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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 : March 7, 2018
Sponsor:
Collaborators:
Stanford University
United States Department of Defense
Information provided by (Responsible Party):
Kevin Daly, Boston Children’s Hospital

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 Type : Interventional  (Clinical Trial)
Estimated Enrollment : 210 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.
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 : January 29, 2018
Estimated Primary Completion Date : September 2021
Estimated Study Completion Date : September 2021


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 Name: Zortress

Drug: Tacrolimus
Tacrolimus capsule or liquid suspension
Other Name: 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 Name: Prograf

Drug: Mycophenolate Mofetil
Mycophenolate Mofetil capsule or liquid suspension
Other Name: Cellcept




Primary Outcome Measures :
  1. 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)

  2. 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)


Secondary Outcome Measures :
  1. Efficacy: Overall patient survival [ Time Frame: Up to 30 months post-randomization ]
    Freedom from death from any cause

  2. Efficacy: Overall allograft survival [ Time Frame: Up to 30 months post-randomization ]
    Freedom from death and re-transplantation

  3. 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

  4. Efficacy: Freedom from CKD event [ Time Frame: Follow-up through 30 months post-randomization ]
    Chronic Kidney Disease (CKD)

  5. Efficacy: Freedom from CAV event [ Time Frame: Follow-up through 30 months post-randomization ]
    Cororonary Artery Vasculopathy (CAV)

  6. Efficacy: Freedom from BP-ACR event [ Time Frame: Follow-up through 30 months post-randomization ]
    Biopsy-proven Acute Cellular Rejection (ACR)

  7. 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

  8. 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

  9. 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.

  10. Safety: Freedom from AMR [ Time Frame: Follow-up through 30 months post-randomization ]
    Pathologic diagnosis of Antibody-Mediated Rejection (AMR)

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

  12. Safety: Freedom from PTLD [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: Follow-up through 30 months post-randomization ]
    Chronic Kidney Disease

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

  17. Safety: Freedom from Level 2 severity ACR Event [ Time Frame: Follow-up through 30 months post-randomization ]
    Biopsy-proven Acute Cellular Rejection

  18. Safety: Freedom from Level 2 severity AMR Event [ Time Frame: Follow-up through 30 months post-randomization ]
    Pathologic diagnosis of Antibody-Mediated Rejection

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

  20. Safety: Freedom from Level 2 severity PTLD Event [ Time Frame: Follow-up through 30 months post-randomization ]
    Post-transplant Lymphoproliferative Disorder



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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) or moderate proteinuria (urine protein to urine creatinine ratio >0.5 mg/mg).
  7. Active infection requiring hospitalization or treatment dose medical therapy.
  8. 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.
  9. 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.
  10. Uncontrolled diabetes mellitus.
  11. Diagnosis of post-transplant lymphoproliferative disorder (PTLD) during the first 6 months post-heart transplant.
  12. History of non-adherence to medical regimens.
  13. Patients who are treated with drugs that are strong inducers or inhibitors of cytochrome P450 3A4 (CYP3A4) and cannot discontinue the treatment
  14. Patients who are pregnant or breast-feeding or intend to get pregnant during the study period.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03386539


Contacts
Contact: Kevin P Daly, MD (617) 355-6329 kevin.daly@cardio.chboston.org
Contact: Christopher S Almond, MD, MPH (650) 723-7913

  Show 22 Study Locations
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

Publications:
Responsible Party: Kevin Daly, Assistant Professor of Pediatrics, Boston Children’s Hospital
ClinicalTrials.gov Identifier: NCT03386539     History of Changes
Other Study ID Numbers: P00025970
PR160574 ( Other Grant/Funding Number: U.S. Department of Defense )
IND 127980 ( Other Identifier: Food and Drug Administration )
First Posted: December 29, 2017    Key Record Dates
Last Update Posted: March 7, 2018
Last Verified: March 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Kevin Daly, 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
Vascular Diseases
Urologic Diseases
Renal Insufficiency
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cardiovascular Diseases
Tacrolimus
Everolimus
Sirolimus
Mycophenolic Acid
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antibiotics, Antitubercular
Antitubercular Agents