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

• Sponsor: Boston Children's Hospital (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03386539
• Collaborator: Stanford University (Other), United States Department of Defense (U.S. Fed)
• Enrollment: 211
• Locations: 25
• Arms: 2
• Anticipated Duration (Months): 60.1
• Patients Per Site: 8.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Pediatric Heart Transplantation; Immunosuppression; Chronic Kidney Diseases; Cardiac Allograft Vasculopathy; Heart Transplant Failure and Rejection; Post-transplant Lymphoproliferative Disorder; Heart Transplant Infection	Drug: Everolimus; Drug: Tacrolimus; Drug: Mycophenolate Mofetil	Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 211 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention 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.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 (Outcomes Assessor)
• Masking Description: 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.
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Jan 29, 2018
• Anticipated Primary Completion Date: Feb 1, 2023
• Anticipated Study Completion Date: Feb 1, 2023

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. EFFICACY: MATE-3 Score [30 months post-randomization]

   MATE-3 is a validated score ranging from 0 to 12. The score represents the cumulative burden of three major adverse transplant events: Cororonary Artery Vasculopathy (CAV), Chronic Kidney Disease (CKD), and Biopsy-proven Acute Cellular Rejection (ACR)

2. SAFETY: MATE-6 Score [30 months post-randomization]

   MATE-6 is a validated score ranging from 0 to 24. The score represents the cumulative burden of all six major adverse transplant events: Cororonary 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)

Secondary Outcome Measures

1. Efficacy: Overall patient survival [Up to 30 months post-randomization]

   Freedom from death from any cause

2. Efficacy: Overall allograft survival [Up to 30 months post-randomization]

   Freedom from death and re-transplantation

3. Efficacy: Change in kidney function [0 to 6 months, 0 to 12 months, 0 to 30 months post-randomization]

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

4. Efficacy: Freedom from CKD event [Follow-up through 30 months post-randomization]

   Chronic Kidney Disease (CKD)

5. Efficacy: Freedom from CAV event [Follow-up through 30 months post-randomization]

   Cororonary Artery Vasculopathy (CAV)

6. Efficacy: Freedom from BP-ACR event [Follow-up through 30 months post-randomization]

   Biopsy-proven Acute Cellular Rejection (ACR)

7. Efficacy: Freedom from composite failure [Follow-up through 30 months post-randomization]

   The qualifying event is the earliest occurrence of death, graft loss, 2R/3R ACR rejection or rejection with HD

8. Efficacy: Lansky and Karnofsky scores [18 and 30 months post-randomization]

   Validated functional performance score, assigned by clinician assessment: Lansky score if < 16 years at randomization; Karnofsky if >=16 years at randomization

9. Efficacy: EuroQOL EQ-5D Y (Youth Version) [18 and 30 months post-randomization]

   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.

10. Safety: Freedom from AMR [Follow-up through 30 months post-randomization]

    Pathologic diagnosis of Antibody-Mediated Rejection (AMR)

11. Safety: Freedom from infection [Follow-up through 30 months post-randomization]

    Infection

12. Safety: Freedom from PTLD [Follow-up through 30 months post-randomization]

    Post-Transplant Lymphoproliferative Disorder (PTLD)

13. Safety: Frequency and incidence of adverse events including, but not limited to, hyperlipidemia, anemia, thrombocytopenia, interstitial lung disease, aphthous stomatitis, proteinuria, and rash [Follow up through 30 months post-randomization]

    These AEs will be reported as individual endpoints as well as a composite.

14. Safety: Freedom from Major Transplant Events (Composite) [Follow-up through 30 months post-randomization]

    The qualifying event is the earliest occurrence of CKD, CAV, ACR, AMR, infection, and PTLD

15. Safety: Freedom from Level 2 severity CKD Event [Follow-up through 30 months post-randomization]

    Chronic Kidney Disease

16. Safety: Freedom from Level 2 severity CAV Event [Follow-up through 30 months post-randomization]

    Coronary artery vasculopathy

17. Safety: Freedom from Level 2 severity ACR Event [Follow-up through 30 months post-randomization]

    Biopsy-proven Acute Cellular Rejection

18. Safety: Freedom from Level 2 severity AMR Event [Follow-up through 30 months post-randomization]

    Pathologic diagnosis of Antibody-Mediated Rejection

19. Safety: Freedom from Level 2 severity Infection Event [Follow-up through 30 months post-randomization]

    Infection

20. Safety: Freedom from Level 2 severity PTLD Event [Follow-up through 30 months post-randomization]

    Post-transplant Lymphoproliferative Disorder

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's of Alabama	Birmingham	Alabama	United States	35233
2	Phoenix Children's Hospital	Phoenix	Arizona	United States	85016
3	Loma Linda University	Loma Linda	California	United States	92354
4	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
5	UCLA Mattel Children's Hospital	Los Angeles	California	United States	90095
6	Stanford University	Palo Alto	California	United States	94304
7	Children's Hospital Colorado	Aurora	Colorado	United States	80045
8	Children's National Medical Center	Washington	District of Columbia	United States	20010
9	University of Florida Congenital Heart Center	Gainesville	Florida	United States	32610-0297
10	Joe DiMaggio Children's Hospital	Hollywood	Florida	United States	33021
11	Children's Healthcare of Atlanta Emory	Atlanta	Georgia	United States	30322
12	Lurie Children's Hospital	Chicago	Illinois	United States	60611
13	Boston Children's Hospital	Boston	Massachusetts	United States	02115
14	University of Michigan Medical Center	Ann Arbor	Michigan	United States	48109
15	Washington University in St. Louis School of Medicine	Saint Louis	Missouri	United States	63110
16	Children's Hospital at Montefiore	Bronx	New York	United States	10803
17	Children's Hospital of New York	New York	New York	United States	10032
18	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
19	The Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
20	Children's Hospital of Pittsburgh of University of Pittsburgh School of Medicine	Pittsburgh	Pennsylvania	United States	15224
21	Children's Health Dallas University of Texas Southwestern	Dallas	Texas	United States	75235
22	Texas Children's Hospital	Houston	Texas	United States	77027
23	Primary Children's Hospital	Salt Lake City	Utah	United States	84132
24	Seattle Children's Hospital	Seattle	Washington	United States	98105
25	Children's Hospital of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

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

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

Study Documents (Full-Text)

None provided.

More Information

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.

• Responsible Party: Kevin Daly, Assistant Professor of Pediatrics, Boston Children's Hospital
• ClinicalTrials.gov Identifier: NCT03386539
• Other Study ID Numbers: P00025970; PR160574; IND 127980
• First Posted: Dec 29, 2017
• Last Update Posted: Sep 5, 2021
• Last Verified: Sep 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Kevin Daly, Assistant Professor of Pediatrics, Boston Children's Hospital: heart transplantation; children; everolimus; tacrolimus; mycophenolate mofetil; randomized clinical trial
• Additional relevant MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Lymphoproliferative Disorders; Mycophenolic Acid; Everolimus; Tacrolimus

Study Results

No Results Posted as of Sep 5, 2021