Title: An open label randomized, multicenter study to evaluate the efficacy and safety of early calcineurin inhibitor withdrawal in recipients of primary renal allografts maintained longterm on mycophenolate mofetil: MMF(CellCept) and sirolimus (Rapamune)

PI: David Cohen, MD

Calcineurin inhibitors (cyclosporine, tacrolimus) have proven to be the most effective immunosuppressive medications for the prevention of rejection of renal transplants. However, long-term use of these medications is associated with several serious adverse effects, such as diabetes mellitus, hypertension, hyperlipidemia, and nephrotoxicity. Sirolimus, a new FDA approved immunosuppressant, is not nephrotoxic, is nondiabetogenic, and does not cause hypertension. Preliminary studies suggest that after 35 months of treatment with a calcineurin inhibitor + sirolimus, renal transplant patients can safely be withdrawn from calcineurin inhibitors and maintained on sirolimus based therapy with improved renal function and no decrease in success rates. This study will compare renal function and rejection rates between renal transplant patients randomized to convert at 16 months after transplantation from a calcineurin inhibitor to sirolimus versus those who remain on calcineurin inhibitor therapy. Follow-up will be for one year. It is anticipated that calcineurin inhibitor nephrotoxicity will be eliminated and renal transplant function will improve in those patients converted to sirolimus, eventually defining a regimen that will lead to improved long-term success rates.

Inclusion Criteria:

1. Male or female patients between the ages of 1875.

2. Patients who are 30-180 days post-renal transplant, living donor or cadaveric.

3. Patients who have been maintained on a regimen of cyclosporine or tacrolimus, and mycophenolate mofetil for at least immediately 14 days prior to randomization. The patient must be expected to be able to maintain a MMF dose of 11.5g BID at study entry and for the duration of the study.

4. Patients capable of understanding the purposes and risks of the study, who can give written informed consent and who are willing to participate in and comply with the study.

5. Patients with no known contraindications to treatment with Sirolimus.

6. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to receiving study medication and may not breastfeed.

7. Women of childbearing potential must use 2 reliable forms of contraception simultaneously, before beginning study drug therapy, for the duration of the study, and for 12 weeks after study conclusion.

Exclusion Criteria:

1. Patients experiencing a steroid resistant biopsy proven rejection episode or who are treated for acute rejection with monoclonal /polyclonal antibody therapy within 90 days prior to study entry.

2. Patients experiencing a corticosteroid sensitive acute rejections episode within 30 days prior to randomization

3. Patients with more than one biopsy proven rejection episode prior to study entry.

4. Patients that have previously received or are receiving a non-renal allograft.

5. Patients with a serum creatinine >2.5mg/dL at the time of screening.

6. Patients with a creatinine clearance <30mL/min via the Cockroft-Gault equation at the time of study entry.

7. Patients who will be unable to provide the necessary urine specimens for GFR determinations or who are allergic to cold iothalamate or iodine.

8. Patients who are receiving less than 500 mg BID of MMF and patients who are receiving between 500 mg BID and 1 g BID of MMF and/or who are not receiving corticosteroids with an MPA AUC of <30 or >60 mg*hr/L.

9. Patients who have received sirolimus prior to study entry.

10. Patients with severe diarrhea or other gastrointestinal disorders that might interfere with their ability or absorb oral medication; diabetic patients diagnosed with diabetic gastroenteropathy or patients with active peptic ulcer disease.

11. Patients with evidence of active systemic infection requiring the continued use of antibiotics, HIV infection or chronic, active Hepatitis B or C.

12. Patients with a history of malignancy in the last 5 years (except for successfully treated localized non-melanotic skin cancer).

13. Patients with severe anemia (Hg <8g/dL), leukopenia (WBC<3000/mm3), or thrombocytopenia (platelets<100,000/mm3).

14. Patients receiving experimental immunosuppressive agents.

15. Patients with total cholesterol levels >300mg/dL or triglycerides >350mg/dL at the time of screening.

16. Patients requiring dialysis at the time of study entry.

17. Patients who require the following medications:

Azathioprine

Methotrexate

Cyclophosphamide

Everolimus

Enteric coated mycophenolate sodium