Everolimus Monotherapy as Immunosuppression After Liver Transplant
Everolimus Monotherapy as Immunosuppression After Liver Transplant
Tacrolimus is the standard immunosuppressive drug used to prevent organ rejection post liver
 transplant. One side effect of Tacrolimus is nephrotoxicity. Everolimus does not have the
 nephrotoxicity side effects of Tacrolimus.

 Replacement of Tacrolimus by Everolimus may have a reduced incidence of renal dysfunction in
 liver transplant patients who have near normal kidney function prior to liver
 transplantation. Other investigators have already shown a benefit in terms of renal function
 with introduction of Everolimus with reduced-exposure tacrolimus at 1 month after liver
 transplantation, this benefit has been shown was maintained to 3 years in patients who
 continued Everolimus therapy with comparable efficacy and no late safety concerns.
 Investigators in this trial are proposing to advance this approach further by completely
 eliminating Tacrolimus from patients' immunosuppression protocol. The rationale for this
 approach is based on a unique induction immunosuppression protocol.

 Liver transplant patients receive potent induction immunosuppression in the form of rabbit
 anti thymocyte globulin.

 Investigators believe that in conjunction with this induction regimen, patients can be
 maintained on Everolimus monotherapy without the risk of rejection. By completely eliminating
 Tacrolimus, investigators believe that there may be further benefit in terms of renal
 function. Additionally, Everolimus is known to induce tolerance in transplant recipients.
 Tolerant patients do not require immunosuppression to accept transplant organs.

 The long-term efficacy and safety of Everolimus monotherapy as the maintenance
 immunosuppression in patients receiving rATG induction is unknown.

 Primary Aim: Assess the effect of Everolimus monotherapy versus Tacrolimus monotherapy on
 long term renal function measured by Glomerular Filtration Rate (GFR).
Following enrollment, subjects will be randomized at one month post transplant to Tacrolimus
 (control) or to Everolimus (study) as maintenance immunosuppression.

 After liver transplant, all patients will receive the standard induction regimen and
 Tacrolimus monotherapy.

 INDUCTION:

 Rabbit anti-thymocyte globulin (rATG) 1.5 mg/kg of actual body weight rounded to nearest 25
 mg and capped at 150 mg for up to three doses given IV on post-operative day (POD) 1, 3, and
 5. Some patients may receive only one dose if considered too frail to need all three doses.

 30 minutes prior to infusion, pre-medicate with the following: Daily steroid dose
 Acetaminophen (Tylenol®) 650 mg PO or per nasogastric (NG) x 1 dose Diphenhydramine
 (Benadryl®) 25 mg IV push x 1 dose

 Steroids:

 Methylprednisolone (Solu-Medrol®) 250 mg IV push x 1 dose on POD 1 (given 30 minutes prior to
 rATG) and 125 mg IV push x 1 dose on POD 3.

 Maintenance:

 Tacrolimus (FK / Prograf®) (titrated to a goal trough of 6 - 8 ng/mL).

 RANDOMIZATION:

 On POD 30, patients meeting study criteria will be randomized to either the study arm or
 control arm. Patients randomized to the study arm will be converted to Everolimus (target
 trough levels 4 - 8 ng/mL) + low dose Tacrolimus (target trough levels 3-5 ng/mL) (study
 arm). The control arm will be maintained on the Tacrolimus monotherapy (target trough levels
 6-8 ng/mL).

 At 3 months, patients in the study arm will be gradually weaned off of Tacrolimus over a
 period of one month to remain on Everolimus monotherapy (target trough levels 4-8 ng/mL).
 Patients in the control arm will remain on tacrolimus monotherapy (target trough levels 6-8
 ng/mL).

 Complete blood counts, liver function panels, and drug levels will be monitored as done
 Standard of Care [SOC]:

 initially twice per week for first month, once per week for next two months, once every other
 week for next three weeks, and then once monthly. Ultrasound, endoscopic retrograde
 cholangiopancreatography (ERCP), biopsy as needed by clinical situation as SOC.

 For characterizing operational tolerance in these patients, investigators will use a 13#gene
 set to predict liver transplant tolerance has been identified and validated by others.
Inclusion Criteria:

 -  Liver transplant recipients >= 18 years old

 -  Normal baseline renal dysfunction (GFR > 60 mL/min)

 -  Rabbit anti-thymocyte globulin (rATG) induction (cumulative dose 1.5 - 5 mg/kg)

 -  Indication for transplant: ethanol, hepatitis C, or nonalcoholic steatohepatitis or
 any combination of these

 Exclusion Criteria:

 -  Increased risk of rejection: autoimmune hepatitis, primary biliary cirrhosis, primary
 sclerosing cholangitis, positive crossmatch, retransplantation

 -  Incompletely healed incision or other wound healing issues at time of randomization

 -  Multiple or previous organ transplantation

 -  Severe, uncontrolled hypercholesterolemia (> 9mmol/L) or hypertriglyceridemia (>8.5
 mmol/L) in the 6 months prior to transplantation

 -  Insurance company unwilling to pay for the cost of the everolimus or patient does not
 qualify for the Novartis Patient Assistance Program.

 -  Pregnant women

 -  Unable to provide informed consent