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

Phase 2

Completed

• Conditions: Liver Transplantation; Liver Transplant
• Interventions: Biological: Immunosuppression withdrawal

• Registration Number: NCT02533180
• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

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 Timeline

• Study First Submitted: 2015-08-21
• Study First Submitted QC: 2015-08-25
• Study First Posted: 2015-08-26
• Study Start: 2015-12-15
• Primary Completion: 2020-02-10
• Results First Submitted: 2021-02-10
• Results First Submitted QC: 2021-02-10
• Results First Posted: 2021-03-05
• Study Completion: 2022-07-08
• Status Verified: 2023-09
• Last Update Submitted: 2023-09-08
• Last Update Posted: 2023-09-14

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 100

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Immunosuppression withdrawal (ISW)	Immunosuppression withdrawal	Gradual immunosuppression withdrawal according to the protocol defined algorithm

Primary Outcome Measures

Name	Time	Method
The Percent of Participants Who Achieve Operational Tolerance 52 Weeks After Completion of Immunosuppression Withdrawal.	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.

Secondary Outcome Measures

Name	Time	Method
The Timing of Acute Rejection, Steroid Resistant Rejection, and Chronic Rejection	From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.	Time is measured as the time (in days) from the initiation of immunosuppression withdrawal to the time of the first biopsy showing rejection (per Banff criteria).
The Incidence of Graft Loss	From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.	A participant is considered to have graft loss when the donated liver needs to be removed and the participant is retransplanted with another donor liver or the participant is listed for retransplant. The endpoint will be summarized with a two-sided, 95% exact binomial confidence interval.
The Proportion of Operationally Tolerant Subjects Who Remain Free of Rejection at 3 Years After Completing Immunosuppression Withdrawal.	From initiation of immunosuppression withdrawal through 3 years after completing immunosuppression withdrawal.	Participants are considered operationally tolerant 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 (as assessed by the central pathologist). This number reflects the participants that continue to show the absence of rejection per the Banff global assessment criteria (as assessed by the central pathologist) in the 3 years following completion of immunosuppression withdrawal. The endpoint will be summarized with a two-sided, 95% exact binomial confidence interval.
Changes in SF-36 in Tolerant Versus Non-tolerant Participants and in All Participants at Baseline Versus the End of Study Participation.	From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.	SF-36 is a patient-reported survey of patient health. There are eight different scales that can be summarized into two summary scores-Mental Component Score and Physical Component Score. Each score ranges from 0-100, with a higher score indicating a better quality of life. Change was calculated as the difference between the questionnaire completed at the initiation of withdrawal and the questionnaire completed closest to the end of study participation. This change was calculated separately for tolerant and non-tolerant subjects.
Proportion of Participants Who Develop Donor-Specific AlloAbs (DSA) or de Novo Anti-human Leukocyte Antigen Human Leukocyte Antigen (HLA) Antibodies	From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.	HLA is a molecule formed by a complex of genes which encode cell-surface proteins responsible for the regulation of the immune system. This molecule is unique for each individual. HLA molecules are present in all cells and are responsible for helping the immune system distinguish between your own cells and foreign cells (like pathogens). However, when our immune system encounters HLA molecules from another individual (like during pregnancy, after blood transfusions or transplantation) it recognizes this as foreign and can generate anti-HLA antibodies. These anti-HLA antibodies could cause harm to the transplanted organ by recognizing its cells as foreign triggering the immune system to attack. This endpoint looks at the development of newly developed donor-specific antibodies (DSA). DSA are a subset of anti-HLA antibodies that are specific against the donor organ. These anti-HLA antibodies are categorized into two classes-class I and class II. The data shown is only for class II DSA.
The Severity of Acute Rejection, Steroid Resistant Rejection, and Chronic Rejection	From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.	Severity is based on the Banff global assessment grade according to the central pathology reading of the liver biopsy. For an individual subject, the worst severity is reported. Acute rejection is categorized into mild (rejection infiltrate in a minority of triads that is generally mild and confined within the portal spaces), moderate (rejection infiltrate expanding most or all of the triads), or severe (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). Chronic rejection is categorized into early (bile duct atrophy/loss and foam cell obliterative arteriopathy in \<50% of the portal tracts) or late (early criteria but \>50% of the portal tracts) stage. Steroid resistant rejection is always considered severe. The endpoint is summarized with a two-sided, 95% exact binomial confidence interval.
The Incidence of Graft Fibrosis in Tolerant Versus Non- Tolerant Patients.	From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.	Fibrosis of the liver is the formation of an excessive accumulation of scar tissue in the liver. Graft fibrosis was measured two ways by the ISHAK scale and by Liver Allograft Fibrosis Score (LAFSc) via a liver biopsy. Both scales range from 0 to 6, with a higher score indicating more severe fibrosis. A subject is considered as having graft fibrosis if the score is greater than or equal to 2 at their last available biopsy after the initiation of immunosuppression withdrawal.
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.	From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.	Glomerular filtration rate (GFR) is a measure of kidney function and helps determine the stage of kidney disease. A value less than 15 indicates kidney failure, 15 to 29 indicates severe loss of kidney function, 30 to 44 indicates moderate to severe loss of kidney function, 45 to 59 mild to moderate loss of kidney function, 60 to 89 indicates mild loss of kidney function, and 90 or higher indicates normal kidney function. The equation developed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) is used to estimate GFR from serum creatinine. The baseline value was selected as the value collected immediately prior to the initiation of immunosuppression withdrawal. The year 1, 2, and 3, values are the values closest to and within 2 months of the expected date. Change was calculated as the year 1, 2, or 3 value minus baseline. A positive value indicates an increase in kidney function.
The Incidence of Acute Rejection, Steroid Resistant Rejection, and Chronic Rejection	From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.	Incidence will be measured as the proportion of participants who have acute rejection (per Banff criteria), steroid resistant rejection (rejection requiring antibody treatment), and chronic rejection (per Banff criteria), separately. The endpoint is summarized with a two-sided, 95% exact binomial confidence interval.
The Incidence of All-Cause Mortality	From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.	This number reflects all deaths observed in all participants in the study period, regardless of the cause. The endpoint will be summarized with a two-sided, 95% exact binomial confidence interval.
The Incidence of Study-related SAEs	From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.	An adverse event is considered a serious adverse event (SAE) if it results it any one of the following: death, life-threatening, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or substation disruption to conduct normal life functions, congenital anomaly or birth defect, or an important medical event. The event is considered study related if the medical monitor deems it to be at least possibly or definitely related to any of the study interventions/procedures (immunosuppression withdrawal, the blood draw, or the liver biopsy). The endpoint will be summarized with a two-sided, 95% exact binomial confidence interval.
The Progression of Graft Fibrosis in Tolerant Versus Non- Tolerant Patients	From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.	Fibrosis of the liver is the formation of an excessive accumulation of scar tissue in the liver. Graft fibrosis was measured two ways by the ISHAK scale and by Liver Allograft Fibrosis Score (LAFSc) via a liver biopsy. Both scales range from 0 to 6, with a higher score indicating more severe fibrosis. Progression was calculated as the final available biopsy score minus the baseline biopsy score. A positive value indicates a worsening of fibrosis.
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.	From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.	NIDDK Liver Transplantation Database Quality of Life Form is a patient-reported survey of patient health. The questionnaire is summarized into five domains-measures of disease (ranges from 0-21 with higher score indicating worse quality), psychological status (ranges from 0-5 with higher score indicating worse quality), personal function (ranges from 0-4 with higher score indicating better quality), social and role function (ranges from 0 to 20 with higher score indicating worse quality), and general health perception (ranges from 0 to 10 with higher score indicating better quality). Change was calculated as the difference between the questionnaire completed at the initiation of withdrawal and the questionnaire completed closest to the end of study participation. This change was calculated separately for tolerant and non-tolerant subjects.
Predictive Value of the Following Parameters With Regard to Operational Tolerance: Time Post-transplant.	From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.	Time post-transplant is calculated as time in years from transplant to enrollment. Participants are considered operationally tolerant 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 (as assessed by the central pathologist). The odds ratio and corresponding 95% confidence interval are presented. The odds ratio represents the probability of achieving operational tolerance per year increase in time post-transplant. An odds ratio greater than 1 means that as the factor increases, operational tolerance is more likely to occur. Whereas less than 1 means operational tolerance is less likely to occur. Since the confidence interval contains 1, this means that as the corresponding factor increases, the likelihood of tolerance does not change.
Predictive Value and the Correlative Value of the Following Parameters With Regard to Operational Tolerance: Recipient Age.	From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.	Recipient age is the age at the time of enrollment. Participants are considered operationally tolerant 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 (as assessed by the central pathologist). The odds ratio and corresponding 95% confidence interval are presented. The odds ratio represents the probability of achieving operational tolerance per year increase in recipient age. An odds ratio greater than 1 means that as the factor increases, operational tolerance is more likely to occur. Whereas less than 1 means operational tolerance is less likely to occur. Since the confidence interval contains 1, this means that as the corresponding factor increases, the likelihood of tolerance does not change.

Trial Locations

Locations (7)

University of California, San Francisco Medical Center; 🇺🇸 San Francisco, California, United States

Northwestern University Feinberg School of Medicine; 🇺🇸 Chicago, Illinois, United States

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

University of Pittsburgh Medical Center; 🇺🇸 Pittsburgh, Pennsylvania, United States

Columbia University Medical Center; 🇺🇸 New York, New York, United States

Baylor University Medical Center at Dallas; 🇺🇸 Dallas, Texas, United States

Hospital of the University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States