Immunosuppression in liver transplantation MedDRA version: 13.1 Level: LLT Classification code 10024716 Term: Liver transplantation System Organ Class: 10042613 - Surgical and medical procedures MedDRA version: 13.1 Level: LLT Classification code 10021510 Term: Immunosuppression NOS System Organ Class: 10021428 - Immune system disorders MedDRA version: 13.1 Level: PT Classification code 10062016 Term: Immunosuppression System Organ Class: 10021428 - Immune system disorders
Conditions
Interventions
Trade Name: Certican
Product Name: Certican
Product Code: RAD001
Pharmaceutical Form: Tablet
Trade Name: Prograf
Product Name: tacrolimus
Pharmaceutical Form: Capsule, hard
Trade Name: Cellcept
Prod
Sponsors
Novartis Pharma Services AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: •Ability and willingness to provide written informed consent and adhere to study regimen. •Recipients who are 18-70 years of age of a primary liver transplant from a deceased donor. •Recipients who have been initiated on an immunosuppressive regimen that contains corticosteroids and tacrolimus, 3-7 days post-transplantation. •Confirmed recipient HCV status at Screening (either by antibody or by PCR). •Allograft is functioning at an acceptable level by the time of randomization as defined by AST, ALT, Total Bilirubin levels =3 times ULN and AlkP and GGT = 5 times ULN. PER AM1- "Elevated GGT alone, in combination with AST, ALT, total bilirubin and AlkP within the defined range does not exclude patients from randomization." • Abbreviated MDRD eGFR = 30 mL/min/1.73m2. PER AM 1" Local and central serum creatinine" results obtained within 5 days prior to randomization are acceptable, however no sooner than Day 25 post-transplantation. • Verification of at least one tacrolimus trough level of = 8 ng/mL in the week prior to randomization. Investigators should make adjustments in tacrolimus dosing to continue to target trough levels above 8 ng/mL prior to randomization. Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 640 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 50
Exclusion criteria
Exclusion criteria: •Patients who are recipients of multiple solid organ or islet cell tissue transplants, or have previously received an organ or tissue transplant. Patients who have a combined liver-kidney transplant. •Recipients of a liver from a living donor, or of a split liver. •History of malignancy of any organ system within the 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 (see next criteria). •Hepatocellular carcinoma that does not fulfill Milan criteria at the time of transplantation as per explant histology of the recipient liver. •Any use of antibody induction therapy. •Patients with a known hypersensitivity to the drugs used on study or their class, or to any of the excipients •Patients who are recipients of ABO incompatible transplant grafts. •Recipients of organs from donors who test positive for Hepatitis B surface antigen or HIV are excluded. •Patients who have any surgical or medical condition, which in the opinion of the investigator, might significantly alter the absorption, distribution, metabolism and excretion of study drug. •Patients with any 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). •PER AM1 "Patients wITH A CONFIRMED spot urine protein/creatinine ratio that indicates = 1.0 g/24 hrs of proteinuria at baseline,AND THAT CANNOT BE EXPLAINED BY IMMEDIATE POST OPERATIVE EFFECTS." •Use of immunosuppressive agents or treatments after baseline that are not utilized in the protocol. •Patients who have severe hypercholesterolemia (>350 mg/dL; >9 mmol/L) or hypertriglyceridemia (>500 mg/dL; >8.5 mmol/L) within 6 months of transplantation. Patients with controlled hyperlipidemia are acceptable at the time of randomization. •Patients with platelet count < 50,000/mm3 at the time of randomization. •Patients with an absolute neutrophil count of < 1,000/mm³ or white blood cell count of < 2,000/mm³ at the time of randomization. •Patients who are unable to take oral medication at time of randomization. •Patients who have tested positive for HIV. Negative laboratory results obtained within 6 months prior to randomization are acceptable. •Patients with clinically significant systemic infection requiring active use of IV antibiotics at the time of randomization. •Patients who are in a critical care setting at the time of randomization requiring life support measures such as mechanical ventilation, dialysis, requirement of vasopressor agents. •Patients who require renal replacement therapy for clearance within 7 days prior to randomization. •The presence of thrombosis via Doppler ultrasound of the 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. •An episode of acute rejection that required antibody therapy or more than one steroid-sensitive episode of acute rejection during the run-in period. This includes patients who have not completed steroid treatment for acute rejection within 7 days prior to randomization.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: ORIGINAL TEXT- To evaluate the use of concentration-controlled everolimus, with the reduction or the elimination of tacrolimus, to provide superior renal function and to provide non-inferior rates of the composite efficacy failure rate compared to the tacrolimus control at 12 months post-transplantation. PER AMENDMENT 1- To compare the composite efficacy failure rate of treated biopsy proven acute rejection (tBPAR), graft loss (GL) or death (D) with early tacrolimus minimization, facilitated by everolimus introduction 4 weeks after liver transplantation, to standard exposure tacrolimus, at 12 months.;Secondary Objective: PER AMENDMENT 1 New Key secondary objective (formerly primary objective)- To evaluate the evolution of renal function, measured by estimated GFR, between early tacrolimus minimization, facilitated by everolimus introduction 4 weeks after liver transplantation, and standard exposure tacrolimus, from randomization to Month 12. OTHER SECONDARY OBJECTIVES SUMMARIZED IN AMENDED PROTOCOL. DETAILS ADDED UNDER ENDPOINTS SECTION E5 BELOW.;Primary end point(s): The primary efficacy endpoint is renal function assessed by eGFR (using abbreviated MDRD) at 12-months post-transplant. An analysis-of-covariance (ANCOVA) model will be used for the primary analysis with eGFR at 12 months as the response variable, and treatment and baseline eGFR as covariates. Each everolimus treatment group will be compared against the control group for superiority on renal function. HCV status is not included in the ANCOVA model since it is not expected to substantially impact on renal function. The co-primary efficacy endpoint is the composite efficacy failure of death, graft loss, or lost to follow-up (D/GL/LFUP) at 12 months post-transplant. Each everolimus treatment group will be compared against the control group for non-inferiority (NI) of efficacy with an NI margin of 10%. PER AMENDMENT 1; The primary efficacy endpoint is the composite efficacy failure of tB | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): OTHER SECONDARY OBJECTIVES PER AM 1- Efficacy related To evaluate the incidence of a composite of treated BPAR, graft loss, death or loss to follow-up. To evaluate the incidence of each component of the composite efficacy endpoint. To evaluate the incidence of a composite of death (D) or graft loss (GL) To evaluate treated BPAR by: (1) incidence, (2) time to event, (3) severity, (4), diagnosis leading to transplantation. To evaluate any acute rejection by: (1) incidence, (2) time to event, (3) severity. To evaluate the incidence of: Suspected acute rejection. Treated acute rejection. Biopsy proven acute rejection. Treated biopsy proven acute rejection. Subclinical acute rejection. Renal function-related To evaluate the evolution of post-randomization renal function over time assessed by the change in estimated GFR (MDRD-4), including to Months 12 and 24. To evaluate renal function by estimated GFR using various methods (MDRD-4/6, Nankivell, Cockcroft-Gault, CKD EPI and Hoek formulae). To evaluate the incidence of patients experiencing a decline in eGFR of < 10, 10<15, 15<20, 20<25, and = 25 mL/min/1.73m2 from Screening, Week 2 post transplantation and randomization to Months 6, 12 and 24. To evaluate serum creatinine at various time points. To evaluate evolution of renal function by chronic kidney disease (CKD) strata. To evaluate renal function and change in estimated GFR from screening, Week 2 post transplantation and randomization to Months 6 and 12 eGFR in following subgroups: age (< 60 and = 60 years), gender, race, region, renal function strata (< 30, 30<45, 45<60, = 60 mL/min/1.73m2, below/above 45 mL/min/1.73m2, below/above 60 mL/min/1.73m2), HCV status, MELD score categories (=14, 15-19, 20-24, 25-29, = 30), and diagnosis leading to transplantation. To evaluate urinary protein/creatinine ratio at various time points. To evaluate the incidence of proteinuria of 0.5<1.0 g/day, 1.0<3.0 g/day and = 3.0 g/day at var | — |
Countries
Argentina, Australia, Belgium, Brazil, Canada, Colombia, Czech Republic, France, Germany, Hungary, Ireland, Israel, Italy, Netherlands, Spain, Sweden, United Kingdom, United States
Outcome results
None listed