Bioavailability and Practicability of Envarsus Versus Advagraf in Liver Transplant Recipients

April 3, 2025 updated by: Edward Geissler

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

Status

Indicates the current recruitment status or the expanded access status.
Active, not recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
268

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

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

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
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).
12 weeks post-randomisation

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Time Frame
Number of IMP dose adjustments
Time Frame: Until 12 weeks post-randomisation
Until 12 weeks post-randomisation
Time to reach the first defined range in target trough level
Time Frame: Time period measured in days, assessed at 12 weeks post-randomisation
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 Frame: Time period measured in days, assessed at 12 weeks post-randomisation
Time period measured in days, assessed at 12 weeks post-randomisation
Dose-normalised trough level (C/D ratio) during long-term follow-up
Time Frame: 1, 2 and 3 years post-randomisation
1, 2 and 3 years post-randomisation
Mean tacrolimus trough level and inter-patient variability (range) of tacrolimus trough levels
Time Frame: 1, 2, 4 and 12 weeks post-randomisation
1, 2, 4 and 12 weeks post-randomisation
Inter-patient variability (range) of tacrolimus total daily dose
Time Frame: Until 12 weeks post-randomisation
Until 12 weeks post-randomisation
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
1, 2, 4 and 12 weeks post-randomisation
Incidence and severity of clinically-confirmed biopsy-proven acute rejection
Time Frame: 12 weeks and 1, 2, 3 years post-randomisation
12 weeks and 1, 2, 3 years post-randomisation
Incidence of graft failure (defined as necessity for re-transplantation)
Time Frame: 12 weeks and 1, 2, 3 years post-randomisation
12 weeks and 1, 2, 3 years post-randomisation
Incidence of death (for any reason)
Time Frame: 12 weeks and 1, 2, 3 years post-randomisation
12 weeks and 1, 2, 3 years post-randomisation
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 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
Time Frame: 3 years post-randomisation
3 years post-randomisation
Incidence of acute rejections requiring treatment
Time Frame: 12 weeks post-randomisation
12 weeks post-randomisation
Incidence of multiple rejection episodes
Time Frame: 12 weeks post-randomisation
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)
Time Frame: 12 weeks and 1, 2, 3 years post-randomisation
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)
Time Frame: 12 weeks and 1, 2, 3 years post-randomisation
12 weeks and 1, 2, 3 years post-randomisation
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
12 weeks and 1, 2, 3 years post-randomisation
Incidence and type of malignancies diagnosed in trial participants
Time Frame: 1, 2 and 3 years post-randomisation
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
Time Frame: 1, 2 and 3 years post-randomisation
1, 2 and 3 years post-randomisation
Degree of liver fibrosis (fibroscan or biopsy)
Time Frame: 12 weeks and 1, 2, 3 years post-randomisation
12 weeks and 1, 2, 3 years post-randomisation
Incidence, type, severity, seriousness and causality of adverse events (AEs)
Time Frame: 3 years post-randomisation
3 years post-randomisation
Change versus baseline in heart rate
Time Frame: 3 years post-randomisation
3 years post-randomisation
Change versus baseline in blood pressure
Time Frame: 3 years post-randomisation
3 years post-randomisation
Change versus baseline in body weight
Time Frame: 3 years post-randomisation
3 years post-randomisation
Incidence of de novo occurrence of tremor or vision impairments
Time Frame: 3 years post-randomisation
3 years post-randomisation
Incidence of post-transplant diabetes mellitus and post-transplant hyperglycaemia
Time Frame: 12 weeks and 1, 2, 3 years post-randomisation
12 weeks and 1, 2, 3 years post-randomisation
Dose-normalised trough level (C/D ratio)
Time Frame: 12 weeks post-transplantation
12 weeks post-transplantation
Number and doses of immunosuppressive medications (incl. other tacrolimus formulations)
Time Frame: At 12 weeks and after 12 weeks (if applicable)
At 12 weeks and after 12 weeks (if applicable)
Recurrence of primary hepatic disease
Time Frame: 3 years post-randomisation
3 years post-randomisation
Incidence of donor-specific antibodies
Time Frame: 12 weeks and 1, 2, 3 years post-randomisation
12 weeks and 1, 2, 3 years post-randomisation
Continuation rate
Time Frame: 12 weeks post-randomisation
12 weeks post-randomisation
Incidence and time to study treatment discontinuation
Time Frame: 3 years post-randomisation
3 years post-randomisation
Incidence of patient withdrawal from the study
Time Frame: 3 years post-randomisation
3 years post-randomisation
Time to patient withdrawal from the study
Time Frame: 3 years post-randomisation
3 years post-randomisation
Reason for patient withdrawal from the study
Time Frame: 3 years post-randomisation
3 years post-randomisation

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Edward Geissler

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Excelya
Chiesi Pharmaceuticals GmbH

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Hans J. Schlitt, MD, University Hospital Regensburg

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
December 23, 2020

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
January 25, 2024

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
October 1, 2026

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 15, 2020

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 21, 2021

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 22, 2021

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
April 6, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 3, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
April 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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