Bioavailability and Practicability of Envarsus Versus Advagraf in Liver Transplant Recipients

NCT ID: NCT04720326

Last Updated: 2025-04-06

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 268 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-12-23
• Study Completion Date: 2026-10-31

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.

Conditions

Prophylaxis Against Liver Transplant Rejection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Envarsus®

Participants take prolonged-release tacrolimus tablets orally once daily and additionally receive standard-of-care immunosuppressive background therapy as per routine practice.

Group Type: EXPERIMENTAL

Tacrolimus Pill

Intervention Type: 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.

Advagraf®

Participants take prolonged-release tacrolimus capsules orally once daily and additionally receive standard-of-care immunosuppressive background therapy as per routine practice.

Group Type: ACTIVE_COMPARATOR

Tacrolimus capsule

Intervention Type: 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.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Envarsus; Advagraf

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)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Chiesi Pharmaceuticals GmbH

INDUSTRY

Sponsor Role: collaborator

Excelya

INDUSTRY

Sponsor Role: collaborator

Edward Geissler

OTHER

Sponsor Role: lead

Responsible Party

Edward Geissler

Head of the Department of Experimental Surgery

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Hans J. Schlitt, MD

Role: PRINCIPAL_INVESTIGATOR

University Hospital Regensburg

Locations

University Hospital Aachen

Aachen, , Germany

Charite - University Medicine Berlin

Berlin, , Germany

University Hospital Essen

Essen, , Germany

University Hospital Frankfurt

Frankfurt, , Germany

University Hospital Hamburg Eppendorf

Hamburg, , Germany

Hannover Medical School

Hanover, , Germany

University Hospital Heidelberg

Heidelberg, , Germany

University Hospital Jena

Jena, , Germany

University Hospital Schleswig-Holstein - Campus Kiel

Kiel, , Germany

University Hospital Leipzig

Leipzig, , Germany

University Hospital Magdeburg

Magdeburg, , Germany

University Hospital Mainz

Mainz, , Germany

University Hospital Muenster

Münster, , Germany

University Hospital Regensburg

Regensburg, , Germany

University Hospital Tuebingen

Tübingen, , Germany

Countries

Germany

References

Wohl DS, James B, Gotz M, Brennfleck F, Holub-Hayles I, Mutzbauer I, Baccar S, Brunner SM, Geissler EK, Schlitt HJ; EnGraft Trial Group. EnGraft: a multicentre, open-label, randomised, two-arm, superiority study protocol to assess bioavailability and practicability of Envarsus(R) versus Advagraf in liver transplant recipients. Trials. 2023 May 11;24(1):325. doi: 10.1186/s13063-023-07344-7.

Reference Type: DERIVED

PMID: 37170284 (View on PubMed)

Other Identifiers

2020-000796-20

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

EnGraft

Identifier Type: -

Identifier Source: org_study_id