The purpose of this study is to compare treatment with the new drug sirolimus (SRL) versus
the standard treatment with cyclosporine (CsA) or tacrolimus in children who have received
kidney transplants. SRL is a new medication that may prevent the body's immune system from
rejecting organ transplants.
After receiving a kidney transplant, the body recognizes the donated kidney as a foreign
invader and triggers the immune system to attack the kidney. This can lead to rejection of
the new kidney and a failed transplant. To help reduce the risk of kidney rejection,
transplant patients are given immunosuppressant drugs, which reduce the body's normal immune
response and allow the transplanted organ to function. CsA or tacrolimus are two drugs that
are often given to transplant patients. However, these are powerful drugs, and it can cause
serious side effects and put a patient at increased risk for infections. SRL is a new drug
that has been shown to reduce a transplant patient's chance of rejecting a new kidney,
without serious side effects. This study is necessary to test the safety and effectiveness
of SRL in children.
Successful kidney transplantation has gradually improved over the years; much of the
improvement has resulted from the use of CsA. However, adequate and tolerable
immunosuppression is difficult to achieve with CsA, and rejection episodes are still
frequent. CsA is nephrotoxic, with drug toxicity often masking rejection episodes. Other
immunosuppressant therapies can result in a range of complications, including metabolic
disturbances, adrenocortical insufficiency, and increased risk for infections. Therefore,
more effective drugs with less toxicity are needed to prevent acute rejection, especially in
the pediatric population where the overall graft survival rate remains significantly lower
when compared with that of adult transplant recipients. SRL is an immunosuppressive agent
being developed for the prophylaxis of acute renal allograft rejection. SRL has a unique
mechanism of action. It inhibits T and B cell activity. In Phase I and II trials in adults,
SRL was generally well tolerated and exhibited no apparent nephrotoxic properties, and
significantly lower rates of rejection were seen with SRL when compared to placebo.
Patients receive extensive prestudy screening, which includes a renal core biopsy, chest
x-ray, bone density study, blood tests, and glomerular filtration rate (GFR). Patients are
then randomly assigned to 1 of 2 study treatment groups in a 2:1 ratio (142 patients receive
SRL, CsA/tacrolimus, and corticosteroids and 71 patients receive standard CsA or
tacrolimus-based double or triple drug therapy). SRL is administered as an oral dose of 3
mg/m2/day. Patients are followed for 3 years on therapy, and then for 1 month of follow-up.
A renal core biopsy is performed at the time of study entry and at Months 6, 18, and at
early termination of patient in study. Patients undergo physical examinations and various
blood tests at specified time intervals during the 37-month study period. Efficacy is
assessed by comparing the composite endpoint of biopsy-proven acute rejection, graft loss,
or death after 36 months of treatment. Safety is assessed by comparing the composite
endpoint of graft loss or death after 36 months of treatment.
Your child may be eligible for this study if he/she:
- Has received a kidney transplant.
- Has experienced 1 or more episodes of acute rejection or chronic rejection; a
rejection episode must have responded to treatment and have occurred at least 30 days
before study enrollment.
- Has stable kidney function at the time of study enrollment.
- Is 20 years of age or younger.
- Has written informed consent of parent or guardian if under the age of 18.
- Agrees to use birth control during the study and for 3 months following treatment.
Your child will not be eligible for this study if he/she:
- Has a history of cancer.
- Has received a multi-organ transplant (more than a kidney).
- Has an active infection.
- Has an abnormal chest X-ray.
- Cannot provide a kidney biopsy at time of study entry.
- Is allergic to sirolimus.
- Has received experimental drugs within 4 weeks of study entry.
- Is pregnant.