Safety and Efficacy of Basiliximab, Delayed Dose Tacrolimus Plus ECMPA (Enteric Coated Mycophenolic Acid) Following Liver Transplantation

Study Overview
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Brief Summary
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This is an investigator initiated study at the University of California, Los Angeles (UCLA) funded by Novartis looking at using a combination of immunosuppressive drugs in liver transplant patients that are at risk of developing kidney problems. Kidney problems following liver transplants is the most problematic issue facing liver transplant patients today. This study will generate information in this area of high unmet medical need utilizing basiliximab and Myfortic and using a reduced dose of tacrolimus, one of the current standard of care medications, after kidney function has normalized.

Detailed Description
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Since basiliximab works on the same receptor system as tacrolimus and has not been shown to cause significant adverse effects, such as nephrotoxicity or the cytokine release syndrome, the investigators are proposing induction therapy with basiliximab in liver transplant patients with concomitant preoperative renal dysfunction. This will combat acute rejection and allow the delay of tacrolimus therapy until post-operative day #7. The delay in tacrolimus therapy should allow renal function to improve and reduce the chance of continued renal dysfunction. Also, the addition of basiliximab to the immunosuppressive regimen should allow for a reduction in tacrolimus dose (normal tacrolimus concentrations at UCLA are 7-10ng/mL. Our goal will be 3-5ng/mL) in the immediate post-transplant period thereby reducing the chance of acute and long-term efficacy-limiting adverse effects associated with the tacrolimus while maintaining adequate immunosuppression to reduce acute rejection episodes. This would be the most convincing prospective randomized study utilizing basiliximab as a renal sparing agent in liver transplantation. Objectives Primary objectives • To evaluate renal recovery/ function following OLT in patients undergoing orthotopic liver transplant at 6 and 12 months post-transplant. Secondary objectives (comparing the two treatment arms) To determine the tolerability and adverse event profile during the first year post-transplant. To determine incidence and severity acute rejection episodes To determine the incidence of death and/or graft failure within the first year post-transplant Study design The study is a single center prospective randomized trial wherein the investigators will have two groups. Patients will be screened and eligible patients will be enrolled pre-transplant. Patients will then be randomized at time of transplant to either the control or treatment arm. Post transplant laboratory data (chemistry, tacrolimus level and liver function tests) will be collected on a daily basis. For the duration of the patients' hospital stay (average 2-3 weeks). This will provide the early data set for early post operative results. Patients will subsequently be followed on a weekly outpatient basis upon discharge as per protocol. During these visits, laboratory data (chemistry, tacrolimus level and liver function tests) are also collected and will provide the continued flow of data for our follow up analysis. Any evidence of rejection will prompt treatment with rescue therapy and if necessary disenrollment from the study.

Official Title
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Safety and Efficacy of Basiliximab, Delayed Dose Tacrolimus Plus ECMPA, Versus Standard Dose Tacrolimus, ECMPA Plus Corticosteroids in Patients Undergoing Liver Transplant

Conditions
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Liver Transplantation

Intervention / Treatment
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* Drug: Basiliximab
* Drug: Tacrolimus
* Drug: Tacrolimus
* Drug: Mycophenolic Acid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients eligible for inclusion in this study have to fulfill all of the following criteria: >18 years old Undergoing first or second OLT MELD (model for end-stage liver disease) score >25 Serum creatinine > 1.5 or ongoing hemodialysis for less than 4 weeks at the time of transplant Able and agreeable to conform to requirements of the study Patients or proxy must give written informed consent before any assessment is performed. Exclusion Criteria: <18 years old Serum creatinine <1.5 MELD Score < 25 Ongoing hemodialysis for 4 or more weeks (those patients become eligible for renal transplants at that point per UCLA practice). Receiving OKT3 (Muromonab-CD3), ATG (Antithymocyte Globulin), or IVIG (Intravenous Immunoglobulin Therapy) therapy around time of transplant Participating in another clinical research study involving the evaluation of another investigational drug or device Prior documented allergy to any of the study medications Active Fungal infection

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Basiliximab<br>Tacrolimus with Basiliximab induction | Drug: Basiliximab<br>* Peri-operative 40 mg IV dose within 4 hours of OLT Postoperative 20mg IV dose Day 4<br>* Other names: Simulect;Drug: Tacrolimus<br>* Day #7 post-transplant or when serum creatinine (SCr) < 1.8 mg/dl 6 months to 1 year: 0.03-0.1 mg.kg q12h po to maintain whole blood trough concentration of 3-5ng/mL<br>* Other names: Prograf;Drug: Mycophenolic Acid<br>* Enteric coated mycophenolic acid 360-720 mg po bid<br>* Other names: Mycophenolate sodium;|
| Active Comparator: Tacrolimus Group<br>Tacrolimus (without basiliximab induction); standard of care group | Drug: Tacrolimus<br>* Day #1 post-transplant to 6 months: 0.03-0.1mg/kg q12h po to maintain whole blood trough concentration of 7-10 ng/mL + 6 months to 1 year: maintain whole blood trough concentration of 5-8ng/mL<br>* Other names: Prograf;Drug: Mycophenolic Acid<br>* Enteric coated mycophenolic acid 360-720 mg po bid<br>* Other names: Mycophenolate sodium;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal Recovery/ Function | Number of participants who experienced dialysis independence or improvement based upon kidney function labs as a measure of renal recovery/ function following OLT in patients after undergoing orthotopic liver transplant | 12 months post-transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Simulect, Myfortic, Orthotopic liver transplantation (OLT), Renal Dysfunction