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CsA Elimination Studies

RAPAMUNE ®. CsA Elimination Studies. Design. Design of Studies Based on Standards of Elimination Trials. CsA Maintenance Therapy. Initial Combination Therapy. CsA Elimination. Author Year Land W 1983 Hall B 1988 Kootte A 1988 Delmoncio FL 1990 Isoniemi H 1990

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CsA Elimination Studies

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  1. RAPAMUNE® CsA Elimination Studies Design

  2. Design of Studies Based on Standards of Elimination Trials CsA Maintenance Therapy Initial Combination Therapy CsA Elimination Author Year Land W 1983 Hall B 1988 Kootte A 1988 Delmoncio FL 1990Isoniemi H 1990 Pedersen E 1993 Heim-Duthoy K 1994 MacPhee I 1998 Abramowicz D 1999

  3. Randomized Withdrawal Trials:Similar Study Designs RAPA + CsA + Steroids Initial Therapy Decreasing Rejection Risk 2 to 3 months Maintenance Therapy RAPA + Steroids RAPA + CsA + Steroids

  4. One Phase III and One Phase II Trial in Renal Transplant Recipients Open-label, controlled, randomized, multicenter trials Study 310 (AU, CA, EU) Study 212 (EU, US) • 57 Centers – 17 Centers • 525 Patients – 246 Patients • Primary (90%) or secondary – Primary allografts (10%) allografts • Cadaver (89%) or HLA- – Cadaver donors mismatched living donors (11%) • Randomization at month 3 – Randomization days 2 to 7

  5. Primary Endpoints • Study 310 • Graft Survival (1 Year) • Study 212 • Renal Function (Month 6)

  6. Study 310 • Patient Survival • Biopsy-ConfirmedAcute Rejection • Renal Function • Efficacy Failure • Treatment Failure • Study 212 • Patient and Graft Survival • Biopsy-Confirmed Acute Rejection • Renal Function Beyond 6 Months • Treatment Failure Major Secondary Endpoints

  7. Criteria for Exclusion from Randomization Study 310 (randomization at month 3) • Banff (1993) grade III acute rejection or vascular rejection within the preceding 4 weeks • Dialysis-dependency • Serum creatinine > 400 µmol/L (> 4.5 mg/dL) • Inadequate renal function* Study 212 (randomization days 2 to 7) • Inadequate renal function* within 48 hourspost-transplant • Ongoing ATN/DGF** at day 7 post-transplant * As determined by the investigator. ** Acute tubular necrosis/delayed graft function.

  8. Studies 310 and 212Included 771 Patients Study 310 Study 212 (N = 525) (N = 246) RAPA + CsA RAPA Nonrandomized Randomized 1:1

  9. RAPA + CsA (n = 215) RAPA 2 mg/day N = 525* CsA: 150-250 ng/mL RAPAMUNE CsA 75 - 200 ng/mL 6 mg 2 mg/day RAPA (n = 215) CsA,ng/mL 15 - 25ng/mL RAPA (Sirolimus 20 - 30 ng/mL) 200 - 400 150 - 300 Reduce CsA 25% / week;discontinue by month 4 1 2 1 2 3 4 5 6 7 8 9 10 11 12 60 Day Month * 95 patients not randomized. Study 310Design and Dosing Regimen R A N D O M I Z A T I O N Time from Transplant

  10. RAPA + CsA (n = 97) RAPA 6 mg 2 mg/day 200to350 200to300 CsA 200 to 400 ng/mL 150 to 250 ng/mL RAPA (n = 100) 10 mg/d 20 mg/d RAPA Sirolimus 10 - 20 ng/mL 100to150 Reduce CsA 25% per week; discontinue by month 3 CsA 100 to 175 ng/mL 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 11 12 Days Month Study 212Dosing Regimen Time from Transplant N = 246; 49 patients not randomized.

  11. Data Presentation • Data from Studies 310 and 212 are not integrated • Time of randomization • Target sirolimus and cyclosporine trough concentration ranges • Complete 12 month safety and efficacy data presented for both studies • Cumulative safety data presented for Study 310

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