A multi-center randomized, open label, controlled study in primary liver transplantation comparing long term renal function in recipients treated with standard dose extended release tacrolimus alone and recipients treated with a combination of low dose extended-release tacrolimus and low dose sirolimus.

Calcineurin inhibitors (CNIs), since their introduction in the 1980s, have been
the cornerstone of maintenance immunosuppressive regimens in liver
transplantation. The use of CNIs has substantially decreased the risk of acute
rejection and improved short-term outcomes. The current most used combination
is tacrolimus, prednisolone and mycophenolate mofetil with in some centers an
induction therapy with IL-2 antagonists basiliximab or dacluzimab. The
incidence of biopsy-proven acute rejection within the first year after
transplantation ranges between 19 - 30 % (Yoshida, Marotta et al. 2005;
Neuberger, Mamelok et al. 2009).
The use of CNI may have a negative influence on kidney function, induce
diabetes mellitus and hypertension, however depending on type of CNI, dosing
regimes and concomitant immunosuppressive medication. Nephrotoxicity is one of
the most serious complications of CNI (Gonwa, Mai et al. 2001). Apart from
intestinal transplants, liver transplant recipients have the highest five-year
incidence of chronic renal failure (CRF) of any non-renal solid organ
transplant recipient; additionally, the risk of death is at least fourfold
higher in patients who develop CRF (Flechner, Goldfarb et al. 2007). These
problems have leaded to the determination of new strategies of
immunosuppressive treatment in liver transplantation patients tot decrease the
use of CNIs. The first option was to replace CNIs by mTor inhibitors, but this
has resulted in a higher incidence of rejection, vena portae thrombosis,
decreased wound healing, thrombocytopenia and proteinuria. An other strategy
was to replace the CNI by a mTor inhibitor when CNI toxicity such as renal
dysfunction has evolved, but also this strategy has resulted in an increased
rejection rate and there was no long term improvement of the renal outcome. The
third approach was to completely avoid CNIs and start from the time of
transplantation with mTor inhibitors in combination with other
immunosuppressive drugs.

To evaluate the effectiveness and safety of concentration controlled
combination of once daily dosed low-dose sirolimus (trough levels: 3-5 ng/ml)
and extended-release tacrolimus (trough levels:3-5 ng/ml), in order to provide
superior renal function while maintaining comparable rates of patient and graft
survival, compared to concentration controlled once - daily extended release
tacrolimus (trough levels:5-10 ng/ml) at 12, 24 and 36 months post-transplant.
Moreover, to compare the incidence of de novo malignancy, the quality of life,
fatigue and side effects between both treatment arms.

A phase III multicenter, randomized, open label study to evaluate the efficacy
and safety up to 3 years of a regimen with a combination of low-dose
extended-release tacrolimus and sirolimus in comparison with standard-dose
extended-release tacrolimus. The patients are randomized between 80 and 100
days after liver transplantation in 2 arms.
- Arm 1 will receive once daily combination therapy of normal dosed
extended-release tacrolimus and prednisone for 3 months and monotherapy once
daily extended-release tacrolimus thereafter up to 4 years after liver
transplantation.
- Arm 2 will receive once daily combination therapy of low doses sirolimus and
extended-release tacrolimus and prednisone for 3 months and combination therapy
of low dose sirolimus and extended-release tacrolimus thereafter for up to 3
years after liver transplantation

During the study period all patients will be seen on regular periods according
to the local out-patient protocol

- Arm 1 will receive once daily combination therapy of normal dosed
extended-release tacrolimus and prednisone for 3 months and monotherapy once
daily extended-release tacrolimus thereafter up to 4 years after liver
transplantation.
- Arm 2 will receive once daily combination therapy of low doses sirolimus and
extended-release tacrolimus and prednisone for 3 months and combination therapy
of low dose sirolimus and extended-release tacrolimus thereafter for up to 3
years after liver transplantation

- extra collection of blood
- adverse events of Sirolimus and possible higher incidence of rejection in the
study arm