Efficacy and Safety of Concentration-controlled Everolimus to Eliminate or to Reduce Tacrolimus Compared to Tacrolimus in de Novo Liver Transplant Recipients

A 24 Month, Multicenter, Open-label, Randomized, Controlled Study to Evaluate the Efficacy and Safety of Concentration-controlled Everolimus to Eliminate or to Reduce Tacrolimus Compared to Tacrolimus in de Novo Liver Transplant Recipients

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.

This 24-month study consisted of a screening period, a baseline period (3 to 7 days post-transplantation) followed by a run-in period that ended on the day of randomization at 30 days (± 5 days) post-transplantation. Patients were screened for eligibility prior to liver transplantation. Patients who had undergone successful liver transplantation were initiated on a tacrolimus-based regimen that included corticosteroids and entered the baseline period (between 3 and 7 days post-transplantation). At 30 (± 5) days post-transplantation, patients who met additional randomization inclusion/exclusion criteria were randomized into the study.

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.