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

Chronic Kidney Diseases Clinical Trial

— TEAMMATE  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03386539
• Other study ID #: P00025970
• Secondary ID: PR160574IND 1279
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: January 29, 2018
• Est. completion date: January 2024

Study information

• Verified date: October 2023
• Source: Boston Children's Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 211
• Est. completion date: January 2024
• Est. primary completion date: April 17, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 21 Years

Eligibility

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.

Related Conditions & MeSH terms

• Cardiac Allograft Vasculopathy
• Chronic Kidney Diseases
• Heart Transplant Failure and Rejection
• Heart Transplant Infection
• Immunosuppression
• Kidney Diseases
• Lymphoproliferative Disorders
• Pediatric Heart Transplantation
• Post-transplant Lymphoproliferative Disorder
• Renal Insufficiency, Chronic

Intervention

Drug:
• Everolimus
Everolimus tablet
• Tacrolimus
Tacrolimus capsule or liquid suspension
• Mycophenolate Mofetil
Mycophenolate Mofetil capsule or liquid suspension

Locations

Country	Name	City	State
United States	University of Michigan Medical Center	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta Emory	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Children's of Alabama	Birmingham	Alabama
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Children's Hospital at Montefiore	Bronx	New York
United States	Lurie Children's Hospital	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Children's Health Dallas University of Texas Southwestern	Dallas	Texas
United States	University of Florida Congenital Heart Center	Gainesville	Florida
United States	Joe DiMaggio Children's Hospital	Hollywood	Florida
United States	Texas Children's Hospital	Houston	Texas
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	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	Children's Hospital of New York	New York	New York
United States	Stanford University	Palo Alto	California
United States	The Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh of University of Pittsburgh School of Medicine	Pittsburgh	Pennsylvania
United States	Washington University in St. Louis School of Medicine	Saint Louis	Missouri
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	Seattle Children's Hospital	Seattle	Washington
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (3)

Lead Sponsor	Collaborator
Boston Children's Hospital	Stanford University, United States Department of Defense

Country where clinical trial is conducted

United States, 

References & Publications (3)

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	Efficacy: Overall patient survival	Freedom from death from any cause	Up to 30 months post-randomization
Secondary	Efficacy: Overall allograft survival	Freedom from death and re-transplantation	Up to 30 months post-randomization
Secondary	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
Secondary	Efficacy: Freedom from CKD event	Chronic Kidney Disease (CKD)	Follow-up through 30 months post-randomization
Secondary	Efficacy: Freedom from CAV event	Coronary Artery Vasculopathy (CAV)	Follow-up through 30 months post-randomization
Secondary	Efficacy: Freedom from BP-ACR event	Biopsy-proven Acute Cellular Rejection (ACR)	Follow-up through 30 months post-randomization
Secondary	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
Secondary	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
Secondary	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
Secondary	Safety: Freedom from AMR	Pathologic diagnosis of Antibody-Mediated Rejection (AMR)	Follow-up through 30 months post-randomization
Secondary	Safety: Freedom from infection	Infection	Follow-up through 30 months post-randomization
Secondary	Safety: Freedom from PTLD	Post-Transplant Lymphoproliferative Disorder (PTLD)	Follow-up through 30 months post-randomization
Secondary	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
Secondary	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
Secondary	Safety: Freedom from Level 2 severity CKD Event	Chronic Kidney Disease	Follow-up through 30 months post-randomization
Secondary	Safety: Freedom from Level 2 severity CAV Event	Coronary artery vasculopathy	Follow-up through 30 months post-randomization
Secondary	Safety: Freedom from Level 2 severity ACR Event	Biopsy-proven Acute Cellular Rejection	Follow-up through 30 months post-randomization
Secondary	Safety: Freedom from Level 2 severity AMR Event	Pathologic diagnosis of Antibody-Mediated Rejection	Follow-up through 30 months post-randomization
Secondary	Safety: Freedom from Level 2 severity Infection Event	Infection	Follow-up through 30 months post-randomization
Secondary	Safety: Freedom from Level 2 severity PTLD Event	Post-transplant Lymphoproliferative Disorder	Follow-up through 30 months post-randomization
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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