Phase III Multicenter Open-label Randomized Clinical Trial Comparing Everolimus and Low Dose Tacrolimus to Tacrolimus and Mycophenolate Mofetil at 6 mo Post-Transplant to Prevent Long-term Complications After Pediatric Heart Transplantation
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 211
- 试验地点
- 39
- 主要终点
- EFFICACY: MATE-3 Score
研究概览
简要总结
The TEAMMATE Trial will enroll 210 pediatric heart transplant patients from 25 centers at 6 months post-transplant and follow each patient for 2.5 years. Half of the participants will receive everolimus and low-dose tacrolimus and the other half will receive tacrolimus and mycophenolate mofetil. The trial will determine which treatment is better at reducing the cumulative risk of coronary artery vasculopathy, chronic kidney disease and biopsy proven-acute cellular rejection without an increase in graft loss due to all causes (e.g. infection, PTLD, antibody mediated rejection).
详细描述
Median survival after pediatric heart transplantation (HT) is 15 years in the current era. This means that a substantial fraction of patients transplanted during childhood fail to survive to adulthood, or require heart re-transplantation, because of complications related to heart transplant. These complications include heart transplant rejection, infection, coronary artery disease, post-transplant lymphoproliferative disorder (PTLD; a form of lymphoma seen in transplant recipients), and kidney failure. Most complications stem not from the heart transplant itself, but from the drugs commonly used to suppress the immune system in order to prevent rejection. In the US, tacrolimus (TAC) and mycophenolate mofetil (MMF), have emerged over the past decade as the standard of care for pediatric heart transplant immunosuppression. While pediatric survival has improved significantly in the era of TAC and MMF, post-HT complications remain a major problem that limits median survival to 15 years. Recently, everolimus (EVL) has emerged as a potential alternative immunosuppressant that may prevent rejection, coronary artery disease and kidney failure more effectively than TAC/MMF when administered in combination with low-dose tacrolimus (LDTAC). Preliminary studies suggest that EVL, and its first-generation analog sirolimus, are well tolerated in children after HT, regardless of whether it is started in response to coronary artery disease, in response to chronic kidney disease, or empirically 4-6 months after transplant in an effort to prevent the development of these complications1. However, studies are generally limited to single-center experiences using historical controls and have inadequate statistical power to demonstrate treatment differences. This will be the first multicenter randomized clinical trial of maintenance immunosuppression in pediatric heart transplantation to systematically evaluate the safety and efficacy of EVL with LDTAC vs. TAC/MMF to prevent long-term complications which lead to death/graft loss. The major adverse transplant event (MATE) score will serve as the primary endpoint to power the trial. Because no Food & Drug Administration (FDA)-approved immunosuppressants currently exist for children after heart transplant (all prescriptions are off-label) and market incentives to support a trial are limited, the investigators have funded the trial through a Fiscal Year 2016 Peer Reviewed Medical Research Program Clinical Trial Award sponsored by the Department of Defense office of the Congressionally Directed Medical Research Programs. It is worth noting that in contrast to adults, children have a substantially longer potential life expectancy if post-transplant complications can be minimized, making the prevention of late complications an urgent priority for the pediatric heart transplant community.
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
- Single (Outcomes Assessor)
盲法说明
The Coronary Angiography Core Laboratory readers will be blinded to treatment assignment and time point (study visit). The Adjudication Committee members will be blinded to treatment assignment.
入排标准
- 年龄范围
- — 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Orthotopic heart transplantation
- •Age < 21 years at time of transplant
- •Stable immunosuppression at the time of randomization with no contraindication to everolimus, tacrolimus, or mycophenolate mofetil
- •Planned follow-up at a study site for the 30 month duration of the study.
- •Subject or legal adult representative capable of providing informed consent (in general, assent will be sought for children aged 12 years or older).
排除标准
- •Multi-organ transplant (e.g. heart-lung or heart-liver).
- •Known hypersensitivity to everolimus, sirolimus, tacrolimus or mycophenolate mofetil (MMF), or to components of the drug products.
- •Patients on maintenance corticosteroid therapy exceeding a dose equivalent of prednisone 0.1 mg/kg/day at randomization.
- •High-risk for rejection defined as active rejection, recurrent (≥ 2 episodes of grade 2R rejection) cellular rejection, recurrent rejection (≥ 2 episodes of any grade) with hemodynamic compromise, steroid-resistant rejection or unresolved antibody-mediated rejection during the first 6 months post-heart transplant
- •Graft dysfunction (LVEF <40% or wedge pressure >22 mmHg or cardiac index <2.2 L/min/m2)
- •Stage 4 or 5 CKD (eGFR <30 ml/min/1.73 m2)
- •Moderate or severe proteinuria
- •Active infection requiring hospitalization or treatment dose medical therapy.
- •Patients with ongoing wound healing problems, clinically significant wound infection requiring continued therapy or other severe surgical complication in the opinion of the Site Principal Investigator.
- •Fasting Serum Cholesterol ≥300 mg/dL OR greater than or equal to 7.75 mmol/L, AND fasting triglycerides ≥2.5x the upper limit of normal (ULN). Note: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication, and reduction of serum cholesterol and triglyceride levels to below exclusion ranges is confirmed.
- •Uncontrolled diabetes mellitus.
- •Diagnosis of post-transplant lymphoproliferative disorder (PTLD) during the first 6 months post-heart transplant.
- •History of non-adherence to medical regimens.
- •Patients who are treated with drugs that are strong inducers or inhibitors of cytochrome P450 3A4 (CYP3A4) and cannot discontinue the treatment
- •Patients who are pregnant or breast-feeding or intend to get pregnant during the study period.
研究组 & 干预措施
Everolimus/Low-Dose Tacrolimus
Everolimus approximately 0.6 mg/m2/dose taken by mouth every 12 hours for 30 months. Everolimus dose will be adjusted to achieve a trough concentration of 3-8 ng/ml.
Tacrolimus 0.0125 mg/kg/dose by mouth every 12 hours for 30 months. (Tacrolimus dose will be adjusted to achieve a trough concentration of 3-5 ng/ml until subjects are 1 year post-heart transplant. After 1 year post-heart transplant the tacrolimus dose will be adjusted to achieve a trough concentration of 2.5-4.5 ng/mL.)
干预措施: Everolimus (Drug)
Tacrolimus/Mycophenolate Mofetil
Tacrolimus 0.05 mg/kg/dose by mouth every 12 hours for 30 months. (Tacrolimus dose will be adjusted to achieve a trough concentration of 7-10 ng/ml until subjects are 1 year post-heart transplant. After 1 year post-heart transplant the tacrolimus dose will be adjusted to achieve a trough concentration of 5-8 ng/mL.)
Mycophenolate mofetil 600 mg/m2/dose by mouth every 12 hours for 30 months.
干预措施: Tacrolimus (Drug)
Everolimus/Low-Dose Tacrolimus
Everolimus approximately 0.6 mg/m2/dose taken by mouth every 12 hours for 30 months. Everolimus dose will be adjusted to achieve a trough concentration of 3-8 ng/ml.
Tacrolimus 0.0125 mg/kg/dose by mouth every 12 hours for 30 months. (Tacrolimus dose will be adjusted to achieve a trough concentration of 3-5 ng/ml until subjects are 1 year post-heart transplant. After 1 year post-heart transplant the tacrolimus dose will be adjusted to achieve a trough concentration of 2.5-4.5 ng/mL.)
干预措施: Tacrolimus (Drug)
Tacrolimus/Mycophenolate Mofetil
Tacrolimus 0.05 mg/kg/dose by mouth every 12 hours for 30 months. (Tacrolimus dose will be adjusted to achieve a trough concentration of 7-10 ng/ml until subjects are 1 year post-heart transplant. After 1 year post-heart transplant the tacrolimus dose will be adjusted to achieve a trough concentration of 5-8 ng/mL.)
Mycophenolate mofetil 600 mg/m2/dose by mouth every 12 hours for 30 months.
干预措施: Mycophenolate Mofetil (Drug)
结局指标
主要结局
EFFICACY: MATE-3 Score
时间窗: 30 months post-randomization
MATE-3 is a validated score ranging from 0 to 12. The score adds together each subscore so that it represents the cumulative burden of three major adverse transplant events: Cardiac Allograft Vasculopathy (CAV), Chronic Kidney Disease (CKD), and Biopsy-proven Acute Cellular Rejection (ACR). Complete details of the score can be found in the study protocol. A higher score represents a worse outcome.
SAFETY: MATE-6 Score
时间窗: 30 months post-randomization
MATE-6 is a validated score ranging from 0 to 24. The score adds together each subscore so that it represents the cumulative burden of all six major adverse transplant events: Coronary Artery Vasculopathy (CAV), Chronic Kidney Disease (CKD), Biopsy-proven Acute Cellular Rejection (ACR), pathologic diagnosis of Antibody-Mediated Rejection (AMR), Infection, and Post-Transplant Lymphoproliferative Disorder (PTLD). Complete details of the score can be found in the study protocol. A higher score represents a worse outcome.
次要结局
- Efficacy: Freedom from BP-ACR event(Follow-up through 30 months post-randomization)
- Safety: Freedom from Level 2 severity Infection Event(Follow-up through 30 months post-randomization)
- Efficacy: Overall patient survival(Up to 30 months post-randomization)
- Efficacy: Overall allograft survival(Up to 30 months post-randomization)
- Efficacy: Freedom from CAV event(Follow-up through 30 months post-randomization)
- Safety: Frequency and incidence of adverse events including, but not limited to, hyperlipidemia, anemia, thrombocytopenia, interstitial lung disease, aphthous stomatitis, proteinuria, and rash(Follow up through 30 months post-randomization)
- Safety: Freedom from Level 2 severity CKD Event(Follow-up through 30 months post-randomization)
- Safety: Freedom from Level 2 severity ACR Event(Follow-up through 30 months post-randomization)
- Efficacy: Change in kidney function(0 to 6 months, 0 to 12 months, 0 to 30 months post-randomization)
- Efficacy: Freedom from CKD event(Follow-up through 30 months post-randomization)
- Efficacy: Freedom from composite of CAV, CKD, BP-ACR, or any CMV infection(Follow-up through 30 months post-randomization)
- Efficacy: Freedom from composite failure(Follow-up through 30 months post-randomization)
- Efficacy: Lansky and Karnofsky scores(18 and 30 months post-randomization)
- Safety: Freedom from AMR(Follow-up through 30 months post-randomization)
- Safety: Freedom from infection(Follow-up through 30 months post-randomization)
- Efficacy: MATE-3 score where CKD score is calculated by change from baseline visit(Baseline visit through 30 months post-randomization)
- Efficacy: EuroQOL EQ-5D Y (Youth Version)(18 and 30 months post-randomization)
- Safety: Freedom from PTLD(Follow-up through 30 months post-randomization)
- Safety: Freedom from Major Transplant Events (Composite)(Follow-up through 30 months post-randomization)
- Safety: Freedom from Level 2 severity CAV Event(Follow-up through 30 months post-randomization)
- Safety: Freedom from Level 2 severity AMR Event(Follow-up through 30 months post-randomization)
- Safety: Freedom from Level 2 severity PTLD Event(Follow-up through 30 months post-randomization)
- Efficacy: Composite score consisting of MATE CAV, MATE BP-ACR, change in MATE CKD score, and any CMV infection.(Baseline visit through 30 months post-randomization)
- Efficacy: Change in CKD stage(Baseline visit through 30 months post-randomization)
- Efficacy: MATE-3 score where CKD score is replaced by change in CKD stage(Baseline visit through 30 months post-randomization)
- Efficacy: Composite score consisting of MATE CAV, MATE BP-ACR, change in CKD stage, and any CMV infection.(Baseline visit through 30 months post-randomization)
- Efficacy: Overall Patient Survival(Up to 30 months post-randomization)
- Efficacy: Overall Allograft Survival(Up to 30 months post-randomization)
- Efficacy: Change in Kidney Function(0 to 6 months, 0 to 12 months, 0 to 30 months post-randomization)
- Efficacy: Freedom From CKD Event(From enrollment to 30 months after enrollment)
- Efficacy: Freedom From CAV Event(From enrollment to 30 months after enrollment)
- Efficacy: Freedom From BP-ACR Event(From enrollment to 30 months after enrollment)
- Efficacy: Freedom From Composite Failure(From enrollment to 30 months after enrollment)
- Efficacy: EuroQOL EQ-5D Y (Youth Version)(30 months post-randomization)
- Safety: Freedom From AMR(From enrollment to 30 months after enrollment)
- Safety: Freedom From Infection(From enrollment to 30 months after enrollment)
- Safety: Freedom From PTLD(From enrollment to 30 months after enrollment)
- Safety: Number of Participants Experiencing Adverse Events(From enrollment to 30 months after enrollment)
- Safety: Freedom From Major Transplant Events (Composite)(From enrollment to 30 months after enrollment)
- Safety: Freedom From Grade 2 or Greater Severity CKD Event(From enrollment to 30 months after enrollment)
- Safety: Freedom From Grade 2 or Greater Severity CAV Event(From enrollment to 30 months after enrollment)
- Safety: Freedom From Grade 2 or Greater Severity ACR Event(From enrollment to 30 months after enrollment)
- Safety: Freedom From Grade 2 or Greater Severity AMR Event(From enrollment to 30 months after enrollment)
- Safety: Freedom From Grade 2 or Greater Severity Infection Event(From enrollment to 30 months after enrollment)
- Safety: Freedom From Grade 2 or Greater Severity PTLD Event(From enrollment to 30 months after enrollment)
- Efficacy: Freedom From Composite of CAV, CKD, BP-ACR, or Any CMV Infection(From enrollment to 30 months after enrollment)
- Efficacy: Change in CKD Stage(Baseline visit through 30 months post-randomization)
- Efficacy: MATE-3 Score Where CKD Score is Calculated by Change From Baseline Visit(Baseline visit through 30 months post-randomization)
- Efficacy: MATE-3 Score Where CKD Score is Replaced by Change in CKD Stage(Baseline visit through 30 months post-randomization)
- Efficacy: Composite Score Consisting of MATE CAV, MATE BP-ACR, MATE CKD Score, and Any CMV Infection.(Baseline visit through 30 months post-randomization)
- Efficacy: Composite Score Consisting of MATE CAV, MATE BP-ACR, Change in CKD Stage, and Any CMV Infection.(Baseline visit through 30 months post-randomization)
- Efficacy: Lansky Scores(Baseline)
- Efficacy: Lansky Scores(18 months post-randomization)
- Efficacy: Lansky Scores(30 months post-randomization)
- Efficacy: Karnofsky Scores(Baseline)
- Efficacy: Karnofsky Scores(18 months post-randomization)
- Efficacy: Karnofsky Scores(30 months post-randomization)
研究者
Kevin Daly
Assistant Professor of Pediatrics
Boston Children's Hospital