Clinical trial NCT04720326: Bioavailability and Practicability of Envarsus Versus Advagraf in Liver Transplant Recipients
Official title: 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 (EnGraft)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Prophylaxis Against Liver Transplant Rejection
Keywords: Liver transplantation
Tacrolimus
Concentration/dose ratio
Immunosuppression
Lead sponsor: University of Regensburg
Sponsor class: OTHER
Collaborators: name: Chiesi Pharmaceuticals GmbH
name: Excelya
First posted: 2021-01-22
Enrollment: 268
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A dynamic allocation technique allocates participants in a 1:1 ratio to one of two treatment arms: Envarsus® tablets (test IMP) or Advagraf® capsules (comparator IMP). Pre-treatment with immediate-release tacrolimus, as well as trial site, are used as stratification factors in the treatment allocation in order to minimise sources of treatment bias.
Primary purpose: PREVENTION

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.


Eligibility criteria: Inclusion Criteria:

1. Signed and dated written informed consent
2. Adult (≥18 years old) male or female
3. Recipient of a whole liver transplant from a deceased donor or a split liver transplant from a deceased or living donor
4. ABO blood type compatible with the organ donor
5. Able to swallow an oral formulation of tacrolimus in tablet or capsule form

Exclusion Criteria:

1. Multi-organ transplantation
2. Any previous organ allograft transplantation
3. Biopsy-proven acute rejection that is ongoing at the time of randomisation
4. Occurrence of post-transplant thrombosis, occlusion or stent placement in any major hepatic arteries, hepatic veins, portal vein or inferior vena cava
5. History of extra-hepatic malignancy that could not be curatively treated
6. Hepatocellular carcinoma with extra-hepatic spread or macrovascular invasion
7. Uncontrolled systemic infection
8. Requirement of life support measures such as ventilation or vasopressor agents (\>20 µg/kg body weight/h) at the time of randomisation
9. 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
10. Ongoing, planned or foreseeable use of cyclosporine or any tacrolimus preparation other than Envarsus® or Advagraf® (except for immediate-release formulations administered before randomisation)
11. Any prolonged-release tacrolimus treatment prior to randomisation
12. 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
13. Female of child-bearing potential, defined as physiologically capable of becoming pregnant, unless using a reliable method of contraception
14. 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
15. 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
16. Inability to freely give informed consent (e.g. individuals under legal guardianship)

Primary outcomes:
measure: Dose-normalised blood trough level of tacrolimus (concentration/dose ratio)
timeFrame: 12 weeks post-randomisation
Secondary outcomes:
measure: Number of IMP dose adjustments
timeFrame: Until 12 weeks post-randomisation
measure: Time to reach the first defined range in target trough level
timeFrame: Time period measured in days, assessed at 12 weeks post-randomisation
measure: Number of measurements above and below the first defined range in target trough level
timeFrame: Time period measured in days, assessed at 12 weeks post-randomisation
measure: Dose-normalised trough level (C/D ratio) during long-term follow-up
timeFrame: 1, 2 and 3 years post-randomisation
measure: Mean tacrolimus trough level and inter-patient variability (range) of tacrolimus trough levels
timeFrame: 1, 2, 4 and 12 weeks post-randomisation
measure: Inter-patient variability (range) of tacrolimus total daily dose
timeFrame: Until 12 weeks post-randomisation
measure: Proportion of patients with trough levels lower, within, or higher than the standard reference range
timeFrame: 1, 2, 4 and 12 weeks post-randomisation
measure: Incidence and severity of clinically-confirmed biopsy-proven acute rejection
timeFrame: 12 weeks and 1, 2, 3 years post-randomisation
measure: Incidence of graft failure (defined as necessity for re-transplantation)
timeFrame: 12 weeks and 1, 2, 3 years post-randomisation
measure: Incidence of death (for any reason)
timeFrame: 12 weeks and 1, 2, 3 years post-randomisation
measure: Treatment failure rate (composite endpoint of biopsy-proven acute rejection, graft failure or death)
timeFrame: 12 weeks and 1, 2, 3 years post-randomisation
measure: Time to treatment failure (composite endpoint of biopsy-proven acute rejection, graft failure or death) after randomisation
timeFrame: 3 years post-randomisation
measure: Incidence of acute rejections requiring treatment
timeFrame: 12 weeks post-randomisation
measure: Incidence of multiple rejection episodes
timeFrame: 12 weeks post-randomisation
measure: Change versus baseline in laboratory measures of liver function (aspartate transaminase, alanine transaminase, alkaline phosphatase, gamma-glutamyltransferase, bilirubin, albumin, cholinesterase, INR)
timeFrame: 12 weeks and 1, 2, 3 years post-randomisation
measure: Change versus baseline in laboratory measures of metabolic profile (triglycerides, HDL cholesterol, LDL cholesterol, total cholesterol, HbA1c, fasting plasma glucose)
timeFrame: 12 weeks and 1, 2, 3 years post-randomisation
measure: Change versus baseline in laboratory measures of renal function (creatinine, estimated glomerular filtration rate)
timeFrame: 12 weeks and 1, 2, 3 years post-randomisation
measure: Incidence and type of malignancies diagnosed in trial participants
timeFrame: 1, 2 and 3 years post-randomisation
measure: Incidence and type of infections (hepatitis C virus, hepatitis B virus, cytomegalovirus, Epstein-Barr virus) experienced by trial participants
timeFrame: 1, 2 and 3 years post-randomisation
measure: Degree of liver fibrosis (fibroscan or biopsy)
timeFrame: 12 weeks and 1, 2, 3 years post-randomisation
measure: Incidence, type, severity, seriousness and causality of adverse events (AEs)
timeFrame: 3 years post-randomisation
measure: Change versus baseline in heart rate
timeFrame: 3 years post-randomisation
measure: Change versus baseline in blood pressure
timeFrame: 3 years post-randomisation
measure: Change versus baseline in body weight
timeFrame: 3 years post-randomisation
measure: Incidence of de novo occurrence of tremor or vision impairments
timeFrame: 3 years post-randomisation
measure: Incidence of post-transplant diabetes mellitus and post-transplant hyperglycaemia
timeFrame: 12 weeks and 1, 2, 3 years post-randomisation
measure: Dose-normalised trough level (C/D ratio)
timeFrame: 12 weeks post-transplantation
measure: Number and doses of immunosuppressive medications (incl. other tacrolimus formulations)
timeFrame: At 12 weeks and after 12 weeks (if applicable)
measure: Recurrence of primary hepatic disease
timeFrame: 3 years post-randomisation
measure: Incidence of donor-specific antibodies
timeFrame: 12 weeks and 1, 2, 3 years post-randomisation
measure: Continuation rate
timeFrame: 12 weeks post-randomisation
measure: Incidence and time to study treatment discontinuation
timeFrame: 3 years post-randomisation
measure: Incidence of patient withdrawal from the study
timeFrame: 3 years post-randomisation
measure: Time to patient withdrawal from the study
timeFrame: 3 years post-randomisation
measure: Reason for patient withdrawal from the study
timeFrame: 3 years post-randomisation
Other outcomes:
Locations:
city: Aachen
country: Germany
facility: University Hospital Aachen
city: Berlin
country: Germany
facility: Charite - University Medicine Berlin
city: Essen
country: Germany
facility: University Hospital Essen
city: Frankfurt
country: Germany
facility: University Hospital Frankfurt
city: Hamburg
country: Germany
facility: University Hospital Hamburg Eppendorf
city: Hannover
country: Germany
facility: Hannover Medical School
city: Heidelberg
country: Germany
facility: University Hospital Heidelberg
city: Jena
country: Germany
facility: University Hospital Jena
city: Kiel
country: Germany
facility: University Hospital Schleswig-Holstein - Campus Kiel
city: Leipzig
country: Germany
facility: University Hospital Leipzig
city: Magdeburg
country: Germany
facility: University Hospital Magdeburg
city: Mainz
country: Germany
facility: University Hospital Mainz
city: Muenster
country: Germany
facility: University Hospital Muenster
city: Regensburg
country: Germany
facility: University Hospital Regensburg
city: Tuebingen
country: Germany
facility: University Hospital Tuebingen
Study officials:
affiliation: University Hospital Regensburg
name: Hans J. Schlitt, MD
role: PRINCIPAL_INVESTIGATOR
References: