Multicentre, open-label, randomised, two-arm, parallel-group, superiority study to assess bioavailability and practicability of Envarsus® compared with Advagraf® in de novo liver transplant recipients
- Conditions
- Prophylaxis of transplant rejection in adult liver allograft recipients
- Registration Number
- 2024-518033-28-00
- Lead Sponsor
- Universitaetsklinikum Regensburg AöR
- Brief Summary
To compare the bioavailability of two once-daily tacrolimus formulations in de novo liver transplant recipients and show superiority of Envarsus® versus Advagraf® in terms of C/D (concentration/dose) ratio after 12 weeks of therapy. The recently identified and postulated parameter C/D ratio is used as an estimate of tacrolimus bioavailability.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Ongoing, recruitment ended
- Sex
- Not specified
- Target Recruitment
- 268
Signed and dated written informed consent
Adult (≥18 years old) male or female
Recipient of a whole liver transplant from a deceased donor or a split liver transplant from a deceased or living donor
ABO blood type compatible with the organ donor
Able to swallow an oral formulation of tacrolimus in tablet or capsule form
Multi-organ transplantation
Ongoing, planned or foreseeable use of cyclosporine or any tacrolimus preparation other than Envarsus® or Advagraf® (except for immediate-release formulations administered before randomisation)
Any prolonged-release tacrolimus treatment prior to randomisation
Pregnant or nursing (lactating) female, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test
Female of child-bearing potential, defined as physiologically capable of becoming pregnant, unless using a reliable method* of contraception
Participation in another interventional clinical trial during the time period from randomisation to study end, if the trial is testing an IMP (AMG study**) or if the intervention and/or follow-up requirements of the trial impede or interfere with either the objectives of EnGraft or the treatment / follow-up requirements of EnGraft
Any condition or factor which, in the judgement of the investigator, would place the subject at undue risk, invalidate communication with the investigator or study team, or hamper compliance with the trial protocol or follow-up schedule
Inability to freely give informed consent (e.g. individuals under legal guardianship)
Any previous organ allograft transplantation
Biopsy-proven acute rejection that is ongoing at the time of randomisation
Occurrence of post-transplant thrombosis, occlusion or stent placement in any major hepatic arteries, hepatic veins, portal vein or inferior vena cava
History of extra-hepatic malignancy that could not be curatively treated
Hepatocellular carcinoma with extra-hepatic spread or macrovascular invasion
Uncontrolled systemic infection
Requirement of life support measures such as ventilation or vasopressor agents (>20 μg/kg BW/h) at the time of randomisation
Known contraindication or hypersensitivity to tacrolimus, and/or to any of the excipients listed in section 6.1 of the Summary of Product Characteristics (SmPC) of both Envarsus® and Advagraf®, and/or to any other macrolides
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Dose-normalised trough level (C/D ratio) measured at 12 weeks Dose-normalised trough level (C/D ratio) measured at 12 weeks
- Secondary Outcome Measures
Name Time Method Number of IMP dose adjustments until 12 weeks Number of IMP dose adjustments until 12 weeks
Time to reach the first defined range in target trough level Time to reach the first defined range in target trough level
Number of measurements above and below the first defined range in target trough level Number of measurements above and below the first defined range in target trough level
Dose-normalised trough level (C/D ratio) measured at 1, 2 and 3 years Dose-normalised trough level (C/D ratio) measured at 1, 2 and 3 years
Mean tacrolimus trough level and inter-patient variability (range) of tacrolimus trough levels at 1, 2, 4 and 12 weeks Mean tacrolimus trough level and inter-patient variability (range) of tacrolimus trough levels at 1, 2, 4 and 12 weeks
Inter-patient variability (range) of tacrolimus total daily dose until 12 weeks Inter-patient variability (range) of tacrolimus total daily dose until 12 weeks
Proportion of patients with trough levels lower, within, or higher than the standard reference range at 1, 2, 4 and 12 weeks Proportion of patients with trough levels lower, within, or higher than the standard reference range at 1, 2, 4 and 12 weeks
Incidence and severity (BANFF criteria) of clinically-confirmed BPAR2 at 12 weeks and 1, 2, 3 years Incidence and severity (BANFF criteria) of clinically-confirmed BPAR2 at 12 weeks and 1, 2, 3 years
Incidence of graft failure (defined as necessity for re-transplantation) at 12 weeks and 1, 2, 3 years Incidence of graft failure (defined as necessity for re-transplantation) at 12 weeks and 1, 2, 3 years
Incidence of death (for any reason) at 12 weeks and 1, 2, 3 years Incidence of death (for any reason) at 12 weeks and 1, 2, 3 years
Treatment failure rate (composite endpoint of BPAR, graft failure or death) at 12 weeks and 1, 2, 3 years Treatment failure rate (composite endpoint of BPAR, graft failure or death) at 12 weeks and 1, 2, 3 years
Time to treatment failure (composite endpoint of BPAR, graft failure3 or death) after randomisation Time to treatment failure (composite endpoint of BPAR, graft failure3 or death) after randomisation
Incidence of acute rejections requiring treatment at 12 weeks Incidence of acute rejections requiring treatment at 12 weeks
Incidence of multiple rejection episodes at 12 weeks Incidence of multiple rejection episodes at 12 weeks
Laboratory measures at 12 weeks and 1, 2, 3 years: liver function, metabolic profile, renal function Laboratory measures at 12 weeks and 1, 2, 3 years: liver function, metabolic profile, renal function
Malignancies at 1, 2 and 3 years Malignancies at 1, 2 and 3 years
Infections (HCV, HBV, CMV, EBV) at 1, 2 and 3 years Infections (HCV, HBV, CMV, EBV) at 1, 2 and 3 years
Degree of liver fibrosis (fibroscan4 or biopsy) at 12 weeks and 1, 2, 3 years Degree of liver fibrosis (fibroscan4 or biopsy) at 12 weeks and 1, 2, 3 years
Incidence, type, severity, seriousness and causality of adverse events (AEs) Incidence, type, severity, seriousness and causality of adverse events (AEs)
Change vs. baseline in vital signs (heart rate, blood pressure) and body weight Change vs. baseline in vital signs (heart rate, blood pressure) and body weight
Incidence of de novo occurrence of tremor or vision impairments Incidence of de novo occurrence of tremor or vision impairments
Incidence of post-transplant diabetes mellitus and post-transplant hyperglycaemia at 12 weeks and 1, 2, 3 years Incidence of post-transplant diabetes mellitus and post-transplant hyperglycaemia at 12 weeks and 1, 2, 3 years
Dose-normalised trough level (C/D ratio) 12 weeks after transplantation Dose-normalised trough level (C/D ratio) 12 weeks after transplantation
Number and doses of immunosuppressive medications (incl. other tacrolimus formulations) at 12 weeks and after 12 weeks (if applicable) Number and doses of immunosuppressive medications (incl. other tacrolimus formulations) at 12 weeks and after 12 weeks (if applicable)
Recurrence of primary hepatic disease Recurrence of primary hepatic disease
Incidence of DSA up to 12 weeks and at 1, 2 and 3 years (optional) Incidence of DSA up to 12 weeks and at 1, 2 and 3 years (optional)
Continuation rate at 12 weeks Continuation rate at 12 weeks
Incidence and time to study treatment discontinuation Incidence and time to study treatment discontinuation
Incidence, time to and reason for patient withdrawal from study Incidence, time to and reason for patient withdrawal from study
Trial Locations
- Locations (15)
Universitaet Leipzig
🇩🇪Leipzig, Germany
Universitaetsklinikum Schleswig-Holstein AöR
🇩🇪Kiel, Germany
Universitaetsklinikum Regensburg AöR
🇩🇪Regensburg, Germany
Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR
🇩🇪Mainz, Germany
Otto Von Guericke Universitaet Magdeburg
🇩🇪Magdeburg, Germany
Universitaetsklinikum Essen AöR
🇩🇪Essen, Germany
Universitaetsklinikum Aachen AöR
🇩🇪Aachen, Germany
Universitaetsklinikum Heidelberg AöR
🇩🇪Heidelberg, Germany
Universitaetsklinikum Tuebingen AöR
🇩🇪Tuebingen, Germany
Charite Universitaetsmedizin Berlin KöR
🇩🇪Berlin, Germany
Scroll for more (5 remaining)Universitaet Leipzig🇩🇪Leipzig, GermanyThomas BergSite contact+493419712200thomas.berg@medizin.uni-leipzig.de