Bioavailability and Practicability of Envarsus Versus Advagraf in Liver Transplant Recipients

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)

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.

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)