Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients
Condition: Liver Transplant Recipients; Liver Transplantation; Immunosuppression
Intervention: Immunosuppression withdrawal
Intervention description: Participants will undergo gradual ISW in no less than 36 weeks and no more than 52 weeks with frequent monitoring of liver tests. All participants will be followed for 48 months ensuring a minimum of 36 months of follow-up after successful ISW.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 161.0
Sex: All
Maximum age: 18 Years
Healthy volunteers: No
Keywords: liver transplant; allograft function; anti-rejection; immunosuppression withdrawal; tolerance

Summary:

      The primary objective of this study is to assess the efficacy of immunosuppression withdrawal
      (ISW) in pediatric liver transplant (tx) recipients.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subject and/or parent guardian must be able to understand and provide informed
             consent;

          -  Is the recipient of a living or deceased donor liver tx when subject was less than or
             equal to 6 years of age;

          -  Is at least 4 years post-tx at the time of study enrollment;

          -  Has normal allograft function defined as Alanine aminotransferase (ALT) < 50 IU/l and
             gamma-glutamyl transferase (GGT) < 50 IU/l;

          -  Has no evidence of acute rejection (AR) or chronic rejection (CR) within the past 2
             years, based on medical history;

          -  Is stable on IS monotherapy with a calcineurin inhibitor (CNI);

          -  For female subjects of childbearing potential, subject must have a negative pregnancy
             test upon study entry;

          -  For female and male subjects with reproductive potential, subject must agree to use
             FDA approved methods of birth control for the duration of the study;

          -  Must be negative for hepatitis B virus (HBV) and hepatitis C virus (HCV) infection
             within one year of enrollment;

          -  Must have screening biopsy that fulfills, based on central pathology reading, the
             following criteria:

               -  Portal inflammation and interface activity: Preferably absent, but minimal to
                  focal mild portal mononuclear inflammation may be present. Interface
                  necro-inflammatory activity is absent or equivocal/minimal and, if present,
                  involves a minority of portal tracts.

               -  Centrizonal/peri-venular inflammation: Preferably absent, but minimal to focal
                  mild perivenular mononuclear inflammation may be present. Perivenular
                  necro-inflammatory activity is absent or equivocal/minimal and, if present,
                  involves a minority of terminal hepatic venules.

               -  Bile duct changes: No lymphocytic bile duct damage, ductopenia and biliary
                  epithelial senescence changes, unless there is an alternative, non-immunologic
                  explanation (e.g. biliary strictures).

               -  Fibrosis: < Ishak Stage 3 (i.e. not more than occasional portal-to-portal
                  bridging). Perivenular fibrosis should be less than "moderate", according to
                  Banff Criteria.

               -  Arteries: Negative for obliterative or foam cell arteriopathy.

        Exclusion Criteria:

          -  Have received a liver tx for autoimmune liver disease, including autoimmune hepatitis
             or primary sclerosing cholangitis;

          -  Have received a liver tx for hepatitis B or hepatitis C;

          -  Have received a second organ transplant before, simultaneously, or after liver tx;

          -  Have a calculated glomerular filtration rate (modified Schwartz formula) of less than
             60 mL/min/1.73 m^2;

          -  Have had a 50 percent (%) dose increase in CNI within 6 months of screening;

          -  Have discontinued a second IS agent within 12 months of screening;

          -  Have any systemic illness requiring or likely to require chronic or recurrent use of
             IS;

          -  Is pregnant or breastfeeding;

          -  Is unwilling or unable to adhere with study requirements and procedures;

          -  Have mental illness or history of drug or alcohol abuse that, in the opinion of the
             investigator, would interfere with the participant's ability to comply with study
             requirements;

          -  Is unwilling or unable to provide consent or comply with the study protocol;

          -  Has used investigational drugs within 4 weeks of enrollment;

          -  Is receiving treatment for HIV infection;

          -  Has received any licensed or investigational live attenuated vaccine(s) within two
             months of enrollment;

          -  Has any medical condition that, in the opinion of the investigator, will interfere
             with safe participation in the trial.