Clinical trial NCT03386539: Tacrolimus/Everolimus vs. Tacrolimus/MMF in Pediatric Heart Transplant Recipients Using the MATE Score
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
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
Lead sponsor: Boston Children's Hospital
Sponsor class: OTHER
Collaborators: name: Stanford University
name: United States Department of Defense
First posted: 2017-12-29
Enrollment: 211
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: EFFICACY: MATE-3 Score
timeFrame: 30 months post-randomization
measure: SAFETY: MATE-6 Score
timeFrame: 30 months post-randomization
Secondary outcomes:
measure: Efficacy: Overall patient survival
timeFrame: Up to 30 months post-randomization
measure: Efficacy: Overall allograft survival
timeFrame: Up to 30 months post-randomization
measure: Efficacy: Change in kidney function
timeFrame: 0 to 6 months, 0 to 12 months, 0 to 30 months post-randomization
measure: Efficacy: Freedom from CKD event
timeFrame: Follow-up through 30 months post-randomization
measure: Efficacy: Freedom from CAV event
timeFrame: Follow-up through 30 months post-randomization
measure: Efficacy: Freedom from BP-ACR event
timeFrame: Follow-up through 30 months post-randomization
measure: Efficacy: Freedom from composite failure
timeFrame: Follow-up through 30 months post-randomization
measure: Efficacy: Lansky and Karnofsky scores
timeFrame: 18 and 30 months post-randomization
measure: Efficacy: EuroQOL EQ-5D Y (Youth Version)
timeFrame: 18 and 30 months post-randomization
measure: Safety: Freedom from AMR
timeFrame: Follow-up through 30 months post-randomization
measure: Safety: Freedom from infection
timeFrame: Follow-up through 30 months post-randomization
measure: Safety: Freedom from PTLD
timeFrame: Follow-up through 30 months post-randomization
measure: Safety: Frequency and incidence of adverse events including, but not limited to, hyperlipidemia, anemia, thrombocytopenia, interstitial lung disease, aphthous stomatitis, proteinuria, and rash
timeFrame: Follow up through 30 months post-randomization
measure: Safety: Freedom from Major Transplant Events (Composite)
timeFrame: Follow-up through 30 months post-randomization
measure: Safety: Freedom from Level 2 severity CKD Event
timeFrame: Follow-up through 30 months post-randomization
measure: Safety: Freedom from Level 2 severity CAV Event
timeFrame: Follow-up through 30 months post-randomization
measure: Safety: Freedom from Level 2 severity ACR Event
timeFrame: Follow-up through 30 months post-randomization
measure: Safety: Freedom from Level 2 severity AMR Event
timeFrame: Follow-up through 30 months post-randomization
measure: Safety: Freedom from Level 2 severity Infection Event
timeFrame: Follow-up through 30 months post-randomization
measure: Safety: Freedom from Level 2 severity PTLD Event
timeFrame: Follow-up through 30 months post-randomization
measure: Efficacy: Freedom from composite of CAV, CKD, BP-ACR, or any CMV infection
timeFrame: Follow-up through 30 months post-randomization
measure: Efficacy: Change in CKD stage
timeFrame: Baseline visit through 30 months post-randomization
measure: Efficacy: MATE-3 score where CKD score is calculated by change from baseline visit
timeFrame: Baseline visit through 30 months post-randomization
measure: Efficacy: MATE-3 score where CKD score is replaced by change in CKD stage
timeFrame: Baseline visit through 30 months post-randomization
measure: Efficacy: Composite score consisting of MATE CAV, MATE BP-ACR, change in MATE CKD score, and any CMV infection.
timeFrame: Baseline visit through 30 months post-randomization
measure: Efficacy: Composite score consisting of MATE CAV, MATE BP-ACR, change in CKD stage, and any CMV infection.
timeFrame: Baseline visit through 30 months post-randomization
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Children's of Alabama
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Loma Linda
country: United States
facility: Loma Linda University
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Los Angeles
country: United States
facility: UCLA Mattel Children's Hospital
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida Congenital Heart Center
state: Florida
city: Hollywood
country: United States
facility: Joe DiMaggio Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta Emory
state: Georgia
city: Chicago
country: United States
facility: Lurie Children's Hospital
state: Illinois
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Medical Center
state: Michigan
city: Saint Louis
country: United States
facility: Washington University in St. Louis School of Medicine
state: Missouri
city: Bronx
country: United States
facility: Children's Hospital at Montefiore
state: New York
city: New York
country: United States
facility: Children's Hospital of New York
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of University of Pittsburgh School of Medicine
state: Pennsylvania
city: Dallas
country: United States
facility: Children's Health Dallas University of Texas Southwestern
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Hospital
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Milwaukee
country: United States
facility: Children's Hospital of Wisconsin
state: Wisconsin
Study officials:
affiliation: Stanford University
name: Christopher S Almond, MD, MPH
role: STUDY_CHAIR
affiliation: Boston Children's Hospital
name: Kevin P Daly, MD
role: STUDY_CHAIR
affiliation: Boston Children's Hospital
name: Lynn A Sleeper, ScD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
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.
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.
citation: 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.