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

STATUS

Recruiting
End date

Dec 31, 2029
participants needed

104
sponsor

Indiana University

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Updated on 19 February 2024

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cancer

diabetes

acute renal failure

renal failure

chronic kidney disease

renal function

glomerular filtration rate

hypertension

immunosuppression

liver transplant

mycophenolate

mycophenolic acid

immunosuppressive agents

antithymocyte globulin

tacrolimus

mycophenolate mofetil

proteinuria

chronic disease

everolimus

nephropathy

renal impairment

hepatitis b

renal injury

renal function test

anti-thymocyte globulin

hyperlipidemia

hepatitis c

organ rejection

nephrotoxicity

rabbit atg

renal toxicity

Summary

Show definitions

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

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.

Details

Condition	Renal Failure, Renal Failure, Nephropathy, Nephropathy
Age	18years - 100years
Treatment	Tacrolimus, Everolimus
Clinical Study Identifier	NCT04258423
Sponsor	Indiana University
Last Modified on	19 February 2024

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Eligibility		Yes	No	Not Sure
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

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