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.
Conditions
Interventions
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
Ot
Sponsors
Wyeth Research Division of Wyeth Pharmaceuticals Inc
Eligibility
Sex/Gender
All
Inclusion criteria
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 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. 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 4,000 cells/mm3) and platelet count greater than or equal to 100.0 x 10 9/L (greater than or equal to 100,000 cells/mm3). 6. Fasting (8 to 12 hours) total cholesterol =65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. Receipt of a kidney from a donor aged > 60 years; from a living donor aged > 65 years. 2. Receipt of a kidney from a donor aged 50 to 60 years and 2 of the following: terminal creatinine >1.5 mg/dL (132 micromol/L), death secondary to cerebral vascular accident, or known history of hypertension requiring medical treatment. 3. Receipt of a kidney from a living-related, HLA-identical donor. 4. Subjects who have had a previous solid organ transplant. 5. Suspected or confirmed active infection that has the potential to become systemic in the opinion of the primary investigator. 6. Evidence of known infiltrate, cavitation, or consolidation on chest radiograph that has not been repeated and interpreted as normal within the past 2 months. 7. Presence of unstable angina or ongoing use of maintenance therapy for a life-threatening arrhythmia. 8. Known or suspected malignancy within 5 years before enrollment into the study (with the exception of adequately treated basal cell or squamous cell carcinomas of the skin). 9. Use of any investigational drug within 4 weeks before randomization. 10. Prior or current use of sirolimus or any of its derivatives. 11. Known hypersensitivity to CsA, basiliximab, MMF, or corticosteroid formulations. 12. Subjects receiving a kidney-pancreas or other multiple organ transplants. 13. Subjects who are receiving pediatric en bloc transplants, or dual adult kidney transplants. 14. Current use of ketoconazole (except topical), voriconazole, terfenadine, cisapride, astemizole, cimetidine, or pimozide. These agents must be discontinued prior to randomization. 15. Positive past medical history for documented human immunodeficiency virus (HIV) infection. 16. Within 6 months before randomization, subjects receiving a kidney from a deceased donor with the most recent HLA panel-reactive antibodies (PRA) > 20%. If a subject has received a transfusion of a blood product within 6 months before randomization, a PRA less than or equal to 20% must have been documented at least 3 weeks after the transfusion. 17. Receipt of a kidney where the total donor kidney ischemia time was > 30 hours. 18. Receipt of kidneys from nonheart-beating donors. 19. Subjects with a known positive B-cell or T-cell cross-match. 20. Subjects with ABO incompatibility with the allograft. 21. Subjects who have a BMI >30 kg/m 2.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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.;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).;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). - Slo | — |
Countries
Czech Republic, Hungary, Italy, Spain, Sweden, United Kingdom
Outcome results
None listed