E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10024714 |
E.1.2 | Term | Liver transplant |
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E.1.3 | Condition being studied is a rare disease | No |
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 endpoint 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: To evaluate renal function by eGFR (abbreviated MDRD equation) and calculated creatinine clearance (Cockcroft-Gault formula); To evaluate the risk of deterioration of renal function; To evaluate the prevalence of CNI-related side effects (as defined by eGRF: hypertension, neurotoxicity); To evaluate the incidence of new onset diabetes. Study-/Study-Drug related findings at 12 and 24 months post-transplantation: To evaluate premature discontinuation of study medication, and discontinuation from study; To evaluate the incidence of dose interruption and dose reduction of study medication; To evaluate the incidence of AEs and SAEs. (sse protocol p. 10) |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
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 (1 nodule ≤5 cm, 2-3 nodules all <3 cm, Appendix 9) 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. Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS (1) they meet the following definition of postmenopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels >40 mIU/m, or (2) have past 6 weeks from surgical bilateral oophorectomy with or without hysterectomy or (3) are using one or more of the following acceptable methods of contraception: surgical sterilization (e.g., bilateral tubal ligation, vasectomy), hormonal contraception (implantable, patch, oral), copper coated IUD and double-barrier methods ( any double combination of male or female condom with spermicidal gel, diaphragm, sponge, cervical cap). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Reliable contraception should be maintained throughout the and for 3 months after study drug discontinuation. 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). |
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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-transplantation. 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 pre-randomization eGFR as covariates. Each everolimus treatment arm will be compared against the tacrolimus control arm 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 followup (D/GL/LFUP) at 12 months post-transplantation. Each everolimus treatment arm will be compared against the control arm for non-inferiority (NI) of efficacy with an NI margin of 10%. The Hochberg multiple testing procedure [Hochberg 1988] will be applied to control the Type I error rate at α = 0.025 (one-sided) for the comparisons between each everolimus treatment group against control. Following the Hochberg procedure, two-sided 95% and 97.5% confidence intervals (CIs) for the difference in the efficacy failure rates between each everolimus group and control will be computed, and the upper limits of the CIs will be compared with the NI margin of 10% to assess non-inferiority. |
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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 | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Information not present in EudraCT |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
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 | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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.8.5 | The trial involves multiple Member States | Yes |
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 | Information not present in EudraCT |
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 | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |