Conversion to Everolimus From Calcineurin Inhibitor With Mycophenolic Acid: Impact on Long Term Renal Function in Liver Transplantation.

Given the increasing proportion of patients having renal failure at the time of transplant,
with the nephrotoxic effect of calcineurin inhibitor based immunosuppression associated with
its long term negative survival impact, this study proposes to examine the renal sparing
impact of conversion to everolimus from a calcineurin inhibitor based immunosuppressive
protocol at 3 months post liver transplant. The 3 month time point was chosen to allow for
the switch to everolimus to occur at a period of stable post transplant liver function when
both technical and rejection risks are lower. The 3 month cut off was also chosen because of
data indicating that worsening renal function at 4 weeks, 3 months and 1 year post transplant
is an independent risk factor for the development of chronic renal failure and end stage
renal disease after orthotopic liver transplantation. 24 patients will be randomized into 2
arms:

Arm A: Conversion to Everolimus immunosuppression combined with mycophenolic acid (Myfortic:
MPA), and complete discontinuation of Calcineurin inhibitor at 3 months post transplant.

Arm B: Continuation with standard immunosuppressive therapy consisting of Calcineurin
inhibitor associated with mycophenolic acid (Myfortic: MPA).

Follow up: 2 years.

Inclusion Criteria:

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

- Primary deceased donor liver transplant recipients 18-70 years of age

- Functioning allograft at randomization (AST, ALT, Total Bilirubin levels ≤3 times ULN,
and AlkP and GGT levels ≤ 5 times ULN). Elevated GGT alone, in combination with AST,
ALT, total bilirubin and AlkP within defined range does not exclude patients from
randomization.

- Recipients on an immunosuppressive regimen of corticosteroids and tacrolimus.

- Confirmed recipient HCV status at Screening (either by serology or PCR).

- Abbreviated MDRD eGFR ≥ 30 mL/min/1.73m2. Local and central serum creatinine results
within 5 days prior to randomization, however no sooner than Day 25
post-transplantation.

- Verification of at least one tacrolimus trough level of ≥ 8 ng/mL one week prior to
randomization. Target trough levels above 8 ng/mL prior to randomization.

- Patients able to take oral medication at time of randomization.

Exclusion Criteria:

- Recipients of multiple solid organ or islet cell tissue transplants, or have
previously received an organ or tissue transplant. Combined liver kidney transplant
recipients.

- Living donor or split liver recipients.

- History of malignancy of any organ system within 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 that does not fulfill Milan criteria (1 nodule ≤ 5 cm, 2-3
nodules all < 3 cm, per explant histology of recipient liver.

- Use of antibody induction therapy.

- Patients with known hypersensitivity to the drugs used on study or their class, or to
any of the excipients.

- Recipients of ABO incompatible transplant grafts.

- Recipients of Hepatitis B surface antigen or HIV donor organs.

- Surgical or medical condition, which might significantly alter absorption,
distribution, metabolism and excretion of study drug.

- Women of child-bearing potential (WOCBP): all women physiologically capable of
becoming pregnant, including women whose career, lifestyle, or sexual orientation
precludes intercourse with a male partner and women whose partners have been
sterilized by vasectomy or other means, UNLESS (1) they meet the following definition
of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of
spontaneous amenorrhea with serum FSH levels >40 mIU/m, or (2) have past 6 weeks from
surgical bilateral oophorectomy with or without hysterectomy or (3) are using one or
more of the following methods of contraception: surgical sterilization (e.g.,
bilateral tubal ligation, vasectomy), hormonal contraception (implantable, patch,
oral), copper coated IUD and double-barrier methods ( any double combination of male
or female condom with spermicidal gel, diaphragm, sponge, cervical cap). Periodic
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and
withdrawal are not acceptable methods of contraception. Reliable contraception should
be maintained throughout and for 3 months after study drug discontinuation.

- 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).

Enrollment Exclusion - Randomization

- Severe hypercholesterolemia (>350 mg/dL; >9 mmol/L) or hypertriglyceridemia (>500
mg/dL; >8.5 mmol/L) within 6 months of transplantation. Controlled hyperlipidemia is
acceptable at time of randomization.

- Platelet count < 50,000/mm3 at randomization.

- Absolute neutrophil count < 1,000/mm³ or white blood cell count <2,000/mm³ at
randomization.

- Patients positive for HIV: Negative laboratory results within 6 months before
randomization are acceptable.

- Clinically significant systemic infection requiring IV antibiotics at randomization.
Patients in a critical care setting at randomization requiring life support measures
such as mechanical ventilation, dialysis, or vasopressor agents.

- Patients on renal replacement therapy within 7 days prior to randomization.

- Thrombosis of major hepatic arteries, major hepatic veins, portal vein and inferior
vena cava. Results obtained within 5 days prior to randomization are acceptable,
however no sooner than Day 25 post-transplantation.

- Acute rejection requiring antibody therapy or more than one steroid sensitive episode
of acute rejection during the run-in period. Includes patients who have not completed
steroid treatment for acute rejection within 7 days prior to randomization.