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临床试验/NCT02533180
NCT02533180已完成2 期

Evaluation of Donor Specific Immune Senescence and Exhaustion as Biomarkers of Operational Tolerance Following Liver Transplantation in Adults (ITN056ST)

National Institute of Allergy and Infectious Diseases (NIAID)13 个研究点 分布在 1 个国家目标入组 100 人开始时间: 2015年12月15日最近更新:
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适应症

试验速览

阶段
2 期
状态
已完成
入组人数
100
试验地点
13
主要终点
The Percent of Participants Who Achieve Operational Tolerance 52 Weeks After Completion of Immunosuppression Withdrawal.
研究概览研究设计入排标准结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

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.

详细描述

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.

研究设计

研究类型
Interventional
分配方式
Na
干预模型
Single Group
主要目的
Treatment
盲法
None

入排标准

年龄范围
18 Years 至 —（Adult, Older Adult）
性别
All
接受健康志愿者
否

入选标准

  • •Recipient participants must meet all of the following criteria to be eligible for this study:
  • •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
  • •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
  • •Prednisone ≤ 7.5 mg daily, or equivalent corticosteroid
  • •Ability to sign informed consent
  • •Living donor participants must meet all of the following criteria to be eligible for this study:
  • •At the time of screening: ≥18 years old
  • •Living donor of the liver allograft of an enrolled recipient participant
  • •Ability to sign informed consent
  • •Willingness to donate appropriate biologic samples

排除标准

  • •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
  • •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
  • •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
  • •Inability to comply with the study visit schedule and required assessments, including frequent liver function monitoring and protocol biopsies
  • •Inability to comply with study directed treatment
  • •Any medical condition that in the opinion of the principal investigator would interfere with safe completion of the trial
  • •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:
  • •Any medical condition, such as anemia, coagulopathy, etc., that in the opinion of the principal investigator would interfere with safe participation in the trial

结局指标

主要结局

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

时间窗: 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.

次要结局

  • 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 Loss(From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.)
  • 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.)
  • 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.)
  • 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 Severity 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.)
  • 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.)
  • 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 Incidence of All-Cause Mortality(From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.)
  • The Incidence of Study-related SAEs(From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.)
  • The Progression of Graft Fibrosis in Tolerant Versus Non- Tolerant Patients(From initiation of immunosuppression withdrawal to study completion, up to 4.5 years.)
  • 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.)
  • 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.)
  • 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.)

研究者

申办方类型
Nih
责任方
Sponsor

研究点 (13)

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