A National Multi-center Randomized, Open Label Study to Evaluate Efficacy and Safety of Everolimus With Enteric-coated Mycophenolate Sodium (EC-MPS) Compared to Standard Treatment Combination Tacrolimus and Enteric-coated Mycophenolate Sodium (EC-MPS) in de Novo Liver Transplant Recipients (SIMCER)

• Treatment failures biopsy proven acute rejection (BPAR), graft loss or death [ Time Frame: randomization to 6 months after transplantation ] [ Designated as safety issue: No ]
  Incidence of treated biopsy proven acute rejection BPAR (score > 3), graft loss or death
• Incidence of biopsy proven acute rejection (BPAR) [ Time Frame: 3 months and 6 months after transplantation ] [ Designated as safety issue: No ]
  Incidence of BPAR
• Treated BPAR [ Time Frame: 3 months and 6 months after transplantation ] [ Designated as safety issue: No ]
  Incidence of treated biopsy proven acute rejection (BPAR)
• Treated BPAR (score > 3) [ Time Frame: 3 months and 6 months after transplantation ] [ Designated as safety issue: No ]
  Incidence of treated BPAR (score > 3)
• BPAR (score > 3) [ Time Frame: 3 months and 6 months after transplantation ] [ Designated as safety issue: No ]
  Incidence of BPAR (score > 3)
• Death or graft loss [ Time Frame: 6 months after transplantation ] [ Designated as safety issue: No ]
  Incidence of death or graft loss
• Change from baseline in renal function [ Time Frame: 3 months and 6 months after transplantation ] [ Designated as safety issue: No ]
  change in renal function parameters (creatininemia, eGFR, estimated creatinine clearance, proteinuria, microalbuminuria and proteninuria/microalbuminuria ratio)
• Assessment of safety [ Time Frame: 3 months and 6 months post-transplantation ] [ Designated as safety issue: Yes ]
  Incidence of Adverse Events (AEs), Serious Adverse Events (SAEs). Incidence of premature study and study treatment discontinuations and discontinuation reasons.

• Treatment failures (biopsy proven acute rejection BPAR, graft loss or death) [ Time Frame: randomization to 6 months after transplantation ] [ Designated as safety issue: No ]
  Incidence of treated biopsy proven acute rejection BPAR (score > 3), graft loss or death
• BPAR [ Time Frame: 3 months and 6 months after transplantation ] [ Designated as safety issue: No ]
  Incidence of BPAR
• Treated BPAR [ Time Frame: 3 months and 6 months after transplantation ] [ Designated as safety issue: No ]
  Incidence of treated BPAR
• Treated BPAR (score > 3) [ Time Frame: 3 months and 6 months after transplantation ] [ Designated as safety issue: No ]
  Incidence of treated BPAR (score > 3)
• BPAR (score > 3) [ Time Frame: 3 months and 6 months after transplantation ] [ Designated as safety issue: No ]
  Incidence of BPAR (score > 3)
• Death or graft loss [ Time Frame: 6 months after transplantation ] [ Designated as safety issue: No ]
  Incidence of death or graft loss
• Change from baseline in renal function [ Time Frame: 3 months and 6 months after transplantation ] [ Designated as safety issue: No ]
  change in renal function parameters (creatininemia, eGFR, estimated creatinine clearance, proteinuria, microalbuminuria and proteninuria/microalbuminuria ratio)
• Assessment of safety [ Time Frame: 3 months and 6 months post-transplantation ] [ Designated as safety issue: Yes ]
  Incidence of Adverse Events (AEs), Serious Adverse Events (SAEs). Incidence of premature study and study treatment discontinuations and discontinuation reasons.

The aims of the study are to evaluate the safety and efficacy of early introduction one month post-transplantation of everolimus associated to EC-MPS with tacrolimus discontinuation in de novo liver transplant recipients and to evaluate if it leads to a better renal function 6 month post-transplantation compared to standard treatment associating tacrolimus and EC-MPS.

The renal function is estimated by glomerular filtration rate.

• Drug: tacrolimus
  Arm 1 : tacrolimus (C0 6-10 ng/ml) from D5 post-transplantation to month 6 post-transplantation. Arm 2 : tacolimus (C0 6-10 ng/ml) from D5 post-transplantation to 16 weeks post-transplantation at the latest.
  Other Name: Prograf®
• Drug: everolimus
  Arm 1: no everolimus Arm 2: everolimus (C0 6-10 ng/ml) from randomization to month 6 post-transplantation
  Other Name: Certican® / RAD001

• Active Comparator: Control group (Arm 1)
  From transplantation to randomization: Simulect® (40mg) at D0 and D4 + Prograf® (C0 6-10 ng/ml) from D5 + Myfortic® 1440 mg/d ± steroids From randomization to month 6 : Prograf® (C0 6-10 ng/ml) + Myfortic® 1440 mg/d ± steroids
  Intervention: Drug: tacrolimus
• Experimental: Everolimus (Arm 2)
  From transplantation to randomization: Simulect® (40mg) at D0 and D4 + Prograf® (C0 6-10 ng/ml) from D5 + Myfortic® 1440 mg/d ± steroids From randomization to month 6 : Certican® (C0 6-10 ng/ml) + Myfortic® 1440 mg/d ± steroids
  Interventions:

  • Drug: tacrolimus
  • Drug: everolimus

Inclusion Criteria:

• Man or woman aged 18 years or greater, recipient of a primary liver transplant from a deceased donor with whole or split liver

Exclusion Criteria:

• Patient recipient of multiple solid organ or islet cell tissue transplants, or have previously received an organ or tissue transplant
• Recipient of a liver from a living donor or cadaveric non heart beating donor
• ABO incompatible transplant graft
• Transplantation following autoimmune liver hepatitis, primitive sclerosing cholangitis or primitive biliary cirrhosis
• Estimated glomerular filtration rate ≤ 30ml/min at selection
• History of malignancy within the 5 past years, other than non-metastatic basal or squamous cell carcinoma and hepatocellular carcinoma
• Alpha-foeto-protein > 1000 ng/ml Other protocol-defined inclusion/exclusion criteria may apply