REnal Function in Liver Transplantation: Everolimus With Calcineurin Inhibitor (CNI)-Sparing sTrategy
Condition: Liver Transplantation
Intervention: Everolimus; Tacrolimus
Intervention description: Commercial product labeled according to local requirements will be provided as 0.25 mg and 0.75 mg tablets for oral administration.; Commercial product labeled according to local requirements will be provided as 0.5 mg, 1.0 mg and 5.0 mg capsules for oral administration.
Intervention MeSH terms: Everolimus; Tacrolimus
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 78.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Liver transplantation, everolimus, CNI-minimization, CNI-elimination, renal function

Summary:

      The purpose of this study was, starting from the Italian clinical practice in liver
      transplantation, to optimize the immunosuppressive therapy, considering specific patient
      characteristics as alcoholic cirrhosis, hepatitis C virus (HCV), hepatocellular carcinoma
      (HCC), and short/long-term implications. Then efficacy and safety of a calcineurin inhibitor
      (CNI)-withdrawal regimen was evaluated in comparison with a CNI-minimization regimen.
    

Eligibility criteria:

        Inclusion criteria at Baseline:

          -  Male and female liver transplant recipients who are ≥ 18 years of age, treated with a
             tacrolimus-based immunosuppressive regimen, who have received an induction therapy or
             i.v. steroids as per local clinical practice.

          -  Recipients of a full-size or technically modified liver allograft will be eligible at
             4 weeks (± 7 days) after liver transplantation.

          -  Allograft is functioning at an acceptable level by the time of Baseline as defined by
             the AST, ALT, total bilirubin levels ≤ 3 times ULN and INR < 1.5 times ULN.

          -  Abbreviated MDRD-4 eGFR ≥ 30 mL/min/1.73m2. Serum creatinine results obtained within 5
             days prior to Baseline are acceptable.

        Inclusion criteria at Randomization:

          -  Effective tacrolimus minimization, confirmed by stable blood trough levels in the two
             months prior to randomization, i.e. verification of last two tacrolimus blood trough
             level ≤ 5 ng/mL in the two months prior to randomization. Investigators should make
             adjustments in tacrolimus dosing to continue to target trough levels ≤ 5 ng/mL prior
             to randomization.

          -  Abbreviated MDRD-4 eGFR ≥ 30 mL/min/1.73m2. Serum creatinine results obtained within 5
             days prior to Visit 5 are acceptable.

        Exclusion criteria at Baseline:

          -  Patients who are recipients of multiple solid organ transplants, (e.g., multivisceral
             or combined liver-kidney transplants), or have previously received an organ or tissue
             transplanted, or who received an AB0 incompatible transplant.

          -  Patients who experienced more than one episode of treated biopsy proven acute
             rejection (BANFF ≥ 3 or RAI ≥ 7) or one steroid-resistant acute rejection.

          -  Patients who require renal replacement therapy.

          -  Patients with a confirmed spot urine protein/creatinine ratio that indicates ≥1.0 g/24
             hrs of proteinuria.

          -  History of malignancy of any organ system within the past 5 years whether or not there
             is evidence of local recurrence or metastases, other than non-metastatic basal or
             squamous cell carcinoma of the skin or HCC.

        Exclusion criteria at Randomization:

          -  Patients who experienced more than two episodes of treated biopsy proven acute
             rejection (BANFF ≥ 3 or RAI ≥ 7) since transplantation or one steroid-resistant acute
             rejection during the run-in period.

          -  Patients with a confirmed spot urine protein/creatinine ratio that indicates ≥ 3.0
             g/24 hrs of proteinuria.