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

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

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

Study Overview

• Status: Terminated
• Conditions: Kidney Failure
• Intervention / Treatment: Drug: Everolimus; Drug: Tacrolimus

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.

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control Arm; Tacrolimus as maintenance immunosuppression	Drug: Tacrolimus; Low dose Tacrolimus; Other Names: Prograf
Experimental: Study Arm; Everolimus as maintenance immunosuppression	Drug: Everolimus; Everolimus; Other Names: Zortress

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Indiana University
• Investigators: Principal Investigator: Chandrashekhar Kubal, MD, Indiana University

Study record dates

Study Major Dates

• Study Start (Actual): December 19, 2019
• Primary Completion (Actual): June 27, 2020
• Study Completion (Actual): June 27, 2020

Study Registration Dates

• First Submitted: January 31, 2020
• First Submitted That Met QC Criteria: February 4, 2020
• First Posted (Actual): February 6, 2020

Study Record Updates

• Last Update Posted (Actual): May 24, 2023
• Last Update Submitted That Met QC Criteria: April 28, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Renal Insufficiency; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protein Kinase Inhibitors; Calcineurin Inhibitors; MTOR Inhibitors; Tacrolimus; Everolimus
• Other Study ID Numbers: 1807596072

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No