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| ID | Type | Description | Link |
|---|---|---|---|
| 2020-000796-20 | EudraCT Number |
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| Name | Class |
|---|---|
| Chiesi Pharmaceuticals GmbH | INDUSTRY |
| Excelya | INDUSTRY |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Envarsus® | Experimental | Participants take prolonged-release tacrolimus tablets orally once daily and additionally receive standard-of-care immunosuppressive background therapy as per routine practice. |
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| 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| 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 |
| Measure | Description | 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Hans J. Schlitt, MD | University Hospital Regensburg | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Hospital Aachen | Aachen | 52074 | Germany | |||
| Charite - University Medicine Berlin |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37170284 | Derived | 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. |
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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.
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| 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. |
|
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| 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 |
| Berlin |
| 13353 |
| Germany |
| University Hospital Essen | Essen | 45147 | Germany |
| University Hospital Frankfurt | Frankfurt | 60590 | Germany |
| University Hospital Hamburg Eppendorf | Hamburg | 20246 | Germany |
| Hannover Medical School | Hanover | 30625 | Germany |
| University Hospital Heidelberg | Heidelberg | 69120 | Germany |
| University Hospital Jena | Jena | 07747 | Germany |
| University Hospital Schleswig-Holstein - Campus Kiel | Kiel | 24105 | Germany |
| University Hospital Leipzig | Leipzig | 04103 | Germany |
| University Hospital Magdeburg | Magdeburg | 39120 | Germany |
| University Hospital Mainz | Mainz | 55131 | Germany |
| University Hospital Muenster | Münster | 48149 | Germany |
| University Hospital Regensburg | Regensburg | 93053 | Germany |
| University Hospital Tuebingen | Tübingen | 72076 | Germany |
| ID | Term |
|---|---|
| D016559 | Tacrolimus |
| ID | Term |
|---|---|
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
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