A 24 month, multi-center, open-label, randomized, controlled study to evaluate the efficacy and safety of concentration controlled everolimus to eliminate or to reduce tacrolimus compared to tacrolimus in de novo liver transplant recipients.

This registration trial is designed to address important issues that impact
recipients of liver allografts as well as clinicians. The introduction of
everolimus may provide superior renal function, by allowing for the reduction
or the discontinuation of tacrolimus early post-transplantation, and possibly
impacting the development or the rate of progression of fibrosis in HCV
positive recipients.

To evaluate the use of concentration-controlled everolimus, with the reduction
or the elimination of tacrolimus, to provide superior renal function and to
provide non-inferior rates of the composite efficacy endpoint compared to the
tacrolimus control at 12 months post-transplantation.

This study is a twenty-four (24) month, multi-center, open-label, randomized,
controlled study that will consist of a screening period, a baseline period (3
to 7 days post-transplantation) followed by a run-in period that ends on the
day of randomization at 30 days (+/- 5 days) post-transplantation.
A total of 690 patients will be stratified and randomized. Stratification will
be based upon HCV status and according to the stratum of renal function
(assessed by abbreviated MDRD equation). Randomization will be to one of the
three treatment arms in a 1:1:1 ratio as follows: 1) tacrolimus elimination
arm; 2) tacrolimus minimization arm; 3) tacrolimus control arm. After
discontinuation of group 1, based on a recommendation by the DSMB the remaining
newly enrolled patients have been randomised 1:1 to groups 2 and 3.

Group 1 (elimination arm): low dose Prograft until month 4 (then elimination) +
Certican + steroids
Group 2 (minimalisation arm): low dose Prograft + Certican + steroids
Group 3 (control arm): standard treatment Prograft + steroids

The burden (number of visits and evaluations) for the patient associated with
participation in this trial does not differ from the burden when following the
standard protocol after liver transplantation. The only additional burden is a
liver biopsy at baseline (for HCV positive patients only). There is a chance of
pain and bleeding after the biopsy. However, these risks do not differ from the
risk at the routine biopsies at 1 and 2 year after transplant, and in case of a
suspected acute rejection, which are all part of the standard treatment.
Patients randomised to one of the two Certican groups may possibly encounter
the side effects of Certican (as described in the 1B text).