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

Phase 3

Terminated

Conditions: Kidney Failure

Interventions: Drug: Tacrolimus
Drug: Everolimus

Registration Number: NCT04258423

Lead Sponsor: Indiana University

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 4

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Control Arm	Tacrolimus	Tacrolimus as maintenance immunosuppression
Study Arm	Everolimus	Everolimus as maintenance immunosuppression

Primary Outcome Measures

Name	Time	Method
Glomerular Filtration Rate in Patients Treated With Tacrolimus	36 months post-transplant	Glomerular Filtration Rate
Glomerular Filtration Rate in Patients Treated With Everolimus	36 months post-transplant	Glomerular Filtration Rate
Number of Patients Who Experience Transplant Rejection	36 months post-transplant	Biopsy