Bioavailability and Practicability of Envarsus Versus Advagraf in Liver Transplant Recipients

Phase 4Active Not RecruitingNCT04720326

Edward Geissler268 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

NONE

Enrollment

268

Conditions

Prophylaxis Against Liver Transplant Rejection

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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)

Outcomes

Primary Outcomes

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).

Time frame: 12 weeks post-randomisation

Secondary Outcomes

Number of IMP dose adjustments

Time frame: 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

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

Dose-normalised trough level (C/D ratio) during long-term follow-up

Time frame: 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

Inter-patient variability (range) of tacrolimus total daily dose

Time frame: 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

Incidence and severity of clinically-confirmed biopsy-proven acute rejection

Time frame: 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

Incidence of death (for any reason)

Time frame: 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

Time to treatment failure (composite endpoint of biopsy-proven acute rejection, graft failure or death) after randomisation

Time frame: 3 years post-randomisation

Incidence of acute rejections requiring treatment

Time frame: 12 weeks post-randomisation

Incidence of multiple rejection episodes

Time frame: 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

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

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

Incidence and type of malignancies diagnosed in trial participants

Time frame: 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

Degree of liver fibrosis (fibroscan or biopsy)

Time frame: 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

Change versus baseline in heart rate

Time frame: 3 years post-randomisation

Change versus baseline in blood pressure

Time frame: 3 years post-randomisation

Change versus baseline in body weight

Time frame: 3 years post-randomisation

Incidence of de novo occurrence of tremor or vision impairments

Time frame: 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

Dose-normalised trough level (C/D ratio)

Time frame: 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)

Recurrence of primary hepatic disease

Time frame: 3 years post-randomisation

Incidence of donor-specific antibodies

Time frame: 12 weeks and 1, 2, 3 years post-randomisation

Continuation rate

Time frame: 12 weeks post-randomisation

Incidence and time to study treatment discontinuation

Time frame: 3 years post-randomisation

Incidence of patient withdrawal from the study

Time frame: 3 years post-randomisation

Time to patient withdrawal from the study

Time frame: 3 years post-randomisation

Reason for patient withdrawal from the study

Time frame: 3 years post-randomisation

Bioavailability and Practicability of Envarsus Versus Advagraf in Liver Transplant Recipients

Overview

Conditions

Interventions

Eligibility

Locations (15)

Outcomes

Primary Outcomes

Secondary Outcomes