# Presentation: 690590

## CsA Elimination Studies

***RAPAMUNE******®***

**CsA Elimination Studies**

**Design**

## Design of Studies Based on Standards of Elimination Trials

**Author****	****	****	****	****Year****	****	**
**Land W****	****	****	****1983**
**Hall B****	****	****	****	****1988**
**Kootte A****	****	****	****1988**
**Delmoncio FL****	****	****1990****Isoniemi H****	****	****	****1990**
**Pedersen E****	****	****1993**
**Heim-Duthoy K****	****1994**
**MacPhee I****	****	****	****1998**
**Abramowicz D****	****	****1999**

**Initial Combination**
**Therapy**

**CsA Maintenance Therapy**

**CsA Elimination**

## Randomized Withdrawal Trials:Similar Study Designs

**Decreasing**
**Rejection Risk**

**RAPA + CsA + Steroids**

**RAPA + Steroids**

**2 to 3 months**

**Initial Therapy**

**Maintenance Therapy**

**RAPA + CsA + Steroids**

## 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

**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**

**One Phase III and One Phase II Trial in Renal Transplant Recipients**

## Primary Endpoints

**Primary Endpoints**

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

## Major Secondary Endpoints

## Criteria for Exclusion from Randomization 

**** Acute tubular necrosis/delayed graft function.**

**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 hours****post-transplant**
**Ongoing ATN/DGF** at day 7 post-transplant**

## Studies 310 and 212Included 771 Patients

**	****Study 310****	****Study 212**
**	****(N = 525)****	****(N = 246)**

**Nonrandomized**

**RAPA + CsA**

**RAPA**

**Randomized 1:1**

## Study 310Design and Dosing Regimen

**Time from Transplant**

**R**
**A**
**N**
**D**
**O**
**M**
**I**
**Z**
**A**
**T**
**I**
**O**
**N**

## Study 212Dosing Regimen

**N = 246; 49 patients not randomized.**

**Time from Transplant**

## 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**