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Liver Transplant RecipientsPhase 2iWITHNCT01638559

Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients

A Phase 2 study testing Immunosuppression withdrawal in people with Liver Transplant Recipients and Liver Transplantation, run by National Institute of Allergy and Infectious Diseases (NIAID) at 12 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

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

Who is it for?
Ages Up to 18 years
What is being tested?
Immunosuppression withdrawal
Could I receive a placebo?
No, everyone receives an active treatment
How many people
161 participants
Where
12 sitesin 2 countries
Study dates
14 Aug 2012to 11 Jun 2018
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 18 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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);
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  • 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.

Who cannot join

  • 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;
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  • 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.

Trial locations and contacts

12 sites in 2 countries.

12 sites in 2 countries

United States11 sites

  • University of Michigan C. S. Mott Children's Hospital

    Ann Arbor, Michigan, 94143

  • Emory University and Children's Hospital of Atlanta

    Atlanta, Georgia, 30322

  • Children's Hospital of Colorado

    Aurora, Colorado, 80045

  • Ann & Robert H. Lurie Children's Hospital of Chicago

    Chicago, Illinois, 60614

  • Cincinnati Children's Hospital

    Cincinnati, Ohio, 45229

  • Texas Children's Hospital

    Houston, Texas, 77030

  • New York Presbyterian Morgan Stanley Children's Hospital - Columbia University Medical Center

    New York, New York, 10032

  • Children's Hospital of Philadelphia

    Philadelphia, Pennsylvania, 19104

  • Children's Hospital of Pittsburgh

    Pittsburgh, Pennsylvania, 15224

  • University of California

    San Francisco, California, 94143-0780

  • St. Louis Children's Hospital - Washington University

    St Louis, Missouri, 63110

Other trials in United States

Canada1 site

  • The Hospital for Sick Children

    Toronto, Ontario, M5G1X8

Other trials in Canada

About this study

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

Read the 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.
Being tested
Immunosuppression withdrawal
Keywords
liver transplant, allograft function, anti-rejection, immunosuppression withdrawal, tolerance

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Immunosuppression withdrawalDrug

    Also called ISW

    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.

Study groups in NCT01638559
Study groupRoleWhat they receive
Immunosuppression withdrawalExperimentalGradual withdrawal of immunosuppressive treatment withdrawal as per protocol.
Receives: Drug: Immunosuppression withdrawal

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 12 Months after complete immunosuppression withdrawal

Secondary outcomes (11)

  1. 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).

    Measured: Time from immunosuppression withdrawal through a minimum of 36 months and a maximum of 48 months of follow-up

  2. 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.

    Measured: Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up

  3. 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.

    Measured: Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up

  4. 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.

    Measured: Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up

  5. 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

    Measured: Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up

  6. 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.

    Measured: Time from start of immunosuppression withdrawal through discontinuation of withdrawal, a maximum of 52 weeks

  7. 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

    Measured: Time from screening biopsy to end of study (month 48) biopsy

  8. 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.

    Measured: Time from immunosuppression withdrawal through a minimum of 36 months and a maximum of 48 months of follow-up

  9. 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.

    Measured: Time from starting immunosuppression withdrawal until immunosuppression withdrawal failure, maximum 52 weeks

  10. 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.

    Measured: Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up

  11. 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.

    Measured: Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted11 Jul 2012 (estimated)
  2. Study start14 Aug 2012
  3. Primary completion31 Mar 2016
  4. Study completion11 Jun 2018

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
161 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01638559
Sponsor's protocol ID
DAIT iWITH
Other IDs
U01AI100807, RTB-001, NIAID DAIT CRMS ID#: 20129
Acronym
iWITH
Status last verified
Sep 2019
First submitted
9 Jul 2012
Last updated
7 Oct 2019
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: The plan is to share data upon completion of the study in ImmPort, a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts.

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.

    PubMed 22253395

  • 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.

    PubMed 25648649

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

    PubMed 16433002

  • Wood-Trageser MA, Lesniak D, Gambella A, Golnoski K, Feng S, Bucuvalas J, Sanchez-Fueyo A, Demetris AJ. Next-generation pathology detection of T cell-antigen-presenting cell immune synapses in human liver allografts. Hepatology. 2023 Feb 1;77(2):355-366. doi: 10.1002/hep.32666. Epub 2022 Aug 1.

    PubMed 35819312

  • Mohammad S, Sundaram SS, Mason K, Lobritto S, Martinez M, Turmelle YP, Bucuvalas J, Feng S, Alonso EM. Improvements in Disease-Specific Health-Related Quality of Life of Pediatric Liver Transplant Recipients During Immunosuppression Withdrawal. Liver Transpl. 2021 May;27(5):735-746. doi: 10.1002/lt.25963.

    PubMed 33280227

  • Feng S, Bucuvalas JC, Mazariegos GV, Magee JC, Sanchez-Fueyo A, Spain KM, Lesniak A, Kanaparthi S, Perito E, Venkat VL, Burrell BE, Alonso EM, Bridges ND, Doo E, Gupta NA, Himes RW, Ikle D, Jackson AM, Lobritto SJ, Jose Lozano J, Martinez M, Ng VL, Rand EB, Sherker AH, Sundaram SS, Turmelle YP, Wood-Trageser M, Demetris AJ. Efficacy and Safety of Immunosuppression Withdrawal in Pediatric Liver Transplant Recipients: Moving Toward Personalized Management. Hepatology. 2021 May;73(5):1985-2004. doi: 10.1002/hep.31520.

    PubMed 32786149

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Immunosuppression withdrawal in people with Liver Transplant Recipients and Liver Transplantation, run by National Institute of Allergy and Infectious Diseases (NIAID) at 12 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 15 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 7 Oct 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 12 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 8 Jun 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Operationally Tolerant Participants (time frame: 12 Months after complete immunosuppression withdrawal). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01638559, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Oct 2019.

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