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

NCT ID: NCT03386539

Last Updated: 2023-10-17

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE3
• Total Enrollment: 211 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-01-29
• Study Completion Date: 2024-01-31

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).

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.

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

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.)

Group Type: EXPERIMENTAL

Everolimus

Intervention Type: DRUG

Everolimus tablet

Tacrolimus

Intervention Type: DRUG

Tacrolimus capsule or liquid suspension

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.

Group Type: ACTIVE_COMPARATOR

Tacrolimus

Intervention Type: DRUG

Tacrolimus capsule or liquid suspension

Mycophenolate Mofetil

Intervention Type: DRUG

Mycophenolate Mofetil capsule or liquid suspension

Interventions

Everolimus

Everolimus tablet

Intervention Type: DRUG

Tacrolimus

Tacrolimus capsule or liquid suspension

Intervention Type: DRUG

Mycophenolate Mofetil

Mycophenolate Mofetil capsule or liquid suspension

Intervention Type: DRUG

Other Intervention Names

Zortress; Prograf; Cellcept

Eligibility Criteria

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.

• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Stanford University

OTHER

Sponsor Role: collaborator

United States Department of Defense

FED

Sponsor Role: collaborator

Boston Children's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Kevin Daly

Assistant Professor of Pediatrics

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Christopher S Almond, MD, MPH

Role: STUDY_CHAIR

Stanford University

Kevin P Daly, MD

Role: STUDY_CHAIR

Boston Children's Hospital

Lynn A Sleeper, ScD

Role: PRINCIPAL_INVESTIGATOR

Boston Children's Hospital

Locations

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

Children's Healthcare of Atlanta Emory

Atlanta, Georgia, United States

Lurie Children's Hospital

Chicago, Illinois, United States

Boston Children's Hospital

Boston, Massachusetts, United States

University of Michigan Medical Center

Ann Arbor, Michigan, United States

Washington University in St. Louis School of Medicine

St Louis, Missouri, United States

Children's Hospital of New York

New York, New York, United States

Children's Hospital at Montefiore

The Bronx, New York, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

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

Pittsburgh, Pennsylvania, United States

Children's Health Dallas University of Texas Southwestern

Dallas, Texas, United States

Texas Children's Hospital

Houston, Texas, United States

Primary Children's Hospital

Salt Lake City, Utah, United States

Seattle Children's Hospital

Seattle, Washington, United States

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 28465118 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28670871 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 36828201 (View on PubMed)

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 Sep 17:e2514338. doi: 10.1001/jama.2025.14338. Online ahead of print.

Reference Type: DERIVED

PMID: 40960806 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33315277 (View on PubMed)

Other Identifiers

PR160574

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

IND 127980

Identifier Type: OTHER

Identifier Source: secondary_id

P00025970

Identifier Type: -

Identifier Source: org_study_id