Efficacy and Safety of Everolimus in Liver Transplant Recipients of Living Donor Liver Transplants

Study Overview
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Brief Summary
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The purpose of this trial was to demonstrate the efficacy and safety of everolimus in combination with reduced tacrolimus, compared to tacrolimus control, in living donor liver transplant recipients.

Detailed Description
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This study was 24 month, multicenter study in 280 living donor liver transplant patients from Asia, Europe and Canada. The study has an long term extension in Japan and approximately 28 patients were to be included to evaluate the long-term efficacy and safety of concentration-controlled everolimus regimen plus reduced tacrolimus compared to standard tacrolimus in recipients of living donor liver transplants in Japan who participated in the CRAD001H2307 study. Data reported here are the CRAD001H2307 core study results and its extension (CRAD001H2307E1).

Official Title
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A 24 Month, Randomized, Controlled, Study to Evaluate the Efficacy and Safety of Concentration-controlled Everolimus Plus Reduced Tacrolimus Compared to Standard Tacrolimus in Recipients of Living Donor Liver Transplants and Long Term Extension to Evaluate the Efficacy and Safety of Concentration-controlled Everolimus Plus Reduced Tacrolimus Compared to Standard Tacrolimus in Recipients of Living Donor Liver Transplants in Japan

Conditions
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Liver Transplantation

Intervention / Treatment
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* Drug: Everolimus + reduced tacrolimus
* Drug: Standard tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Written informed consent Subject aged ≥18 years of a primary, orthotopic liver allograft, from a living donor Subject negative for HIV Incusion criteria at Randomization: - Subject was initated on tacrolimus-based immunosuppressive regimen with steroids and other immunosuppression Exclusion criteria: Subjects transplanted for acute liver failure HCV negativesubjects receiving a transplant from HCV positive donor Subjects receiving multiple solid organ (including multiple liver lobes/segments) or islet cell tissue transplants, or have previously received an organ or tissue transplant. Subjects receiving an ABO incompatible allograft. MELD-score > 35 within 1 month prior to transplantation. Use of immunosuppressive or antibody induction agents not specified in the protocol. History of malignancy of any organ system (except hepatocellular carcinoma or localized basal cell carcinoma of the skin) Hepatocellular carcinoma with extrahepatic spread or macrovascular invasion Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 2 weeks after the last dose of study medication History of hypersensitivity to any of the study drugs or to drugs with similar chemical class, or to any of the excipients Exclusion criteria at Randomization: Any post-transplant history of thrombosis, occlusion or stent placement in any major hepatic arteries, hepatic veins, portal vein or inferior vena cava at any time during the run-in period prior to randomization. Subjects with a confirmed spot urine protein/creatinine ratio that indicates ≥ 1.0 g/24 hrs of proteinuria Subjects who have severe hypercholesterolemia (>350 mg/dL; >9.1 mmol/L) or hypertriglyceridemia (>500 mg/dL; >5.6 mmol/L) at randomization. Subjects with platelet count < 30,000/mm3. Subjects with an absolute neutrophil count of < 1,000/mm³ or white blood cell count of < 2,000/mm³. Subjects with systemic infection requiring active use of IV antibiotics. Subjects requiring life support measures such as ventilation, dialysis, vasopressor agents. Subjects who require renal replacement therapy within 7 days prior to randomization. Subjects with detectable HBV DNA at time of randomization Subjects meeting the following criteria for acute rejection during the run in period: Any acute rejection in the week prior to randomization. 2 treated acute rejections. Any rejection requiring antibody treatment. Any severe cellular (and/or any humoral) rejection. Long term extension for patients in Japan: Inclusion criteria Written informed consent must be obtained before any extension specific assessment is performed. Ability and willingness to adhere to study regimen. Completed Month 24 visit of core study and continuously being treated with assigned regimen. Exclusion criteria: Use of medication that is prohibited by the study protocol at Month 24. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test. History of hypersensitivity to any of the study drugs or to drugs with similar chemical class, or to any of the excipients

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: This was a 24-month, multicenter, open-label, randomized, controlled study. It included the extension to the 24-month, randomized, controlled, open-label CRAD001H2307 study in recipients of living donor liver transplants in Japan.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Everolimus + reduced tacrolimus<br>Everolimus + reduced tacrolimus ± corticosteroids | Drug: Everolimus + reduced tacrolimus<br>* Everolimus was initiated at Week 4 post transplantation. The dose was adjusted to maintain the everolimus trough blood levels between 3-8 ng/mL for the duration of the study. Tacrolimus was reduced to 3-5 ng/mL.<br>|
| Active Comparator: Standard tacrolimus<br>Standard tacrolimus ± corticosteroids | Drug: Standard tacrolimus<br>* Tacrolimus was initiated as soon as possible after transplantation according to approved labeling recommendations. The trough level should've been 5-15 ng/mL until randomization, 8-12 ng/mL from randomization until month 4 and after month 4 until end of study reduced to 6 -10 ng/mL.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Composite Efficacy Failure of Treated Biopsy Proven Acute Rejection, Graft Loss or Death in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus | Rate of composite efficacy failure of treated biopsy proven acute rejection (tBPAR ≥ RAI score 3), graft loss (GL) or death (D) in everolimus with reduced tacrolimus group compared to standard tacrolimus at 12 months | 12 months post transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal Function by Estimated Glomerular Filtration Rate (eGFR) From Randomization | Renal function (change in estimated glomerular filtration rate (eGFR)) from randomization to Month 12 post transplantation with everolimus (EVR) in combination with reduced tacrolimus (rTAC) compared to standard exposure tacrolimus (TAC) in living donor liver transplant recipients. | From randomization to month 12 | 
| Compare Renal Function Over Time Assessed by the Change by eGFR, Post-randomization | Change in renal function from randomization to month 24 assessed by the change in estimated GFR (MDRD-4). Rate of change of renal function. | From randomziation to month 24 | 
| Number of Participants With Composite of tBPAR, Graft Loss, and Death | Compare between the treatment group EVR with rTAC vs standard TAC: incidence of a composite of tBPAR, graft loss, death | Month 24 post transplantation | 
| Compare Incidence of tBPAR | Compare between the treatment group EVR with rTAC vs standard TAC: Incidence of tBPAR | Month 12 and Month 24 post transplantation | 
| Compare Incidence of BPAR | Compare between the treatment group EVR with rTAC vs standard TAC: incidence of a composite of biopsy proven acute rejection (BPAR) | Month 12 and Month 24 post transplantation | 
| Compare Incidence of Graft Loss | Compare between the treatment group EVR with rTAC vs standard TAC: incidence of graft loss | Month 12 and Month 24 post transplantation | 
| Compare Incidence of a Composite of Death or Graft Loss | Compare between the treatment group EVR with rTAC vs standard TAC: Incidence of a composite of death or graft loss | Month 12 and Month 24 post transplantation | 
| Compare Incidence of Death | Compare between the treatment group EVR with rTAC vs standard TAC: incidence of death | Month 12 and Month 24 post transplantation | 
| Compare Incidence of AR | Compare between the treatment group EVR with rTAC vs standard TAC: incidence of acute rejection (AR) | Month 12 and Month 24 post transplantation | 
| Compare Incidence of tAR | Compare between the treatment group EVR with rTAC vs standard TAC: incidence of treated acute rejection (tAR). | Month 12 and Month 24 post transplantation | 
| Number of Participants With Time to Recurrence of HCC in Subjects With a Diagnosis of HCC at the Time of Liver Transplantation | Patients transplanted for HCC or with HCC diagnosed at time of transplantation were monitored for HCC recurrence according to local practice. For example routine laboratory monitoring/tests, tumor markers, hepatic ultrasound, computed tomography scans (CAT, CT) or MRI (especially Fe-MRI) on a regular basis per local practice. | Month 12 and Month 24 | 
| Number of Subjects Experiencing Adverse Events/Infections by SOC |  | Month 24 | 
| Compare Incidence of Notable Safety Events (SAEs, Infections and Serious Infections Leading to Premature Discontinuation) | Notable events include death, Serious AE/infection,, and AE/infection leading to discontinuation of study medication. | Month 24 | 
| Composite Efficacy Failure of Treated Biopsy in Everolimus With Reduced Tacrolimus Group Compared to Standard Tacrolimus in Patients From Japan Only | Rate of composite efficacy failure of treated biopsy in everolimus with reduced tacrolimus group compared to standard tacrolimus from randomization in core study up to 36 months in the extension study. Composite endpoint = treated BPAR, graft loss or death. AR = Acute rejection; tAR = treated AR; BPR = biopsy proven rejection; BPAR = biopsy proven acute rejection; tBPAR = treated BPAR | randomization, 36 months post transplantion | 
| Renal Function by Estimated Glomerular Filtration Rate (All Extension Patients) | Renal function (change in estimated glomerular filtration rate (eGFR)) from randomization to Month 36 post transplantation with everolimus (EVR) in combination with reduced tacrolimus (rTAC) compared to standard exposure tacrolimus (TAC) in living donor liver transplant recipients in Japan | randomization, at 36 months post transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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everolimus, tacrolimus, liver transplantation, reduced calcineuron inhibitor, renal function, living donor, RAD001H2307, RAD001H