Study Comparing in Livertransplantation Recipients With Tacrolimus Alone Versus Tacrolimus&Sirolimus

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.

2.1 Primary objectives: To evaluate the effectiveness and safety of concentration controlled combination of 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:-10 ng/ml) control at 12, 24 and 36 months post-transplant.

2.2. Secondary objectives:

* To compare the incidence of de novo and recurrence of cancer between study arm and control arm at 36 months.
* To compare the incidence and severity of biopsy proven acute rejection between study arm and control arm at 12, 24 and 36 months.
* To evaluate renal function at 12, 24 and 36 months (calculated GFR).
* To evaluate the development of new onset diabetes mellitus at 12, 24 and 36 months post transplant
* To evaluate the prevalence of CNI side effects at 12, 24 and 36 months
* To evaluate quality of life (Eq5D) and fatigue severity score at 12, 24 and 36 months
* To evaluate the percentage of patients on combination tacrolimus and sirolimus and converted back to tacrolimus mono-therapy.

• Tacrolimus and Sirolimus (Drug), also known as Advagraf [Astellas Pharma bv), Rapamune: Arm 1 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 3 years after liver transplantation. Arm 2 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 Continue Advagraf (5-10 ng/ml) and 7.5 mg prednison; lower or discontinue steroids after day 180 at the discretion of the treating physician Conversion to sirolimus (3-5 ng/ml) and decrease Advagraf (3-5 ng/ml); 7.5 mg prednisone and lower or discontinue steroids after day 180 at the discretion of the treating physician
• Tacrolimus (Drug), also known as Advagraf: Patient received standard-dose of Tracrolimus Advagraf (5-10 ng/ml) and 7.5 mg prednison; lower or discontinue steroids after day 180 at the discretion of the treating physician

Primary outcomes

• Renal function [3 years]: Percentage of patients with cGFR < 60ml/min

Secondary outcomes

• Malignancies [3 years]: number of de novo malignancies
• Diabetes Mellitus [3 years]: Incidence of De novo diabetes mellitus

Sex: All, ages: 18 Years to 70 Years

Inclusion Criteria:

* Primary liver transplantation or retransplantation within 14 days after first transplantation
* Use of Advagraf at least 2 weeks prior to randomization
* Patent hepatic artery
* Closed abdominal wound
* Stable graft function
* Positive informed consent at time of randomization
* Age 18-70 years

Exclusion Criteria:

* Treatment with investigational drugs within 3 months before start of therapy
* Multi organ transplantation
* cGFR < 30 ml/min
* Proteinuria > 800 mg/24 h
* Hyperlipidemia refractory to optimal medical management (Cholesterol > 9 mmol/l and/or triglycerides > 8.5 mmol/l). Patients with controlled hyperlipidemia are acceptable at the time of randomization.
* Known hypersensitivity to sirolimus or its derivatives
* Thrombocytes < 50 x 109 /L
* Leukocytes < 2.5 x 109 /L
* Haemoglobin < 6 mmol/L
* Biopsy proven rejection 2 weeks prior to randomization
* HIV positivity
* Signs of recurrent or de novo cancer
* Patients with non-HCC malignancies within the past 5 years (excluding successfully treated squamous cell carcinoma and basal cell carcinoma of the skin)
* Evidence of significant local or systemic infection
* Pregnancy or breast feeding
* Women of child-bearing potential not willing to take oral contraception
* Any other condition which in the opinion of the investigator would make the patient unsuitable for enrollment, or could interfere with the patient participating in and completing the study

• Herold J Metselaar, MD PhD, Principal investigator, Erasmus Medical Center