Rituximab in Kidney Transplantation

Organ rejection occurs when a patient's body does not recognize the new organ and attacks
it. Data suggest that the development of anti-human leukocyte antigen (HLA) antibodies is an
early clinical indication that organ rejection may occur. Rituximab is a genetically
engineered monoclonal antibody directed against the CD20 antigen on B cells and is known to
deplete B cells when administered intravenously; it is FDA-approved for the treatment of
non-Hodgkin's lymphoma. In a previous small study, kidney transplant patients with either
acute humoral rejection (AHR) or chronic humoral rejection (CHR) were given rituximab and
other antilymphocyte therapy. Patients with AHR had lower or undetectable levels of
circulating anti-HLA antibodies after study treatment, and patients with CHR had a sustained
decrease of anti-HLA antibodies to undetectable after 6 to 9 months. This new study will
evaluate the safety and efficacy of rituximab in preventing organ rejection and promoting
long-term survival of donor kidneys in people who undergo kidney transplantation.

The study will last 8 years. The study will enroll participants for 3 years, and patients
will participate in the study for 2 to 5 years. This study involves two stages.

Stage 1 begins 3 to 36 months after transplant. During Stage 1, blood collection will occur
every 3 months for up to 36 months after transplant to test for anti-HLA antibodies. When
these antibodies are detected twice within 1 month, the patient will undergo a baseline
kidney biopsy and have his or her glomerular filtration rate (GFR) measured to determine
kidney function. If a patient meets certain study criteria, he or she will enter Step 2.

If anti-HLA antibodies are not detected in a patient's blood during Stage 1, the patient's
participation will be complete.

In Stage 2, patients will be randomly assigned to one of two study treatment groups:

- Group 1 adult participants, 18 years of age or older, will receive an intravenous
infusion of 1000mg of rituximab at Days 0 and 14. Group 1 pediatric participants, 18
years of age or younger, will receive an intravenous infusion of 375 mg/m2 of rituximab
at Days 0, 8, 15 and 22.

- Group 2 adult participants, 18 years of age or older, will receive an intravenous
infusion of 1000mg of placebo at Days 0 and 14. Group 2 pediatric participants, 18
years of age or younger, will receive an intravenous infusion of 375 mg/m2 of placebo
at Days 0, 8, 15, and 22.

All participants will also receive standard of care immunosuppressive drugs. Adult
participants, 18 years of age or older, will have 9 study visits over 24 months. Pediatric
participants, 18 years of age or younger, will have 11 study visits over 24 months. A
physical exam, medication history, adverse events assessment, and blood and urine collection
will occur at all visits. A biopsy of the kidney transplant will occur at Stage 2 entry and
Month 24.