This is a study to determine the safety, efficacy, and tolerability of taking away the anti-rejection medicine, tacrolimus, in liver transplant recipients in conjunction with everolimus monotherapy to preserve renal function. Two hundred - seventy (270) subjects will be randomized 2:1 into one of two groups between 2-3 months post-transplant. Seventy participants will be placed into an observational group and will remain on their current post-transplant medications. The duration of the study from time of enrollment is 18-20 months.
Subject and/or legal guardian must be able to understand and provide informed consent
Adult (age greater than or equal to 18 years of age at time of informed consent) recipient of first liver transplant alone (de novo)
Estimated glomerular filtration rate >=30 ml/min/1.73m² at enrollment using the CKD-EPI 2021 equation
Treatment with tacrolimus therapy, with or without mycophenolic acid derivatives and/or corticosteroids
Inability or unwillingness of a participant to give written informed consent or comply with study protocol
Active unresolved systemic viral, bacterial, fungal, or parasitic infection requiring oral or intravenous anti-infective therapy
History of autoimmune liver disease including autoimmune hepatitis, primary sclerosing cholangitis, and/or primary biliary cirrhosis, or other contraindications to drug withdrawal
History of non-hepatic autoimmune disease requiring current or future systemic immunosuppressive therapy other than per study protocol
Parallel
Everolimus
Drug* The first step is the addition of everolimus to participants in this group pre-randomization. * Participants on a mycophenolate compound will stop taking it within 7 days of initiating everolimus, either by immediate discontinuation or a 7-day taper. * Participants taking prednisone will taper off prednisone by 6 months post-transplant. * The second step is tacrolimus minimization and withdrawal to everolimus monotherapy in this group after randomization.
Tacrolimus (continued reduction)
Drug* Participants randomized in this cohort will have their tacrolimus dose reduced by 50% following randomization. * They will maintain this daily dose for 4 weeks/1 month (28-30 days). Tacrolimus withdrawal will occur in intervals of 30 days or 4 weeks. * Each subsequent reduction will be based on LFT stability over the prior time interval before the next reduction
Tacrolimus (maintain 50% reduction)
Drug\- Participants randomized in this cohort maintain initial reduced dose of Tacrolimus and everolimus for study duration.
Everolimus
Drug* The first step is the addition of everolimus to participants in the interventional group pre-randomization. * Participants on a mycophenolate compound will stop taking it within 7 days of initiating everolimus, either by immediate discontinuation or a 7-day taper. * Participants taking prednisone will taper off prednisone by 6 months post-transplant. * The second step is to continue on the reduced tacrolimus and everolimus regimen.
Percent change in estimated glomerular filtration rate (eGFR) by CKD-EPI 2021 equation. Between Cohorts INT-1 and INT-2
Proportion of subjects with treated Biopsy Proven Acute Rejection (tBPAR) per local pathology. Between cohorts INT-1 and INT-2
Percent change in estimated Glomerular Filtration Rate (eGFR)
Percentage of subjects with treated Biopsy Proven Acute Rejection (tBPAR)
Changes in liver graft function: Total bilirubin
Changes in liver graft function: Direct bilirubin
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