Adults with end stage liver disease patients requiring a liver transplant. MedDRA version: 16.0 Level: LLT Classification code 10024716 Term: Liver transplantation System Organ Class: 100000004865
Conditions
Interventions
Trade Name: Certican
Product Name: Certican 0.5mg
Product Code: RAD001
Pharmaceutical Form: Tablet
INN or Proposed INN: Everolimus
CAS Number: 159351-69-6
Current Sponsor code: RAD001
Other descriptiv
Sponsors
Novartis Farma SpA
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Written informed consent must be obtained before any assessment is performed. 2. Subject aged =18 years of a primary, orthotopic liver allograft, from a living donor. 3. Subject negative for HIV (result obtained 6 months prior to screening is acceptable). 4. Subject HCV and HBV status must be known. 5. Subject was initiated on TAC-based immunosuppressive regimen with steroids and other immunosuppression, as per protocol. 6. Allograft condition acceptable at time of randomization as defined by AST, ALT, total Bilirubin levels =3 times ULN. 7. Abbreviated MDRD eGFR = 30 mL/min/1.73m2. Local serum creatinine results obtained no more than 5 d prior randomization but no sooner than 25 d post-transplantation are acceptable. 8. Subject must be able to take oral medication at time of randomization. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 450 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 20
Exclusion criteria
Exclusion criteria: 1. Subjects transplanted for acute liver failure. 2. HCV negative subjects receiving transplant from HCV positive donor. 3. Subjects receiving multiple solid organ (including multiple liver lobes/segments) or islet cell tissue transplants, or have previously received organ or tissue transplant. 4. Subjects receiving ABO incompatible allograft. 5. MELD-score > 35 within 1 mo prior to transplantation. 6. Use of immunosuppressive or antibody induction agents not specified in the protocol. 7. History of malignancy of any organ system (except HCC or localized skin BCC), treated or untreated, within the past 5 y, regardless of evidence of local recurrence or metastases. 8. HCC with extrahepatic spread or macrovascular invasion. 9. Subjects with history of coagulopathy or medical condition requiring long-term anticoagulation precluding liver biopsy after transplantation (low dose aspirin treatment or interruption of chronic anticoagulant is allowed). 10. Any surgical, medical, mental conditions, other than the current transplantation, which, in the opinion of the investigator, might interfere with the objectives of the study. 11. Pregnant or nursing (lactating) women (pregnancy defined as state of a female after conception and until the termination of gestation, confirmed by a positive hCG test). 12. Women of child-bearing potential, unless using highly effective contraception methods during dosing and for 2 wks of the last dose of study medication. Highly effective contraception methods are described in the protocol. 13. History of hypersensitivity to any of the study drugs or to drugs with similar chemical class, or to any of the excipients. 14. Use of other investigational drugs at screening, or within 30 d or 5 half-lives of screening, whichever is longer. 15. Subjects who are requiring the administration of strongly interacting drugs of the CYP450 3A4 system. 16. Full-size, split, auxiliary, dual and or/domino liver allografts. 17. Small-for-size allograft, defined as allograft to recipient weight ratio (GRWR) of 30%. 21. 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. For subjects without such history Doppler confirmed absence of any hepatic vessel thrombosis or occlusion within 5 d prior to randomization, but no sooner than Day 25 post transplantation is required for randomization. 22. Subjects with a confirmed spot urine protein/creatinine ratio that indicates = 1.0 g/24 hrs of proteinuria and that cannot be explained by other effects. 23. Subjects with severe hypercholesterolemia (>350 mg/dL; >9 mmol/L) or hypertriglyceridemia (>500 mg/dL; >8.5 mmol/L) at randomization. Subjects with controlled hyperlipidemia are acceptable at the time of randomization. 24. Subjects with platelet count < 30,000/mm3. 25. Subjects with an absolute neutrophil count of < 1,000/mm³ or white blood cell count of < 2,000/mm³. 26. Subjects with systemic infection requiring active use of IV antibiotics. 27. Subjects requiring life support measures such as ventilation, dialysis, vasopressor agents. 28. Subjects who require renal replacement therapy within 7
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To demonstrate comparable efficacy as measured by the composite efficacy failure of tBPAR, graft loss or death with EVR in combination with rTAC compared to standard exposure TAC, at 12 months post-transplantation, in living donor liver transplant recipients.;Secondary Objective: As the key secondary objective to demonstrate at least comparable renal function, measured by change in eGFR from randomization to Month 12 post-Tx, with EVR in combination with rTAC, compared to standard exposure TAC, in living donor liver transplant recipients.;Primary end point(s): Composite efficacy failure of treated biopsy proven acute rejection (tBPAR), graft loss (GL) or death (D) at 12 months post-transplantation, in living donor liver transplant recipients.;Timepoint(s) of evaluation of this end point: At 12-month after transplantation. | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: At 12-month and 24-month after start of everolimus based regimen ;Secondary end point(s): Demonstrate at least comparable renal function (change in eGFR from randomization to Month 12 post-Tx, with EVR in combination with rTAC, compared to standard exposure TAC, in living donor liver transplant recipients. 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. Compare tBPAR and tAR by severity (RAI grading) as well as diagnosis leading to Tx at Months 6, 12, and 24 post-Tx. Incidence of tBPAR by time to event, severity, and diagnosis leading to Tx. Compare evolution of post-randomization renal function over time assessed by change in eGFR (MDRD-4), including changes from randomization to Months 12 and 24; rate of change of renal function from randomization to Months 12 and 24. Renal function by eGFR using MDRD-4/6, Nankivell, Cockcroft-Gault, CKD EPI and Hoek formulae. Incidence of subjects experiencing either a decline or increase in eGFR of 1.0 g/d according to urine protein composition in a subset of subjects with this condition. To analyze this study by pooling of key efficacy and safety parameters with pivotal study H2304. | — |
Countries
Canada, Egypt, Germany, India, Italy, Japan, Korea, Republic of, Taiwan, Turkey, United States
Contacts
Public ContactDrug Regulatory Affairs
Novartis Farma SpA
Outcome results
None listed