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.

Study Overview

• Status: Active, not recruiting
• Conditions: Prophylaxis Against Liver Transplant Rejection
• Intervention / Treatment: Drug: Tacrolimus Pill; Drug: Tacrolimus capsule

• Study Type: Interventional
• Enrollment (Actual): 268
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Edward K. Geissler, PhD; Phone Number: 6964 +49 941 944; Email: edward.geissler@ukr.de

Study Locations

• Germany
  • Aachen, Germany, 52074
    • University Hospital Aachen
  • Berlin, Germany, 13353
    • Charité - University Medicine Berlin
  • Essen, Germany, 45147
    • University Hospital Essen
  • Frankfurt, Germany, 60590
    • University Hospital Frankfurt
  • Hamburg, Germany, 20246
    • University Hospital Hamburg Eppendorf
  • Hannover, Germany, 30625
    • Hannover Medical School
  • Heidelberg, Germany, 69120
    • University Hospital Heidelberg
  • Jena, Germany, 07747
    • University Hospital Jena
  • Kiel, Germany, 24105
    • University Hospital Schleswig-Holstein - Campus Kiel
  • Leipzig, Germany, 04103
    • University Hospital Leipzig
  • Magdeburg, Germany, 39120
    • University Hospital Magdeburg
  • Mainz, Germany, 55131
    • University Hospital Mainz
  • Muenster, Germany, 48149
    • University Hospital Muenster
  • Regensburg, Germany, 93053
    • University Hospital Regensburg
  • Tuebingen, Germany, 72076
    • University Hospital Tuebingen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Envarsus®; Participants take prolonged-release tacrolimus tablets orally once daily and additionally receive standard-of-care immunosuppressive background therapy as per routine practice.	Drug: Tacrolimus Pill; 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
Active Comparator: Advagraf®; Participants take prolonged-release tacrolimus capsules orally once daily and additionally receive standard-of-care immunosuppressive background therapy as per routine practice.	Drug: Tacrolimus capsule; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose-normalised blood trough level of tacrolimus (concentration/dose ratio)	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).	12 weeks post-randomisation

Secondary Outcome Measures

Outcome Measure	Time Frame
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
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
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

Collaborators and Investigators

• Sponsor: Edward Geissler
• Collaborators: Excelya; Chiesi Pharmaceuticals GmbH
• Investigators: Principal Investigator: Hans J. Schlitt, MD, University Hospital Regensburg

Study record dates

Study Major Dates

• Study Start (Actual): December 23, 2020
• Primary Completion (Actual): January 25, 2024
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: December 15, 2020
• First Submitted That Met QC Criteria: January 21, 2021
• First Posted (Actual): January 22, 2021

Study Record Updates

• Last Update Posted (Estimated): February 15, 2024
• Last Update Submitted That Met QC Criteria: February 13, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Liver transplantation; Immunosuppression; Tacrolimus; Concentration/dose ratio
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: EnGraft; 2020-000796-20 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No