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Evaluation of Donor Specific Immune Senescence and Exhaustion as Biomarkers of Tolerance Post Liver Transplantation (OPTIMAL)

This study is currently recruiting participants.
Verified August 2017 by National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor:
ClinicalTrials.gov Identifier:
NCT02533180
First Posted: August 26, 2015
Last Update Posted: August 22, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
Immune Tolerance Network (ITN)
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
  Purpose
The primary aim of this study is to determine whether a peripheral blood or graft lymphocyte phenotype of immune senescence or exhaustion is different between operationally tolerant and non-tolerant liver allograft recipients.

Condition Intervention Phase
Liver Transplant Liver Transplantation Biological: Immunosuppression withdrawal Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Evaluation of Donor Specific Immune Senescence and Exhaustion as Biomarkers of Operational Tolerance Following Liver Transplantation in Adults (ITN056ST)

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Proportion of participants who achieve operational tolerance [ Time Frame: 52 weeks after completion of immunosuppression withdrawal ]

    Immunosuppression withdrawal defined by:

    1. No evidence of rejection since enrollment in the study
    2. A liver biopsy at 52 weeks following discontinuation of all immunosuppression demonstrating absence of rejection per the Banff global assessment criteria. The central pathology read will be used for this determination.
    3. A liver biopsy at 52 weeks following discontinuation of all immunosuppression demonstrating histological stability consistent with operational tolerance per Banff 2012 criteria, defined as the absence of the histological findings. The central pathology read will be used for this determination.

    For the purposes of evaluating donor-specific exhaustion, operationally tolerant participants will be compared to those who fail immunosuppression withdrawal.



Secondary Outcome Measures:
  • Proportion of participants who develop Donor-Specific AlloAbs (DSA) or de novo anti-human leukocyte antigen human leukocyte antigen (HLA) antibodies [ Time Frame: 3 years after completing immunosuppression withdrawal ]
  • The incidence of acute rejection, steroid resistant rejection, and chronic rejection [ Time Frame: 3 years after completing immunosuppression withdrawal ]
  • The severity of acute rejection, steroid resistant rejection, and chronic rejection [ Time Frame: 3 years after completing immunosuppression withdrawal ]
  • The timing of acute rejection, steroid resistant rejection, and chronic rejection [ Time Frame: 3 years after completing immunosuppression withdrawal ]
  • The incidence of graft fibrosis in tolerant versus non- tolerant patients. [ Time Frame: 3 years after completing immunosuppression withdrawal ]
  • The progression of graft fibrosis in tolerant versus non- tolerant patients [ Time Frame: 3 years after completing immunosuppression withdrawal ]
  • The incidence of graft loss [ Time Frame: 3 years after completing immunosuppression withdrawal ]
  • The incidence of all-cause mortality [ Time Frame: 3 years after completing immunosuppression withdrawal ]
  • The incidence of study-related SAEs [ Time Frame: 3 years after completing immunosuppression withdrawal ]
  • Proportion of operationally tolerant subjects who remain free of rejection. [ Time Frame: 3 years after completing immunosuppression withdrawal ]
  • Changes in renal function in tolerant versus non-tolerant participants [ Time Frame: Baseline, 1, 2 and 3 years after completing immunosuppression withdrawal ]
    Changes in renal function defined as estimated GFR calculated by CKD-EPI: http://www.qxmd.com/calculate-online/nephrology/ckd-epi-egfr.

  • Changes in Quality of Life in tolerant versus non-tolerant participants and in all participants [ Time Frame: Baseline and 3 years after completing immunosuppression withdrawal ]
    Changes in Quality of Life as measured by the NIDDK Liver Transplantation Database Quality of Life Form

  • Changes in SF-36 in tolerant versus non-tolerant participants and in all participants [ Time Frame: Baseline and 3 years after completing immunosuppression withdrawal ]
  • Predictive value of time post-transplant with regard to operational tolerance [ Time Frame: 3 years after completing immunosuppression withdrawal ]
  • Correlative value of time post-transplant with regard to operational tolerance [ Time Frame: 3 years after completing immunosuppression withdrawal ]
  • Predictive value of recipient age with regard to operational tolerance [ Time Frame: 3 years after completing immunosuppression withdrawal ]
  • Correlative value of recipient age with regard to operational tolerance [ Time Frame: 3 years after completing immunosuppression withdrawal ]

Estimated Enrollment: 60
Study Start Date: October 2015
Estimated Study Completion Date: October 2021
Estimated Primary Completion Date: October 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Immunosuppression withdrawal (ISW)
Gradual immunosuppression withdrawal according to the protocol defined algorithm
Biological: Immunosuppression withdrawal

Participants will initiate calcineurin inhibitor (CNI) withdrawal after at least 3 weeks of stable liver function, as documented by liver function tests (direct bilirubin, alanine aminotransferase and gamma-glutamyl transferase) separated by at least 1 week in the 3 week period prior to withdrawal.

CNI withdrawal will occur in eight 3 week intervals with each subsequent reduction based on liver function tests over the prior 3 week interval.

Participants on CNI and prednisone will undergo withdrawal from the two therapies concurrently.

If participants are weaned off the CNI successfully, they will initiate non-CNI withdrawal. The non-CNI withdrawal includes two dose reductions of approximately 50% over a 6 week period each, after which the drug will be discontinued.

Other Name: ISW

Detailed Description:

People who have liver transplants must take anti-rejection medication (immunosuppression) for the rest of their lives. If they stop, their immune system may reject the transplanted liver. All anti-rejection medications have side effects. Because of the side effects of anti-rejection medications, an important goal of transplant research is to allow people to accept their transplanted organ without long term use of anti-rejection medications. This is called tolerance. In this study, participants who received a liver transplant will have their anti-rejection medication(s) gradually reduced over a period of time and then stopped. The study calls this 'immunosuppression withdrawal'.

The purpose of this research study is to see how many people will develop tolerance after immunosuppression withdrawal. The researchers also want to find out if there are blood or liver biopsy tests that can help transplant doctors in the future predict whether it is safe to decrease or stop anti-rejection medications in people who received a liver transplant.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Recipient participants must meet all of the following criteria to be eligible for this study:

  1. At the time of screening:

    • 18 to 50 years old and more than 6 years post-transplant OR
    • Greater than 50 years old and more than 3 years post-transplant
  2. Recipient of either deceased or living donor liver transplant. Recipients of living donor transplants must have a donor who is also willing to enroll.
  3. Recipient of single organ transplant only
  4. Must have a screening liver biopsy that fulfills the following criteria based on the central pathology reading:

    • Portal inflammation and interface activity is 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 and not generally associated with fibrosis.
    • Negative for perivenular inflammation.
    • Lymphocytic bile duct damage, ductopenia, and biliary epithelial senescence changes are absent unless there is an alternative, non-immunological explanation (e.g. biliary strictures).
    • Fibrosis (if present) should be mild overall, and portal-to-portal bridging should not be more than rare. Perivenular and peri-sinusoidal fibrosis should not be more than mild according to the Banff criteria.
    • Findings for obliterative or foam cell arteriopathy are negative.
  5. Liver function tests (Direct bilirubin, alanine aminotransferase (ALT)), less than twice the upper limit of normal (ULN). ULN values for liver function tests will be defined by ranges from Harrison's Principles of Internal Medicine, 18th edition.
  6. Receiving calcineurin inhibitor (CNI) based maintenance immunosuppression. Participants may also concurrently receive:

    • Low dose mycophenolate mofetil (MMF ≤ 1500 mg daily) or mycophenolic acid (≤ 1080 mg daily), OR
    • Prednisone ≤ 7.5 mg daily, or equivalent corticosteroid..
  7. Ability to sign informed consent

Living donor participants must meet all of the following criteria to be eligible for this study:

  1. At the time of screening: ≥18 years old
  2. Living donor of the liver allograft of an enrolled recipient participant
  3. Ability to sign informed consent
  4. Willingness to donate appropriate biologic samples

Exclusion Criteria:

Recipient participants who meet any of the following criteria will not be eligible for this study:

  1. History of hepatitis C virus (HCV) infection (defined as a positive HCV antibody test).
  2. Positive antigen-antibody immunoassay for human immunodeficiency virus, HIV-1/2.
  3. Serum positivity for HBV surface antigen or HBV-DNA.
  4. History of immune-mediated liver disease in which immunosuppression discontinuation is inadvisable (autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis).
  5. Any medical condition associated with a likely need for systemic corticosteroid administration, e.g., reactive airways disease.
  6. Prospective baseline liver biopsy showing any of the following: (see recipient inclusion criteria #4)

    • acute rejection according to the Banff global assessment criteria;
    • early or late chronic rejection according to the Banff global assessment criteria
    • inflammatory activity and/or fibrosis in excess of permissive criteria according to Banff 2012 criteria;
    • any other histological findings that might make participation in the trial unsafe. Eligibility will be determined by the findings on the central biopsy reading.
  7. Rejection within the 52 weeks prior to screening.
  8. Estimated glomerular filtration rate (GFR) <40 ml/min as calculated by CKD-EPI method (to mitigate the risk of worsening renal failure should rejection occur and high level of CNI be required).
  9. The need for chronic anti-coagulation that cannot be safely discontinued for a minimum of 1 week to safely perform a liver biopsy.
  10. Pregnant females and females of childbearing age who are not using an effective method of birth control.
  11. Current drug or alcohol dependency.
  12. Inability to comply with the study visit schedule and required assessments, including frequent liver function monitoring and protocol biopsies.
  13. Inability to comply with study directed treatment.
  14. Any medical condition that in the opinion of the principal investigator would interfere with safe completion of the trial.
  15. Participation in another interventional clinical trial within the 4 weeks prior to screening.

Living donor participants who meet any of the following criteria will not be eligible for this study:

1. Any medical condition, such as anemia, coagulopathy, etc., that in the opinion of the principal investigator would interfere with safe participation in the trial.

  Contacts and Locations
Information from the National Library of Medicine

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): NCT02533180


Locations
United States, California
University of California, San Francisco Medical Center Recruiting
San Francisco, California, United States, 94143
Contact: Sharon Blaschka, MSN,FNP-BC    415-476-3229    BlaschkaS@surgery.ucsf.edu   
Principal Investigator: Sandy Feng, MD, PhD         
United States, Illinois
Northwestern University Feinberg School of Medicine Recruiting
Chicago, Illinois, United States, 60611
Contact: Laura Bezler    312-694-0260    laura.bezler@northwestern.edu   
Principal Investigator: Josh Levitsky, MD         
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Victor Luu    617-643-5657    vluu@mgh.harvard.edu   
Principal Investigator: James F. Markmann, MD, PhD         
United States, New York
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Contact: Claudia Musat    212-342-0258    cm2065@cumc.columbia.edu   
Principal Investigator: Jean Emond, MD         
United States, Pennsylvania
Hospital of the University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Mary Shaw    215-614-0528    mary.shaw@uphs.upenn.edu   
Contact: Abraham Shaked, MD, PhD         
University of Pittsburgh Medical Center Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Stephenie Dermont    412-682-1645    dermontsm@upmc.edu   
Principal Investigator: Abhinav Humar, MD         
United States, Texas
Baylor University Medical Center at Dallas Recruiting
Dallas, Texas, United States, 75246
Contact: Anne Elizabeth Farrow    214-820-1822    anne.farrow@baylorhealth.edu   
Principal Investigator: Goran Klintmalm, MD, PhD         
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Immune Tolerance Network (ITN)
Investigators
Study Chair: James F. Markmann, MD, PhD Massachusetts General Hospital: Transplantation
  More Information

Additional Information:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT02533180     History of Changes
Other Study ID Numbers: DAIT ITN056ST
First Submitted: August 21, 2015
First Posted: August 26, 2015
Last Update Posted: August 22, 2017
Last Verified: August 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Liver allograft recipient
Immunosuppression withdrawal
Calcineurin inhibitor (CNI) based immunosuppression
Living Donor (of the Respective Liver Transplant Recipient)

Additional relevant MeSH terms:
Liver Extracts
Calcineurin Inhibitors
Hematinics
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action