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

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.

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.