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

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

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Chronic Kidney Diseases; Post-transplant Lymphoproliferative Disorder; Immunosuppression; Pediatric Heart Transplantation; Cardiac Allograft Vasculopathy; Heart Transplant Failure and Rejection; Heart Transplant Infection
• Intervention / Treatment: Drug: Everolimus; Drug: Tacrolimus; Drug: Mycophenolate Mofetil

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 211
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Children's of Alabama
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • California
    • Loma Linda, California, United States, 92354
      • Loma Linda University
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Los Angeles, California, United States, 90095
      • UCLA Mattel Children's Hospital
    • Palo Alto, California, United States, 94304
      • Stanford University
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610-0297
      • University of Florida Congenital Heart Center
    • Hollywood, Florida, United States, 33021
      • Joe DiMaggio Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta Emory
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Lurie Children's Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University in St. Louis School of Medicine
  • New York
    • Bronx, New York, United States, 10803
      • Children's Hospital at Montefiore
    • New York, New York, United States, 10032
      • Children's Hospital of New York
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of University of Pittsburgh School of Medicine
  • Texas
    • Dallas, Texas, United States, 75235
      • Children's Health Dallas University of Texas Southwestern
    • Houston, Texas, United States, 77027
      • Texas Children's Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Primary Children's Hospital
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.)	Drug: Everolimus; Everolimus tablet; Other Names: Zortress; Drug: Tacrolimus; Tacrolimus capsule or liquid suspension; Other Names: Prograf
Active Comparator: 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.	Drug: Tacrolimus; Tacrolimus capsule or liquid suspension; Other Names: Prograf; Drug: Mycophenolate Mofetil; Mycophenolate Mofetil capsule or liquid suspension; Other Names: Cellcept

What is the study measuring?

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 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
Efficacy: Freedom from CAV event	Coronary Artery Vasculopathy (CAV)	Follow-up through 30 months post-randomization

Collaborators and Investigators

• Sponsor: Boston Children's Hospital
• Collaborators: United States Department of Defense; Stanford University
• Investigators: Study Chair: Christopher S Almond, MD, MPH, Stanford University; Study Chair: Kevin P Daly, MD, Boston Children's Hospital; Principal Investigator: Lynn A Sleeper, ScD, Boston Children's Hospital

Publications and helpful links

General Publications

• Almond CS, Hoen H, Rossano JW, Castleberry C, Auerbach SR, Yang L, Lal AK, Everitt MD, Fenton M, Hollander SA, Pahl E, Pruitt E, Rosenthal DN, McElhinney DB, Daly KP, Desai M; Pediatric Heart Transplant Study (PHTS) Group Registry. Development and validation of a major adverse transplant event (MATE) score to predict late graft loss in pediatric heart transplantation. J Heart Lung Transplant. 2018 Apr;37(4):441-450. doi: 10.1016/j.healun.2017.03.013. Epub 2017 Mar 24.
• Castleberry C, Ziniel S, Almond C, Auerbach S, Hollander SA, Lal AK, Fenton M, Pahl E, Rossano JW, Everitt MD, Daly KP. Clinical practice patterns are relatively uniform between pediatric heart transplant centers: A survey-based assessment. Pediatr Transplant. 2017 Aug;21(5). doi: 10.1111/petr.13013. Epub 2017 Jul 3.
• Grimm K, Lehner A, Fernandez Rodriguez S, Orban M, Fischer M, Rosenthal LL, Jakob A, Haas NA, Dalla Pozza R, Kozlik-Feldmann R, Ulrich SM. Conversion to everolimus in pediatric heart transplant recipients is a safe treatment option with an impact on cardiac allograft vasculopathy and renal function. Clin Transplant. 2021 Mar;35(3):e14191. doi: 10.1111/ctr.14191. Epub 2020 Dec 30.
• Almond CS, Sleeper LA, Rossano JW, Bock MJ, Pahl E, Auerbach S, Lal A, Hollander SA, Miyamoto SD, Castleberry C, Lee J, Barkoff LM, Gonzales S, Klein G, Daly KP. The teammate trial: Study design and rationale tacrolimus and everolimus against tacrolimus and MMF in pediatric heart transplantation using the major adverse transplant event (MATE) score. Am Heart J. 2023 Jun;260:100-112. doi: 10.1016/j.ahj.2023.02.002. Epub 2023 Feb 23.

Study record dates

Study Major Dates

• Study Start (Actual): January 29, 2018
• Primary Completion (Actual): April 17, 2023
• Study Completion (Estimated): January 1, 2024

Study Registration Dates

• First Submitted: December 18, 2017
• First Submitted That Met QC Criteria: December 21, 2017
• First Posted (Actual): December 29, 2017

Study Record Updates

• Last Update Posted (Actual): October 17, 2023
• Last Update Submitted That Met QC Criteria: October 13, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: children; everolimus; mycophenolate mofetil; randomized clinical trial; heart transplantation; tacrolimus
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Lymphatic Diseases; Immunoproliferative Disorders; Urologic Diseases; Disease Attributes; Renal Insufficiency; Chronic Disease; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Renal Insufficiency, Chronic; Lymphoproliferative Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Protein Kinase Inhibitors; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; MTOR Inhibitors; Tacrolimus; Mycophenolic Acid; Everolimus
• Other Study ID Numbers: P00025970; PR160574 (Other Grant/Funding Number: U.S. Department of Defense); IND 127980 (Other Identifier: Food and Drug Administration)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No