Everolimus Monotherapy as Immunosuppression After Liver Transplant

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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Protection of Renal Function After Liver Transplant Using Everolimus Monotherapy as the Immunosuppression Regimen

Conditions
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Kidney Failure

Intervention / Treatment
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* Drug: Tacrolimus
* Drug: Everolimus


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Tacrolimus as maintenance immunosuppression
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control Arm<br>Tacrolimus as maintenance immunosuppression | Drug: Tacrolimus<br>* Tacrolimus (FK / Prograf) titrated to a goal trough of 6 - 8 ng/ml<br>* Other names: Prograf;|
| Experimental: Study Arm<br>Everolimus monotherapy maintenance immunosuppression | Drug: Everolimus<br>* Everolimus monotherapy - target trough levels 4 - 8 ng/ml as maintenance immunosuppression<br>* Other names: Zortress;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Long-Term Renal Function With Tacrolimus Monotherapy | Glomerular Filtration Rate | 36 months post-transplant | 
| Long-Term Renal Function With Everolimus Monotherapy | Glomerular Filtration Rate | 36 months post-transplant |