D-1

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CsA Elimination Studies
RAPAMUNE

• Design

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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
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Randomized Withdrawal TrialsSimilar Study
Designs
RAPA CsA Steroids
Initial Therapy
Decreasing Rejection Risk
2 to 3 months
Maintenance Therapy
RAPA Steroids
RAPA CsA Steroids
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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

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Primary Endpoints

• Study 310
• Graft Survival (1 Year)
• Study 212
• Renal Function (Month 6)

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Major Secondary Endpoints
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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 gt 400 µmol/L (gt 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.
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Studies 310 and 212Included 771 Patients
Study 310 Study 212 (N 525) (N 246)
Nonrandomized
RAPA CsA
RAPA
Randomized 11
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Study 310Design and Dosing Regimen
R A N D O M I Z A T I O N
Time from Transplant
10
Study 212Dosing Regimen
Time from Transplant
N 246 49 patients not randomized.
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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