Use of Daclizumab for the Prevention of Allograft Rejection in Pediatric Heart Transplant Patients

Initial studies in renal and recent studies in adult cardiac transplant patients have shown
Zenapax(R) to be both efficacious and safe when used in several different dosing schedules.
Little data is available regarding pharmacokinetics, safety and appropriate dosing in
pediatric heart transplant patients. Yet this ever-increasing group of patients presents a
significant challenge for the prevention of primary rejection and the appropriate
maintenance of immunosuppression. Induction of long term allograft acceptance through
peripheral tolerance has been shown in animal models to be more easily induced in young
animals. Once established however, allograft rejection and immunologic responses in the
young are quite vigorous. This dichotomy makes young allograft recipients a particularly
attractive population for the study of immune modulators targeted at preventing
proliferative expansion of alloreactive T cell clones. This is precisely the mode of action
of anti-IL2R monoclonal reagents such as Zenapax(R).

Although some pharmacokinetic data have been generated in adult heart transplant patients on
multidrug immunosuppressive regimens including both Zenapax(R) and mycophenolate mofetil
(MMF), detailed pharmacokinetic data on this combination in multidrug immunosuppressive
regimens is not available for pediatric heart transplant subjects.

Objectives:

- Determination of pharmacokinetics of Zenapax(R) in pediatric patients receiving a
uniform multidrug immunosuppressive regimen for primary induction.

- Determine whether there are any unusual drug interactions peculiar to the pediatric
population that would require dosing modification.

Secondary objectives:

- Investigate long term effects of Zenapax(R) containing induction regimen on pediatric
patients.

Inclusion Criteria:

- Patients must be undergoing their first cardiac allograft transplant.

- Male or female must be less than or equal to 18 years of age.

- Women of childbearing potential must have a negative serum pregnancy test within 48
hours prior to transplantation. The sensitivity must be equal to at least 50 mIU/ml.
(Urine test is allowed in addition to serum test in patients where serum results are
delayed.)

- Women of childbearing potential must use two reliable forms of contraception
simultaneously.

- Effective contraception must be used before beginning study drug therapy, and for 4
months following discontinuation of study drug therapy.

- Patients and/or their guardians must be willing and be capable of understanding the
purpose and risks of the study and must sign a statement of informed consent.

Exclusion Criteria:

- Patients with a history of hypersensitivity reactions to any of the constituents of
the Zenapax(R) preparation or having had hypersensitivity reactions to human or
murine immune globulin preparations in the past.

- Women lactating, pregnant or of childbearing potential not using, or who are
unwilling to use two reliable forms of contraception simultaneously during the study

- History of a psychological illness or condition which would interfere with the
patient's ability to understand the requirements of the study

- White blood count < 2500/mm^3, platelets < 50,000 /mm^3 or hemoglobin < 6 g/dL.

- HIV-1 infection or the presence of positive hepatitis B surface antigen (HBsAg) or
chronic hepatitis C.

- Active peptic ulcer disease

- Severe diarrhea or other gastrointestinal disorders which might interfere with the
ability to absorb oral medication

- Malignancies within the past 5 years, excluding skin carcinomas (basal or squamous
cell) that have been adequately treated

- Patients who have received within the past 30 days or require concomitant treatment
with other investigational drugs or immunosuppressive medications that are prohibited
for this study

- Inability to start microemulsion form of cyclosporine within 72 hours