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

• ClinicalTrials.gov Identifier: NCT02533180
• Recruitment Status: Completed
• First Posted: August 26, 2015
• Results First Posted: March 5, 2021
• Last Update Posted: February 24, 2023
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Immune Tolerance Network (ITN); PPD; Rho Federal Systems Division, Inc.
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information

• First Submitted Date: August 21, 2015
• First Posted Date: August 26, 2015
• Results First Submitted Date: February 10, 2021
• Results First Posted Date: March 5, 2021
• Last Update Posted Date: February 24, 2023
• Actual Study Start Date: December 15, 2015
• Actual Primary Completion Date: February 10, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 10, 2021)

The Percent of Participants Who Achieve Operational Tolerance 52 Weeks After Completion of Immunosuppression Withdrawal. [ Time Frame: From initiation of immunosuppression withdrawal through 52 weeks after stopping all immunosuppression ]

Participants are considered as successfully withdrawn from immunosuppression if they remain off immunosuppression for at least 52 weeks without evidence of rejection since enrollment and have a liver biopsy at 52 weeks following completion of immunosuppression withdrawal demonstrating histological stability and the absence of rejection per Banff global assessment criteria. This biopsy is assessed by the central pathologist. All participants who fail to complete immunosuppression withdrawal, regardless of reason, or fail to have a biopsy 52 weeks after completion of immunosuppression withdrawal will be considered to have failed.

Original Primary Outcome Measures (submitted: August 25, 2015)

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.

Current Secondary Outcome Measures (submitted: January 25, 2023)

• 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 ]
• Predictive Value of Recipient Age With Regard to Operational Tolerance [ Time Frame: 3 years after completing immunosuppression withdrawal ]

Original Secondary Outcome Measures (submitted: August 25, 2015)

• 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 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• 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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Liver Transplant
• Liver Transplantation

Intervention

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

Study Arms

Immunosuppression withdrawal (ISW)

Gradual immunosuppression withdrawal according to the protocol defined algorithm

Intervention: Biological: Immunosuppression withdrawal

• Publications *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 10, 2021): 100
• Original Estimated Enrollment (submitted: August 25, 2015): 60
• Actual Study Completion Date: July 8, 2022
• Actual Primary Completion Date: February 10, 2020 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02533180
• Other Study ID Numbers: DAIT ITN056ST
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• Original Responsible Party: Same as current
• Current Study Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Original Study Sponsor: Same as current

Collaborators

• Immune Tolerance Network (ITN)
• PPD
• Rho Federal Systems Division, Inc.

Investigators

• Study Chair: James F. Markmann, MD, PhD; Massachusetts General Hospital: Transplantation

• PRS Account: National Institute of Allergy and Infectious Diseases (NIAID)
• Verification Date: February 2023