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Everolimus Monotherapy as Immunosuppression After Liver Transplant

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ClinicalTrials.gov Identifier: NCT04063865
Recruitment Status : Recruiting
First Posted : August 21, 2019
Last Update Posted : September 23, 2019
Sponsor:
Information provided by (Responsible Party):
Chandrashekhar Kubal, 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 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).


Condition or disease Intervention/treatment Phase
Kidney Failure Drug: Tacrolimus Drug: Everolimus Phase 3

Detailed Description:

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 104 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Tacrolimus as maintenance immunosuppression
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Protection of Renal Function After Liver Transplant Using Everolimus Monotherapy as the Immunosuppression Regimen
Actual Study Start Date : May 9, 2019
Estimated Primary Completion Date : December 2027
Estimated Study Completion Date : December 2028

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Control Arm
Tacrolimus as maintenance immunosuppression
Drug: Tacrolimus
Tacrolimus (FK / Prograf) titrated to a goal trough of 6 - 8 ng/ml
Other Name: Prograf

Experimental: Study Arm
Everolimus monotherapy maintenance immunosuppression
Drug: Everolimus
Everolimus monotherapy - target trough levels 4 - 8 ng/ml as maintenance immunosuppression
Other Name: Zortress




Primary Outcome Measures :
  1. Long-Term Renal Function with Tacrolimus monotherapy [ Time Frame: 36 Months ]
    Glomerular Filtration Rate

  2. Long-Term Renal Function with Everolimus monotherapy [ Time Frame: 36 Months ]
    Glomerular Filtration Rate



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04063865


Contacts
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Contact: Chandrashekhar Kubal, MD 317-944-0821 sakubal@iupui.edu
Contact: Benjamin Maccaby 317-278-3769 bmaccaby@indiana.edu

Locations
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United States, Indiana
IU Health University Hospital Recruiting
Indianapolis, Indiana, United States, 46202
Sponsors and Collaborators
Indiana University
Investigators
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Principal Investigator: Chandrashekhar Kubal, MD Indiana University

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Responsible Party: Chandrashekhar Kubal, Princial Investigator, Indiana University
ClinicalTrials.gov Identifier: NCT04063865     History of Changes
Other Study ID Numbers: 1807401376
First Posted: August 21, 2019    Key Record Dates
Last Update Posted: September 23, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Renal Insufficiency
Kidney Diseases
Urologic Diseases
Sirolimus
Everolimus
Tacrolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents