efficacy and safety of concentration-controlled everolimus to eliminate or to reduce tacrolimus compared to tacrolimus in de novo liver transplant recipients

Conditions: Liver Transplantation

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.

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.

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.

Keywords: liver transplantation everolimus calcineurin inhibitors tacrolimus renal function mdrd formula progression of fibrosis