Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients

Phase 2

Completed

Conditions: Immunosuppression
Liver Transplant Recipients
Liver Transplantation

Interventions: Drug: Immunosuppression withdrawal

Registration Number: NCT01638559

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 161

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Immunosuppression withdrawal	Immunosuppression withdrawal	Gradual withdrawal of immunosuppressive treatment withdrawal as per protocol.

Primary Outcome Measures

Name	Time	Method
Number of Operationally Tolerant Participants	12 Months after complete immunosuppression withdrawal	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.

Secondary Outcome Measures

Name	Time	Method
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	This composite endpoint is comprised of clinical complications related to immunosuppression withdrawal and is defined as the occurrence of any of the following: death or graft loss, histologic evidence of refractory acute rejection or biopsy confirmed chronic rejection (CR).
Clinical Severity of Acute Rejection	Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up	The clinical severity of acute rejection was descriptively analyzed using hierarchical categories, as follows: * Dose increase: Increase in IS dose and/or frequency but to a level less than the regimen at study entry, prior to initiating ISW * Reinstitution: Returning to the regimen at study entry, prior to ISW * Intensification: Increased IS dose compared with the dose at study entry, prior to ISW * Conversion: Change to different IS drug * Addition: Initiation of a second IS drug; * Corticosteroids: Administration of any intravenous or oral corticosteroids * Antibody (Ab) treatment: Administration of any rabbit thymoglobulin; usually with corticosteroids
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	The median time (in days) from start of withdrawal from immunosuppression drugs to increasing or re-starting immunosuppression.
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	Number of biopsies that were diagnosed as histologic acute rejection in participants who initiated immunosuppression withdrawal by severity of rejection episode. Rejection severity (mild, moderate, severe) is based on the Banff global assessment grade according to the central pathology reading of the liver biopsy. Mild severity criteria: rejection infiltrate in a minority of triads that is generally mild and confined within the portal spaces. Moderate rejection criteria: rejection infiltrate expanding most or all of the triads. Severe rejection criteria: rejection infiltrate expanding most or all of the triads with spillover into periportal areas and moderate to severe perivenular inflammation that extends into the hepatic parenchyma and is associated with perivenular hepatocyte necrosis. BPAR: biopsy-proven acute rejection.
Reason for Discontinuation of Withdrawal	Time from start of immunosuppression withdrawal through discontinuation of withdrawal, a maximum of 52 weeks	Reasons participants discontinued immunosuppression withdrawal, such as Biopsy Proven Acute Rejection, Chronic Rejection, Clinical Rejection, Death, Pregnancy, etc.). Only the root cause for discontinuation for each subject is presented in these results if multiple events led to discontinuation of immunosuppression withdrawal.
Change in Immunosuppression Medication (Calcineurin Inhibitor) Dose From Start of Immunosuppression Withdrawal to the Time of Immunosuppression Withdrawal Failure	Time from starting immunosuppression withdrawal until immunosuppression withdrawal failure, maximum 52 weeks	The mean percent of immunosuppression (IS) dose reduction from baseline to the time of immunosuppression withdrawal failure. Immunosuppression withdrawal failure is defined as any incidence of increasing immunosuppression medications instead of completing withdrawal.
Time to Resolution of Rejection	Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up	The median time (in weeks) from biopsy proven rejection to resolution of rejection defined as both liver function tests Alanine Aminotransferase (ALT) and Gamma-Glutamyl Transferase (GGT) returning to ≤ 1.5 the baseline values.
Change in Child Health Related Quality of Life Scores Between Tolerant and Non-tolerant Subjects	Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up	Health related quality of life was measured by the PedsQL 4.0 Generic Core scale, the Multidimensional Fatigue scale, and the PedsQL 3.0 Transplant module. Change was calculated as the difference between the questionnaire completed at the initiation of withdrawal and at month 36 for the total generic score, the total fatigue score, and total transplant score. This change was calculated separately for tolerant and non-tolerant subjects. Each score ranges from 0-100, with a higher score indicating a better quality of life.
Impact of Immunosuppression Withdrawal (ISW) on Allograft Histology	Time from screening biopsy to end of study (month 48) biopsy	The impact of ISW on allograft fibrosis using the Ishak scoring system to measure the change in fibrosis from the screening liver biopsy to the end-of-study (month-48) liver biopsy. In the Ishak histologic scoring system, the higher the score/stage, the more fibrosis: Scores range from 0 to 6, with 6 representing the most fibrosis: 0=No fibrosis; 1=Fibrous expansion of some portal areas, with or without short fibrous septa; 2=Fibrous expansion of most portal areas, with or without short fibrous septa; 3=Fibrous expansion of most portal areas, with occasional portal to portal bridging; 4=Fibrous expansion of portal areas with marked bridging (portal to portal) as well as portal to central; 5=Marked bridging (portal to portal and/or portal to central) with occasional nodules (incomplete cirrhosis); and 6=Cirrhosis, probable or definite. Decrease in score from screening (baseline) indicates improvement
Duration of Operational Tolerance	Time from immunosuppression withdrawal through a minimum of 36 months and a maximum of 48 months of follow-up	Median participant duration of operational tolerance. Duration of operational tolerance is defined as the number of days that participants are not taking immunosuppression medications.
Change in Immunosuppression Medication Dose From Study Initiation of Withdrawal to the End of the Study	Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up	Change of immunosuppression (IS) dose from baseline to end of study for all participants not deemed tolerant by the trial definition either due to discontinuing IS withdrawal or completing withdrawal but not meeting the criteria for tolerance on the primary endpoint biopsy assessment.

Trial Locations

Locations (12): Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
The Hospital for Sick Children
🇨🇦
Toronto, Ontario, Canada
Texas Children's Hospital
🇺🇸
Houston, Texas, United States
University of California
🇺🇸
San Francisco, California, United States
Cincinnati Children's Hospital
🇺🇸
Cincinnati, Ohio, United States
Children's Hospital of Colorado
🇺🇸
Aurora, Colorado, United States
University of Michigan C. S. Mott Children's Hospital
🇺🇸
Ann Arbor, Michigan, 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
New York Presbyterian Morgan Stanley Children's Hospital - Columbia University Medical Center
🇺🇸
New York, New York, United States
St. Louis Children's Hospital - Washington University
🇺🇸
Saint Louis, Missouri, United States
Children's Hospital of Pittsburgh
🇺🇸
Pittsburgh, Pennsylvania, United States