Clinical trial NCT01998789: Everolimus Post Orthotopic Liver Transplant
Official title: A Single Center, Open-label, Randomized, Controlled Pilot Trial to Evaluate the Efficacy and Safety of Everolimus Conversion Versus Standard Immunosuppression in Liver Transplant Recipients
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Orthotopic Liver Transplant
Keywords: Liver Transplantation
Everolimus
Immunosuppression
Lead sponsor: Columbia University
Sponsor class: OTHER
First posted: 2013-12-02
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Key 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

Primary outcomes:
measure: Change in estimated Glomerular Filtration Rate (eGFR)
timeFrame: Baseline and 12 months post transplant
Secondary outcomes:
measure: Change in estimated Glomerular Filtration Rate (eGFR)
timeFrame: Baseline and 24 months post liver transplantation
measure: Proportion of HCV patients who develop stage 2 of 4 or greater fibrosis, liver failure, or fibrosing cholestatic hepatitis (FCH) at month 12 and 24
timeFrame: Up to 24 months post liver transplantation
measure: Composite Efficacy Failure Rate
timeFrame: Up to 24 months
measure: Incidence of Hepatocellular Carcinoma (HCC) Recurrence
timeFrame: Up to 12 months post transplant
Other outcomes:
Locations:
city: New York
country: United States
facility: Columbia University Medical Center-NYPH
state: New York
Study officials:
affiliation: Columbia University
name: Tomoaki Kato, MD
role: PRINCIPAL_INVESTIGATOR
References: