iWITH: Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01638559
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH), Immune Tolerance Network (ITN) (Other)
• Enrollment: 161
• Locations: 12
• Arm: 1
• Actual Duration (Months): 69.9
• Patients Per Site: 13.4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Liver Transplant Recipients; Liver Transplantation; Immunosuppression	Drug: Immunosuppression withdrawal	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 161 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients
• Actual Study Start Date: Aug 14, 2012
• Actual Primary Completion Date: Mar 31, 2016
• Actual Study Completion Date: Jun 11, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Immunosuppression withdrawal Gradual withdrawal of immunosuppressive treatment withdrawal as per protocol.	Drug: Immunosuppression withdrawal; 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.; Other Names: ISW

Outcome Measures

Primary Outcome Measures

1. 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

1. 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).

2. 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.

3. 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.

4. 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.

5. 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

6. 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.

7. 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

8. 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.

9. 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.

10. 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.

11. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California	San Francisco	California	United States	94143-0780
2	Children's Hospital of Colorado	Aurora	Colorado	United States	80045
3	Emory University and Children's Hospital of Atlanta	Atlanta	Georgia	United States	30322
4	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60614
5	University of Michigan C. S. Mott Children's Hospital	Ann Arbor	Michigan	United States	94143
6	St. Louis Children's Hospital - Washington University	Saint Louis	Missouri	United States	63110
7	New York Presbyterian Morgan Stanley Children's Hospital - Columbia University Medical Center	New York	New York	United States	10032
8	Cincinnati Children's Hospital	Cincinnati	Ohio	United States	45229
9	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
10	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania	United States	15224
11	Texas Children's Hospital	Houston	Texas	United States	77030
12	The Hospital for Sick Children	Toronto	Ontario	Canada	M5G1X8

Sponsors and Collaborators

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

Investigators

• Principal Investigator: S Feng, M.D., Ph.D., University of California, San Francisco
• Study Chair: J Bucuvalas, M.D., Children's Hospital Medical Center, Cincinnati

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

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

Publications

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

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT01638559
• Other Study ID Numbers: DAIT iWITH; U01AI100807; RTB-001; NIAID DAIT CRMS ID#: 20129
• First Posted: Jul 11, 2012
• Last Update Posted: Oct 7, 2019
• Last Verified: Sep 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): liver transplant; allograft function; anti-rejection; immunosuppression withdrawal; tolerance

Study Results

Participant Flow

Recruitment Details	161 participants were enrolled (11 sites in the US,1 site in Canada) between August 2012 and April 2014. N=88 of the enrolled participants were eligible to initiate immunosuppression withdrawal (ISW) and the remaining N=73 participants were terminated (e.g., ineligible to proceed with ISW) based on biopsy findings or other pre-specified criteria.
Pre-assignment Detail	Informed consent was obtained from eligible individuals who then underwent a study-mandated biopsy to determine if they were eligible to initiate immunosuppression withdrawal, based on pre-specified histologic and other criteria.

Arm/Group Title	Participants That Initiated Immunosuppression Withdrawal (ISW)
Arm/Group Description	Pediatric liver transplant recipients with stable liver tests (ALT and GGT), no evidence of rejection in the preceding 2 years, and at least 4 years post-transplant, and a qualifying liver biopsy at screening underwent gradual Immunosuppression withdrawal in no less than 36 weeks and no more than 52 weeks with frequent monitoring of liver tests. All participants were followed for 48 months ensuring a minimum of 36 months of follow-up after successful Immunosuppression withdrawal..
Period Title: Overall Study
STARTED	88
COMPLETED	85
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Participants That Initiated Immunosuppression Withdrawal (ISW)
Arm/Group Description	Pediatric liver transplant recipients with stable liver tests (ALT and GGT), no evidence of rejection in the preceding 2 years, and at least 4 years post-transplant, and a qualifying liver biopsy at screening underwent gradual Immunosuppression withdrawal in no less than 36 weeks and no more than 52 weeks with frequent monitoring of liver tests. All participants were followed for 48 months ensuring a minimum of 36 months of follow-up after successful Immunosuppression withdrawal.
Overall Participants	88
Age (Count of Participants)
<=18 years	88 100%
Between 18 and 65 years	0 0%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	10.4 (3.4)
Sex: Female, Male (Count of Participants)
Female	49 55.7%
Male	39 44.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	12 13.6%
Not Hispanic or Latino	74 84.1%
Unknown or Not Reported	2 2.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	4 4.5%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	4 4.5%
White	76 86.4%
More than one race	0 0%
Unknown or Not Reported	4 4.5%
Region of Enrollment (participants) [Number]
Canada	6 6.8%
United States	82 93.2%
Entry Calcineurin Inhibitor (CNI) Daily Dose (mg) [Mean (Standard Deviation) ]
Cyclosporine	65.7 (22.99)
Tacrolimus	2.1 (1.33)
Screening Biopsy Ishak Stage (Count of Participants)
0	19 21.6%
1	57 64.8%
2	12 13.6%
Screening Child Health Related Quality of Life Scores on a Scale (Quality of Life Scores on a Scale) [Mean (Standard Deviation) ]
All Participants - Total Generic Score	80.7 (13.69)
All Participants - Total Fatigue Score	74.9 (17.75)
All Participants - Total Transplant Score	85.6 (9.54)
Tolerant Participants - Total Generic Score	80.7 (14.59)
Tolerant Participants - Total Fatigue Score	75.6 (15.82)
Tolerant Participants - Total Transplant Score	86.0 (10.16)
Non-Tolerant Participants - Total Generic Score	80.6 (13.26)
Non-Tolerant Participants - Total Fatigue Score	74.5 (18.94)
Non-Tolerant Participants - Total Transplant Score	85.4 (9.27)

Outcome Measures

1. Primary Outcome

Title	Number of Operationally Tolerant Participants
Description	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.
Time Frame	12 Months after complete immunosuppression withdrawal

Outcome Measure Data

Analysis Population Description

Intent-to-Treat

Arm/Group Title	Participants That Initiated Immunosuppression Withdrawal (ISW)
Arm/Group Description	Pediatric liver transplant recipients with stable liver tests (ALT and GGT), no evidence of rejection in the preceding 2 years, and at least 4 years post-transplant, and a qualifying liver biopsy at screening underwent gradual Immunosuppression withdrawal in no less than 36 weeks and no more than 52 weeks with frequent monitoring of liver tests. All participants were followed for 48 months ensuring a minimum of 36 months of follow-up after successful Immunosuppression withdrawal..
Measure Participants	88
Count of Participants [Participants]	33 37.5%

2. Secondary Outcome

Title	Number of Participants With Clinical Complications Usually Attributed to Immunosuppression
Description	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 Frame	Time from immunosuppression withdrawal through a minimum of 36 months and a maximum of 48 months of follow-up

Outcome Measure Data

Analysis Population Description

Intent-to-Treat

Arm/Group Title	Participants That Initiated Immunosuppression Withdrawal (ISW)
Arm/Group Description	Pediatric liver transplant recipients with stable liver tests (ALT and GGT), no evidence of rejection in the preceding 2 years, and at least 4 years post-transplant, and a qualifying liver biopsy at screening underwent gradual Immunosuppression withdrawal in no less than 36 weeks and no more than 52 weeks with frequent monitoring of liver tests. All participants were followed for 48 months ensuring a minimum of 36 months of follow-up after successful Immunosuppression withdrawal.
Measure Participants	88
Count of Participants [Participants]	0 0%

3. Secondary Outcome

Title	Time to Increased Immunosuppression or Re-Initiation of Immunosuppression
Description	The median time (in days) from start of withdrawal from immunosuppression drugs to increasing or re-starting immunosuppression.
Time Frame	Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up

Outcome Measure Data

Analysis Population Description

Participants that either restarted immunosuppression or increased their dose of immunosuppression

Arm/Group Title	Participants That Increased IS Dosing or Restarted IS
Arm/Group Description	Pediatric liver transplant recipients with stable liver tests (ALT and GGT), no evidence of rejection in the preceding 2 years, and at least 4 years post-transplant, and a qualifying liver biopsy at screening underwent gradual Immunosuppression (IS) withdrawal in no less than 36 weeks and no more than 52 weeks with frequent monitoring of liver tests. All participants were followed for 48 months ensuring a minimum of 36 months of follow-up after successful IS withdrawal. These participants either failed IS withdrawal or restarted IS after completing withdrawal.
Measure Participants	50
Median (95% Confidence Interval) [days]	204

4. Secondary Outcome

Title	Time to Resolution of Rejection
Description	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 Frame	Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up

Outcome Measure Data

Analysis Population Description

Intent-to-Treat

Arm/Group Title	Participants That Experienced BPAR
Arm/Group Description	A subset of the participants that Initiated Immunosuppression Withdrawal (ISW) and experienced biopsy-proved acute rejection (BPAR) with elevated liver function tests at the time of the biopsy were examined for this endpoint.
Measure Participants	35
Median (95% Confidence Interval) [Weeks]	13

5. Secondary Outcome

Title	Number and Severity of Biopsies Read as Histologic Acute Rejection
Description	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 Frame	Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up

Outcome Measure Data

Analysis Population Description

Intent-to-Treat

Arm/Group Title	Participants That Initiated Immunosuppression Withdrawal (ISW)
Arm/Group Description	Pediatric liver transplant recipients with stable liver tests (ALT and GGT), no evidence of rejection in the preceding 2 years, and at least 4 years post-transplant, and a qualifying liver biopsy at screening underwent gradual Immunosuppression withdrawal in no less than 36 weeks and no more than 52 weeks with frequent monitoring of liver tests. All participants were followed for 48 months ensuring a minimum of 36 months of follow-up after successful Immunosuppression withdrawal.
Measure Participants	88
Mild	43
Moderate	7
Severe	0

6. Secondary Outcome

Title	Clinical Severity of Acute Rejection
Description	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 Frame	Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up

Outcome Measure Data

Analysis Population Description

Participants who experienced rejection (biopsy-proven or clinical)

Arm/Group Title	Participants With Adverse Events of BPAR or Clinical Rejection
Arm/Group Description	All participants that initiated withdrawal were at risk for a rejection event and are included in the denominator of the proportion. Participants that had one or more adverse events of Biopsy-Proven Acute Rejection (BPAR) or Clinical Rejection and were treated with each specific treatment regimen are included in the numerator.
Measure Participants	88
Dose increase	0.068
Reinstitution	0.261
Intensification	0.227
Conversion	0.011
Addition	0.023
Corticosteroids	0.364
Ab treatment	0

7. Secondary Outcome

Title	Reason for Discontinuation of Withdrawal
Description	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 Frame	Time from start of immunosuppression withdrawal through discontinuation of withdrawal, a maximum of 52 weeks

Outcome Measure Data

Analysis Population Description

Participants who failed immunosuppression withdrawal.

Arm/Group Title	Participants That Discontinued Immunosuppression Withdrawal
Arm/Group Description	A subset of the Participants that Initiated Withdrawal and discontinued Immunosuppression Withdrawal (ISW) prior to completing withdrawal.
Measure Participants	33
Biopsy Proven Acute Rejection	30 34.1%
Clinical Rejection	3 3.4%

8. Secondary Outcome

Title	Impact of Immunosuppression Withdrawal (ISW) on Allograft Histology
Description	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 Frame	Time from screening biopsy to end of study (month 48) biopsy

Outcome Measure Data

Analysis Population Description

Intent-to-Treat -Of the original 88 participants, 3 participants did not finish the study and 1 participant did not complete the final liver biopsy.

Arm/Group Title	Participants That Had Both Screening and End-of-Study Biopsies
Arm/Group Description	Pediatric liver transplant recipients with stable liver tests (ALT and GGT), no evidence of rejection in the preceding 2 years, and at least 4 years post-transplant, and a qualifying liver biopsy at screening underwent gradual Immunosuppression withdrawal in no less than 36 weeks and no more than 52 weeks with frequent monitoring of liver tests. All participants were followed for 48 months ensuring a minimum of 36 months of follow-up after successful Immunosuppression withdrawal.
Measure Participants	84
Ishak Score Change of -1	18 20.5%
Ishak Score Change of 0	43 48.9%
Ishak Score Change of 1	19 21.6%
Ishak Score Change of 2	3 3.4%
Ishak Score Change of 3	1 1.1%

9. Secondary Outcome

Title	Duration of Operational Tolerance
Description	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 Frame	Time from immunosuppression withdrawal through a minimum of 36 months and a maximum of 48 months of follow-up

Outcome Measure Data

Analysis Population Description

Participants that Completed Withdrawal and were Operationally Tolerant

Arm/Group Title	Participants Deemed Tolerant by Trial Definition
Arm/Group Description	Pediatric liver transplant recipients with stable liver tests (ALT and GGT), no evidence of rejection in the preceding 2 years, and at least 4 years post-transplant, and a qualifying liver biopsy at screening underwent gradual Immunosuppression withdrawal in no less than 36 weeks and no more than 52 weeks with frequent monitoring of liver tests. All participants were followed for 48 months ensuring a minimum of 36 months of follow-up after successful Immunosuppression withdrawal.
Measure Participants	33
Median (95% Confidence Interval) [days]	1209.5

10. Secondary Outcome

Title	Change in Immunosuppression Medication (Calcineurin Inhibitor) Dose From Start of Immunosuppression Withdrawal to the Time of Immunosuppression Withdrawal Failure
Description	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 Frame	Time from starting immunosuppression withdrawal until immunosuppression withdrawal failure, maximum 52 weeks

Outcome Measure Data

Analysis Population Description

Intent-to-Treat who failed immunosuppression withdrawal

Arm/Group Title	Participants That Discontinued Immunosuppression Withdrawal
Arm/Group Description	A subset of the Participants that Initiated Withdrawal and discontinued Immunosuppression Withdrawal prior to completing withdrawal.
Measure Participants	33
Mean (95% Confidence Interval) [percentage of dose]	-76.1

11. Secondary Outcome

Title	Change in Immunosuppression Medication Dose From Study Initiation of Withdrawal to the End of the Study
Description	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 Frame	Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up

Outcome Measure Data

Analysis Population Description

Intent-to-Treat participants who were not operationally tolerant and who remained on the same medication throughout the study. Three subjects that were not operationally tolerant converted to alternate immunosuppression medications.

Arm/Group Title	Participants Not Deemed Tolerant by the Trial Definition
Arm/Group Description	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.
Measure Participants	52
Mean (95% Confidence Interval) [percentage of dose]	0.4

12. Secondary Outcome

Title	Change in Child Health Related Quality of Life Scores Between Tolerant and Non-tolerant Subjects
Description	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 Frame	Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up

Outcome Measure Data

Analysis Population Description

Intent-to-Treat

Arm/Group Title	Participants Were Operationally Tolerant	Participants Who Were Not Operationally Tolerant
Arm/Group Description	Participants that Completed Withdrawal and were Operationally Tolerant	Participants who were not operationally tolerant.
Measure Participants	33	55
Total Generic Score	3.4	1.2
Total Fatigue Score	5.0	2.0
Total Transplant Score	5.7	0.9

Adverse Events

Time Frame	Time of enrollment through end of study participation (e.g., up to 48 months).
Adverse Event Reporting Description	Safety tables include N=161 participants,inclusive of those that were not eligible (N=73) and eligible (N=88) to proceed with immunosuppression withdrawal (ISW): Adverse events (AEs) were collected from the time of enrollment (i.e., assessment for eligibility to initiate immunosuppression withdrawal [ISW]) through the end of study participation; Prior to initiating ISW, only AEs temporally related to study procedures were collected; and, All AEs were collected ≥initiation of ISW.
Arm/Group Title	All Enrolled Participants
Arm/Group Description	Pediatric liver transplant recipients with stable liver function tests, no evidence of rejection in the past 2 years, and at least 4 years post-transplant, and a qualifying liver biopsy at screening underwent gradual Immunosuppression withdrawal in no less than 36 weeks and no more than 52 weeks with frequent monitoring of liver tests. All participants were followed for 48 months ensuring a minimum of 36 months of follow-up after successful Immunosuppression withdrawal.
All Cause Mortality
	All Enrolled Participants
	Affected / at Risk (%)	# Events
Total	0/161 (0%)
Serious Adverse Events
	All Enrolled Participants
	Affected / at Risk (%)	# Events
Total	23/161 (14.3%)
Gastrointestinal disorders
Abdominal pain	1/161 (0.6%)	2
Intestinal obstruction	1/161 (0.6%)	1
Hepatobiliary disorders
Bile duct stenosis	2/161 (1.2%)	2
Cholangitis	2/161 (1.2%)	2
Immune system disorders
Transplant rejection	3/161 (1.9%)	4
Infections and infestations
Cellulitis	1/161 (0.6%)	1
Gastroenteritis	2/161 (1.2%)	2
Gastroenteritis viral	2/161 (1.2%)	5
Pharyngitis	1/161 (0.6%)	1
Pneumonia	1/161 (0.6%)	1
Post procedural cellulitis	1/161 (0.6%)	1
Varicella	1/161 (0.6%)	1
Viral infection	2/161 (1.2%)	2
Injury, poisoning and procedural complications
Post procedural bile leak	1/161 (0.6%)	1
Procedural pain	2/161 (1.2%)	2
Subdural haematoma	1/161 (0.6%)	1
Ulna fracture	1/161 (0.6%)	1
Investigations
Liver function test abnormal	1/161 (0.6%)	1
Metabolism and nutrition disorders
Dehydration	1/161 (0.6%)	1
Nervous system disorders
Grand mal convulsion	1/161 (0.6%)	1
Psychiatric disorders
Aggression	1/161 (0.6%)	1
Depression	1/161 (0.6%)	1
Major depression	1/161 (0.6%)	1
Oppositional defiant disorder	1/161 (0.6%)	1
Suicidal ideation	2/161 (1.2%)	2
Reproductive system and breast disorders
Menorrhagia	2/161 (1.2%)	2
Respiratory, thoracic and mediastinal disorders
Asthma	2/161 (1.2%)	2
Skin and subcutaneous tissue disorders
Eczema	1/161 (0.6%)	1
Other (Not Including Serious) Adverse Events
	All Enrolled Participants
	Affected / at Risk (%)	# Events
Total	87/161 (54%)
Gastrointestinal disorders
Abdominal pain	17/161 (10.6%)	25
Diarrhoea	16/161 (9.9%)	21
Vomiting	9/161 (5.6%)	12
General disorders
Influenza like illness	16/161 (9.9%)	36
Pyrexia	14/161 (8.7%)	19
Immune system disorders
Hypersensitivity	10/161 (6.2%)	11
Transplant rejection	37/161 (23%)	43
Infections and infestations
Ear infection	13/161 (8.1%)	26
Gastroenteritis	14/161 (8.7%)	17
Gastroenteritis viral	21/161 (13%)	28
Influenza	14/161 (8.7%)	16
Nasopharyngitis	35/161 (21.7%)	140
Pharyngitis streptococcal	16/161 (9.9%)	20
Sinusitis	12/161 (7.5%)	24
Upper respiratory tract infection	21/161 (13%)	36
Viral infection	19/161 (11.8%)	39
Investigations
Liver function test abnormal	24/161 (14.9%)	39
Nervous system disorders
Headache	17/161 (10.6%)	37
Respiratory, thoracic and mediastinal disorders
Cough	15/161 (9.3%)	21
Skin and subcutaneous tissue disorders
Rash	10/161 (6.2%)	10

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.