London-based), Royal Victoria Hospital Liver Patients Group (based in Belfast), ALTA (Cambridge), and Birmingham Liver Transplant Support Group.
4. Disseminate the results through the regular meetings of the Comprehensive Local Research
Network for liver
5. Participation in the EU BIO-DrIM Consortium will facilitate dissemination at European level.
6. Share our results with the US Immune Tolerance Network, a NIH-supported research consortium focused in promoting the performance of immune tolerance clinical trials in transplantation and autoimmunity
There are no restrictions on this dissemination.

Intention to publish date

Participant level data

Not provided at time of registration

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes