Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients

Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients

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

Anti-rejection medicines, also known as immunosuppressive drugs, are prescribed to organ transplant recipients to prevent rejection of the new organ. Long-term use of these medicines places transplant recipients at higher risk of serious infections and certain types of cancer.

This study seeks to:

• Find out if it is safe to slowly reduce and then completely stop the immunosuppression taken by children who have received liver transplants. This process is called 'immunosuppression withdrawal'or ISW.
• Find blood or liver biopsy tests that can help transplant doctors in the future to predict if it is safe to decrease or stop immunosuppression drugs in children who have had a liver transplant.

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.