Withdrawal of Immunosuppression in Pediatric Liver Transplant Recipients (WISP-R)

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

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 The purpose of this study is to determine whether immunosuppressive drugs can be safely withdrawn over a minimum of 9 months from children who received liver transplants at least 4 years ago.

Study Overview

• Status: Completed
• Conditions: Liver Transplantation; Liver Transplant
• Intervention / Treatment: Drug: Immunosuppression Withdrawal

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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Immunosuppression Withdrawal; 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; 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.; 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)

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Immune Tolerance Network (ITN)
• Investigators: Principal Investigator: Sandy Feng, MD, University of California, San Francisco

Publications and helpful links

General Publications

• Reding R. Long-term complications of immunosuppression in pediatric liver recipients. Acta Gastroenterol Belg. 2005 Oct-Dec;68(4):453-6.
• 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.
• 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.
• Feng S, Demetris AJ, Spain KM, Kanaparthi S, Burrell BE, Ekong UD, Alonso EM, Rosenthal P, Turka LA, Ikle D, Tchao NK. Five-year histological and serological follow-up of operationally tolerant pediatric liver transplant recipients enrolled in WISP-R. Hepatology. 2017 Feb;65(2):647-660. doi: 10.1002/hep.28681. Epub 2016 Jul 27.

Helpful Links

• National Institute of Allergy and Infectious Diseases (NIAID)
• Division of Allergy, Immunology, and Transplantation (DAIT)
• Immune Tolerance Network website

Study record dates

Study Major Dates

• Study Start (Actual): June 5, 2006
• Primary Completion (Actual): November 30, 2009
• Study Completion (Actual): March 13, 2017

Study Registration Dates

• First Submitted: April 28, 2006
• First Submitted That Met QC Criteria: May 2, 2006
• First Posted (Estimate): May 3, 2006

Study Record Updates

• Last Update Posted (Actual): September 20, 2018
• Last Update Submitted That Met QC Criteria: August 22, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: tolerance; immunosuppression withdrawal (IS); anti-rejection drugs; allograft function
• Other Study ID Numbers: DAIT ITN029ST

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Participant level data and additional study materials are available to the public in: 1.) the Immunology Database and Analysis Portal (ImmPort), a long-term archive of clinical and mechanistic data from Division of Allergy, Immunology, and Transplantation (DAIT)-funded grants and contracts and 2.) TrialShare, the Immune Tolerance Network (ITN) Clinical Trials Research Portal.
• IPD Sharing Time Frame: Already available to the public.
• IPD Sharing Access Criteria: Available to the public. Study ID is SDY662:WISP-R ITN029ST

Study Data/Documents

1. Individual Participant Data Set
   Information identifier: SDY662:WISP-R ITN029ST
   Information comments: ImmPort study identifier is Study ID is SDY662:WISP-R ITN029ST
2. Study summary, -schematic, -detailed description, -download packages et al.
   Information identifier: SDY662:WISP-R ITN029ST
   Information comments: ImmPort study identifier is Study ID is SDY662:WISP-R ITN029ST
3. Individual Participant Data Set
   Information identifier: WISP-R ITN029ST
   Information comments: TrialShare is a clinical trials research portal developed by the Immune Tolerance Network (ITN) that makes data from the consortium's clinical trials publicly available without charge. Creating an account for ITN TrialShare is free and allows for searching studies of interest.
4. Study protocol synopsis, -navigator, abstracts and manuscripts, datasets et al.
   Information identifier: WISP-R ITN029ST
   Information comments: TrialShare is a clinical trials research portal developed by the Immune Tolerance Network (ITN) that makes data from the consortium's clinical trials publicly available without charge. Creating an account for ITN TrialShare is free and allows for searching studies of interest.