Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients

NCT01638559 | Completed Phase 2 Results DMC FDA Drug

• 4 other identifiers: DAIT iWITHU01AI100807RTB-001NIAID DAIT CRMS ID#: 20129
• Study Type: interventional
• Target: 161
• Locations: 2 countries
• Sites: 12

Brief Summary

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

Conditions

Liver Transplant Recipients; Liver Transplantation; Immunosuppression

Keywords

liver transplant; allograft function; anti-rejection; immunosuppression withdrawal; tolerance

Outcome Measures

Primary Outcomes (1)

• Number of Operationally Tolerant Participants

  Number of participants that are operationally tolerant, defined as those who successfully withdraw from immunosuppression and maintain normal allograft status as assessed by liver biopsy and liver tests 12 months after complete immunosuppression withdrawal.

  12 Months after complete immunosuppression withdrawal

Secondary Outcomes (11)

• Number of Participants With Clinical Complications Usually Attributed to Immunosuppression

  Time from immunosuppression withdrawal through a minimum of 36 months and a maximum of 48 months of follow-up

• Time to Increased Immunosuppression or Re-Initiation of Immunosuppression

  Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up

• Time to Resolution of Rejection

  Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up

• Number and Severity of Biopsies Read as Histologic Acute Rejection

  Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up

• Clinical Severity of Acute Rejection

  Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up

Study Arms (1)

Immunosuppression withdrawal

EXPERIMENTAL

Gradual withdrawal of immunosuppressive treatment withdrawal as per protocol.

Drug: Immunosuppression withdrawal

Interventions

Immunosuppression withdrawal 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.

Also known as: ISW

Immunosuppression withdrawal

Eligibility Criteria

• Age: Up to 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator
• Immune Tolerance Network (ITN): collaborator

Study Sites (12)

University of California

San Francisco, California, 94143-0780, United States

Location

Children's Hospital of Colorado

Aurora, Colorado, 80045, United States

Location

Emory University and Children's Hospital of Atlanta

Atlanta, Georgia, 30322, United States

Location

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

Chicago, Illinois, 60614, United States

Location

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

Ann Arbor, Michigan, 94143, United States

Location

St. Louis Children's Hospital - Washington University

St Louis, Missouri, 63110, United States

Location

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

New York, New York, 10032, United States

Location

Cincinnati Children's Hospital

Cincinnati, Ohio, 45229, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, 15224, United States

Location

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

The Hospital for Sick Children

Toronto, Ontario, M5G1X8, Canada

Location

Related Publications (6)

• 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.

  PMID: 22253395 BACKGROUND

• 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.

  PMID: 25648649 BACKGROUND

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

  PMID: 16433002 BACKGROUND

• 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.

  PMID: 35819312 DERIVED

• 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.

  PMID: 33280227 DERIVED

• 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.

  PMID: 32786149 DERIVED

Related Links

• National Institute of Allergy and Infectious Diseases (NIAID)
• Immune Tolerance Network (ITN)

Results Point of Contact

• Title: Director, Clinical Research Operations Program
• Organization: DAIT/NIAID

DAITClinicalTrialsGov@niaid.nih.gov

301-594-7669

Study Officials

• S Feng, M.D., Ph.D.

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

• J Bucuvalas, M.D.

  Children's Hospital Medical Center, Cincinnati

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 9, 2012
• First Posted: July 11, 2012
• Study Start: August 14, 2012
• Primary Completion: March 31, 2016
• Study Completion: June 11, 2018
• Last Updated: October 7, 2019
• Results First Posted: June 8, 2017

Record last verified: 2019-09

Data Sharing

• IPD Sharing: Will share
• Time Frame: The aim is to share data available to the public within 24 months upon completion of the study.
• Access Criteria: ImmPort public data access.

Locations

US (11); CA (1)