A clinical trial to work out how safe it is to gradually withdraw immunosuppressive drugs in people who had a liver transplant

• Register: EUCTR
• Last refreshed on: 28 December 2015
• Main ID: EUCTR2014-004557-14-ES
• Date of registration: 10/12/2015
• Prospective Registration: Yes
• Primary sponsor: King's College London
• Public title: A clinical trial to work out how safe it is to gradually withdraw immunosuppressive drugs in people who had a liver transplant
• Scientific title: Prospective randomised marker-based trial to assess the clinical utility and safety of biomarker-guided immunosuppression withdrawal in liver transplantation - LIFT
• Date of first enrolment: 17/12/2015
• Target sample size: 148
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-004557-14
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: yes Other specify the comparator: Immunosuppression withdrawal performed without the guidance of the stratifying biomarker test Number of treatment arms in the trial: 3

Countries of recruitment

Spain, United Kingdom

Contacts

• Name: Prof Alberto Sanchez-Fueyo
• Affiliation: King's College London

• Name: Prof Alberto Sanchez-Fueyo
• Affiliation: King's College London

Key inclusion & exclusion criteria

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 ( ? 1500 mg daily); or on mycophenolate/mycopheolic acid 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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 148
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 148

Exclusion criteria:
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 <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 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. Elligibility 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.
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.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Diagnosis [E01]

Immunosuppression withdrawal in liver transplantation
MedDRA version: 18.1 Level: LLT Classification code 10024716 Term: Liver transplantation System Organ Class: 100000004865

Intervention(s)

Product Name: Tacrolimus
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: TACROLIMUS
CAS Number: 104987113
Other descriptive name: TACROLIMUS MONOHYDRATE
Concentration unit: µg/kg microgram(s)/kilogram
Concentration type: up to
Concentration number: 200-

Product Name: Mycophenolic acid
Pharmaceutical Form: Capsule
INN or Proposed INN: MYCOPHENOLIC ACID
CAS Number: 24280-93-1
Other descriptive name: Mycophenolate
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1440-

Product Name: ciclosporin
Pharmaceutical Form: Capsule
INN or Proposed INN: Cyclosporin
CAS Number: 59865-13-3
Other descriptive name: cyclosporine, cyclosporin, ciclosporin A, cyclosporine A, cyclosporin
Concentration unit: mg/kg milligram(s)/kilogram
Concentration type: up to
Concentration number: 15-

Product Name: Mycophenolate mofetil
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: mycophenolate mofetil
Other descriptive name: MYCOPHENOLATE MOFETIL
Concentration unit: g gram(s)
Concentration type: equal
Concentration number: 2-

Primary Outcome(s)

Main Objective: To determine if the use of a liver tissue transcriptional test of tolerance to stratify liver recipients prior to immunosuppression (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.

Primary end point(s): The primary endpoint is defined as the successful discontinuation of IS with maintainance of normal allograft status as assessed by liver biopsy and liver tests 12 months after IS withdrawal (operational tolerance). For the purposes of validating the clinical usefulness of the tolerance biomarker, successful IS withdrawal is considered the Gold Standard. Since this outcome is strictly restricted to the IS withdrawal process and by definition cannot be observed in Arm B-, the analysis of the primary outcome will be restricted to Arms A and B+.

Timepoint(s) of evaluation of this end point: 12 months after IS withdrawal

Secondary Objective: 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 Outcome(s)

Timepoint(s) of evaluation of this end point: Throughout the trial

Secondary end point(s): Rejection (incidence, severity, timing, steroid resistant rejection, chronic rejection).
Reasons for failure of IS withdrawal.
Progression of graft fibrosis in tolerant participants and those on maintenance IS.
Graft loss.
All?cause mortality.
Proportion of tolerant participants remaining free of rejection at 3 years post IS withdrawal.
Renal function at 1, 2 and 3 years after enrollment.
Change in co-morbidities associated with IS use (hypertension, cardiovascular risk profile, diabetes mellitus, hyperlipidemia, malignancy).
HrQOL changes associated with IS withdrawal
Pharmacoeconomic impact of IS withdrawal


The secondary mechanistic endpoints of the trial are:
Intra-hepatic and systemic iron parameters.
Time post-trasnplant, age, sex and type of IS.
Markers of immune-exhaustion on blood and liver tissue.
Gut microbiome profile.
Blood and intra-hepatic lymphocite subsets (including regulatory T cells).
Development of anti-HLA antibodies(before and after initiation of IS withdrawal).

Secondary ID(s)

2014-004557-14-GB

ASF/001-01

LIFT

Source(s) of Monetary Support

NIHR - EME grant

Secondary Sponsor(s)

King?s College Hospital NHS Foundation Trust