Bioavailability and Practicability of Envarsus Versus Advagraf in Liver Transplant Recipients

NCT04720326 | Active Not Recruiting Phase 4

• 2 other identifiers: EnGraft2020-000796-20
• Study Type: interventional
• Target: 268
• Locations: 1 country
• Sites: 15

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

Keywords

Liver transplantation; Tacrolimus; Concentration/dose ratio; Immunosuppression

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (35)

• 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

Study Arms (2)

Envarsus®

EXPERIMENTAL

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

Advagraf®

ACTIVE COMPARATOR

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

Interventions

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.

Also known as: Envarsus

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.

Also known as: Advagraf

Advagraf®

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Edward Geissler: lead
• Chiesi Pharmaceuticals GmbH: collaborator
• Excelya: collaborator

Study Sites (15)

University Hospital Aachen

Aachen, 52074, Germany

Location

Charite - University Medicine Berlin

Berlin, 13353, Germany

Location

University Hospital Essen

Essen, 45147, Germany

Location

University Hospital Frankfurt

Frankfurt, 60590, Germany

Location

University Hospital Hamburg Eppendorf

Hamburg, 20246, Germany

Location

Hannover Medical School

Hanover, 30625, Germany

Location

University Hospital Heidelberg

Heidelberg, 69120, Germany

Location

University Hospital Jena

Jena, 07747, Germany

Location

University Hospital Schleswig-Holstein - Campus Kiel

Kiel, 24105, Germany

Location

University Hospital Leipzig

Leipzig, 04103, Germany

Location

University Hospital Magdeburg

Magdeburg, 39120, Germany

Location

University Hospital Mainz

Mainz, 55131, Germany

Location

University Hospital Muenster

Münster, 48149, Germany

Location

University Hospital Regensburg

Regensburg, 93053, Germany

Location

University Hospital Tuebingen

Tübingen, 72076, Germany

Location

Related Publications (1)

• 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.

  PMID: 37170284 DERIVED

MeSH Terms

Interventions

Tacrolimus

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Officials

• Hans J. Schlitt, MD

  University Hospital Regensburg

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Head of the Department of Experimental Surgery

Model Details: 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.

Study Record Dates

• First Submitted: December 15, 2020
• First Posted: January 22, 2021
• Study Start: December 23, 2020
• Primary Completion: January 25, 2024
• Study Completion (Estimated): October 1, 2026
• Last Updated: April 6, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

DE (15)