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RAPAMUNE ®. CsA Elimination Studies. Design. Design of Studies Based on Standards of Elimination Trials. CsA Maintenance Therapy. Initial Combination Therapy. CsA Elimination. AuthorYear Land W1983 Hall B1988 Kootte A1988 Delmoncio FL1990 Isoniemi H1990

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Csa elimination studies

RAPAMUNE®

CsA Elimination Studies

Design


Design of studies based on standards of elimination trials
Design of Studies Based on Standards of Elimination Trials

CsA Maintenance Therapy

Initial Combination

Therapy

CsA Elimination

AuthorYear

Land W1983

Hall B1988

Kootte A1988

Delmoncio FL1990Isoniemi H1990

Pedersen E1993

Heim-Duthoy K1994

MacPhee I1998

Abramowicz D1999


Randomized withdrawal trials similar study designs
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


One phase iii and one phase ii trial in renal transplant recipients
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


Primary endpoints
Primary Endpoints Recipients

  • Study 310

    • Graft Survival (1 Year)

  • Study 212

    • Renal Function (Month 6)


Major secondary endpoints

  • Study 310 Recipients

    • 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


Criteria for exclusion from randomization
Criteria for Exclusion from Randomization Recipients

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.


Studies 310 and 212 included 771 patients
Studies 310 and 212 RecipientsIncluded 771 Patients

Study 310Study 212

(N = 525)(N = 246)

RAPA + CsA

RAPA

Nonrandomized

Randomized 1:1


Study 310 design and dosing regimen

RAPA + CsA Recipients (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


Study 212 dosing regimen

RAPA + CsA Recipients (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.


Data presentation
Data Presentation Recipients

  • 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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