Study Evaluating A Planned Transition From Tacrolimus To Sirolimus In Kidney Transplant Recipients

• Graft Rejection
• Kidney Transplant
• Renal Allograft Recipients
• Renal Transplant

• Drug: Tacrolimus
  During the screening phase, tacrolimus is provided by the investigator (not the Sponsor) and is dosed to achieve a target trough level determined by the investigator. Therefore, the dosage form, dosage, and frequency are determined by the investigator. Duration of treatment is from transplantation until randomization (from 90 to 150 days).
  Other Name: Prograf, Adagraf
• Drug: Sirolimus
  Following randomization, sirolimus is provided by the Sponsor in 1 and 2 mg oral tablets. Sirolimus is dosed once daily to achieve a target trough level of 7 to 15 ng/mL in the 1st year post-transplant and 5 - 15 ng/mL in the 2nd year post-transplant. Duration of treatment is from randomization through 2 years post-transplant (19 to 21 months).
  Other Name: Rapamune
• Drug: Tacrolimus
  During the study, tacrolimus is provided by the investigator (not the Sponsor) and is dosed to achieve a target trough level determined by the investigator. Therefore, the dosage form, dosage, and frequency are determined by the investigator. Duration of treatment is 2 years post-transplant.
  Other Name: Prograf, adagraf

• Experimental: Group I - Planned transition to sirolimus from tacrolimus
  Interventions:

  • Drug: Tacrolimus
  • Drug: Sirolimus
• Active Comparator: Group II - Continuation of tacrolimus
  Intervention: Drug: Tacrolimus

Inclusion Criteria:

At Screening:

• Male or female subjects aged 18 years or older.
• Recipients who are 14 days prior to transplantation up through 14 days after transplantation.
• Recipients of a primary, living- or deceased-donor renal allograft.
• All female and male subjects who are biologically capable of having children must agree and commit to the use of a reliable method of birth control for the duration of the study and for 3 months after the last dose of test article. A subject is biologically capable of having children even if he or she is using contraceptives or if his or her sexual partner is sterile or using contraceptives.

At Randomization:

• Ninety (90) to 150 days post-transplantation.
• Treatment with tacrolimus and an inosine monophosphate dehydrogenase (IMPDH) inhibitor initiated less than or equal to 30 days of transplantation and has remained on both for the 30 days prior to randomization.

Exclusion Criteria:

At Screening:

• Recipients of multiple organ transplants (i.e., any prior or concurrent transplantation of any organs including prior renal transplant. )
• Recipients of adult or pediatric en bloc kidney transplants.
• Recipients who required or will require desensitization protocols.
• Known history of focal segmental glomerulosclerosis (FSGS) or membranoproliferative glomerulonephritis (MPGN).
• Evidence of active systemic or localized major infection, as determined by the investigator.
• Received any investigational drugs or devices less than or equal to 30 days prior to transplantation.
• Known or suspected allergy to sirolimus (SRL), tacrolimus (TAC), inosine-monophosphate dehydrogenase (IMPDH) inhibitor, macrolide antibiotics, iothalamate, iodine, iodine-containing products, including contrast media other compounds related to these products/classes of medication, or shellfish.
• History of malignancy less than or equal to 3 years of screening (except for adequately treated basal cell or squamous cell carcinoma of the skin).
• Recipients who are known to be human immunodeficiency virus (HIV) positive.
• Women who are biologically capable of having children with a positive urine or serum pregnancy test at screening.
• Breastfeeding women.

At Randomization:

• Any major illness/condition that, in the investigator's judgment, will substantially increase the risk associated with the subject's participation in and completion of the study, or could preclude the evaluation of the subject's response.
• Planned treatment with immunosuppressive therapies other than those described in the protocol.
• Subjects who underwent corticosteroids withdrawal or avoidance and did not receive antibody induction at the time of transplantation with anti-thymocyte globulin (rabbit) (rATG) (Thymoglobulin®), anti-thymocyte globulin (equine) (Atgam®), or alemtuzumab (Campath®).
• Subjects who have had corticosteroid (CS) discontinued less than or equal to 30 days before randomization.
• Calculated glomerular filtration rate (GFR) less than 40 mL/min/1.73m2 using the simplified Modification of Diet in Renal Disease (MDRD) formula less than or equal to 2 weeks prior to randomization.
• Spot urine protein to creatinine ratio (UPr/Cr) greater than or equal to 0.5 less than or equal to 2 weeks prior to randomization.
• Banff (2007) grade 2 or higher acute T-cell-mediated or any acute antibody-mediated rejection at any time post-transplantation.
• Any acute rejection (biopsy-confirmed or presumed) less than or equal to 30 days before randomization.
• More than 1 episode of acute rejection (biopsy-confirmed or presumed).
• Known Banff (2007) interstitial fibrosis and tubular atrophy (IF/TA) greater than or equal to grade 2 or recurrent/de novo glomerular disease.
• Major surgery less than or equal to 2 weeks prior to randomization.
• Active post-operative complication, e.g. infection, delayed wound healing.
• Total white blood cell count less than 2,000/mm3 or absolute neutrophil count (ANC) less than 1000 or platelet count less than 100,000/mm3 less than or equal to 2 weeks prior to randomization.
• Fasting triglycerides greater than 400 mg/dL (greater than 4.5 mmol/L) or fasting total cholesterol greater than 300 mg/dL (greater than 7.8 mmol/L) less than or equal to 2 weeks prior to randomization regardless of whether or not on lipid-lowering therapy.
• Women who are biologically capable of having children with a positive urine or serum pregnancy test at randomization.
• Breastfeeding women.