Bioavailability and Practicability of Envarsus Versus Advagraf in Liver Transplant Recipients
- Conditions
- Prophylaxis Against Liver Transplant Rejection
- Interventions
- Registration Number
- NCT04720326
- Lead Sponsor
- Edward Geissler
- Brief Summary
Trial participants are randomised within 14 days after liver transplantation surgery in a 1:1 ratio to two alternative treatment arms containing either Envarsus® (test arm) or Advagraf® (comparator arm) as first-line calcineurin inhibitor within a standard-of-care immunosuppressive regimen. Tacrolimus blood trough levels and drug doses are monitored at regular intervals to assess drug bioavailability and the ease and accuracy of achieving the targeted blood concentration range. Dose-normalised trough level (concentration/dose ratio) is measured at 12 weeks post-randomisation as an estimate of tacrolimus bioavailability. It is hypothesised that treatment with Envarsus® will confer a superior (higher) C/D ratio after 12 weeks of therapy owing to the superior bioavailability of this galenic drug formulation (proprietary MeltDose® technology). To test whether an elevated C/D ratio is also associated with improved clinical outcomes, a range of other pharmacokinetic, efficacy and safety variables are evaluated at 10 study visits spanning a period of 3 years.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- 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
- 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 body weight/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 of both Envarsus® and Advagraf®, and/or to any other macrolides
- 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 human chorionic gonadotropin 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 Investigational Medicinal Product 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)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Envarsus® Tacrolimus Pill Participants take prolonged-release tacrolimus tablets orally once daily and additionally receive standard-of-care immunosuppressive background therapy as per routine practice. Advagraf® Tacrolimus capsule Participants take prolonged-release tacrolimus capsules orally once daily and additionally receive standard-of-care immunosuppressive background therapy as per routine practice.
- Primary Outcome Measures
Name Time Method Dose-normalised blood trough level of tacrolimus (concentration/dose ratio) 12 weeks post-randomisation To calculate C/D ratio, "concentration" is the blood trough level of tacrolimus measured in a blood sample collected immediately prior to drug dosing on the day of the 12-week trial visit and "dose" is the daily dose taken by the patient on the day prior to the visit. C/D ratio is measured as a surrogate for tacrolimus bioavailability (i.e. systemic exposure per mg of drug).
- Secondary Outcome Measures
Name Time Method Mean tacrolimus trough level and inter-patient variability (range) of tacrolimus trough levels 1, 2, 4 and 12 weeks post-randomisation Inter-patient variability (range) of tacrolimus total daily dose Until 12 weeks post-randomisation Number of IMP dose adjustments Until 12 weeks post-randomisation Time to reach the first defined range in target trough level Time period measured in days, assessed at 12 weeks post-randomisation Number of measurements above and below the first defined range in target trough level Time period measured in days, assessed at 12 weeks post-randomisation Dose-normalised trough level (C/D ratio) during long-term follow-up 1, 2 and 3 years post-randomisation Proportion of patients with trough levels lower, within, or higher than the standard reference range 1, 2, 4 and 12 weeks post-randomisation Incidence and severity of clinically-confirmed biopsy-proven acute rejection 12 weeks and 1, 2, 3 years post-randomisation Incidence of graft failure (defined as necessity for re-transplantation) 12 weeks and 1, 2, 3 years post-randomisation Incidence of death (for any reason) 12 weeks and 1, 2, 3 years post-randomisation Treatment failure rate (composite endpoint of biopsy-proven acute rejection, graft failure or death) 12 weeks and 1, 2, 3 years post-randomisation Time to treatment failure (composite endpoint of biopsy-proven acute rejection, graft failure or death) after randomisation 3 years post-randomisation Incidence of acute rejections requiring treatment 12 weeks post-randomisation Incidence of multiple rejection episodes 12 weeks post-randomisation Change versus baseline in laboratory measures of liver function (aspartate transaminase, alanine transaminase, alkaline phosphatase, gamma-glutamyltransferase, bilirubin, albumin, cholinesterase, INR) 12 weeks and 1, 2, 3 years post-randomisation Change versus baseline in laboratory measures of metabolic profile (triglycerides, HDL cholesterol, LDL cholesterol, total cholesterol, HbA1c, fasting plasma glucose) 12 weeks and 1, 2, 3 years post-randomisation Change versus baseline in laboratory measures of renal function (creatinine, estimated glomerular filtration rate) 12 weeks and 1, 2, 3 years post-randomisation Incidence and type of malignancies diagnosed in trial participants 1, 2 and 3 years post-randomisation Incidence and type of infections (hepatitis C virus, hepatitis B virus, cytomegalovirus, Epstein-Barr virus) experienced by trial participants 1, 2 and 3 years post-randomisation Degree of liver fibrosis (fibroscan or biopsy) 12 weeks and 1, 2, 3 years post-randomisation Incidence, type, severity, seriousness and causality of adverse events (AEs) 3 years post-randomisation Change versus baseline in heart rate 3 years post-randomisation Change versus baseline in blood pressure 3 years post-randomisation Change versus baseline in body weight 3 years post-randomisation Incidence of de novo occurrence of tremor or vision impairments 3 years post-randomisation Incidence of post-transplant diabetes mellitus and post-transplant hyperglycaemia 12 weeks and 1, 2, 3 years post-randomisation Dose-normalised trough level (C/D ratio) 12 weeks post-transplantation Number and doses of immunosuppressive medications (incl. other tacrolimus formulations) At 12 weeks and after 12 weeks (if applicable) Recurrence of primary hepatic disease 3 years post-randomisation Incidence of donor-specific antibodies 12 weeks and 1, 2, 3 years post-randomisation Continuation rate 12 weeks post-randomisation Incidence and time to study treatment discontinuation 3 years post-randomisation Incidence of patient withdrawal from the study 3 years post-randomisation Time to patient withdrawal from the study 3 years post-randomisation Reason for patient withdrawal from the study 3 years post-randomisation
Trial Locations
- Locations (15)
University Hospital Hamburg Eppendorf
🇩🇪Hamburg, Germany
University Hospital Essen
🇩🇪Essen, Germany
University Hospital Magdeburg
🇩🇪Magdeburg, Germany
University Hospital Leipzig
🇩🇪Leipzig, Germany
University Hospital Regensburg
🇩🇪Regensburg, Germany
University Hospital Mainz
🇩🇪Mainz, Germany
University Hospital Jena
🇩🇪Jena, Germany
University Hospital Schleswig-Holstein - Campus Kiel
🇩🇪Kiel, Germany
University Hospital Aachen
🇩🇪Aachen, Germany
Hannover Medical School
🇩🇪Hannover, Germany
University Hospital Heidelberg
🇩🇪Heidelberg, Germany
University Hospital Muenster
🇩🇪Muenster, Germany
University Hospital Tuebingen
🇩🇪Tuebingen, Germany
Charite - University Medicine Berlin
🇩🇪Berlin, Germany
University Hospital Frankfurt
🇩🇪Frankfurt, Germany