Liver Transplantation
Conditions
Interventions
investigational material(s)
Generic name etc : RAD001
INN of investigational material : Everolimus
Therapeutic category code : 399 Agents affecting metabolism, n.e.c.
Dosage and Administration for Inv
Sponsors
Novartis Pharma K.K.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Inclusion criteria: -Written informed consent -Subject aged more than or equal to 18 years of a primary, orthotopic liver allograft, from a living donor -Subject negative for HIV Inclusion criteria at Randomization: -Subject was initiated on tacrolimus-based immunosuppressive regimen with steroids and other immunosuppression Long term extension for patients in Japan: -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
Exclusion criteria: 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 more than 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 of 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 artery, major/reconstructed hepatic vein, 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 more than or equal to 1.0 g/24 hrs of proteinuria -Subjects who have severe hypercholesterolemia (more than 350 mg/dL; more than 9 mmol/L) or hypertriglyceridemia (more than 500 mg/dL; more than 8.5 mmol/L) at randomization. -Subjects with platelet count less than 30,000/mm3. -Subjects with an absolute neutrophil count of less than 1,000/mm3 or white blood cell count of less than 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. Other protocol-defined inclusion/exclusion criteria may apply. Long term extension for patients in Japan: -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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| efficacy Composite efficacy failure of treated biopsy proven acute rejection, graft loss or death in everolimus with reduced tacrolimus group compared to standard tacrolimus [ Time Frame: at 12 months post transplantation ] Rate of composite efficacy failure of treated biopsy proven acute rejection (tBPAR more than or equal to RAI score 3), graft loss (GL) or death (D) in everolimus with reduced tacrolimus group compared to standard tacrolimus at 12 months | — |
Secondary
| Measure | Time frame |
|---|---|
| efficacy Renal function by estimated Glomerular Filtration Rate [ Time Frame: Randomization, Month 12 ] 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 efficacy Compare incidence of a composite of tBPAR, graft loss, death. Incidence of each component of the composite. Incidence of a composite of death or graft loss. Incidence of BPAR, tAR and AR. [ Time Frame: Month 12 and Month 24 post transplantation ] Compare between the treatment group EVR with rTAC vs standard TAC: incidence of a composite of tBPAR, graft loss, death. Incidence of each component of the composite. Incidence of a composite of death or graft loss. Incidence of BPAR, tAR and AR. efficacy Compare evolution of post-randomization renal function over time assessed by the change by eGFR [ Time Frame: Randomization, Month 12 and Month 24 ] Compare evolution of post-randomization renal function over time assessed by the change in estimated GFR (MDRD-4), including changes from randomization to Months 12 and 24. Rate of change of renal function. efficacy Urinary protein/creatinine ratio at various time points [ Time Frame: Month 24 ] Urinary protein/creatinine ratio at various time points efficacy Compare rate of recurrence and time to recurrence of HCC in subjects with a diagnosis of HCC at the time of liver transplantation [ Time Frame: Randomization, Month12 and Month 24 ] Compare rate of recurrence and time to recurrence of HCC in subjects with a diagnosis of HCC at the time of liver transplantation efficacy Compare HCV viral load (overall and by genotype). [ Time Frame: Month 12 and 24 ] Compare HCV viral load (overall and by genotype). safety Compare incidence of AEs and SAEs including infections and serious infections, overall, by body system and preferre | — |
Countries
Africa, Asia except Japan, Europe, Japan, North America
Outcome results
None listed