Everolimus Post Orthotopic Liver Transplant

NCT ID: NCT01998789

Last Updated: 2017-08-10

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 50 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-10-31
• Study Completion Date: 2019-02-28

Brief Summary

The purpose of this study is to evaluate the efficacy of an everolimus conversion (EVR) protocol as compared to the standard tacrolimus (TAC) based protocol in liver transplant recipients, as determined by renal function, rejection rates, and progression to fibrosis (in HCV positive subjects). Additionally, safety profile and tolerability of these regimens will be assessed.

Detailed Description

The mainstay of maintenance immunosuppression post-transplantation includes a calcineurin inhibitor, either cyclosporine or tacrolimus. The introduction of calcineurin inhibitors led to a significant improvement in graft and patient outcomes post solid organ transplantation. However, one of the severe limitations of this class of drugs, is its associated nephrotoxicity. Data from the Scientific Registry of Transplant Recipients reveal that the incidence of stage 4 chronic kidney disease or stage 5 Chronic Kidney Disease (CKD) after Orthotopic Liver Transplantation (OLT) at 1, 3, and 5 years is 8%, 14%, and 18%, respectively, increasing to approximately 25% by 10 years after transplantation.Furthermore, renal dysfunction is associated with a four-fold increase in patient mortality post solid organ transplantation.

Several calcineurin inhibitor sparing and minimizing regimens have been studied. Most recently, in the phase III, randomized study in de novo liver transplant recipients,demonstrated significantly improved renal function in the tacrolimus minimization arm (everolimus plus tacrolimus one year post transplant.In fact superior renal function was achieved with the tacrolimus minimization arm one month after randomization and was maintained to Month 12. With this pilot study, we aim to compare the efficacy of the standard immunosupression post liver transplant with Tacrolimus and Mycophenolic acid (Myfortic)with calcineurin sparing regimen using the combination of everolimus and enteric coated mycophenolic acid, as determined by the estimated Glomerular filtration rate (GFR) at one year post transplant, with acceptable rates of biopsy proven rejection.

Conditions

Orthotopic Liver Transplant

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Everolimus Conversion Arm

Everolimus will be initiated within 24 hours of baseline at a dose of 1 mg po BID (2 mg/day). Therapeutic Drug Monitoring will be performed throughout the study. Tacrolimus should be eliminated when the everolimus target range has been reached. Complete tacrolimus elimination will not occur earlier than 90 days post transplant and no later than 120 days post transplant. Enteric coated mycopenolic acid will be maintained for the duration of the study. Oral corticosteroids may not be eliminated sooner than 180 days post transplantation.

Everolimus doses will be adjusted based on local lab results of everolimus trough levels.

Group Type: EXPERIMENTAL

Everolimus

Intervention Type: DRUG

Everolimus will be initiated within 24 hours of baseline at a dose of 1 mg po BID (2 mg/day).

Standard Tacrolimus Immunosuppresion Arm

Subjects will be maintained on standard maintenance immunosuppression per local protocol, consisting of a tacrolimus plus enteric coated mycophenolic acid. Oral corticosteroids may not be eliminated sooner than 180 days post transplantation.

Tacrolimus doses will be adjusted based on local lab results of tacrolimus trough levels.

Group Type: ACTIVE_COMPARATOR

Standard Tacrolimus

Intervention Type: DRUG

Subjects will be maintained on standard maintenance immunosuppression per local protocol, consisting of a tacrolimus plus enteric coated mycophenolic acid. Oral corticosteroids may not be eliminated sooner than 180 days post transplantation.

Tacrolimus doses will be adjusted based on local lab results of tacrolimus trough levels.

Interventions

Everolimus

Everolimus will be initiated within 24 hours of baseline at a dose of 1 mg po BID (2 mg/day).

Intervention Type: DRUG

Standard Tacrolimus

Subjects will be maintained on standard maintenance immunosuppression per local protocol, consisting of a tacrolimus plus enteric coated mycophenolic acid. Oral corticosteroids may not be eliminated sooner than 180 days post transplantation.

Tacrolimus doses will be adjusted based on local lab results of tacrolimus trough levels.

Intervention Type: DRUG

Other Intervention Names

Zortress; Prograf

Eligibility Criteria

Inclusion Criteria

• Ability and willingness to provide informed consent and adhere to study regimen
• Recipients of primary liver transplant from deceased or living donor
• 18 years of age or greater
• Lab Model For End-Stage Liver Disease (MELD) score ≤ 30
• Abbreviated Modification of Diet in Renal Disease (MDRD) eGFR ≥ 30 mL/min/1.73

Exclusion Criteria

• Recipient of multiple solid or organ transplant, or have previously received and organ transplant
• Women of child-bearing potential unless they are willing to participate in adequate contraception methods as outlined in the study.
• HIV infection (results obtained 6 months prior to screening is acceptable)

Key Exclusion-Baseline/ Randamization

• Severe hypercholesterolemia (> 350 mg/dL) or hypertriglyceridemia (> 500 mg/dL) within 30 days prior to baseline.
• Thrombocytopenia (platelets < 50,000/mm3)
• Absolute neutrophil count of < 1000/mm3 or white blood cell count of < 2000/mm3
• Subjects in a critical care unit requiring life support measures such as mechanical ventilation, dialysis, requirement of vasopressor agents
• Liver allograft is functioning at an unacceptable level as defined by the Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Total Bilirubin levels > 3 times upper limit of normal (ULN) and Alkaline Phosphatase (AlkP) and Gamma-glutamyltransferase (GGT) levels > 5 times ULN
• Diagnosis of autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis
• Hepatocellular carcinoma with evidence of macrovascular invasion on explanted liver or evidence of extrahepatic spread
• Inability to take medications by mouth
• Renal insufficiency, as defined by abbreviated MDRD eGFR < 30 mL/min/1.73m2, or requirement of dialysis, that does not recover prior to baseline
• Episode of acute rejection requiring antibody therapy or more than one steroid treated episode of acute rejection
• Subjects with a confirmed spot urine protein/creatinine ratio that indicates ≥1g/24h of proteinuria.
• Subtherapeutic trough levels of tacrolimus during the week prior to baseline (subject must have at least one tacrolimus level ≥ 8 ng/mL)
• The presence of thrombosis via Doppler ultrasound of the major hepatic arteries, major hepatic veins, portal vein and inferior vena cava.
• Presence of clinically significant wound

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Tomoaki Kato

OTHER

Sponsor Role: lead

Responsible Party

Tomoaki Kato

Chief, Division of Abdominal Organ Transplantation

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Tomoaki Kato, MD

Role: PRINCIPAL_INVESTIGATOR

Columbia University

Locations

Columbia University Medical Center-NYPH

New York, New York, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Theresa Lukose, PharmD

Role: CONTACT

tt2103@columbia.edu

Marcela Laurito, MD

Role: CONTACT

ml3727@cumc.columbia.edu

212-305-3839

Facility Contacts

Tomoaki Kato, M.D

Role: primary

tk2388@columbia.edu

Theresa Lukose, PharmD

Role: backup

tt2103@columbia.edu

Other Identifiers

AAAL1602

Identifier Type: -

Identifier Source: org_study_id