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.

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