Tacrolimus/Everolimus vs. Tacrolimus/MMF in Pediatric Heart Transplant Recipients Using the MATE Score

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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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

Conditions
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Pediatric Heart Transplantation, Immunosuppression, Chronic Kidney Diseases, Cardiac Allograft Vasculopathy, Heart Transplant Failure and Rejection, Post-transplant Lymphoproliferative Disorder, Heart Transplant Infection

Intervention / Treatment
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* Drug: Everolimus
* Drug: Tacrolimus
* Drug: Mycophenolate Mofetil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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). Exclusion Criteria: 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.

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicenter open-label randomized clinical trial with randomization within 4 strata, defined by donor-specific antibody status and center annual transplant volume. There are 2 parallel groups of equal sizes for randomization: everolimus/low-dose tacrolimus and tacrolimus/mycophenolate mofetil.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Everolimus/Low-Dose Tacrolimus<br>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.) | Drug: Everolimus<br>* Everolimus tablet<br>* Other names: Zortress;Drug: Tacrolimus<br>* Tacrolimus capsule or liquid suspension<br>* Other names: Prograf;|
| Active Comparator: Tacrolimus/Mycophenolate Mofetil<br>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. | Drug: Tacrolimus<br>* Tacrolimus capsule or liquid suspension<br>* Other names: Prograf;Drug: Mycophenolate Mofetil<br>* Mycophenolate Mofetil capsule or liquid suspension<br>* Other names: Cellcept;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EFFICACY: MATE-3 Score | MATE-3 is a validated score ranging from 0 to 12. The score represents the cumulative burden of three major adverse transplant events: Coronary Artery Vasculopathy (CAV), Chronic Kidney Disease (CKD), and Biopsy-proven Acute Cellular Rejection (ACR) | 30 months post-randomization | 
| SAFETY: MATE-6 Score | MATE-6 is a validated score ranging from 0 to 24. The score 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) | 30 months post-randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy: Overall patient survival | Freedom from death from any cause | Up to 30 months post-randomization | 
| Efficacy: Overall allograft survival | Freedom from death and re-transplantation | Up to 30 months post-randomization | 
| Efficacy: Change in kidney function | Change in estimated glomerular filtration rate (eGFR) using the modified Schwartz equation | 0 to 6 months, 0 to 12 months, 0 to 30 months post-randomization | 
| Efficacy: Freedom from CKD event | Chronic Kidney Disease (CKD) | Follow-up through 30 months post-randomization | 
| Efficacy: Freedom from CAV event | Coronary Artery Vasculopathy (CAV) | Follow-up through 30 months post-randomization | 
| Efficacy: Freedom from BP-ACR event | Biopsy-proven Acute Cellular Rejection (ACR) | Follow-up through 30 months post-randomization | 
| Efficacy: Freedom from composite failure | The qualifying event is the earliest occurrence of death, graft loss, 2R/3R ACR rejection or rejection with HD | Follow-up through 30 months post-randomization | 
| Efficacy: Lansky and Karnofsky scores | Validated functional performance score, assigned by clinician assessment: Lansky score if < 16 years at randomization; Karnofsky if >=16 years at randomization | 18 and 30 months post-randomization | 
| Efficacy: EuroQOL EQ-5D Y (Youth Version) | Completed by study participant except for: EQ-5D-Y Proxy version will be used for children ≥ 4 years but less than 8 years at randomization or children ≥ 8 years who are unable to complete the EQ-5D-Y. | 18 and 30 months post-randomization | 
| Safety: Freedom from AMR | Pathologic diagnosis of Antibody-Mediated Rejection (AMR) | Follow-up through 30 months post-randomization | 
| Safety: Freedom from infection | Infection | Follow-up through 30 months post-randomization | 
| Safety: Freedom from PTLD | Post-Transplant Lymphoproliferative Disorder (PTLD) | 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 | These AEs will be reported as individual endpoints as well as a composite. | Follow up through 30 months post-randomization | 
| Safety: Freedom from Major Transplant Events (Composite) | The qualifying event is the earliest occurrence of CKD, CAV, ACR, AMR, infection, and PTLD | Follow-up through 30 months post-randomization | 
| Safety: Freedom from Level 2 severity CKD Event | Chronic Kidney Disease | Follow-up through 30 months post-randomization | 
| Safety: Freedom from Level 2 severity CAV Event | Coronary artery vasculopathy | Follow-up through 30 months post-randomization | 
| Safety: Freedom from Level 2 severity ACR Event | Biopsy-proven Acute Cellular Rejection | Follow-up through 30 months post-randomization | 
| Safety: Freedom from Level 2 severity AMR Event | Pathologic diagnosis of Antibody-Mediated Rejection | Follow-up through 30 months post-randomization | 
| Safety: Freedom from Level 2 severity Infection Event | Infection | Follow-up through 30 months post-randomization | 
| Safety: Freedom from Level 2 severity PTLD Event | Post-transplant Lymphoproliferative Disorder | Follow-up through 30 months post-randomization | 
| Efficacy: Freedom from composite of CAV, CKD, BP-ACR, or any CMV infection | The event is the earliest occurrence of CAV, MATE CKD, BP-ACR, or any CMV infection. | Follow-up through 30 months post-randomization | 
| Efficacy: Change in CKD stage | Change in chronic kidney disease stage where improvements in CKD stage can take on a negative value. | Baseline visit through 30 months post-randomization | 
| Efficacy: MATE-3 score where CKD score is calculated by change from baseline visit | MATE-3 score where the CKD score is the change in MATE-CKD score from baseline visit through 30 months post-randomization. | Baseline visit through 30 months post-randomization | 
| Efficacy: MATE-3 score where CKD score is replaced by change in CKD stage | MATE-3 score where the CKD score is replaced by change in CKD stage from baseline visit through 30 months post-randomization. | Baseline visit through 30 months post-randomization | 
| Efficacy: Composite score consisting of MATE CAV, MATE BP-ACR, change in MATE CKD score, and any CMV infection. | Efficacy: Composite score consisting of MATE CAV, MATE BP-ACR, change in MATE CKD score from baseline visit, 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. | Efficacy: Composite score consisting of MATE CAV, MATE BP-ACR, change in CKD stage from baseline visit, and any CMV infection. | Baseline visit through 30 months post-randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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heart transplantation, children, everolimus, tacrolimus, mycophenolate mofetil, randomized clinical trial