Clinical trial NCT02533180: Evaluation of Donor Specific Immune Senescence and Exhaustion as Biomarkers of Tolerance Post Liver Transplantation
Official title: Evaluation of Donor Specific Immune Senescence and Exhaustion as Biomarkers of Operational Tolerance Following Liver Transplantation in Adults (ITN056ST)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Liver Transplant
Liver Transplantation
Keywords: Liver allograft recipient
Immunosuppression withdrawal
Calcineurin inhibitor (CNI) based immunosuppression
Living Donor (of the Respective Liver Transplant Recipient)
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Immune Tolerance Network (ITN)
name: PPD Development, LP
name: Rho Federal Systems Division, Inc.
First posted: 2015-08-26
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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 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

Primary outcomes:
measure: The Percent of Participants Who Achieve Operational Tolerance 52 Weeks After Completion of Immunosuppression Withdrawal.
timeFrame: From initiation of immunosuppression withdrawal through 52 weeks after stopping all immunosuppression
Secondary outcomes:
measure: Proportion of Participants Who Develop Donor-Specific AlloAbs (DSA) or de Novo Anti-human Leukocyte Antigen Human Leukocyte Antigen (HLA) Antibodies
timeFrame: From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.
measure: The Incidence of Acute Rejection, Steroid Resistant Rejection, and Chronic Rejection
timeFrame: From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.
measure: The Severity of Acute Rejection, Steroid Resistant Rejection, and Chronic Rejection
timeFrame: From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.
measure: The Timing of Acute Rejection, Steroid Resistant Rejection, and Chronic Rejection
timeFrame: From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.
measure: The Incidence of Graft Fibrosis in Tolerant Versus Non- Tolerant Patients.
timeFrame: From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.
measure: The Progression of Graft Fibrosis in Tolerant Versus Non- Tolerant Patients
timeFrame: From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.
measure: The Incidence of Graft Loss
timeFrame: From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.
measure: The Incidence of All-Cause Mortality
timeFrame: From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.
measure: The Incidence of Study-related SAEs
timeFrame: From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.
measure: The Proportion of Operationally Tolerant Subjects Who Remain Free of Rejection at 3 Years After Completing Immunosuppression Withdrawal.
timeFrame: From initiation of immunosuppression withdrawal through 3 years after completing immunosuppression withdrawal.
measure: Changes in Renal Function (Defined as Estimated GFR Calculated by the CKD-EPI Creatine Equation 2021) in Tolerant Versus Non-tolerant Participants at 1, 2 and 3 Years After Completing Immunosuppression Withdrawal.
timeFrame: From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.
measure: Changes in Quality of Life in Tolerant Versus Non-tolerant Participants and in All Participants at Baseline Versus the End of Study Participation, as Measured by the NIDDK Liver Transplantation Database Quality of Life Form.
timeFrame: From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.
measure: Changes in SF-36 in Tolerant Versus Non-tolerant Participants and in All Participants at Baseline Versus the End of Study Participation.
timeFrame: From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.
measure: Predictive Value of the Following Parameters With Regard to Operational Tolerance: Time Post-transplant.
timeFrame: From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.
measure: Predictive Value and the Correlative Value of the Following Parameters With Regard to Operational Tolerance: Recipient Age.
timeFrame: From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California, San Francisco Medical Center
state: California
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Dallas
country: United States
facility: Baylor University Medical Center at Dallas
state: Texas
Study officials:
affiliation: Massachusetts General Hospital: Transplantation
name: James F. Markmann, MD, PhD
role: STUDY_CHAIR
References:
citation: Sanchez-Fueyo A, Markmann JF. Immune Exhaustion and Transplantation. Am J Transplant. 2016 Jul;16(7):1953-7. doi: 10.1111/ajt.13702. Epub 2016 Feb 16.