Withdrawal of Immunosuppression in Pediatric Liver Transplant Recipients

Study Overview
=================
Brief Summary
-----------------
Antirejection medicines, also known as immunosuppressive drugs, are prescribed to organ transplant recipients to prevent their bodies from rejecting the new organ. Long-term use of these drugs places transplant recipients at higher risk of serious infections and certain types of cancer. The purpose of this study is to determine whether immunosuppressive drugs can be safely withdrawn over a minimum of 9 months from children who received liver transplants at least 4 years ago.

Detailed Description
-----------------
In order to prevent the rejection of transplanted organs, transplant recipients are prescribed a strict, lifelong regimen of immunosuppressive drugs. While these drugs help prevent the body from rejecting the transplant, they carry numerous complications, including increased risk of serious infections and certain types of cancer. However, there is mounting evidence that a significant percentage of liver transplant recipients can maintain a healthy, functioning transplant without ongoing immunosuppression. This study will determine whether gradual withdrawal and eventual discontinuation of all immunosuppressive medication can be safely accomplished in children who received a liver transplant from a parent. Twenty eligible participants who were under 18 years old at the time of transplant, whose donor was a parent, and who received the transplant at least four years ago will be enrolled in the study. Liver recipients will have an initial screening assessment consisting of a medical history, liver biopsy, and urine and blood collection. Eligible recipients will be placed on a modified medication schedule to gradually decrease their immunosuppression medication slowly over a 9- to 12-month period, during which time they will be closely monitored by study staff. Immunosuppressive drugs will not be provided by this study. For a minimum of 3 and up to a maximum of 7 years, monthly telephone consultations and quarterly study visits will occur. Visits will include physical exams and blood collection to monitor the children's health during the withdrawal phase. The exact schedule of immunosuppressant withdrawal will be determined by study physicians based on participant's health and immune function test results. Donor and nondonor parents will be asked to each provide one blood sample during the initial study visits for immunologic and genetic testing. *** IMPORTANT NOTICE: *** The National Institute of Allergy and Infectious Diseases and the Immune Tolerance Network do not recommend the discontinuation of immunosuppressive therapy for recipients of cell, organ, or tissue transplants outside of physician-directed, controlled clinical studies. Discontinuation of prescribed immunosuppressive therapy can result in serious health consequences and should only be performed in certain rare circumstances, upon the recommendation and with the guidance of your health care provider.

Official Title
-----------------
Immunosuppression Withdrawal for Pediatric Living-donor Liver Transplant Recipients (ITN029ST)

Conditions
-----------------
Liver Transplant, Liver Transplantation

Intervention / Treatment
-----------------
* Drug: Immunosuppression Withdrawal


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria for Liver Recipients: Received liver from living parent donor Received transplant at least 4 years prior to study entry Less than 18 years of age at time of transplant Parent or guardian willing to provide informed consent Inclusion Criteria for Liver Donors: Willing to participate in this study Exclusion Criteria for Liver Recipients: Underwent transplant because of liver failure related to autoimmune disease Underwent transplant of a second organ simultaneously with or after liver transplant OR liver retransplantation Receiving immunosuppression with more than one drug 50% increase in dose of current immunosuppressive drug HIV infection Hepatitis B or C virus infection Pregnancy or breastfeeding

Ages Eligible for Study
-----------------
Minimum Age: 4 Years
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Recipients of parental living-donor liver allografts will undergo gradual withdrawal as tolerated of immunosuppression with the goal of complete withdrawal.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Immunosuppression Withdrawal<br>Recipients of parental living donor liver transplants 4 or more years prior to trial enrollment, who also had stable allograft function during the preceding 6 months while taking a single immunosuppressive drug were permitted to undergo withdrawal of immunosuppression therapy. With high dose, daily dose reduction by 25% for 8 weeks. With low dose, daily dose reduction by 25% for 4 weeks. Participants are carefully evaluated/monitored throughout the study by assessments including but not limited to liver biopsy, liver tests and clinic visits, alloantibodies, autoantibodies and quantitative immunoglobulin G test results. | Drug: Immunosuppression Withdrawal<br>* Gradual withdrawal of immunosuppressive medication. With high dose, daily dose reduction by 25% for 8 weeks. With low dose, daily dose reduction by 25% for 4 weeks.<br>* Other names: ISW;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants Successfully Withdrawn From Immunosuppression | Participants were considered successfully withdrawn from immunosuppression if they remained off immunosuppression for at least one year with normal allograft function. | 1 year after completion of immunosuppression withdrawal | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Suffered Graft Loss or Died Following Initiation of Immunosuppression Withdrawal | Participants who died while on the study for any reason as well as participants that experienced the loss of their transplant while a participant in the study. | Enrollment through end of study (up to 9.5 years) | 
| Time From Start of Immunosuppression Withdrawal to the First Episode of Acute Rejection, Second Episode of Rejection That Did Not Require Treatment, or to Diagnosis of Chronic Rejection | The number of days between the start of immunosuppression (IS) withdrawal and the first episode of acute rejection (either clinical rejection or based on BANFF criteria), second episode of rejection that did not require treatment, or the first diagnosis of chronic rejection. | From the start of immunosuppression withdrawal to first acute rejection, second episode of rejection that did not require treatment, or diagnosis of chronic rejection through end of study (up to 9.5 years) | 
| Immunosuppression-Free Duration | The number of months between the end of immunosuppression withdrawal and either the end of trial participation or the time of restarting immunosuppression | Completion of Withdrawal to either end of trial participation (up to 9.5 years) or time to restarting immunosuppression | 
| Distribution of Histologic Severity Among Rejection Episodes | The number of participants within each level of histologic severity based on BANFF grading criteria (Mild, Moderate, Severe). | Start of immunosuppressive withdrawal to rejection through end of study (up to 9.5 years) | 
| Number of Participants Experiencing Adverse Events by Severity | The results provide the total number of participants experiencing adverse events (AEs). Participants experiencing AEs are stratified into five severity categories: mild, moderate, severe, life-threatening, and death, based on National Cancer Institute--Common Terminology Criteria (NCI-CTCAE) Version 3.0. | Enrollment through end of study (up to 9.5 years) | 
| Percent Change From Baseline in Renal Function Measured by the Glomerular Filtration Rate (GFR) | Percent change from baseline at each annual visit. The bedside Schwartz equation was used to estimate GFR from serum creatinine and height in children. Baseline serum creatinine was utilized in the equation, defined as the creatinine value at the start of IS tapering. Baseline height was utilized in the equation, defined as the last height recorded prior to the start of IS tapering. Serum creatinine measurements and height measurements at the annual visits were used to calculate the annual GFR. When height value was not available, the height collected prior to the annual visit was used in the GFR calculation. M12 and M24 visits represent Medium Frequency visits; L12 and L24 represent low frequency visits, and E12-48 represent extended follow-up visits. | Enrollment through end of study (up to 9.5 years) | 
| Percent Change From Baseline in Total Cholesterol | Percent change from baseline in total serum cholesterol. Cholesterol is a waxy substance your body needs to build cells, but too much can be a problem since it can build-up in arteries. Narrowed arteries can result in heart attack or stroke. This outcome looks at the percent change from baseline (cholesterol level at the start of IS tapering) to each annual visit. M12 and M24 visits represent Medium Frequency visits; L12 and L24 represent low frequency visits, and E12-48 represent extended follow-up visits. | Enrollment through end of study (up to 9.5 years) | 
| Percent Change From Baseline in Blood Glucose | Glucose, a sugar, is an energy source that the body relies on to properly function. If levels are too high for a long period of time, diabetes can develop. Diabetes can result in many long-term complications such as eye, kidney, and nerve damage, stroke, and cardiovascular complications. The outcome looks at the percent change from baseline (glucose level at the start of tapering) to each annual visit. M12 and M24 visits represent Medium Frequency visits; L12 and L24 represent low frequency visits, and E12-48 represent extended follow-up visits. | Enrollment through end of study (up to 9.5 years) | 
| Percent Change From Baseline in Systolic Blood Pressure | Systolic blood pressure (BP) measures the pressure on the blood vessels when the heart is beats and thus is pushing blood to the rest of the body. This outcome assesses the percent change from baseline (systolic blood pressure measurement at the start of tapering) to each annual visit. M12 and M24 visits represent Medium Frequency visits; L12 and L24 represent low frequency visits, and E12-48 represent extended follow-up visits. | Enrollment through end of study (up to 9.5 years) | 
| Percent Change From Baseline in Diastolic Blood Pressure | Diastolic blood pressure (BP) measures the pressure in the arteries when the heart is a rest and is thus filled with blood. This outcome assesses the percent change from baseline (diastolic blood pressure measurement at the start of IS tapering) to each annual visit. M12 and M24 visits represent Medium Frequency visits; L12 and L24 represent low frequency visits, and E12-48 represent extended follow-up visits. | Enrollment through end of study (up to 9.5 years) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
immunosuppression withdrawal (IS), anti-rejection drugs, tolerance, allograft function