Everolimus Plus Mycophenolic Acid for Kidney Preservation in Liver Transplant Recipients With Impaired Kidney Function

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 already have chronic kidney disease or peri-operative acute kidney injury. 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. Additionally, Everolimus is known to induce tolerance in transplant recipients. Tolerant patients do not require immunosuppression to accept transplant organs. Tacrolimus is a widely used in liver transplant recipients for immunosuppression, however it is associated with nephrotoxicity. Everolimus, on the other hand lacks nephrotoxicity. Whether replacement of tacrolimus by Everolimus preserves kidney function in patients with pre-existing chronic kidney disease or acute kidney injury is not well established. Also, the efficacy and safety of reduced-dose Everolimus with or without Mycophenolate Mofetil in prevention of rejection is unknown. Primary Aim Assess the effect of Everolimus with or without Mycophenolate Mofetil versus Tacrolimus plus Mycophenolate Mofetil therapy on renal function measured by Glomerular Filtration Rate (GFR). Secondary Aims Compare the efficacy of Everolimus plus Mycophenolate Mofetil versus Tacrolimus plus Mycophenolate Mofetil therapy as measured by the following: Biopsy-confirmed acute rejection Hyperlipidemia Proteinuria % regulatory T-cells in circulation NODAT [New Onset Diabetes mellitus After Transplant], hypertension and malignancy Tolerance measured by gene profiling at year 1, 2 and 3

Detailed Description
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Following transplant, prior to the one month post transplant visit, subjects will be approached either in the transplant unit in the hospital or at the transplant clinic in the hospital for study participation. Following enrollment, subjects will be randomized at one month post transplant to reduced dose Tacrolimus plus Mycophenolate Mofetil immunosuppression (control group) or to Everolimus plus Mycophenolate Mofetil (study group) 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 NG x 1 dose B - Lay Summary & Research Design 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: Low dose Tacrolimus (FK / Prograf®) (titrated to a goal trough of 6 ± 1 ng/mL) plus Mycophenolate Mofetil 500 mg BID. 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) plus Mycophenolate Mofetil 500 mg BID therapy. The control arm will be maintained on the low dose Tacrolimus plus Mycophenolate Mofetil therapy. At 3 months, patients with GFR <=60 will proceed to reduced dose Everolimus (target trough levels 3-6 ng/mL) plus Mycophenolate Mofetil 500 mg BID therapy. Patients with GFR >60 will proceed to Everolimus monotherapy (target trough levels 4-8 ng/mL). Complete blood counts, liver function panels, and drug levels will be monitored per 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, ERCP, biopsy as needed by clinical situation as SOC.

Official Title
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Preservation of Renal Function After Liver Transplant for Patients With Pre-existing Chronic Kidney Disease or Peri-operative Acute Kidney Injury Using Everolimus Plus Mycophenolate Mofetil 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 Baseline renal dysfunction (GFR ≤ 60 mL/min) Rabbit anti-thymocyte globulin (rATG) induction (cumulative dose 3 - 5 mg/kg) Indication for transplant: ethanol, hepatitis C, or nonalcoholic steatohepatitis 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 mo prior to transplantation Insurance company unwilling to pay for the cost of the everolimus 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, then randomized to Everolimus plus Mycophenolate Mofetil, discontinuing Tacrolimus once Everolimus level within goal range OR randomized to continued maintenance with Tacrolimus plus Mycophenolate Mofetil.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control Arm<br>Tacrolimus as maintenance immunosuppression | Drug: Tacrolimus<br>* Low dose Tacrolimus<br>* Other names: Prograf;|
| Experimental: Study Arm<br>Everolimus as maintenance immunosuppression | Drug: Everolimus<br>* Everolimus<br>* Other names: Zortress;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glomerular Filtration Rate in Patients Treated With Tacrolimus | Glomerular Filtration Rate | 36 months post-transplant | 
| Glomerular Filtration Rate in Patients Treated With Everolimus | Glomerular Filtration Rate | 36 months post-transplant | 
| Number of Patients Who Experience Transplant Rejection | Biopsy | 36 months post-transplant |