Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients

NCT ID: NCT01638559

Last Updated: 2019-10-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 161 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-08-14
• Study Completion Date: 2018-06-11

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.

Conditions

Liver Transplant Recipients; Liver Transplantation; Immunosuppression

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Immunosuppression withdrawal

Gradual withdrawal of immunosuppressive treatment withdrawal as per protocol.

Group Type: EXPERIMENTAL

Immunosuppression withdrawal

Intervention Type: DRUG

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.

Interventions

Immunosuppression withdrawal

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.

Intervention Type: DRUG

Other Intervention Names

ISW

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.

• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

Immune Tolerance Network (ITN)

NETWORK

Sponsor Role: collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

S Feng, M.D., Ph.D.

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

J Bucuvalas, M.D.

Role: STUDY_CHAIR

Children's Hospital Medical Center, Cincinnati

Locations

University of California

San Francisco, California, United States

Children's Hospital of Colorado

Aurora, Colorado, United States

Emory University and Children's Hospital of Atlanta

Atlanta, Georgia, United States

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, United States

University of Michigan C. S. Mott Children's Hospital

Ann Arbor, Michigan, United States

St. Louis Children's Hospital - Washington University

St Louis, Missouri, United States

New York Presbyterian Morgan Stanley Children's Hospital - Columbia University Medical Center

New York, New York, United States

Cincinnati Children's Hospital

Cincinnati, Ohio, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, United States

Texas Children's Hospital

Houston, Texas, United States

The Hospital for Sick Children

Toronto, Ontario, Canada

Countries

United States; Canada

References

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.

Reference Type: BACKGROUND

PMID: 22253395 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25648649 (View on PubMed)

Reding R. Long-term complications of immunosuppression in pediatric liver recipients. Acta Gastroenterol Belg. 2005 Oct-Dec;68(4):453-6.

Reference Type: BACKGROUND

PMID: 16433002 (View on PubMed)

Wood-Trageser MA, Lesniak D, Gambella A, Golnoski K, Feng S, Bucuvalas J, Sanchez-Fueyo A, Demetris AJ. Next-generation pathology detection of T cell-antigen-presenting cell immune synapses in human liver allografts. Hepatology. 2023 Feb 1;77(2):355-366. doi: 10.1002/hep.32666. Epub 2022 Aug 1.

Reference Type: DERIVED

PMID: 35819312 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33280227 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32786149 (View on PubMed)

Related Links

https://www.niaid.nih.gov/

National Institute of Allergy and Infectious Diseases (NIAID)

http://www.immunetolerance.org

Immune Tolerance Network (ITN)

Other Identifiers

U01AI100807

Identifier Type: NIH

Identifier Source: secondary_id

View Link

RTB-001

Identifier Type: OTHER

Identifier Source: secondary_id

NIAID DAIT CRMS ID#: 20129

Identifier Type: OTHER

Identifier Source: secondary_id

DAIT iWITH

Identifier Type: -

Identifier Source: org_study_id