Conversion Prograf® to Advagraf® at D7 Versus D90 After Liver Transplantation
Condition: Immunosuppression After Liver Transplantation
Study type: Interventional
Phase: Phase 4

Summary: 
      The best period for the conversion from Prograf (tacrolimus administered twice daily) to
      Advagraf (once-daily prolonged-release tacrolimus) remains unknown. The aim of this
      prospective, randomized, multicenter trial is to prove the non-inferiority of the early
      conversion (at D7) versus the conversion at D90 after liver transplantation. The primary
      objective will be to evaluate the incidence of a first biopsy-proven acute rejection in the 6
      first months, and prove the non-inferiority of the conversion at D7 + / - 3 versus the
      conversion at D90 + / - 5 (reference group). If non-inferiority is proved, the two strategies
      will be compared in terms of superiority. 250 patients will be included. Three ancillary
      studies will be added : a PK study in a subgroup of 40 patients (20 patients per arm), an
      assay of the calcineurin activity on a subgroup of 40 patients, and a medicoeconomic study in
      all patients
    

Detailed description: 
      Rationale :

      Conversion from Prograf (tacrolimus administered twice daily) to Advagraf (once-daily
      prolonged-release tacrolimus) is currently proposed in both stable and de novo liver
      transplant recipients. However, the early conversion (around D7 after transplantation),
      during hospitalization, may be difficult due to the more frequent need of dose adjustments
      under Advagraf than under Prograf, so that there is no consensus on the best period for the
      conversion. The aim of this prospective, randomized, multicenter trial is to prove the
      non-inferiority - in terms of efficacy - of the early conversion (at D7) versus the
      conversion at D90 after liver transplantation.

      Primary objective :

      To evaluate the incidence of biopsy-proven acute rejection in the 6 first months after liver
      transplantation, and prove the non-inferiority of the conversion at D7 + / - 3 versus the
      conversion at D90 + / - 5 (reference group).

      Secondary objectives :

      Compare the two strategies in terms of:

        -  Severity of acute rejection (criteres of Banff 97)

        -  Steroid-resistant acute rejection

        -  Number of dose adjustments to obtain the target trough level after conversion

        -  Patient and graft survival Analyse the PK profile of two subgroups (20 patients in each
           arm) under Advagraf Measure the calcineurin activity in the two groups (in the patients
           selected for the PK analysis) Evaluate tolerance, with a particular focus on the renal
           function at 6 months (glomerular filtration rate using MDRD4) and on adverse events.

      Primary endpoint:

      Percentage of patients with a first episode of biopsy-proven acute rejection.

      Methodology :

      Multicenter (13 French liver transplant centers), randomized (central randomisation), open
      study, of non-inferiority, comparing the efficacy at 6 months of two strategies of conversion
      from Prograf to Advagraf (D7 + / - 3 versus D90 + / - 5), in addition to mycophenolate
      mofetil and steroids, in liver transplant recipients. If non-inferiority is proved, the two
      strategies will be compared in terms of superiority. Inclusion of 250 patients (to analyse at
      least 112 patients in each arm). Calculation of the sample size is based on the following
      data: Incidence of acute rejection at 6 months = 20% in the 2 groups, Non-inferiority margin
      = 15%, alpha risk = 2.5%, power = 80%).

      Treatments :

        -  Prograf introduced at 0,1 - 0,2 mg/kg/day

        -  Mycophenolate mofetil : 1g TD

        -  Steroids according to the current use in each center Trough blood concentration of
           tacrolimus will be 8 - 15 ng/mL during the first 3 months, then 5 à 12 ng/mL thereafter.

      PK study: For the 40 patients included in the PK study (20 patients per arm), the PK profile
      (C0, Cmax and AUC) will be established on 9 points : 0 (before Advagraf administration) then
      at 20min, 40 min, 60 min, 2h, 3h, 4h, 6h, 8h.

        -  7 days after conversion in the first group (early conversion)

        -  14 + / - 5 days after conversion in the other group (conversion at D90) Calcineurin
           activity will be assayed on the blood samples used for the trough concentration
           determination at D5, D7, M1, M3 and M6 and on a baseline sample.

      Medicoeconomic study : The costs induced by liver transplantation will be calculated in all
      the patients included and randomized according to the French recommendations.
    

Intervention name(s): Conversion at day 7 ± 3 Prograf® to Advagraf®; Conversion at day 90±5 Prograf® to Advagraf®
Intervention type(s): Drug; Drug
Intervention description(s): Conversion from Prograf® (tacrolimus administered twice daily) to Advagraf® (once-daily prolonged-release tacrolimus) at day 7±3; Conversion from Prograf® (tacrolimus administered twice daily) to Advagraf® (once-daily prolonged-release tacrolimus) at day 90±5
Intervention MeSH terms: Tacrolimus
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Liver transplantation,; Conversion (Prograf® to Advagraf®),; Prograf® ,; Advagraf® ,; acute rejection,; GFR