Conversion to Everolimus From Calcineurin Inhibitor With Mycophenolic Acid: Impact on Long Term Renal Function in Liver Transplantation.

Study Overview
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Brief Summary
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This study will examine the renal sparing impact of implementing a strategy of conversion to everolimus from a calcineurin inhibitor based immunosuppressive protocol at 3 months post liver transplant

Detailed Description
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Given the increasing proportion of patients having renal failure at the time of transplant, with the nephrotoxic effect of calcineurin inhibitor based immunosuppression associated with its long term negative survival impact, this study proposes to examine the renal sparing impact of conversion to everolimus from a calcineurin inhibitor based immunosuppressive protocol at 3 months post liver transplant. The 3 month time point was chosen to allow for the switch to everolimus to occur at a period of stable post transplant liver function when both technical and rejection risks are lower. The 3 month cut off was also chosen because of data indicating that worsening renal function at 4 weeks, 3 months and 1 year post transplant is an independent risk factor for the development of chronic renal failure and end stage renal disease after orthotopic liver transplantation. 24 patients will be randomized into 2 arms: Arm A: Conversion to Everolimus immunosuppression combined with mycophenolic acid (Myfortic: MPA), and complete discontinuation of Calcineurin inhibitor at 3 months post transplant. Arm B: Continuation with standard immunosuppressive therapy consisting of Calcineurin inhibitor associated with mycophenolic acid (Myfortic: MPA). Follow up: 2 years.

Official Title
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A Randomized Prospective Trial of Conversion to Everolimus Therapy From Calcineurin Inhibitor Based Maintenance Immunosuppression in Association With Mycophenolic Acid in Liver Transplantation: Examination of Impact on Long Term Renal Function.

Conditions
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Immunosuppression, Renal Failure

Intervention / Treatment
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* Drug: Arm A: Everolimus
* Drug: Calcineurin Inhibitor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability and willingness to provide written informed consent and adhere to study regimen. Primary deceased donor liver transplant recipients 18-70 years of age Functioning allograft at randomization (AST, ALT, Total Bilirubin levels ≤3 times ULN, and AlkP and GGT levels ≤ 5 times ULN). Elevated GGT alone, in combination with AST, ALT, total bilirubin and AlkP within defined range does not exclude patients from randomization. Recipients on an immunosuppressive regimen of corticosteroids and tacrolimus. Confirmed recipient HCV status at Screening (either by serology or PCR). Abbreviated MDRD eGFR ≥ 30 mL/min/1.73m2. Local and central serum creatinine results within 5 days prior to randomization, however no sooner than Day 25 post-transplantation. Verification of at least one tacrolimus trough level of ≥ 8 ng/mL one week prior to randomization. Target trough levels above 8 ng/mL prior to randomization. Patients able to take oral medication at time of randomization. Exclusion Criteria: Recipients of multiple solid organ or islet cell tissue transplants, or have previously received an organ or tissue transplant. Combined liver kidney transplant recipients. Living donor or split liver recipients. History of malignancy of any organ system within past 5 years whether or not there is evidence of local recurrence or metastases, other than non-metastatic basal or squamous cell carcinoma of the skin or HCC. Hepatocellular carcinoma that does not fulfill Milan criteria (1 nodule ≤ 5 cm, 2-3 nodules all < 3 cm, per explant histology of recipient liver. Use of antibody induction therapy. Patients with known hypersensitivity to the drugs used on study or their class, or to any of the excipients. Recipients of ABO incompatible transplant grafts. Recipients of Hepatitis B surface antigen or HIV donor organs. Surgical or medical condition, which might significantly alter absorption, distribution, metabolism and excretion of study drug. Women of child-bearing potential (WOCBP): all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS (1) they meet the following definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels >40 mIU/m, or (2) have past 6 weeks from surgical bilateral oophorectomy with or without hysterectomy or (3) are using one or more of the following methods of contraception: surgical sterilization (e.g., bilateral tubal ligation, vasectomy), hormonal contraception (implantable, patch, oral), copper coated IUD and double-barrier methods ( any double combination of male or female condom with spermicidal gel, diaphragm, sponge, cervical cap). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Reliable contraception should be maintained throughout and for 3 months after study drug discontinuation. History of coagulopathy or medical condition requiring long-term anticoagulation which would preclude liver biopsy after transplantation. (Low dose aspirin treatment or interruption of chronic anticoagulant is allowed). Enrollment Exclusion - Randomization Severe hypercholesterolemia (>350 mg/dL; >9 mmol/L) or hypertriglyceridemia (>500 mg/dL; >8.5 mmol/L) within 6 months of transplantation. Controlled hyperlipidemia is acceptable at time of randomization. Platelet count < 50,000/mm3 at randomization. Absolute neutrophil count < 1,000/mm³ or white blood cell count <2,000/mm³ at randomization. Patients positive for HIV: Negative laboratory results within 6 months before randomization are acceptable. Clinically significant systemic infection requiring IV antibiotics at randomization. Patients in a critical care setting at randomization requiring life support measures such as mechanical ventilation, dialysis, or vasopressor agents. Patients on renal replacement therapy within 7 days prior to randomization. Thrombosis of major hepatic arteries, major hepatic veins, portal vein and inferior vena cava. Results obtained within 5 days prior to randomization are acceptable, however no sooner than Day 25 post-transplantation. Acute rejection requiring antibody therapy or more than one steroid sensitive episode of acute rejection during the run-in period. Includes patients who have not completed steroid treatment for acute rejection within 7 days prior to randomization.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Calcineurin Inhibitor with Mycophenolic Acid<br>Calcineurin inhibitor immunosuppression with mycophenolic acid | Drug: Calcineurin Inhibitor<br>* Comparison Arm: Continuation with standard immunosuppressive therapy consisting of Calcineurin inhibitor associated with mycophenolic acid (Myfortic: MPA).<br>* Other names: Mycophenolic Acid (Myfortic);|
| Experimental: Everolimus with Mycophenolic Acid<br>Conversion to Everolimus immunosuppression combined with mycophenolic acid (Myfortic: MPA), and complete discontinuation of Calcineurin inhibitor at 3 months post transplant. | Drug: Arm A: Everolimus<br>* Conversion to Everolimus immunosuppression combined with mycophenolic acid (Myfortic: MPA), and complete discontinuation of Calcineurin inhibitor at 3 months post transplant.<br>* Other names: Zortress; Mycophenolic Acid (Myfortic);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal Function as Measured by 24 Hour Urine Creatinine Clearance | Renal Function was assessed by 24 hr urine collection creatinine clearance measured (mL/min). 24 Hr urine collection was assessed at baseline, 6 months, 1 year, and 2 years post transplant. | 6 months, 1 year, and 2 years | 
| Renal Function as Measured by Serum Creatinine Level | Serum creatinine levels were assessed at 6 months, 1 year, and 2 years post transplant | 6 months, 1 year, and 2 years | 
| Renal Function as Measured by Cockcroft Gault Creatinine Clearance | The Cockcroft-Gault formula for estimating creatinine clearance was determined at 6 months, 1 year, and 2 years post transplant | 6 months, 1 year, and 2 years | 
| Renal Function as Measured by Modification of Diet in Renal Disease (MDRD) Estimated Glomerular Filtration Rate (eGFR) | Modification of Diet in Renal Disease (MDRD) estimated Glomerular Filtration Rate (eGFR) was assessed at 6 months, 1 year, and 2 years post transplant. | 6 months, 1 year, and 2 years | 
| Renal Function as Measured by Iothalamate Clearance | Iothalamate Clearance was assessed at 6 months, 1 year, and 2 years post transplant. | 6 months, 1 year, and 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tacrolimus, Everolimus, Zortress, Renal Function, Cyclosporine, Myfortic, Mycophenolic Acid, Liver Transplantation