Everolimus + Very Low Tacrolimus vs Enteric-coated Mycophenolate Sodium + Low Tacrolimus in de Novo Renal Transplant
Condition: Transplantation Infection; Cytomegalovirus Infections
MeSH terms: Infections; Communicable Diseases; Cytomegalovirus Infections
Study type: Interventional
Phase: Phase 4

Summary: 
      This is a 12-month single center, randomized, open-label, single center study designed to
      compare the safety and efficacy of everolimus and very low dose tacrolimus versus
      enteric-coated sodium mycophenolate and low tacrolimus exposure in de novo kidney transplant
      recipients.

      The purpose of this study is to compare safety and efficacy of two immunosuppressive regimens
      based on low tacrolimus exposure combined to everolimus or to enteric-coated mycophenolate
      sodium (EC-MPS) in de novo kidney transplant recipients.
    

Detailed description: 
      The study will consist of two periods: an initial period of 3 months during which all
      patients in both groups will be monitored in accordance with the same variation of C-0h
      tacrolimus and a second study period of 9 months (from month 4 to month 12) in which patients
      will be monitored according to two different targets of C-0h tacrolimus.

      At the screening visit and before any assessment related to the study, patients must give
      their informed consent in writing.

      All patients will receive induction with rabbit Thymoglobulin (r-ATG) in four doses of 1.5
      mg/kg (maximum total dose of 6 mg/kg), administered according to center local practice.

      The evaluations of baseline visit occur within 24 hours after transplantation and prior to
      the first dose of study drug.

      Randomization will be performed within 24 hours after transplantation and after the baseline
      visit assessments. Patients will be randomized in a 1:1 ratio to one of two groups
      (everolimus with very low dose of tacrolimus versus sodium mycophenolate with low dose of
      tacrolimus).

      Approximately 120 patients who meet the inclusion criteria will receive their first dose
      everolimus (initial dose of 1 mg twice a day) or sodium mycophenolate (initial dose of 720 mg
      twice a day) not more than 24 hours after transplantation. Everolimus trough blood levels
      will be measured at pre-specified timepoints in order to ensure that trough levels are above
      3 ng/ml and below 8 ng/ml for the duration of the study.

      Tacrolimus will be started within 48 hours after graft reperfusion at an initial dose of 0.1
      mg/kg/day. The dose of tacrolimus will be adjusted to target the C-0h value within the
      pre-established desired range.

      In the everolimus group with very low dose of tacrolimus, tacrolimus dose should be reduced
      at the end of months three after transplantation. Patients with either acute rejection grade
      ≥ Banff IIB or more than one treated acute rejection since entering the study and patients
      with either acute rejection during the third month will not have the dose of tacrolimus
      reduced; however, they will be encouraged to remain in the study. These patients will be
      excluded from the per protocol population analysis, but will be analyzed in the Intention To
      Treat population.

      If patients present delayed graft function (DGF), the start of tacrolimus can be postponed
      for up to and including 7 days.

      During the 12 months treatment period, patient visits will occur at the selection visit,
      baseline visit, at 1, 2, 4 and 8 weeks and at 3, 6 and 12 months. Day 1 is the day of the
      first administration of everolimus or sodium mycophenolate.

      Population: Study population will consist of a group of male or female transplant recipients
      18-75 years of age undergoing primary renal transplantation and who received an organ from a
      living or deceased donor.
    

Intervention name(s): Everolimus; Very Low Tacrolimus; Low Tacrolimus; Steroids; Thymoglobulin; Sodium Mycophenolate
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Everolimus: initial dose of 1 mg twice a day starting at Day 1. Dose will be adjusted to keep everolimus trough levels between 3 and 8 ng/mL.; Tacrolimus: initial dose of 0.05 mg/kg twice a day starting at Day 1. Dose will be adjusted to keep tacrolimus trough levels between 4 and 7 ng/mL during the first 3 months and 2 and 4 ng/mL thereafter.; Tacrolimus: initial dose of 0.05 mg/kg twice a day starting at Day 1. Dose will be adjusted to keep tacrolimus trough levels between 4 and 7 ng/mL.; Corticoids: endovenous Methylprednisolone will be administered 30-60 minutes before the first 3 doses of r-ATG: 250 mg (D0) and 125 mg (D2 and D4); Prednisone, 10 mg per oral, will be administered before the last dose of r-ATG (D6). Maintenance with Prednisone at post-transplant period will be performed in accordance with center local practice, i.e., only in patients with chronic previous use of corticosteroids, as well as in patients with autoimmune disease (systemic lupus erythematous, rheumatoid arthritis, etc).; All patients will receive induction with rabbit Thymoglobulin (r-ATG) in four doses of 1.5 mg/kg (maximum total dose of 6 mg/kg), administered according to center local practice (before graft revascularization and at days 2, 4, and 6 post-transplant).; Sodium Mycophenolate: initial dose of 720 mg twice a day starting at Day 1.
Other intervention name(s): Certican, Zortress; Very low Prograf; Low Prograf; Prednisone; Methylprednisolone; ATG; rabbit Thymoglobulin (r-ATG); Myfortic
Intervention MeSH terms: Mycophenolic Acid; Prednisone; Methylprednisolone; Everolimus; Tacrolimus; Thymoglobulin; Antilymphocyte Serum
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Everolimus; Tacrolimus; Sodium Mycophenolate; CMV; Graft function; Acute rejection