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NCT Number: NCT04720326

Bioavailability and Practicability of Envarsus Versus Advagraf in Liver Transplant Recipients

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.

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Key information

Conditions

Prophylaxis Against Liver Transplant Rejection

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

University Hospital Aachen, Aachen, Germany

Loading trial locations.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • 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

Exclusion criteria

  • 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)

Treatment and study plan

Tacrolimus Pill

Drug

Envarsus® tablets dosed to achieve and maintain whole blood trough levels of tacrolimus within a patient-specific therapeutic range (interval of 3 ng/ml) that lies within a wider reference range of 3-12 ng/ml.

Other names: Envarsus

Tacrolimus capsule

Drug

Advagraf® capsules dosed to achieve and maintain whole blood trough levels of tacrolimus within a patient-specific therapeutic range (interval of 3 ng/ml) that lies within a wider reference range of 3-12 ng/ml.

Other names: Advagraf

Primary outcomes

  1. Dose-normalised blood trough level of tacrolimus (concentration/dose ratio)

    Time frame: 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 outcomes

  1. Number of IMP dose adjustments

    Time frame: Until 12 weeks post-randomisation

  2. Time to reach the first defined range in target trough level

    Time frame: Time period measured in days, assessed at 12 weeks post-randomisation

  3. Number of measurements above and below the first defined range in target trough level

    Time frame: Time period measured in days, assessed at 12 weeks post-randomisation

  4. Dose-normalised trough level (C/D ratio) during long-term follow-up

    Time frame: 1, 2 and 3 years post-randomisation

  5. Mean tacrolimus trough level and inter-patient variability (range) of tacrolimus trough levels

    Time frame: 1, 2, 4 and 12 weeks post-randomisation

  6. Inter-patient variability (range) of tacrolimus total daily dose

    Time frame: Until 12 weeks post-randomisation

  7. Proportion of patients with trough levels lower, within, or higher than the standard reference range

    Time frame: 1, 2, 4 and 12 weeks post-randomisation

  8. Incidence and severity of clinically-confirmed biopsy-proven acute rejection

    Time frame: 12 weeks and 1, 2, 3 years post-randomisation

  9. Incidence of graft failure (defined as necessity for re-transplantation)

    Time frame: 12 weeks and 1, 2, 3 years post-randomisation

  10. Incidence of death (for any reason)

    Time frame: 12 weeks and 1, 2, 3 years post-randomisation

  11. Treatment failure rate (composite endpoint of biopsy-proven acute rejection, graft failure or death)

    Time frame: 12 weeks and 1, 2, 3 years post-randomisation

  12. Time to treatment failure (composite endpoint of biopsy-proven acute rejection, graft failure or death) after randomisation

    Time frame: 3 years post-randomisation

  13. Incidence of acute rejections requiring treatment

    Time frame: 12 weeks post-randomisation

  14. Incidence of multiple rejection episodes

    Time frame: 12 weeks post-randomisation

  15. Change versus baseline in laboratory measures of liver function (aspartate transaminase, alanine transaminase, alkaline phosphatase, gamma-glutamyltransferase, bilirubin, albumin, cholinesterase, INR)

    Time frame: 12 weeks and 1, 2, 3 years post-randomisation

  16. Change versus baseline in laboratory measures of metabolic profile (triglycerides, HDL cholesterol, LDL cholesterol, total cholesterol, HbA1c, fasting plasma glucose)

    Time frame: 12 weeks and 1, 2, 3 years post-randomisation

  17. Change versus baseline in laboratory measures of renal function (creatinine, estimated glomerular filtration rate)

    Time frame: 12 weeks and 1, 2, 3 years post-randomisation

  18. Incidence and type of malignancies diagnosed in trial participants

    Time frame: 1, 2 and 3 years post-randomisation

  19. Incidence and type of infections (hepatitis C virus, hepatitis B virus, cytomegalovirus, Epstein-Barr virus) experienced by trial participants

    Time frame: 1, 2 and 3 years post-randomisation

  20. Degree of liver fibrosis (fibroscan or biopsy)

    Time frame: 12 weeks and 1, 2, 3 years post-randomisation

  21. Incidence, type, severity, seriousness and causality of adverse events (AEs)

    Time frame: 3 years post-randomisation

  22. Change versus baseline in heart rate

    Time frame: 3 years post-randomisation

  23. Change versus baseline in blood pressure

    Time frame: 3 years post-randomisation

  24. Change versus baseline in body weight

    Time frame: 3 years post-randomisation

  25. Incidence of de novo occurrence of tremor or vision impairments

    Time frame: 3 years post-randomisation

  26. Incidence of post-transplant diabetes mellitus and post-transplant hyperglycaemia

    Time frame: 12 weeks and 1, 2, 3 years post-randomisation

  27. Dose-normalised trough level (C/D ratio)

    Time frame: 12 weeks post-transplantation

  28. Number and doses of immunosuppressive medications (incl. other tacrolimus formulations)

    Time frame: At 12 weeks and after 12 weeks (if applicable)

  29. Recurrence of primary hepatic disease

    Time frame: 3 years post-randomisation

  30. Incidence of donor-specific antibodies

    Time frame: 12 weeks and 1, 2, 3 years post-randomisation

  31. Continuation rate

    Time frame: 12 weeks post-randomisation

  32. Incidence and time to study treatment discontinuation

    Time frame: 3 years post-randomisation

  33. Incidence of patient withdrawal from the study

    Time frame: 3 years post-randomisation

  34. Time to patient withdrawal from the study

    Time frame: 3 years post-randomisation

  35. Reason for patient withdrawal from the study

    Time frame: 3 years post-randomisation

Sponsors and collaborators

Lead sponsor

Edward Geissler

Other

Collaborators

  • Chiesi Pharmaceuticals GmbH
  • Excelya

Registry information

Official study 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)

Important dates

Study start
2020
Primary completion
2024
Study completion
2026
First posted
Jan 22, 2021
Registry last updated
Apr 6, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.