Everolimus + Very Low Tacrolimus vs Enteric-coated Mycophenolate Sodium + Low Tacrolimus in de Novo Renal Transplant

Everolimus in Association With Very Low-dose Tacrolimus Versus Enteric-coated Mycophenolate Sodium With Low-dose Tacrolimus in de Novo Renal Transplant Recipients - A Prospective Single Center Study

This is a 12-month single center, randomized, open-label, single center study designed to compare the safety and efficacy of everolimus and very low dose tacrolimus versus enteric-coated sodium mycophenolate and low tacrolimus exposure in de novo kidney transplant recipients.

The purpose of this study is to compare safety and efficacy of two immunosuppressive regimens based on low tacrolimus exposure combined to everolimus or to enteric-coated mycophenolate sodium (EC-MPS) in de novo kidney transplant recipients.

The study will consist of two periods: an initial period of 3 months during which all patients in both groups will be monitored in accordance with the same variation of C-0h tacrolimus and a second study period of 9 months (from month 4 to month 12) in which patients will be monitored according to two different targets of C-0h tacrolimus.

At the screening visit and before any assessment related to the study, patients must give their informed consent in writing.

All patients will receive induction with rabbit Thymoglobulin (r-ATG) in four doses of 1.5 mg/kg (maximum total dose of 6 mg/kg), administered according to center local practice.

The evaluations of baseline visit occur within 24 hours after transplantation and prior to the first dose of study drug.

Randomization will be performed within 24 hours after transplantation and after the baseline visit assessments. Patients will be randomized in a 1:1 ratio to one of two groups (everolimus with very low dose of tacrolimus versus sodium mycophenolate with low dose of tacrolimus).

Approximately 120 patients who meet the inclusion criteria will receive their first dose everolimus (initial dose of 1 mg twice a day) or sodium mycophenolate (initial dose of 720 mg twice a day) not more than 24 hours after transplantation. Everolimus trough blood levels will be measured at pre-specified timepoints in order to ensure that trough levels are above 3 ng/ml and below 8 ng/ml for the duration of the study.

Tacrolimus will be started within 48 hours after graft reperfusion at an initial dose of 0.1 mg/kg/day. The dose of tacrolimus will be adjusted to target the C-0h value within the pre-established desired range.

In the everolimus group with very low dose of tacrolimus, tacrolimus dose should be reduced at the end of months three after transplantation. Patients with either acute rejection grade ≥ Banff IIB or more than one treated acute rejection since entering the study and patients with either acute rejection during the third month will not have the dose of tacrolimus reduced; however, they will be encouraged to remain in the study. These patients will be excluded from the per protocol population analysis, but will be analyzed in the Intention To Treat population.

If patients present delayed graft function (DGF), the start of tacrolimus can be postponed for up to and including 7 days.

During the 12 months treatment period, patient visits will occur at the selection visit, baseline visit, at 1, 2, 4 and 8 weeks and at 3, 6 and 12 months. Day 1 is the day of the first administration of everolimus or sodium mycophenolate.

Population: Study population will consist of a group of male or female transplant recipients 18-75 years of age undergoing primary renal transplantation and who received an organ from a living or deceased donor.

Inclusion Criteria:

• Male or female renal recipients 18-75 years of age undergoing kidney transplantation, from a primary deceased donor (including expanded criteria donor organs), living unrelated or non-HLA identical living related donor kidney;
• Recipient of a kidney with a cold ischemia time < 30 hours;
• Graft must be functional (producing greater than or equal to 300 ml of urine within 24 hours after transplantation) at time of randomization.

Exclusion Criteria:

• Donor organ with a cold ischemic time > 30 hours;
• Patients who produce less than 300 ml of urine in the first 24 hours post-transplantation;
• Patients who are recipients of multiple organ transplants;
• Patients who are recipients of ABO incompatible transplants, or T or B cell cross match positive transplant;
• Patients with current Panel Reactive Antibodies (PRA) level ≥ 50%;
• Patients with severe hypercholesterolemia (350 mg/dl) or hypertriglyceridemia (500 mg/dl). Patients on lipid lowering treatment with controlled hyperlipidemia are acceptable;
• HIV positive patients;
• Females of childbearing potential who are planning to become pregnant, who are pregnant and/or lactating, who are unwilling to use effective means of contraception;
• Decisional impaired subjects who are not medically or mentally capable of providing consent themselves.