The RETIRE Trial: A Randomized Phase 2 Trial of Adoptive Therapy With Treg Adoptive Cell Transfer (TRACT) To Prevent Rejection in Living Donor Kidney Transplant Recipients
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 34
- 试验地点
- 8
- 主要终点
- Development of de novo donor-specific antibodies
研究概览
简要总结
The goal of this multi-national, multi-center, open-label, randomized Phase 2 trial is to determine the safety and efficacy of administering expanded regulatory T cells (TRK-001) to prevent allograft rejection in living donor renal transplant recipients.
Enrolled subjects will be randomized to one of 2 study arms:
Arm 1 subjects will receive standard of care immunosuppression
Arm 2 subjects will receive initial standard of care (SOC) immunosuppression and a single infusion of TRK-001. Three months after the transplant, Arm 2 subjects may be able to begin reducing their immunosuppression medication to a 1-drug regimen.
The primary outcome measures of trial are to evaluate several components indicating immunologic problems with the transplanted organ at 1-year post-transplant and to evaluate the ability for the study subjects given TRK-001 to wean to a 1-drug immunosuppression regimen.
All enrolled subjects will be followed for 5 years post-transplant.
详细描述
This is a prospective, multi-national, multi-center, open-label, randomized Phase 2 trial to determine the safety and efficacy of administering autologous expanded regulatory T cells (TRK-001) to prevent allograft rejection in living donor renal transplant recipients.
All subjects will be followed for 5 years post-transplant, comprising of a 2-year post-transplant follow-up period and a 3-year surveillance period.
Subjects with end-stage renal disease undergoing a living donor kidney transplant will be enrolled into the trial as follows:
Arm 1 SOC: Standard of care immunosuppression (N=14)
Arm 2 TRACT/MONO: TRK-001 and initial SOC immunosuppression weaned to monotherapy (N=20)
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •All inclusion criteria must be met prior to randomization.
- •Males or females aged 18-65 years as of the date of informed consent who will undergo a single organ, living donor kidney transplant.
- •Donor aged 18-65 years as of the date of organ donation. A certain degree of HLA matching between the donor and the recipient is not required.
- •Blood type compatibility between recipient and donor must be established as follows.
- •Recipient A to Donor A or O; Recipient B to Donor B or O; Recipient AB to Donor A, B, AB, or O; Recipient O to Donor O.
- •No prior organ transplant of any kind.
- •Women of childbearing potential must agree to use a medically acceptable method of contraception throughout the trial. A list of the medically acceptable methods of contraception are listed in the informed consent document.
- •Male patients must agree to use birth control following the initiation of standard-of-care immunosuppression and for a minimum of 6 months following kidney transplant.
- •Subjects (recipients) must be able to understand the consent form and give written informed consent prior to any trial procedure.
- •If donor informed consent is required by IRB/IEC, donor must be able to understand the consent form and give written informed consent prior to any trial procedure. Note: Donor informed consent is required for donors participating in the research assay collections.
排除标准
- •Based on SOC Pre-Transplant Evaluation
- •The following exclusion criteria must be determined prior to randomization per SOC pre-transplant evaluation.
- •Known sensitivity or contraindication to thymoglobulin, everolimus, sirolimus, or tacrolimus or other immunosuppression medication prescribed.
- •Subjects with a positive crossmatch by virtual cross matching or complement-dependent cytotoxicity (CDC) cross matching or flow cytometry cross matching (FCXM).
- •Subjects with PRA >80% per SOC pre-transplant assessment. PRA must be repeated prior to transplant if patient receives a blood product transfusion after the initial assessment.
- •Subjects with current or historic donor specific antibodies.
- •Body Mass Index (BMI) of < 16 kg/m2 or > 38 kg/m2 per SOC pre-transplant evaluation.
- •Subjects who are pregnant or nursing mothers.
- •Subjects whose life expectancy is severely limited by diseases other than renal disease, per judgement of an investigator.
- •Ongoing active drug or alcohol substance abuse, per judgement of an investigator.
- •Major ongoing psychiatric illness or recent history of noncompliance with current medical therapy, per judgement of an investigator.
- •Significant cardiovascular disease (e.g.):
- •Significant non-correctable coronary artery disease, per judgement of an investigator
- •Ejection fraction below 30% per SOC echocardiogram if an echocardiogram is performed for an individual subject as part of their pre-transplant evaluation
- •History of recent (< 12 months) myocardial infarction at time of informed consent
- •History of recent (within 3 months) vascular intervention(s) for coronary artery disease at the time of informed consent
- •Documented arrhythmias that require a pacemaker or medical therapy for control.
- •Subjects who require use of chronic anticoagulation medications. Use of anti-platelet medications will be allowed in absence of a documented arrhythmia.
- •Malignancy within 3 years, excluding non-melanoma skin cancers such as basal cell carcinoma and squamous cell carcinoma.
- •Serologic evidence of active infection with HCV, HIV or HBV per SOC pre-transplant evaluation. Historical data within three months of transplant are acceptable.
- •Subjects with a total white blood cell count < 4,000/mm3; platelet count < 50,000/mm3; triglyceride > 400 mg/dL; total cholesterol > 300 mg/dL, prothrombin time <8.4 seconds or >15.7 seconds, activated partial thromboplastin time <21.6 or > 42.3 seconds, fibrinogen <177 mg/dL or >598 mg/dL, and INR <0.64 or >1.
- •Subjects with underlying renal disease etiologies with high risk of disease recurrence such as primary focal segmental glomerulosclerosis and others per investigator discretion.
- •Subjects requiring the use of chronic immunosuppressive medication to control an underlying renal disease, or a disease with extrarenal manifestations (i.e., inflammatory bowel disease). Subjects requiring chronic or intermittent use of inhaled corticosteroids for respiratory conditions will be allowed.
- •Diabetic subjects with an HbA1c of >8%.
- •The following exclusion criteria must be determined prior to transplant per SOC pre-transplant evaluation.
- •Subjects with an active infection considered clinically significant by an investigator that has not resolved prior to transplant.
- •Exclusion Criteria Prior to Leukapheresis (Arm 2)
- •Subjects with an active infection considered clinically significant by an investigator that has not resolved prior to leukapheresis.
- •Subjects with PRA >80%, if repeated after SOC pre-transplant assessment. (PRA must be repeated prior to leukapheresis if patient receives a blood product transfusion after the initial assessment).
- •Subjects who are pregnant or nursing.
- •Subjects who received an investigational drug within 30 days prior to leukapheresis.
- •Subjects who received anti-T cell therapy within 30 days prior to leukapheresis.
- •Subjects who do not meet pre-leukapheresis clearance parameters per institutional practices or per investigator discretion.
- •Exclusion Criteria Prior to TRACT Cellular Product Infusion (Arm 2)
- •Subjects with an active infection considered clinically significant by the investigator that has not resolved prior to planned Treg infusion.
- •Subjects with a new, clinically significant medical condition that, per investigator opinion, would impact the ability to safely administer TRK-
- •Subjects who experience a rejection episode of the kidney graft prior to the planned Treg infusion.
- •Subjects who are pregnant or nursing. Women who are of childbearing potential must have a negative urine or serum pregnancy test before infusion of TRK-
- •Subjects who received an investigational drug within 30 days prior to infusion.
- •Subjects who received anti-T cell therapy within 30 days prior to infusion.
研究组 & 干预措施
Arm 1: Standard of Care (SOC)
Arm 1: SOC-Subjects randomized to Arm 1 will be followed on the prescribed 2-drug SOC immunosuppression throughout the trial.
The study allowed SOC regimen is tacrolimus + sirolimus or everolimus.
干预措施: Arm 1: SOC (mTOR + CNI) (Drug)
Arm 2A: TRACT/MONO mTOR
Arm 2: TRACT/MONO- At the beginning of the trial, subjects randomized to Arm 2 will be maintained on the prescribed 2-drug SOC immunosuppression and have a single infusion of expanded Tregs (TRK-001) at Day +53 to +67 following living donor kidney transplantation.
At Month 3 post-transplant, Arm 2 TRACT/MONO subjects will be further randomized to either Arm 2A: TRACT/MONO mTOR or Arm 2B: TRACT/MONO CNI.
Subjects randomized to Arm 2A: TRACT/MONO mTOR who have a normal biopsy and no de novo donor specific antibodies at Month 3 will begin weaning of tacrolimus and will remain on a 1-drug regimen with either everolimus or sirolimus until the end of the trial.
干预措施: Arm 2A: TRACT/MONO mTOR (Biological)
Arm 2B: TRACT/MONO CNI
Arm 2: TRACT/MONO- At the beginning of the trial, subjects randomized to Arm 2 will be maintained on the prescribed 2-drug SOC immunosuppression and have a single infusion of expanded Tregs (TRK-001) at Day +53 to +67 following living donor kidney transplantation.
At Month 3 post-transplant, Arm 2 TRACT/MONO subjects will be further randomized to either Arm 2A: TRACT/MONO mTOR or Arm 2B: TRACT/MONO CNI.
Subjects randomized to Arm 2B: TRACT/MONO CNI who have a normal biopsy and no de novo donor specific antibodies at Month 3 will begin weaning of the mTOR medication and will remain on a 1-drug regimen with low dose tacrolimus until the end of the trial.
干预措施: Arm 2B: TRACT/MONO CNI (Biological)
结局指标
主要结局
Development of de novo donor-specific antibodies
时间窗: Month 12 Post-transplant
A primary outcome measure for this study is to evaluate a composite endpoint of immunologic events against the allograft, where a failure is defined as patient-experienced immunologic events including the development of de novo donor-specific antibodies.
Biopsy-proven acute rejection
时间窗: Month 12 Post-transplant
A primary outcome measure for this study is to evaluate a composite endpoint of immunologic events against the allograft, where a failure is defined as patient-experienced immunologic events including biopsy-proven acute rejection.
Successful taper to monotherapy (Arm 2)
时间窗: Month 12 Post-transplant
A primary outcome measure for this study is to evaluate the ability for Arm 2 subjects to successfully taper to monotherapy by one-year post-transplant.
Biopsy-proven subclinical rejection
时间窗: Month 12 Post-transplant
A primary outcome measure for this study is to evaluate a composite endpoint of immunologic events against the allograft, where a failure is defined as patient-experienced immunologic events including biopsy-proven subclinical rejection.
Development of significant (2+) interstitial fibrosis/tubular atrophy
时间窗: Month 12 Post-transplant
A primary outcome measure for this study is to evaluate a composite endpoint of immunologic events against the allograft, where a failure is defined as patient-experienced immunologic events including the development of significant (2+) interstitial fibrosis/tubular atrophy.
次要结局
- Development of de novo donor-specific antibodies(To Month 60 Post-transplant)
- Development of significant (2+) interstitial fibrosis/tubular atrophy(To Month 60 Post-transplant)
- Successful maintenance of monotherapy (Arm 2)(Month 24 Post-transplant)
- Infections(To Month 60 Post-transplant)
- Metabolic anomalies(To Month 60 Post-transplant)
- Graft loss(To Month 24 Post-transplant)
- Biopsy-proven subclinical rejection(To Month 60 Post-transplant)
- Malignancy(To Month 60 Post-transplant)
- Death (all cause)(To Month 24 Post-transplant)
- Quality of Life Measures by using KDQOL-SF(To Month 60 Post-transplant)
- Biopsy-proven acute rejection(To Month 24 Post-transplant)
- Quality of Life Measures by using EQ-5D-5L(To Month 60 Post-transplant)
- Safety- Adverse Events(To Month 60 Post-transplant)
- Biopsy-proven acute rejection(To Month 60 Post-transplant)
- Graft loss(To Month 60 Post-transplant)