Effect of Rapamycin on Tolerance-related Biomarkers on Stable Liver Transplant Recipients
试验速览
- 阶段
- 2 期
- 入组人数
- 52
- 试验地点
- 1
- 主要终点
- Effects of conversion from calcineurin inhibitors to sirolimus on tolerance-related biomarkers of tolerance in human liver transplant recipients.
研究概览
简要总结
In contrast to calcineurin inhibitors, sirolimus is known to exert remarkable tolerance-promoting properties in multiple animal transplant models. Whether sirolimus is capable of enhancing tolerance-related pathways and/or promoting complete withdrawal of immunosuppressive drugs in human transplant recipients has not been previously addressed. The goal of the investigators study is to evaluate the effects of sirolimus on previously identified tolerogenic pathways in humans and, indirectly, to assess the capacity of this drug to enhance the proportion of liver recipients undergoing successful immunosuppression weaning.
详细描述
Objective:To test in liver transplant recipients identified as non-tolerant whether discontinuation of calcineurin inhibitors followed by 6-month treatment with sirolimus modifies the pattern of expression of the set of genes associated with tolerance
Background: Sirolimus is an immunosuppressive drug used to counter autoimmunity and to prevent acute graft rejection in human and has remarkable tolerance-promoting properties in animal transplant models.
Hypothesis/Specific Aims:We hypothesize that sirolimus promotes tolerogenic pathways in human liver transplantation.
- To test in liver transplant recipients identified as non-tolerant whether discontinuation of calcineurin inhibitors followed by 6-month treatment with sirolimus modifies the pattern of expression of the set of genes associated with tolerance
- To test in liver transplant recipients identified as non-tolerant whether conversion from calcineurin inhibitors to sirolimus modifies memory type immune responses.
- To test in liver transplant recipients identified as non-tolerant whether conversion from calcineurin inhibitor monotherapy to sirolimus affects the frequency, phenotype and function of potentially immunoregulatory peripheral blood lymphocyte subsets
- To test in liver transplant recipients identified as non-tolerant whether conversion from calcineurin inhibitors to sirolimus promotes epigenetic changes related to immunoregulation and cancer development/progression
Proposed Methods:Gene expression experiments: we will quantify the expression in peripheral blood of a set of genes previously identified as predictive of successful immunosuppression withdrawal in stable liver transplant recipients. Blood samples will be obtained before and 6 months after conversion to sirolimus treatment. Measurement of gene expression levels will be conducted employing real-time TaqMan PCR. Classification of patients in the tolerant/non-tolerant categories will be conducted utilizing thresholds and predictive algorithms developed in our laboratory.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 years and weight ≥ 40 kg
- •Women of childbearing potential must have a negative serum pregnancy test result before random assignment and must agree to use a medically acceptable method of contraception throughout the treatment period and for 3 months after discontinuation of randomly assigned treatment. Any woman becoming pregnant during the treatment period must withdraw from the study
- •Subjects receiving immunosuppressive therapy with a stable regimen of calcineurin inhibitor or a combination of calcineurin inhibitor with corticosteroids and/or antimetabolite therapy for a minimum of 4 weeks prior to randomization
- •Recipient of a liver transplantation with >3 years follow-up Cockcroft-Gault GFR values ≥ 40 mL/min
- •Total white blood cell count >3.0 x 109/L (>3,000/mm3), platelet count >75 x109/L (>75,000/mm3), fasting triglycerides <3.95 mmol/L (<350 mg/dL), fasting cholesterol <7.8 mmol/L (<300 mg/dL). If subjects are currently untreated for elevated cholesterol and/or triglycerides and are excluded from the study based on the above criteria, subjects will be offered antihyperlipidemic therapy.
- •Stable liver function defined as: a) normal liver function tests (AST, ALT, ALP, GGT) during the previous 6 months; or alternatively b) minor alterations in liver function tests that have not changed over the previous 6 months (AST/ALT < 2 fold normal levels; ALP < 1.5 fold normal levels; GGT < 3 fold normal levels; bilirubin < 3 mg/dL).
- •Absence of treatment with interferon for hepatitis C virus infection
- •Absence of autoimmune diseases requiring immunosuppressive therapy
- •Absence of autoimmune liver disease as indication for transplantation
- •Absence of any rejection episodes in the 12 previous months
- •Peripheral blood gene expression profile characteristic of non-tolerant recipients (likelihood of successful weaning <5%)
- •Written, signed, and dated IRB- or IEC-approved informed consent
排除标准
- •Requirement for treatment with immunosuppressive drugs for any indications other than prevention of rejection
- •Proteinuria levels > 0.8 g/day
- •Evidence of systemic infection (e,g., sepsis, bacteremia, pneumonia, etc.) at time of random assignment.
- •History of documented human immunodeficiency virus infection.
- •Hypercoagulable states or any history of deep vein thrombosis, HAT, or portal vein thrombosis. (Exception: incidental vascular thrombosis at the time of liver explant, which in the opinion of the investigator, does not place the subject at increased risk of thrombotic events.)
- •Transplant of other graft in addition to the liver
研究组 & 干预措施
Sirolimus
Patients randomized to this arm will discontinue maintenance immunosuppression based on calcineurin inhibitors and start treatment with sirolimus.
干预措施: Sirolimus (Drug)
Calcineurin inhibitor
Patients randomized to this arm will keep the same maintenance immunosuppression based on calcineurin inhibitors.
干预措施: Calcineurin inhibitor (Drug)
结局指标
主要结局
Effects of conversion from calcineurin inhibitors to sirolimus on tolerance-related biomarkers of tolerance in human liver transplant recipients.
时间窗: 12 months
次要结局
未报告次要终点