A Randomized, Open-Label, Comparative Evaluation of the Safety and Efficacy of Sirolimus versus Cyclosporine when Combined in a Regimen Containing Basiliximab, Mycophenolate Mofetil, and Corticosteroids in Primary De Novo Renal Allograft Recipients.

INTERVENTION:

Trade Name: Rapamune 1mg Coated Tablets Product Name: Rapamune 1mg Coated Tablets Pharmaceutical Form: Coated tablet INN or Proposed

INN:

Sirolimus CAS Number: 53123‐88‐9 Current Sponsor code: 0468 Other descriptive name: Rapamycin Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 1‐ Trade Name: Rapamune 2mg Coated Tablets Product Name: Rapamune 2mg Coated Tablets Pharmaceutical Form: Coated tablet INN or Proposed

INN:

Sirolimus CAS Number: 53123‐88‐9 Current Sponsor code: 0468 Other descriptive name: Rapamycin Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 2‐ Trade Name: Rapamune 5mg Coated Tablets Product Name: Rapamune 5mg Coated Tablets Pharmaceutical Form: Coated tablet INN or Proposed

INN:

Sirolimus CAS Number: 53123‐88‐9 Current Sponsor code: 0468 Other descriptive name: Rapamycin Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 5‐ Trade Name: Rapamune 1mg/ml Oral Solution Product Name: Rapamune 1mg/ml Oral Solution Pharmaceutical Form: Oral solution INN or Proposed

INN:

Sirolimus CAS Number: 53123‐88‐9 Current Sponsor code: 0468 Other descriptive name: Rapamycin Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 1‐

CONDITION:

The rationale for the present study is to assess whether a CNI‐free regimen including antibody induction, sirolimus, and mycophenolate mofetil (MMF) results in improved long‐term renal function without having a negative impact on safety or immunosuppressive efficacy, and to further examine the potential of sirolimus to reduce the severity and/or progression of Chronic allograft nephropathy (CAN), which could represent a major advance in the field of transplantation.

INCLUSION CRITERIA:

1. Age > 13 years and weight > 40 kg (age > 18 years in some regions per local regulations; see section H of this application form for requested subject age range in the region reviewing the application). 2. Subjects on dialysis with end‐stage renal disease (ESRD) who will receive a primary renal allograft from a deceased donor, a living‐unrelated donor, or a human leukocyte antigen (HLA)‐mismatched living‐related donor. An HLA mismatch is the number of HLA antigens that a donor has that a recipient does not share. 3. Subjects who receive a primary transplant before the initiation of maintenance dialysis, where the calculated creatinine clearance (CrCl) of the native kidney(s) must be <20 mL/min within 24 hours before transplantation from a deceased donor, a living‐unrelated donor, or an HLA‐mismatched living‐related donor. 4. All female subjects at risk for pregnancy (ie are not surgically sterile or postmenopausal) must have a negative qu

PRIMARY OUTCOME:

Main Objective: Efficacy: to demonstrate superiority of the sirolimus regimen versus Cyclosporine by intent‐to‐treat (ITT) analysis of renal function at 52 weeks, measured by mean calculated glomerular filtration rate (GFR). ; ; Safety: to demonstrate non‐inferiority at 52 weeks in the composite endpoint of the incidence of the first occurrence of graft loss or death. Primary end point(s): The primary efficacy endpoint of this study is renal function at 52 weeks, measured by mean calculated GFR (Nankivell method), to be analyzed in accordance with the ITT principles. The ITT group is defined as all subjects who are randomly assigned to study therapy and undergo transplantation. ; ; The following secondary efficacy endpoints will also be evaluated:; ; ‐ The incidence and severity of BCAR at 12, 24, 52, 104, 156 and 208 weeks. The histologic grade of severity of BCAR will also be evaluated at these time points.; ; ‐ The mean on‐therapy calculated Nankivell GFR at 12, 24, 52, 104, 156 and 208 weeks.; ; ‐ Mean Nankivell GFR at 24, 104, 156 and 208 weeks for all randomly assigned subjects in both groups (ITT).; ; ‐ Slopes of 1/creatinine versus time at 24, 52, 104, 156 and 208 weeks (on‐therapy and ITT).; ; ‐ Slopes of Nankivell GFR versus time at 24, 52, 104, 156 and 208 weeks (on‐therapy and ITT).; ; ‐ Mean GFR as measured by radionuclide or comparable methodology at 24, 52, and 104 weeks (on‐therapy) (at centers that elect to participate).; ; ‐ Progression of chronic allograft nephropathy at 52 weeks (protocol‐mandated biopsies at centers that elect to participate).; ; ‐ Quality of life outcomes at 24, 52, and 104 weeks. Secondary Objective: Secondary Efficacy objectives include:; 1. Incidence of the first occurrence of biopsy‐confirmed acute rejection (BCAR) at 12, 24, 52, 104, 156 and 208 weeks.; 2. Histologic grade of severity of BCAR at 12, 24, 52, 104, 156 and 208 weeks.; 3. Mean on‐therapy calculated Nankivell GFR at 24, 52, 104, 156 and 208 weeks.; 4. Mean Nankivell GFR at 24, 104, 156 and 208 weeks for all randomly assigned subjects in both groups (ITT).; ; Secondary Safety objectives include:; 1. Incidence of patient survival and graft survival at 12, 24, 104, 156 and 208 weeks.; 2. Mean systolic and diastolic blood pressure at 52 and 104 weeks.; 3. Incidence of infection at 52 and 104 weeks. ; 4. Incidence of malignancy (including histologically confirmed lymphoproliferative disease) at 52, 104 and 208 weeks.; ; (See protocol for full list of secondary efficacy and safety objectives).