Immunosuppression withdrawal in liver transplantation MedDRA version: 20.0 Level: LLT Classification code 10024716 Term: Liver transplantation System Organ Class: 100000004865
Conditions
Interventions
Product Name: Tacrolimus
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: TACROLIMUS
CAS Number: 104987113
Other descriptive name: TACROLIMUS MONOHYDRATE
Concentration unit: mg milligram(s)
Co
Sponsors
King's College London
King’s College Hospital NHS Foundation Trust
Eligibility
Sex/Gender
All
Inclusion 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 =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) 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), sirolimus/everolimus or on monotherapy with sirolimus/everolimus or mycophenolate/mycophenolic 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. 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
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 <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. 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 (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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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.;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;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 and 24 months after IS withdrawal (operational tolerance) and stable liver tests (12, 24 and 36 months after IS withdrawal). 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
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Rejection (incidence, severity, timing, steroid resistant rejection, chronic rejection). - Reasons for failure of IS withdrawal. - Requirement for IS re-institution despite successful IS withdrawal on the basis of the histological criteria described in Table 5. - 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). - Stability of the biomarker signature between baseline and last study visit. - HrQOL changes associated with IS withdrawal. - Pharmacoeconomic impact of IS withdrawal. - Fibroscan: 1 To assess if drug withdrawal results in sequential changes in liver stiffness over time in patients considered tolerant. 2 To evaluate if development of an episode of rejection in patients who do not successfully discontinue immunosuppression increases liver stiffness measurements. 3 To compare changes in liver stiffness over time in patients who remain on maintenance immunosuppression and those who undergo drug weaning. The secondary mechanistic endpoints of the trial are: - Intra-hepatic and systemic iron parameters. - Time post-transplant, age, sex and type of IS. - Markers of immune-exhaustion in blood and liver tissue. - Gut microbiome profile. - Blood and intra-hepatic lymphocyte subsets (including regulatory T cells). - Development of anti-HLA antibodies (before and after initiation of IS withdrawal). ;Timepoint(s) of evaluation of this end point: Throughout the trial | — |
Countries
Belgium, Germany, Spain, United Kingdom
Contacts
Public ContactProf Alberto Sanchez-Fueyo
King's College London
Outcome results
None listed