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

NCT02533180 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: DAIT ITN056ST
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 7

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.

Conditions

Liver Transplant; Liver Transplantation

Keywords

Liver allograft recipient; Immunosuppression withdrawal; Calcineurin inhibitor (CNI) based immunosuppression; Living Donor (of the Respective Liver Transplant Recipient)

Outcome Measures

Primary Outcomes (1)

• The Percent of Participants Who Achieve Operational Tolerance 52 Weeks After Completion of Immunosuppression Withdrawal.

  Participants are considered as successfully withdrawn from immunosuppression if they remain off immunosuppression for at least 52 weeks without evidence of rejection since enrollment and have a liver biopsy at 52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.

  From initiation of immunosuppression withdrawal through 52 weeks after stopping all immunosuppression

Secondary Outcomes (15)

• 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.

• The Incidence of Acute Rejection, Steroid Resistant Rejection, and Chronic Rejection

  From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.

• The Severity of Acute Rejection, Steroid Resistant Rejection, and Chronic Rejection

  From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.

• The Timing of Acute Rejection, Steroid Resistant Rejection, and Chronic Rejection

  From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.

• The Incidence of Graft Fibrosis in Tolerant Versus Non- Tolerant Patients.

  From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.

Study Arms (1)

Immunosuppression withdrawal (ISW)

OTHER

Gradual immunosuppression withdrawal according to the protocol defined algorithm

Biological: Immunosuppression withdrawal

Interventions

Immunosuppression withdrawal BIOLOGICAL

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.

Also known as: ISW

Immunosuppression withdrawal (ISW)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Recipient participants must meet all of the following criteria to be eligible for this study:
• At the time of screening:
• to 50 years old and more than 6 years post-transplant OR
• Greater than 50 years old and more than 3 years post-transplant
• Recipient of either deceased or living donor liver transplant. Recipients of living donor transplants must have a donor who is also willing to enroll
• Recipient of single organ transplant only
• 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
• 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
• 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

You may not qualify if:

• Recipient participants who meet any of the following criteria will not be eligible for this study:
• History of hepatitis C virus (HCV) infection (defined as a positive HCV antibody test)
• Positive antigen-antibody immunoassay for human immunodeficiency virus, HIV-1/2
• Serum positivity for HBV surface antigen or HBV-DNA
• History of immune-mediated liver disease in which immunosuppression discontinuation is inadvisable (autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis)
• Any medical condition associated with a likely need for systemic corticosteroid administration, e.g., reactive airways disease
• 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
• Rejection within the 52 weeks prior to screening
• 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)
• The need for chronic anti-coagulation that cannot be safely discontinued for a minimum of 1 week to safely perform a liver biopsy
• Pregnant females and females of childbearing age who are not using an effective method of birth control
• Current drug or alcohol dependency

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Immune Tolerance Network (ITN): collaborator
• PPD Development, LP: collaborator
• Rho Federal Systems Division, Inc.: collaborator

Study Sites (7)

University of California, San Francisco Medical Center

San Francisco, California, 94143, United States

Location

Northwestern University Feinberg School of Medicine

Chicago, Illinois, 60611, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15213, United States

Location

Baylor University Medical Center at Dallas

Dallas, Texas, 75246, United States

Location

Related Publications (1)

• 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.

  PMID: 26729653 DERIVED

Related Links

• ITN OPTIMAL Study Website
• Division of Allergy, Immunology, and Transplantation (DAIT)
• National Institute of Allergy and Infectious Diseases (NIAID)
• Immune Tolerance Network (ITN)

Results Point of Contact

• Title: Director, Clinical Research Operations Program
• Organization: DAIT/NIAID

DAITClinicalTrialsGov@niaid.nih.gov

301-594-7669

Study Officials

• James F. Markmann, MD, PhD

  Massachusetts General Hospital: Transplantation

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 21, 2015
• First Posted: August 26, 2015
• Study Start: December 15, 2015
• Primary Completion: February 10, 2020
• Study Completion: July 8, 2022
• Last Updated: September 14, 2023
• Results First Posted: March 5, 2021

Record last verified: 2023-09

Locations

US (7)