Bioavailability and Practicability of Envarsus Versus Advagraf in Liver Transplant Recipients

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Prophylaxis Against Liver Transplant Rejection

Intervention / Treatment
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* Drug: Tacrolimus Pill
* Drug: Tacrolimus capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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 Inability to freely give informed consent (e.g. individuals under legal guardianship)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Envarsus®<br>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<br>* 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.<br>* Other names: Envarsus;|
| Active Comparator: Advagraf®<br>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<br>* 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.<br>* Other names: Advagraf;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver transplantation, Tacrolimus, Concentration/dose ratio, Immunosuppression