Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients (iWITH)
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|ClinicalTrials.gov Identifier: NCT01638559|
Recruitment Status : Completed
First Posted : July 11, 2012
Results First Posted : June 8, 2017
Last Update Posted : October 7, 2019
|Condition or disease||Intervention/treatment||Phase|
|Liver Transplant Recipients Liver Transplantation Immunosuppression||Drug: Immunosuppression withdrawal||Phase 2|
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 Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||161 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients|
|Actual Study Start Date :||August 14, 2012|
|Actual Primary Completion Date :||March 31, 2016|
|Actual Study Completion Date :||June 11, 2018|
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 Name: ISW
- Number of Operationally Tolerant Participants [ Time Frame: 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.
- Number of Participants With Clinical Complications Usually Attributed to Immunosuppression [ Time Frame: 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).
- Time to Increased Immunosuppression or Re-Initiation of Immunosuppression [ Time Frame: 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.
- Time to Resolution of Rejection [ Time Frame: 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.
- Number and Severity of Biopsies Read as Histologic Acute Rejection [ Time Frame: 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.
- Clinical Severity of Acute Rejection [ Time Frame: 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
- Reason for Discontinuation of Withdrawal [ Time Frame: 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.
- Impact of Immunosuppression Withdrawal (ISW) on Allograft Histology [ Time Frame: 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 Frame: 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 (Calcineurin Inhibitor) Dose From Start of Immunosuppression Withdrawal to the Time of Immunosuppression Withdrawal Failure [ Time Frame: 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.
- Change in Immunosuppression Medication Dose From Study Initiation of Withdrawal to the End of the Study [ Time Frame: 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.
- Change in Child Health Related Quality of Life Scores Between Tolerant and Non-tolerant Subjects [ Time Frame: 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01638559
|United States, California|
|University of California|
|San Francisco, California, United States, 94143-0780|
|United States, Colorado|
|Children's Hospital of Colorado|
|Aurora, Colorado, United States, 80045|
|United States, Georgia|
|Emory University and Children's Hospital of Atlanta|
|Atlanta, Georgia, United States, 30322|
|United States, Illinois|
|Ann & Robert H. Lurie Children's Hospital of Chicago|
|Chicago, Illinois, United States, 60614|
|United States, Michigan|
|University of Michigan C. S. Mott Children's Hospital|
|Ann Arbor, Michigan, United States, 94143|
|United States, Missouri|
|St. Louis Children's Hospital - Washington University|
|Saint Louis, Missouri, United States, 63110|
|United States, New York|
|New York Presbyterian Morgan Stanley Children's Hospital - Columbia University Medical Center|
|New York, New York, United States, 10032|
|United States, Ohio|
|Cincinnati Children's Hospital|
|Cincinnati, Ohio, United States, 45229|
|United States, Pennsylvania|
|Children's Hospital of Philadelphia|
|Philadelphia, Pennsylvania, United States, 19104|
|Children's Hospital of Pittsburgh|
|Pittsburgh, Pennsylvania, United States, 15224|
|United States, Texas|
|Texas Children's Hospital|
|Houston, Texas, United States, 77030|
|The Hospital for Sick Children|
|Toronto, Ontario, Canada, M5G1X8|
|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|