A study to compare the bioavailability and practicability of two immunosuppressive drugs (Envarsus® and Advagraf®) containing the same active substance used to prevent graft rejection in patients who have received a liver transplant for the first time.

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) - EnGraft Study

Status

Active, not recruiting

Phases

Phase 4

Study type

Interventional

Source

EU CTR

Registry ID

EUCTR2020-000796-20-DE

Enrollment

268

Registered

2020-05-04

Start date

2020-09-01

Completion date

Unknown

Last updated

2024-11-04

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Prophylaxis of transplant rejection in adult liver allograft recipients MedDRA version: 21.1 Level: LLT Classification code 10050434 Term: Prophylaxis against liver transplant rejection System Organ Class: 10042613 - Surgical and medical procedures

Interventions

Trade Name: Envarsus® Pharmaceutical Form: Prolonged-release tablet INN or Proposed INN: TACROLIMUS CAS Number: 104987-11-3 Concentration unit: mg milligram(s) Concentration type: equal Concentration

Eligibility

Sex/Gender

All

Inclusion 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 (tablet / capsule) Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 268 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 268

Exclusion criteria

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 BW/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 (SmPC) 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. Participation in another interventional clinical trial during the time period from randomisation to study end, if the trial is testing an IMP (AMG study) 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

Design outcomes

Primary

Measure	Time frame
Main Objective: To compare the bioavailability of two once-daily tacrolimus formulations in de novo liver transplant recipients and show superiority of Envarsus® versus Advagraf® in terms of C/D (concentration/dose) ratio after 12 weeks of therapy. C/D ratio is used as an estimate of tacrolimus bioavailability.;Secondary Objective: To compare practicability (handling) of Envarsus® versus Advagraf® in terms of ease of dosing and stability of blood trough level using various pharmacokinetic parameters including time to reach the first defined range in target trough level, number of measurements above and below the target trough level, and number of dose adjustments of Envarsus® vs. Advagraf® until 12 weeks, especially in fast metabolisers (i.e. the one third of all patients with the lowest C/D ratio within their treatment group), intermediate (middle third) and slow metabolisers (top third). Additionally, to compare: • Hepatic and renal function at 12 weeks • Incidence of treatment failure as a composite endpoint (BPAR, graft failure or death) and incidence of the individual components at 12 weeks • Long-term efficacy, safety and continuation of Envarsus® versus Advagraf® over 3 years;Primary end point(s): Dose-normalised trough level (C/D ratio) measured 12 weeks after randomisation;Timepoint(s) of evaluation of this end point: C/D ratio will be evaluated at 12 weeks after patient randomisation.	—

Measure

Time frame

Main Objective: To compare the bioavailability of two once-daily tacrolimus formulations in de novo liver transplant recipients and show superiority of Envarsus® versus Advagraf® in terms of C/D (concentration/dose) ratio after 12 weeks of therapy. C/D ratio is used as an estimate of tacrolimus bioavailability.;Secondary Objective: To compare practicability (handling) of Envarsus® versus Advagraf® in terms of ease of dosing and stability of blood trough level using various pharmacokinetic parameters including time to reach the first defined range in target trough level, number of measurements above and below the target trough level, and number of dose adjustments of Envarsus® vs. Advagraf® until 12 weeks, especially in fast metabolisers (i.e. the one third of all patients with the lowest C/D ratio within their treatment group), intermediate (middle third) and slow metabolisers (top third). Additionally, to compare: • Hepatic and renal function at 12 weeks • Incidence of treatment failure as a composite endpoint (BPAR, graft failure or death) and incidence of the individual components at 12 weeks • Long-term efficacy, safety and continuation of Envarsus® versus Advagraf® over 3 years;Primary end point(s): Dose-normalised trough level (C/D ratio) measured 12 weeks after randomisation;Timepoint(s) of evaluation of this end point: C/D ratio will be evaluated at 12 weeks after patient randomisation.

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Secondary

Measure	Time frame
Secondary end point(s): Pharmacokinetic variables to assess treatment practicability: • Number of IMP dose adjustments until 12 weeks • Time to reach the first defined range in target trough level • Number of measurements above and below the first defined range in target trough level • Dose-normalised trough level (C/D ratio) measured at 1, 2 and 3 years • Mean tacrolimus trough level and inter-patient variability (range) of tacrolimus trough levels at 1, 2, 4 and 12 weeks • Inter-patient variability (range) of tacrolimus total daily dose until 12 weeks • Proportion of patients with trough levels lower, within, or higher than the standard reference range at 1, 2, 4 and 12 weeks Efficacy variables: • Incidence and severity (BANFF criteria) of clinically-confirmed BPAR at 12 weeks and 1, 2, 3 years • Incidence of graft failure (defined as necessity for re-transplantation) at 12 weeks and 1, 2, 3 years • Incidence of death (for any reason) at 12 weeks and 1, 2, 3 years • Treatment failure rate (composite endpoint of BPAR, graft failure or death) at 12 weeks and 1, 2, 3 years • Time to treatment failure (composite endpoint of BPAR, graft failure or death) after randomisation • Incidence of acute rejections requiring treatment at 12 weeks • Incidence of multiple rejection episodes at 12 weeks Safety variables: • Laboratory measures at 12 weeks and 1, 2, 3 years: Liver function (GOT, GPT, AP, GGT, bilirubin, albumin, ChE, INR), Metabolic profile (triglycerides, HDL cholesterol, LDL cholesterol, total cholesterol, HbA1c, fasting plasma glucose), Renal function (creatinine, eGFR) • Malignancies at 1, 2 and 3 years • Infections (HCV, HBV, CMV, EBV) at 1, 2 and 3 years • Degree of liver fibrosis (fibroscan or biopsy) at 12 weeks and 1, 2, 3 years • Incidence, type, severity, seriousness and causality of adverse events (AEs) • Change vs. baseline in vital signs (heart rate, blood pressure) and body weight • Incidence of de novo occurrence of tremor or vision impairments •	—

Measure

Time frame

Secondary end point(s): Pharmacokinetic variables to assess treatment practicability: • Number of IMP dose adjustments until 12 weeks • Time to reach the first defined range in target trough level • Number of measurements above and below the first defined range in target trough level • Dose-normalised trough level (C/D ratio) measured at 1, 2 and 3 years • Mean tacrolimus trough level and inter-patient variability (range) of tacrolimus trough levels at 1, 2, 4 and 12 weeks • Inter-patient variability (range) of tacrolimus total daily dose until 12 weeks • Proportion of patients with trough levels lower, within, or higher than the standard reference range at 1, 2, 4 and 12 weeks Efficacy variables: • Incidence and severity (BANFF criteria) of clinically-confirmed BPAR at 12 weeks and 1, 2, 3 years • Incidence of graft failure (defined as necessity for re-transplantation) at 12 weeks and 1, 2, 3 years • Incidence of death (for any reason) at 12 weeks and 1, 2, 3 years • Treatment failure rate (composite endpoint of BPAR, graft failure or death) at 12 weeks and 1, 2, 3 years • Time to treatment failure (composite endpoint of BPAR, graft failure or death) after randomisation • Incidence of acute rejections requiring treatment at 12 weeks • Incidence of multiple rejection episodes at 12 weeks Safety variables: • Laboratory measures at 12 weeks and 1, 2, 3 years: Liver function (GOT, GPT, AP, GGT, bilirubin, albumin, ChE, INR), Metabolic profile (triglycerides, HDL cholesterol, LDL cholesterol, total cholesterol, HbA1c, fasting plasma glucose), Renal function (creatinine, eGFR) • Malignancies at 1, 2 and 3 years • Infections (HCV, HBV, CMV, EBV) at 1, 2 and 3 years • Degree of liver fibrosis (fibroscan or biopsy) at 12 weeks and 1, 2, 3 years • Incidence, type, severity, seriousness and causality of adverse events (AEs) • Change vs. baseline in vital signs (heart rate, blood pressure) and body weight • Incidence of de novo occurrence of tremor or vision impairments •

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Countries

Germany

Contacts

Public ContactcoTrial Associates

University Hospital Regensburg

ben.james@ukr.de+499419444895

Outcome results

None listed

Source: EU CTR (via WHO ICTRP) · Data processed: Feb 4, 2026