| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Immunosuppression in liver transplantation |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 14.0 |
| 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 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| 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 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| 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 |
|
| 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. |
|
| 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. |
|
| 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 posttransplantation.
•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 posttransplantation.
• 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. |
|
| 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. |
|
| 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-ofcovariance
(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 posttransplant.
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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 Months post transplantation |
|
| 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 posttransplantation:
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 (exposureefficacy)
in combination with reduced exposure tacrolimus relative to
standard exposure tacrolimus. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 12 and 24 Months post transplantation |
|
| 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 |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 4 |
| 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 |
|
| 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
|
When all randomized patients have completed their final visit ie. Month
24 assessments. |
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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