Transplantation, LiverPhase 4LIFTNCT02498977
Liver Immunosuppression Free Trial
A Phase 4 study testing Biomarker and Tacrolimus, cyclosporine and/or mycophenolic acid, mycophenolate mofetil or azathioprine in people with Transplantation, Liver, run by King's College London at 2 sites in United Kingdom.
Trial summary
LIFT is prospective randomised marker-based trial to assess the clinical utility and safety of biomarker-guided immunosuppression withdrawal in liver transplantation. 'LIFT' aims to validate a biomarker test of operational tolerance to stratify liver transplant recipients before withdrawing immunosuppressive… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Transplantation, Liver
- What is being tested?
- Biomarker and Tacrolimus, cyclosporine and/or mycophenolic acid, mycophenolate mofetil or azathioprine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 116 participants
- Where
- 2 sitesUnited Kingdom
- Study dates
- Oct 2015to 31 Dec 2021
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- At the time of screening: more than 3 years post-transplant if participants are ≥50 years old, OR more than 6 years post-transplant if participant age is 18-49 years old.
- Recipient of either deceased or living donor liver transplant.
- Recipient of single organ transplant only
- Liver function tests: direct bilirubin ≤17.1 umol/L and Alanine aminotransferase (ALT) ≤60 IU/L at the screening visit.
- 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).
- Ability to sign informed consent.
Who cannot join
- Serum positivity for Hepatitis C virus (HCV-RNA)
- Serum positivity for HIV-1 infection, Hepatitis B virus (HBV) surface antigen or HBV-DNA
- Immune-mediated liver disease in which IS discontinuation is inadvisable (autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis).
- Acute or chronic rejection within the 52 weeks prior to screening.
- Glomerular filtration rate (GFR) <40 mL/min (to mitigate the risk of worsening renal failure should rejection occur and high level of CNI be required).
- The need for chronic anti-coagulation that cannot be safely discontinued to safely perform for a liver biopsy.
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- 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; f) any other findings that might make participation in the trial unsafe. Eligibility will be determined by the central pathologist.
- Patient age <18 years old at the time of transplant.
- Pregnant females and females of childbearing age not using effective contraception.
- Current illicit drug or alcohol abuse.
- Inability to participate in frequent monitoring of liver function (every 3 weeks) and clinical visits during IS withdrawal.
- Inability to comply with study directed treatment.
- Any medical condition that in the opinion of the principal investigator would interfere with safe completion of the trial.
- Participation in another clinical trial during the month prior to enrollment.
Trial locations and contacts
2 sites in 1 country.
United Kingdom2 sites
King's College Hospital NHS Foundation Trust
London, SE5 9RS
The Newcastle upon Tyne Hospitals NHS Foundation Trust
Newcastle, NE7 7DN
About this study
Official title: Prospective Randomised Marker-based Trial to Assess the Clinical Utility and Safety of Biomarker-guided Immunosuppression Withdrawal in Liver Transplantation
LIFT is prospective randomised marker-based trial to assess the clinical utility and safety of biomarker-guided immunosuppression withdrawal in liver transplantation. 'LIFT' aims to validate a biomarker test of operational tolerance to stratify liver transplant recipients before withdrawing immunosuppressive medication. Primary objective is clinical utility and risk/benefit ratio of employing a transcriptional test of tolerance to stratify liver recipients prior to immunosuppression withdrawal. Secondary objectives are: safety of biomarker-guided immunosuppression withdrawal; health-economic and quality of life impact of biomarker-guided immunosuppression withdrawal; improvement in drug-related co-morbidities; prevalence of tolerance over time; role of donor-specific anti-human leukocyte antigen (HLA) antibodies; identify mechanisms of liver allograft tolerance. It is a prospective, multi-centre, phase IV, biomarker-strategy design trial with a randomized control group in which adult liver transplant recipients will undergo immunosuppression withdrawal. The sample size is 148 patients.
Read the detailed description
This is a prospective, multi-centre, phase IV, biomarker-strategy design trial with a randomised control group in which adult liver transplant recipients will undergo immunosuppression (IS) withdrawal. Immunosuppression drugs (IS) are: Tacrolimus, cyclosporine and/or mycophenolic acid, mycophenolate mofetil or azathioprine.
Enrolled participants will be randomised 1:1 to either: 1) Non-Biomarker-based IS weaning (Weaning-All; Arm A); or 2) Biomarker-based IS weaning (Arm B). In participants allocated to Arm A IS will be withdrawn regardless of the result of the biomarker test. Among participants allocated to Arm B, only those found to be biomarker-positive (Arm B+, i.e. potentially tolerant) will be offered IS withdrawal, while biomarker-negative participants (Arm B-, i.e. potentially non-tolerant) will remain on their baseline maintenance IS. This will allow us to demonstrate that the biomarker is a useful test to personalise IS by offering drug withdrawal only to those participants who are likely to complete the process successfully, avoiding unnecessary rejections among those who have not developed tolerance. Comparing the outcome of IS withdrawal between arms A and B+ will provide direct evidence of the clinical usefulness of the test as a function of its predictive accuracy. We have established that for the biomarker to drive safe IS withdrawal its Positive Predictive Value should be no less than 0.80, and its sensitivity at least 070. To account for centre effects, we will use stratified randomization. Furthermore, to avoid biases, participants undergoing drug withdrawal and their physicians will be blinded to the biomarker results. Participants randomized to Arm B- will know their biomarker status, and will be maintained in the study until its termination and contribute to secondary clinical outcomes and to the evaluation of the stability of the tolerance signature.
Cost and quality of life (HrQOL) assessments will be conducted alongside the trial to estimate the health-economic implications of the 2 different strategies. Furthermore, sequential biological specimens will be collected to conduct ancillary mechanistic studies. Recruitment will take place in 11 European liver transplant units (King's College Hospital, Royal Free London, Newcastle, Birmingham, Leeds, Edinburgh, Cambridge, Leuven, Hannover, Berlin and Barcelona).
- Conditions
- Transplantation, Liver
- Being tested
- Biomarker, Tacrolimus, cyclosporine and/or mycophenolic acid, mycophenolate mofetil or azathioprine
- Keywords
- Liver, Transplant, Immunosuppression
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BiomarkerGenetic
Real time polymerase chain reaction (PCR) gene expression measurement
Tacrolimus, cyclosporine and/or mycophenolic acid, mycophenolate mofetil or azathioprineDrug
Also called IS
Immunosuppression drugs as per protocol
| Study group | Role | What they receive |
|---|---|---|
| Arm A (weaning) | Active comparator | All participants satisfying clinical criteria will be weaned off immunosuppression drugs irrespective of biomarker result. Receives: Drug: Tacrolimus, cyclosporine and/or mycophenolic acid, mycophenolate mofetil or azathioprine |
| Arm B+ (weaning- positive biomarker) | Active comparator | Participants with a positive biomarker will be weaned of immunosuppression drugs. Receives: Genetic: Biomarker |
| Arm B- (maintenance) | Active comparator | Participant with negative biomarker test result will be informed of the result and will remain on baseline maintenance immunosuppression drugs. Receives: Genetic: Biomarker |
What is being measured
The primary outcome is the main question the study is designed to answer.
Successful discontinuation of IS with maintenance of normal allograft status
Number of patients with successful discontinuation of IS with maintenance of normal allograft status as assessed by liver biopsy and liver tests 12 months after IS withdrawal (operational tolerance)
Measured: 12 months from IS withdrawal
Secondary outcomes (5)
Proportion of tolerant participants remaining free of rejection
Measures of rejection in patients (incidence, severity, timing, steroid resistant rejection, chronic rejection) and to investigate if liver transplant recipients under IS become operationally tolerant over time.
Measured: 3 years post IS withdrawal
Renal function at 1, 2 and 3 years after enrollment and change in co-morbidities
To determine the extent to which IS withdrawal improve drug-related co-morbidities associated with IS use (hypertension, cardiovascular risk profile, diabetes mellitus, hyperlipidemia, malignancy) and to explore the association between operational liver transplant tolerance, iron metabolism, immunosenescence, and specific gut microbiome profiles.
Measured: 3 years post IS withdrawal
Development of anti-HLA antibodies (before and after initiation of IS withdrawal).
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.
Measured: 3 years post IS withdrawal
Change in Health related quality of life (HrQOL)
To assess the effect of IS withdrawal on the quality of life of liver transplant recipients.
Measured: 3 years post IS withdrawal
Costs of treatment
Measuring pharmacoeconomic impact of IS withdrawal.
Measured: 3 years post IS withdrawal
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Jul 2015 (estimated)
- Study startOct 2015
- Primary completion31 Dec 2021
- Study completion31 Dec 2021
Why it stopped: Primary endpoint not reached.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Transplantation, LiverStudies of the same condition, open and under way.
- More trials run by King's College LondonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Health services research
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 116 participants (actual)
Sponsor and investigators
- Lead sponsor
- King's College London
- Sponsor type
- University, hospital or other
- Collaborators
- King's College Hospital NHS Trust, National Institute for Health Research, United Kingdom
- Responsible party
- Sponsor
- Investigators
- Alberto Sanchez-Fueyo, Principal investigator, King's College London
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02498977
- Sponsor's protocol ID
- ASF/001-01
- Other IDs
- 2014-004557-14, 2014
- Acronym
- LIFT
- Status last verified
- Mar 2024
- First submitted
- 11 Jun 2015
- Last updated
- 7 Mar 2024
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 7 Mar 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prospective Randomised Marker-based Trial to Assess the Clinical Utility and Safety of Biomarker-guided Immunosuppression Withdrawal in Liver Transplantation
- ClinicalTrials.gov ID
- NCT02498977
- Acronym / sponsor ID
- LIFT / ASF/001-01
- Conditions
- Transplantation, Liver
- Keywords
- Liver, Transplant, Immunosuppression
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Primary endpoint not reached.
- Enrolment
- 116 participants (actual)
- Lead sponsor
- King's College LondonUniversity, hospital or other
- Collaborators
- King's College Hospital NHS Trust, National Institute for Health Research, United Kingdom
- Study start
- Oct 2015 (actual)
- Primary completion
- 31 Dec 2021 (actual)
- Study completion
- 31 Dec 2021 (actual)
- First posted
- 15 Jul 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
LIFT is prospective randomised marker-based trial to assess the clinical utility and safety of biomarker-guided immunosuppression withdrawal in liver transplantation. 'LIFT' aims to validate a biomarker test of operational tolerance to stratify liver transplant recipients before withdrawing immunosuppressive medication. Primary objective is clinical utility and risk/benefit ratio of employing a transcriptional test of tolerance to stratify liver recipients prior to immunosuppression withdrawal. Secondary objectives are: safety of biomarker-guided immunosuppression withdrawal; health-economic and quality of life impact of biomarker-guided immunosuppression withdrawal; improvement in drug-related co-morbidities; prevalence of tolerance over time; role of donor-specific anti-human leukocyte antigen (HLA) antibodies; identify mechanisms of liver allograft tolerance. It is a prospective, multi-centre, phase IV, biomarker-strategy design trial with a randomized control group in which adult liver transplant recipients will undergo immunosuppression withdrawal. The sample size is 148 patients.
Detailed description
This is a prospective, multi-centre, phase IV, biomarker-strategy design trial with a randomised control group in which adult liver transplant recipients will undergo immunosuppression (IS) withdrawal. Immunosuppression drugs (IS) are: Tacrolimus, cyclosporine and/or mycophenolic acid, mycophenolate mofetil or azathioprine.
Enrolled participants will be randomised 1:1 to either: 1) Non-Biomarker-based IS weaning (Weaning-All; Arm A); or 2) Biomarker-based IS weaning (Arm B). In participants allocated to Arm A IS will be withdrawn regardless of the result of the biomarker test. Among participants allocated to Arm B, only those found to be biomarker-positive (Arm B+, i.e. potentially tolerant) will be offered IS withdrawal, while biomarker-negative participants (Arm B-, i.e. potentially non-tolerant) will remain on their baseline maintenance IS. This will allow us to demonstrate that the biomarker is a useful test to personalise IS by offering drug withdrawal only to those participants who are likely to complete the process successfully, avoiding unnecessary rejections among those who have not developed tolerance. Comparing the outcome of IS withdrawal between arms A and B+ will provide direct evidence of the clinical usefulness of the test as a function of its predictive accuracy. We have established that for the biomarker to drive safe IS withdrawal its Positive Predictive Value should be no less than 0.80, and its sensitivity at least 070. To account for centre effects, we will use stratified randomization. Furthermore, to avoid biases, participants undergoing drug withdrawal and their physicians will be blinded to the biomarker results. Participants randomized to Arm B- will know their biomarker status, and will be maintained in the study until its termination and contribute to secondary clinical outcomes and to the evaluation of the stability of the tolerance signature.
Cost and quality of life (HrQOL) assessments will be conducted alongside the trial to estimate the health-economic implications of the 2 different strategies. Furthermore, sequential biological specimens will be collected to conduct ancillary mechanistic studies. Recruitment will take place in 11 European liver transplant units (King's College Hospital, Royal Free London, Newcastle, Birmingham, Leeds, Edinburgh, Cambridge, Leuven, Hannover, Berlin and Barcelona).
Study design
- Primary purpose
- Health services research
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (participant)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Arm A (weaning) | Active comparator | Drug: Tacrolimus, cyclosporine and/or mycophenolic acid, mycophenolate mofetil or azathioprineAll participants satisfying clinical criteria will be weaned off immunosuppression drugs irrespective of biomarker result. |
| Arm B+ (weaning- positive biomarker) | Active comparator | Genetic: BiomarkerParticipants with a positive biomarker will be weaned of immunosuppression drugs. |
| Arm B- (maintenance) | Active comparator | Genetic: BiomarkerParticipant with negative biomarker test result will be informed of the result and will remain on baseline maintenance immunosuppression drugs. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- At the time of screening: more than 3 years post-transplant if participants are ≥50 years old, OR more than 6 years post-transplant if participant age is 18-49 years old.
- Recipient of either deceased or living donor liver transplant.
- Recipient of single organ transplant only
- Liver function tests: direct bilirubin ≤17.1 umol/L and Alanine aminotransferase (ALT) ≤60 IU/L at the screening visit.
- 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).
Key exclusion criteria (14 listed)
- Serum positivity for Hepatitis C virus (HCV-RNA)
- Serum positivity for HIV-1 infection, Hepatitis B virus (HBV) surface antigen or HBV-DNA
- Immune-mediated liver disease in which IS discontinuation is inadvisable (autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis).
- Acute or chronic rejection within the 52 weeks prior to screening.
- Glomerular filtration rate (GFR) <40 mL/min (to mitigate the risk of worsening renal failure should rejection occur and high level of CNI be required).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BiomarkerReal time polymerase chain reaction (PCR) gene expression measurement | Genetic | Arm B+ (weaning- positive biomarker), Arm B- (maintenance) |
| Tacrolimus, cyclosporine and/or mycophenolic acid, mycophenolate mofetil or azathioprineAlso: ISImmunosuppression drugs as per protocol | Drug | Arm A (weaning) |
Primary outcome
Successful discontinuation of IS with maintenance of normal allograft status
Time frame: 12 months from IS withdrawal
Number of patients with successful discontinuation of IS with maintenance of normal allograft status as assessed by liver biopsy and liver tests 12 months after IS withdrawal (operational tolerance)
5 secondary outcomes
Proportion of tolerant participants remaining free of rejection
Time frame: 3 years post IS withdrawal
Renal function at 1, 2 and 3 years after enrollment and change in co-morbidities
Time frame: 3 years post IS withdrawal
Development of anti-HLA antibodies (before and after initiation of IS withdrawal).
Time frame: 3 years post IS withdrawal
Change in Health related quality of life (HrQOL)
Time frame: 3 years post IS withdrawal
Costs of treatment
Time frame: 3 years post IS withdrawal
Results and safety
The study was stopped early (reason given: Primary endpoint not reached.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Mar 2024.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Alberto Sanchez-Fueyo principal investigator
King's College London
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Biomarker and Tacrolimus, cyclosporine and/or mycophenolic acid, mycophenolate mofetil or azathioprine in people with Transplantation, Liver, run by King's College London at 2 sites in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 7 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Primary endpoint not reached.). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Successful discontinuation of IS with maintenance of normal allograft status (time frame: 12 months from IS withdrawal). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Mar 2024.