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

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Brief Title

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

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 Phase

Phase 3

Study Type

Interventional


Primary Outcome

EFFICACY: MATE-3 Score

Secondary Outcome

 Efficacy: Overall patient survival

Condition

Pediatric Heart Transplantation

Intervention

Everolimus

Study Arms / Comparison Groups

 Everolimus/Low-Dose Tacrolimus
Description:  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.)

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

211

Start Date

January 29, 2018

Completion Date

February 2023

Primary Completion Date

February 2023

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.
      

Gender

All

Ages

N/A - 21 Years

Accepts Healthy Volunteers

No

Contacts

Christopher S Almond, MD, MPH, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT03386539

Organization ID

P00025970

Secondary IDs

PR160574

Responsible Party

Principal Investigator

Study Sponsor

Boston Children's Hospital

Collaborators

 Stanford University

Study Sponsor

Christopher S Almond, MD, MPH, Study Chair, Stanford University


Verification Date

September 2021