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

Boston Children's Hospital211 enrolled

Overview

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).

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.

Eligibility

Sex: ALLMax age: 21 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Orthotopic heart transplantation 2. Age \< 21 years at time of transplant 3. Stable immunosuppression at the time of randomization with no contraindication to everolimus, tacrolimus, or mycophenolate mofetil 4. Planned follow-up at a study site for the 30 month duration of the study. 5. 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: 1. Multi-organ transplant (e.g. heart-lung or heart-liver). 2. Known hypersensitivity to everolimus, sirolimus, tacrolimus or mycophenolate mofetil (MMF), or to components of the drug products. 3. Patients on maintenance corticosteroid therapy exceeding a dose equivalent of prednisone 0.1 mg/kg/day at randomization. 4. 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 5. Graft dysfunction (LVEF \<40% or wedge pressure \>22 mmHg or cardiac index \<2.2 L/min/m2) 6. Stage 4 or 5 CKD (eGFR \<30 ml/min/1.73 m2) 7. Moderate or severe proteinuria 8. Active infection requiring hospitalization or treatment dose medical therapy. 9. 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. 10. 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. 11. Uncontrolled diabetes mellitus. 12. Diagnosis of post-transplant lymphoproliferative disorder (PTLD) during the first 6 months post-heart transplant. 13. History of non-adherence to medical regimens. 14. Patients who are treated with drugs that are strong inducers or inhibitors of cytochrome P450 3A4 (CYP3A4) and cannot discontinue the treatment 15. Patients who are pregnant or breast-feeding or intend to get pregnant during the study period.

Locations (25)

Children's of Alabama

Birmingham, Alabama, United States

Phoenix Children's Hospital

Phoenix, Arizona, United States

Loma Linda University

Loma Linda, California, United States

Children's Hospital Los Angeles

Los Angeles, California, United States

UCLA Mattel Children's Hospital

Los Angeles, California, United States

Stanford University

Palo Alto, California, United States

Children's Hospital Colorado

Aurora, Colorado, United States

Children's National Medical Center

Washington D.C., District of Columbia, United States

University of Florida Congenital Heart Center

Gainesville, Florida, United States

Joe DiMaggio Children's Hospital

Hollywood, Florida, United States

...and 15 more locations

Outcomes

Primary Outcomes

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)

Time frame: 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)

Time frame: 30 months post-randomization

Secondary Outcomes

Efficacy: Overall patient survival

Freedom from death from any cause

Time frame: Up to 30 months post-randomization

Efficacy: Overall allograft survival

Freedom from death and re-transplantation

Time frame: Up to 30 months post-randomization

Efficacy: Change in kidney function

Change in estimated glomerular filtration rate (eGFR) using the modified Schwartz equation

Time frame: 0 to 6 months, 0 to 12 months, 0 to 30 months post-randomization

Efficacy: Freedom from CKD event

Chronic Kidney Disease (CKD)

Time frame: Follow-up through 30 months post-randomization

Efficacy: Freedom from CAV event

Coronary Artery Vasculopathy (CAV)

Time frame: Follow-up through 30 months post-randomization

Efficacy: Freedom from BP-ACR event

Biopsy-proven Acute Cellular Rejection (ACR)

Time frame: 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

Time frame: 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

Time frame: 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.

Time frame: 18 and 30 months post-randomization

Safety: Freedom from AMR

Pathologic diagnosis of Antibody-Mediated Rejection (AMR)

Time frame: Follow-up through 30 months post-randomization

Safety: Freedom from infection

Infection

Time frame: Follow-up through 30 months post-randomization

Safety: Freedom from PTLD

Post-Transplant Lymphoproliferative Disorder (PTLD)

Time frame: 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.

Time frame: 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

Time frame: Follow-up through 30 months post-randomization

Safety: Freedom from Level 2 severity CKD Event

Chronic Kidney Disease

Time frame: Follow-up through 30 months post-randomization

Safety: Freedom from Level 2 severity CAV Event

Coronary artery vasculopathy

Time frame: Follow-up through 30 months post-randomization

Safety: Freedom from Level 2 severity ACR Event

Biopsy-proven Acute Cellular Rejection

Time frame: Follow-up through 30 months post-randomization

Safety: Freedom from Level 2 severity AMR Event

Pathologic diagnosis of Antibody-Mediated Rejection

Time frame: Follow-up through 30 months post-randomization

Safety: Freedom from Level 2 severity Infection Event

Infection

Time frame: Follow-up through 30 months post-randomization

Safety: Freedom from Level 2 severity PTLD Event

Post-transplant Lymphoproliferative Disorder

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline visit through 30 months post-randomization

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

Overview

Conditions

Interventions

Eligibility

Locations (25)

Outcomes

Primary Outcomes

Secondary Outcomes