Clinical trial NCT01638559: Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients
Official title: Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Liver Transplant Recipients
Liver Transplantation
Immunosuppression
Keywords: liver transplant
allograft function
anti-rejection
immunosuppression withdrawal
tolerance
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Immune Tolerance Network (ITN)
First posted: 2012-07-11
Enrollment: 161
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Detailed description: 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.

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.

Primary outcomes:
measure: Number of Operationally Tolerant Participants
timeFrame: 12 Months after complete immunosuppression withdrawal
Secondary outcomes:
measure: Number of Participants With Clinical Complications Usually Attributed to Immunosuppression
timeFrame: Time from immunosuppression withdrawal through a minimum of 36 months and a maximum of 48 months of follow-up
measure: Time to Increased Immunosuppression or Re-Initiation of Immunosuppression
timeFrame: Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up
measure: Time to Resolution of Rejection
timeFrame: Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up
measure: Number and Severity of Biopsies Read as Histologic Acute Rejection
timeFrame: Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up
measure: Clinical Severity of Acute Rejection
timeFrame: Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up
measure: Reason for Discontinuation of Withdrawal
timeFrame: Time from start of immunosuppression withdrawal through discontinuation of withdrawal, a maximum of 52 weeks
measure: Impact of Immunosuppression Withdrawal (ISW) on Allograft Histology
timeFrame: Time from screening biopsy to end of study (month 48) biopsy
measure: Duration of Operational Tolerance
timeFrame: Time from immunosuppression withdrawal through a minimum of 36 months and a maximum of 48 months of follow-up
measure: Change in Immunosuppression Medication (Calcineurin Inhibitor) Dose From Start of Immunosuppression Withdrawal to the Time of Immunosuppression Withdrawal Failure
timeFrame: Time from starting immunosuppression withdrawal until immunosuppression withdrawal failure, maximum 52 weeks
measure: Change in Immunosuppression Medication Dose From Study Initiation of Withdrawal to the End of the Study
timeFrame: Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up
measure: Change in Child Health Related Quality of Life Scores Between Tolerant and Non-tolerant Subjects
timeFrame: Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California
state: California
city: Aurora
country: United States
facility: Children's Hospital of Colorado
state: Colorado
city: Atlanta
country: United States
facility: Emory University and Children's Hospital of Atlanta
state: Georgia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Ann Arbor
country: United States
facility: University of Michigan C. S. Mott Children's Hospital
state: Michigan
city: Saint Louis
country: United States
facility: St. Louis Children's Hospital - Washington University
state: Missouri
city: New York
country: United States
facility: New York Presbyterian Morgan Stanley Children's Hospital - Columbia University Medical Center
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
Study officials:
affiliation: University of California, San Francisco
name: S Feng, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital Medical Center, Cincinnati
name: J Bucuvalas, M.D.
role: STUDY_CHAIR
References:
citation: Feng S, Ekong UD, Lobritto SJ, Demetris AJ, Roberts JP, Rosenthal P, Alonso EM, Philogene MC, Ikle D, Poole KM, Bridges ND, Turka LA, Tchao NK. Complete immunosuppression withdrawal and subsequent allograft function among pediatric recipients of parental living donor liver transplants. JAMA. 2012 Jan 18;307(3):283-93. doi: 10.1001/jama.2011.2014.
citation: Perito ER, Mohammad S, Rosenthal P, Alonso EM, Ekong UD, Lobritto SJ, Feng S. Posttransplant metabolic syndrome in the withdrawal of immunosuppression in Pediatric Liver Transplant Recipients (WISP-R) pilot trial. Am J Transplant. 2015 Mar;15(3):779-85. doi: 10.1111/ajt.13024. Epub 2015 Feb 3.
citation: Reding R. Long-term complications of immunosuppression in pediatric liver recipients. Acta Gastroenterol Belg. 2005 Oct-Dec;68(4):453-6.
citation: Mohammad S, Sundaram SS, Mason K, Lobritto S, Martinez M, Turmelle YP, Bucuvalas J, Feng S, Alonso EM. Improvements in Disease-Specific Health-Related Quality of Life of Pediatric Liver Transplant Recipients During Immunosuppression Withdrawal. Liver Transpl. 2021 May;27(5):735-746. doi: 10.1002/lt.25963.
citation: Feng S, Bucuvalas JC, Mazariegos GV, Magee JC, Sanchez-Fueyo A, Spain KM, Lesniak A, Kanaparthi S, Perito E, Venkat VL, Burrell BE, Alonso EM, Bridges ND, Doo E, Gupta NA, Himes RW, Ikle D, Jackson AM, Lobritto SJ, Jose Lozano J, Martinez M, Ng VL, Rand EB, Sherker AH, Sundaram SS, Turmelle YP, Wood-Trageser M, Demetris AJ. Efficacy and Safety of Immunosuppression Withdrawal in Pediatric Liver Transplant Recipients: Moving Toward Personalized Management. Hepatology. 2021 May;73(5):1985-2004. doi: 10.1002/hep.31520.