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

NCT03386539 | Unknown Phase 3 DMC FDA Drug

• 3 other identifiers: P00025970PR160574IND 127980
• Study Type: interventional
• Target: 211
• Locations: 1 country
• Sites: 25

Brief Summary

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).

Conditions

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

Keywords

heart transplantation; children; everolimus; tacrolimus; mycophenolate mofetil; randomized clinical trial

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (26)

• 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

  Follow-up through 30 months post-randomization

• Efficacy: Freedom from CAV event

  Follow-up through 30 months post-randomization

Study Arms (2)

Everolimus/Low-Dose Tacrolimus

EXPERIMENTAL

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; Drug: Tacrolimus

Tacrolimus/Mycophenolate Mofetil

ACTIVE COMPARATOR

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; Drug: Mycophenolate Mofetil

Interventions

Everolimus DRUG

Everolimus tablet

Also known as: Zortress

Everolimus/Low-Dose Tacrolimus

Tacrolimus DRUG

Tacrolimus capsule or liquid suspension

Also known as: Prograf

Everolimus/Low-Dose Tacrolimus; Tacrolimus/Mycophenolate Mofetil

Mycophenolate Mofetil DRUG

Mycophenolate Mofetil capsule or liquid suspension

Also known as: Cellcept

Tacrolimus/Mycophenolate Mofetil

Eligibility Criteria

• Age: Up to 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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).

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Boston Children's Hospital: lead
• Stanford University: collaborator
• United States Department of Defense: collaborator

Study Sites (25)

Children's of Alabama

Birmingham, Alabama, 35233, United States

Location

Phoenix Children's Hospital

Phoenix, Arizona, 85016, United States

Location

Loma Linda University

Loma Linda, California, 92354, United States

Location

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

UCLA Mattel Children's Hospital

Los Angeles, California, 90095, United States

Location

Stanford University

Palo Alto, California, 94304, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

University of Florida Congenital Heart Center

Gainesville, Florida, 32610-0297, United States

Location

Joe DiMaggio Children's Hospital

Hollywood, Florida, 33021, United States

Location

Children's Healthcare of Atlanta Emory

Atlanta, Georgia, 30322, United States

Location

Lurie Children's Hospital

Chicago, Illinois, 60611, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

University of Michigan Medical Center

Ann Arbor, Michigan, 48109, United States

Location

Washington University in St. Louis School of Medicine

St Louis, Missouri, 63110, United States

Location

Children's Hospital of New York

New York, New York, 10032, United States

Location

Children's Hospital at Montefiore

The Bronx, New York, 10803, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Children's Hospital of Pittsburgh of University of Pittsburgh School of Medicine

Pittsburgh, Pennsylvania, 15224, United States

Location

Children's Health Dallas University of Texas Southwestern

Dallas, Texas, 75235, United States

Location

Texas Children's Hospital

Houston, Texas, 77027, United States

Location

Primary Children's Hospital

Salt Lake City, Utah, 84132, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Related Publications (5)

• 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.

  PMID: 28465118 BACKGROUND

• 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.

  PMID: 28670871 BACKGROUND

• 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.

  PMID: 36828201 BACKGROUND

• Almond CS, Daly KP, Albers EL, Alejos JC, Ameduri R, Auerbach SR, Barkoff L, Barnes AP, Bock MJ, Butto A, Carlo WF, Castleberry CD, Chrisant MR, Deshpande SR, Dreyer WJ, Everitt MD, Feingold B, Gonzales S, Hollander SA, Kindel SJ, Klein GL, Lal AK, Lamour JM, Lee J, Lu M, Lytrivi ID, Miyamoto SD, Pahl E, Peng DM, Ryan TD, Singh TP, Su JA, Sutcliffe DL, Ybarra AM, Zangwill S, Rossano JW, Sleeper LA; TEAMMATE Trial Investigators. Everolimus and Low-Dose Tacrolimus After Heart Transplant in Children: A Randomized Clinical Trial. JAMA. 2025 Oct 21;334(15):1339-1348. doi: 10.1001/jama.2025.14338.

  PMID: 40960806 DERIVED

• 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.

  PMID: 33315277 DERIVED

MeSH Terms

Conditions

Renal Insufficiency, Chronic; Rejection, Psychology

Interventions

Everolimus; Tacrolimus; Mycophenolic Acid

Condition Hierarchy (Ancestors)

Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Social Behavior; Behavior

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids

Study Officials

• Christopher S Almond, MD, MPH

  Stanford University

  STUDY CHAIR

• Kevin P Daly, MD

  Boston Children's Hospital

  STUDY CHAIR

• Lynn A Sleeper, ScD

  Boston Children's Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Pediatrics

Model Details: 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.

Study Record Dates

• First Submitted: December 18, 2017
• First Posted: December 29, 2017
• Study Start: January 29, 2018
• Primary Completion: April 17, 2023
• Study Completion: January 1, 2024
• Last Updated: October 17, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (25)