Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients

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

Detailed Description
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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.

Official Title
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Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients

Conditions
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Liver Transplant Recipients, Liver Transplantation, Immunosuppression

Intervention / Treatment
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* Drug: Immunosuppression withdrawal


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Immunosuppression withdrawal<br>Gradual withdrawal of immunosuppressive treatment withdrawal as per protocol. | Drug: Immunosuppression withdrawal<br>* 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.<br>* Other names: ISW;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinical Complications Usually Attributed to Immunosuppression | 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). | 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 | The median time (in days) from start of withdrawal from immunosuppression drugs to increasing or re-starting immunosuppression. | Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up | 
| Time to Resolution of Rejection | 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. | 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 | 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. | Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up | 
| Clinical Severity of Acute Rejection | 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 from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up | 
| Reason for Discontinuation of Withdrawal | 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. | Time from start of immunosuppression withdrawal through discontinuation of withdrawal, a maximum of 52 weeks | 
| Impact of Immunosuppression Withdrawal (ISW) on Allograft Histology | 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 | Time from screening biopsy to end of study (month 48) biopsy | 
| Duration of Operational Tolerance | Median participant duration of operational tolerance. Duration of operational tolerance is defined as the number of days that participants are not taking immunosuppression medications. | Time from immunosuppression withdrawal through a minimum of 36 months and a maximum of 48 months of follow-up | 
| Change in Immunosuppression Medication (Calcineurin Inhibitor) Dose From Start of Immunosuppression Withdrawal to the Time of Immunosuppression Withdrawal Failure | 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 from starting immunosuppression withdrawal until immunosuppression withdrawal failure, maximum 52 weeks | 
| Change in Immunosuppression Medication Dose From Study Initiation of Withdrawal to the End of the Study | 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. | Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up | 
| Change in Child Health Related Quality of Life Scores Between Tolerant and Non-tolerant Subjects | 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. | Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anti-rejection, liver transplant, allograft function, immunosuppression withdrawal, tolerance