E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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. |
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E.2.2 | Secondary objectives of the trial |
•To evaluate the composite efficacy endpoint of treated biopsy proven acute rejection (BPAR), graft loss, death or loss to follow-up at 12 and 24 months post-transplantation. •Evolution of renal function /calcineurin inhibitor (CNI)-related side effects at 12 and 24 months post-transplantation: •Study-/Study-Drug related findings at 12 and 24 months post-transplantation. •Evolution of HCV and HCV related fibrosis at 12 and 24 months post-transplantation: •To evaluate the rate of recurrence of hepatocellular carcinoma at 12 and 24 months post-transplantation in patients with a diagnosis of HCC prior to liver transplantation.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. • Abbreviated MDRD eGFR ≥ 30 mL/min/1.73m2. 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.
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E.4 | Principal 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).
•Patients who have a spot urine protein/creatinine ratio that indicates ≥ 1.0 g/24 hrs of proteinuria at baseline. •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.
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E.5 End points |
E.5.1 | 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%.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Information not present in EudraCT |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.3.1 | Comparator description |
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E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | No |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 18 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 18 |