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

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ClinicalTrials.gov Identifier: NCT03386539
Recruitment Status : Recruiting
First Posted : December 29, 2017
Last Update Posted : June 6, 2019
Sponsor:
Collaborators:
Stanford University
United States Department of Defense
Information provided by (Responsible Party):
Kevin Daly, Boston Children’s Hospital

Tracking Information
First Submitted Date  ICMJE December 18, 2017
First Posted Date  ICMJE December 29, 2017
Last Update Posted Date June 6, 2019
Actual Study Start Date  ICMJE January 29, 2018
Estimated Primary Completion Date April 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 21, 2017)
  • EFFICACY: MATE-3 Score [ Time Frame: 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)
  • SAFETY: MATE-6 Score [ Time Frame: 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)
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03386539 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 21, 2017)
  • Efficacy: Overall patient survival [ Time Frame: Up to 30 months post-randomization ]
    Freedom from death from any cause
  • Efficacy: Overall allograft survival [ Time Frame: Up to 30 months post-randomization ]
    Freedom from death and re-transplantation
  • Efficacy: Change in kidney function [ Time Frame: 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
  • Efficacy: Freedom from CKD event [ Time Frame: Follow-up through 30 months post-randomization ]
    Chronic Kidney Disease (CKD)
  • Efficacy: Freedom from CAV event [ Time Frame: Follow-up through 30 months post-randomization ]
    Cororonary Artery Vasculopathy (CAV)
  • Efficacy: Freedom from BP-ACR event [ Time Frame: Follow-up through 30 months post-randomization ]
    Biopsy-proven Acute Cellular Rejection (ACR)
  • Efficacy: Freedom from composite failure [ Time Frame: 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
  • Efficacy: Lansky and Karnofsky scores [ Time Frame: 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
  • Efficacy: EuroQOL EQ-5D Y (Youth Version) [ Time Frame: 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.
  • Safety: Freedom from AMR [ Time Frame: Follow-up through 30 months post-randomization ]
    Pathologic diagnosis of Antibody-Mediated Rejection (AMR)
  • Safety: Freedom from infection [ Time Frame: Follow-up through 30 months post-randomization ]
    Infection
  • Safety: Freedom from PTLD [ Time Frame: Follow-up through 30 months post-randomization ]
    Post-Transplant Lymphoproliferative Disorder (PTLD)
  • Safety: Frequency and incidence of adverse events including, but not limited to, hyperlipidemia, anemia, thrombocytopenia, interstitial lung disease, aphthous stomatitis, proteinuria, and rash [ Time Frame: Follow up through 30 months post-randomization ]
    These AEs will be reported as individual endpoints as well as a composite.
  • Safety: Freedom from Major Transplant Events (Composite) [ Time Frame: Follow-up through 30 months post-randomization ]
    The qualifying event is the earliest occurrence of CKD, CAV, ACR, AMR, infection, and PTLD
  • Safety: Freedom from Level 2 severity CKD Event [ Time Frame: Follow-up through 30 months post-randomization ]
    Chronic Kidney Disease
  • Safety: Freedom from Level 2 severity CAV Event [ Time Frame: Follow-up through 30 months post-randomization ]
    Coronary artery vasculopathy
  • Safety: Freedom from Level 2 severity ACR Event [ Time Frame: Follow-up through 30 months post-randomization ]
    Biopsy-proven Acute Cellular Rejection
  • Safety: Freedom from Level 2 severity AMR Event [ Time Frame: Follow-up through 30 months post-randomization ]
    Pathologic diagnosis of Antibody-Mediated Rejection
  • Safety: Freedom from Level 2 severity Infection Event [ Time Frame: Follow-up through 30 months post-randomization ]
    Infection
  • Safety: Freedom from Level 2 severity PTLD Event [ Time Frame: Follow-up through 30 months post-randomization ]
    Post-transplant Lymphoproliferative Disorder
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Tacrolimus/Everolimus vs. Tacrolimus/MMF in Pediatric Heart Transplant Recipients Using the MATE Score
Official Title  ICMJE 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
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE 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.
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
Condition  ICMJE
  • Pediatric Heart Transplantation
  • Immunosuppression
  • Chronic Kidney Diseases
  • Cardiac Allograft Vasculopathy
  • Heart Transplant Failure and Rejection
  • Post-transplant Lymphoproliferative Disorder
  • Heart Transplant Infection
Intervention  ICMJE
  • Drug: Everolimus
    Everolimus tablet
    Other Name: Zortress
  • Drug: Tacrolimus
    Tacrolimus capsule or liquid suspension
    Other Name: Prograf
  • Drug: Mycophenolate Mofetil
    Mycophenolate Mofetil capsule or liquid suspension
    Other Name: Cellcept
Study Arms  ICMJE
  • 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.)

    Interventions:
    • Drug: Everolimus
    • Drug: Tacrolimus
  • 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.

    Interventions:
    • Drug: Tacrolimus
    • Drug: Mycophenolate Mofetil
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 21, 2017)
210
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 2022
Estimated Primary Completion Date April 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 21 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Kevin P Daly, MD (617) 355-6329 kevin.daly@cardio.chboston.org
Contact: Christopher S Almond, MD, MPH (650) 723-7913
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03386539
Other Study ID Numbers  ICMJE P00025970
PR160574 ( Other Grant/Funding Number: U.S. Department of Defense )
IND 127980 ( Other Identifier: Food and Drug Administration )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Kevin Daly, Boston Children’s Hospital
Study Sponsor  ICMJE Boston Children’s Hospital
Collaborators  ICMJE
  • Stanford University
  • United States Department of Defense
Investigators  ICMJE
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
PRS Account Boston Children’s Hospital
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP