| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Immunosuppression in liver transplantation |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Surgical Procedures, Operative [E04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 13.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10024716 |
| E.1.2 | Term | Liver transplantation |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 13.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10021510 |
| E.1.2 | Term | Immunosuppression NOS |
| E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 13.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10062016 |
| E.1.2 | Term | Immunosuppression |
| E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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| 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 |
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. |
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| E.2.2 | Secondary objectives of the trial |
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. |
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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. 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.
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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).
•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.
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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%.
PER AMENDMENT 1;
The primary efficacy endpoint is the composite efficacy failure of tBPAR, graft loss, or death (tBPAR/GL/D) at 12 months post-transplantation. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 Months post transplantation |
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| E.5.2 | 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 various time points.
To evaluate the incidence of and time to renal replacement therapy.
Safety related
To evaluate the incidence of AE/Infections/SAEs.
To evaluate the incidence of treatment-related side effects and other AEs of interest, including incidence of NODM, evolution of metabolic parameters as subdivisions of serum/plasma lipid panel, neurotoxicity and hypertension.
To evaluate the incidence and reason (e.g. AE) of premature discontinuation of study medication and premature discontinuation from the study.
To evaluate the incidence and reason (e.g. AE) of interruption and dose adjustment of study medication.
To evaluate the incidence of patients in the tacrolimus elimination arm that needed CNI treatment.
HCV and HCC related
Evolution of HCV and HCV related fibrosis at 12 and 24 months post-transplantation:
To evaluate HCV viral load (HCV-RNA levels overall and by genotype).;
To evaluate rates of progression of HCV related allograft fibrosis.
To evaluate incidence of and response to HCV antiviral treatment.
Recurrence of HCC and incidence of de novo HCC malignancies
To evaluate the rate of recurrence of hepatocellular carcinoma at 12 and 24 months post-transplantation in patients with a diagnosis of HCC at the time prior to of liver transplantation adjusting for various risk factors, such as number of tumor nodules, total tumor diameter, alpha fetoprotein level, etc..
To evaluate the incidence of de novo HCC malignancies.
Exploratory
To describe the change in patterns of specific biomarkers for renal injury in the urine throughout the study.
To explore the immunosuppressive potency of everolimus (exposure-efficacy) in combination with reduced exposure tacrolimus relative to standard exposure tacrolimus.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 12 and 24 Months post transplantation |
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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) | 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 | Yes |
| E.8.2.3.1 | Comparator description |
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| 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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 39 |
| 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 |
| Argentina |
| Australia |
| Belgium |
| Brazil |
| Canada |
| Colombia |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Ireland |
| Israel |
| Italy |
| Spain |
| Sweden |
| United Kingdom |
| United States |
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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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| When all randomized patients have completed their final visit ie. Month 24 assessments. |
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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