Efficacy and Safety of Concentration-controlled Everolimus to Eliminate or to Reduce Tacrolimus Compared to Tacrolimus in de Novo Liver Transplant Recipients
Condition: Liver Transplantation
Intervention: Tacrolimus (reduced tacrolimus); Tacrolimus (tacrolimus elimination); Tacrolimus (tacrolimus control); Everolimus (reduced tacrolimus); Everolimus (tacrolimus elimination); Corticosteroids
Intervention description: After everolimus whole blood trough levels were confirmed to be in the target range of 3-8 ng/mL, tacrolimus tapering began, achieving a target tacrolimus whole blood trough level of 3-5 ng/mL by 3 weeks after randomization, a level which was maintained for the duration of the study.; After everolimus whole blood trough levels were confirmed to be in the target range of 3-8 ng/mL, tacrolimus tapering began, achieving a target tacrolimus whole blood trough level of 3-5 ng/mL by 3 weeks after randomization. Tacrolimus elimination was started beginning at Month 4. Tacrolimus was tapered after everolimus whole blood trough levels were within the target range of 6-10 ng/mL. Tacrolimus was completely eliminated by the end of Month 4.; Tacrolimus trough levels were targeted to be maintained at 8-12 ng/mL until Month 4. At Month 4, tacrolimus whole blood trough levels were decreased to a target trough level of 6-10 ng/mL for the remainder of the study.; Everolimus was started within 24 hours of randomization at a dose of 1.0 mg twice a day (bid, 2 mg daily dose). The dose was adjusted to maintain everolimus trough blood levels between 3-8 ng/mL for the duration of the study.; Everolimus was started within 24 hours of randomization at a dose of 1.0 mg twice a day (bid, 2 mg daily dose). The dose was adjusted to maintain everolimus trough blood levels between 3-8 ng/mL until Month 4; beginning with Month 4, the dose was adjusted to maintain everolimus trough blood levels between 6-10 ng/mL.; For patients in all groups, corticosteroids were initiated at or prior to the time of transplantation according to local practice. Corticosteroids could be used for the duration of the study but could not be eliminated before Month 6.
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: 719.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Liver transplantation; everolimus; calcineurin inhibitors; tacrolimus; renal function; MDRD formula; progression of fibrosis

Summary:

      This trial was designed to address important issues that impact recipients of liver
      allografts as well as clinicians, ie, renal function, reduction or discontinuation of
      tacrolimus early post-transplantation, and progression rate of fibrosis in hepatitis C virus
      (HCV) positive patients.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Ability and willingness to provide written informed consent and adhere to study
             regimen.

          -  Recipients who are 18-70 years of age of a primary liver transplant from a deceased
             donor.

          -  Recipients who have been initiated on an immunosuppressive regimen that contains
             corticosteroids and tacrolimus, 3-7 days post-transplantation.

          -  Confirmed recipient hepatitis C virus (HCV) status at Screening (either by antibody or
             by PCR (polymerase chain reaction).

          -  Allograft is functioning at an acceptable level by the time of randomization as
             defined by protocol specific laboratory values.

          -  Abbreviated Modification of Diet in Renal Disease estimated glomerular filtration rate
             (MDRD eGFR) ≥ 30 mL/min/1.73m2. Results obtained within 5 days prior to randomization
             are acceptable, however, no sooner than Day 25 post-transplantation.

          -  Verification of at least 1 tacrolimus trough level of ≥ 8 ng/mL in the week prior to
             randomization. Investigators should make adjustments in tacrolimus dosing to continue
             to target trough levels above 8 ng/mL prior to randomization.

        Exclusion Criteria

          -  Patients who are recipients of multiple solid organ or islet cell tissue transplants,
             or have previously received an organ or tissue transplant. Patients who have a
             combined liver-kidney transplant.

          -  Recipients of a liver from a living donor, or of a split liver.

          -  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 (hepatocellular carcinoma) (see next
             criteria).

          -  Hepatocellular carcinoma that does not fulfill Milan criteria (1 nodule ≤ 5 cm, 2-3
             nodules all < 3 cm) at the time of transplantation as per explant histology of the
             recipient liver.

          -  Any use of antibody induction therapy.

          -  Patients with a known hypersensitivity to the drugs used on study or their class, or
             to any of the excipients.

          -  Patients who are recipients of ABO incompatible transplant grafts.

          -  Recipients of organs from donors who test positive for Hepatitis B surface antigen or
             HIV are excluded.

          -  Patients who have any surgical or medical condition, which in the opinion of the
             investigator, might significantly alter the absorption, distribution, metabolism and
             excretion of study drug.

          -  Women of child-bearing potential (WOCBP).

          -  Patients with any history of coagulopathy or medical condition requiring long-term
             anticoagulation which would preclude liver biopsy after transplantation. (Low dose
             aspirin treatment or interruption of chronic anticoagulant is allowed).

        Other protocol-defined inclusion/exclusion criteria may apply.