| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adults with end stage liver disease patients requiring a liver transplant. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Adult patients, who have received a liver from a another person and need medication to avoid the loss of the organ. |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10024716 |
| E.1.2 | Term | Liver transplantation |
| E.1.2 | System Organ Class | 100000004865 |
|
| 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 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. |
|
| E.2.2 | Secondary objectives of the trial |
| 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. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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. |
|
| E.4 | Principal 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 < 0.7% or a liver volume < 30% of standard estimated volume.
18. HIV positive donors.
19. HBsAg positive donors.
20. Donor with hepatic steatosis > 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 days prior to randomization.
29. Subjects with detectable HBV DNA at time of randomization (results from Day 20 post transplant onwards are acceptable).
30. Subjects meeting the following criteria for acute rejection during the run in period: Any acute rejection in the week prior to randomization. Two treated acute rejections. Any rejection requiring antibody treatment. Any severe cellular (and/or any humoral) rejection (RAI ≥ 7). |
|
| E.5 End points |
| E.5.1 | 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At 12-month after transplantation. |
|
| E.5.2 | 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 <10, 10<15, 15<20, 20<25, and ≥25 mL/min/1.73m2 from randomization to Months 6, 12 and 24. Evolution of renal function by CKD strata. Renal function and change in eGFR from randomization to Months 6 and 12. eGFR in subgroups including age (<60 and ≥60 y), gender, race, region, renal function strata, HCV status, MELD score categories, and diagnosis leading to Tx. Urinary protein/creatinine ratio at various time points. Incidence of proteinuria of 0.5-<1.0 g/d, 1.0-<3.0 g/d and ≥ 3.0 g/d at various time points. Incidence of and time to renal replacement therapy.
Compare rate of recurrence and time to recurrence of HCC at 12/24 months post-Tx in subjects with a diagnosis of HCC at the time of liver Tx. Tumor-free survival.
Compare HCV viral load at Months 12/24 (overall and by genotype). Rate of progression of HCV related allograft fibrosis. Incidence of HCV antiviral treatment.
Compare incidence of AEs and SAEs including infections and serious infections, overall, by body system and preferred term. Compare incidence of treatment-related side effects and other AEs of interest. Compare the incidence of biliary complications and treatments.
Explore liver regeneration rate in a subset of subjects on EVR with rTAC compared to TAC control. Explore PK of EVR in co-exposure with TAC in a sub-study at selected centers. PK and exposure samples may be used to support diagnostic development. Explore change in serum markers of liver fibrosis (e.g. APRI, Hepascore). Explore incidence, frequency and characteristics of circulating tumor cells in venous blood in subjects transplanted for HCC. Explore the outcome among HCC subjects with respect to explant histology staining for pEGFR and pRPS5. Characterize proteinuria >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. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
At 12-month and 24-month after start of everolimus based regimen
|
|
| 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 | Yes |
| 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) | 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.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| 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 | No |
| 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 |
| Canada |
| Egypt |
| Germany |
| India |
| Italy |
| Japan |
| Korea, Republic of |
| Taiwan |
| Turkey |
| United States |
|
| 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
|
The study will be completed when LPLV occurs.
The study will be ended after:
- all patients have completed the month 24 visit,
- all data have been cleaned and the database has been locked,
- statistical outputs have been received. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 38 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 42 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
