Everolimus Post Orthotopic Liver Transplant

The mainstay of maintenance immunosuppression post-transplantation includes a calcineurin
inhibitor, either cyclosporine or tacrolimus. The introduction of calcineurin inhibitors led
to a significant improvement in graft and patient outcomes post solid organ transplantation.
However, one of the severe limitations of this class of drugs, is its associated
nephrotoxicity. Data from the Scientific Registry of Transplant Recipients reveal that the
incidence of stage 4 chronic kidney disease or stage 5 Chronic Kidney Disease (CKD) after
Orthotopic Liver Transplantation (OLT) at 1, 3, and 5 years is 8%, 14%, and 18%,
respectively, increasing to approximately 25% by 10 years after transplantation.Furthermore,
renal dysfunction is associated with a four-fold increase in patient mortality post solid
organ transplantation.

Several calcineurin inhibitor sparing and minimizing regimens have been studied. Most
recently, in the phase III, randomized study in de novo liver transplant
recipients,demonstrated significantly improved renal function in the tacrolimus minimization
arm (everolimus plus tacrolimus one year post transplant.In fact superior renal function was
achieved with the tacrolimus minimization arm one month after randomization and was
maintained to Month 12. With this pilot study, we aim to compare the efficacy of the standard
immunosupression post liver transplant with Tacrolimus and Mycophenolic acid (Myfortic)with
calcineurin sparing regimen using the combination of everolimus and enteric coated
mycophenolic acid, as determined by the estimated Glomerular filtration rate (GFR) at one
year post transplant, with acceptable rates of biopsy proven rejection.

Inclusion Criteria:

- Ability and willingness to provide informed consent and adhere to study regimen

- Recipients of primary liver transplant from deceased or living donor

- 18 years of age or greater

- Lab Model For End-Stage Liver Disease (MELD) score ≤ 30

- Abbreviated Modification of Diet in Renal Disease (MDRD) eGFR ≥ 30 mL/min/1.73

Key Exclusion Criteria:

- Recipient of multiple solid or organ transplant, or have previously received and organ
transplant

- Women of child-bearing potential unless they are willing to participate in adequate
contraception methods as outlined in the study.

- HIV infection (results obtained 6 months prior to screening is acceptable)

Key Exclusion-Baseline/ Randamization

- Severe hypercholesterolemia (> 350 mg/dL) or hypertriglyceridemia (> 500 mg/dL) within
30 days prior to baseline.

- Thrombocytopenia (platelets < 50,000/mm3)

- Absolute neutrophil count of < 1000/mm3 or white blood cell count of < 2000/mm3

- Subjects in a critical care unit requiring life support measures such as mechanical
ventilation, dialysis, requirement of vasopressor agents

- Liver allograft is functioning at an unacceptable level as defined by the Aspartate
Aminotransferase (AST), Alanine Aminotransferase (ALT), Total Bilirubin levels > 3
times upper limit of normal (ULN) and Alkaline Phosphatase (AlkP) and
Gamma-glutamyltransferase (GGT) levels > 5 times ULN

- Diagnosis of autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing
cholangitis

- Hepatocellular carcinoma with evidence of macrovascular invasion on explanted liver or
evidence of extrahepatic spread

- Inability to take medications by mouth

- Renal insufficiency, as defined by abbreviated MDRD eGFR < 30 mL/min/1.73m2, or
requirement of dialysis, that does not recover prior to baseline

- Episode of acute rejection requiring antibody therapy or more than one steroid treated
episode of acute rejection

- Subjects with a confirmed spot urine protein/creatinine ratio that indicates ≥1g/24h
of proteinuria.

- Subtherapeutic trough levels of tacrolimus during the week prior to baseline (subject
must have at least one tacrolimus level ≥ 8 ng/mL)

- The presence of thrombosis via Doppler ultrasound of the major hepatic arteries, major
hepatic veins, portal vein and inferior vena cava.

- Presence of clinically significant wound