Comparative Study of Tacrolimus Bioavailability: Envarsus vs. Advagraf in De Novo Liver Transplant Recipients

The primary objective of this study is to compare the **bioavailability** of two once-daily tacrolimus formulations, Envarsus® and Advagraf®, in de novo liver transplant recipients. The study aims to demonstrate the superiority of Envarsus® over Advagraf® in terms of the concentration/dose (C/D) ratio after 12 weeks of therapy. The C/D ratio is a recently identified parameter used to estimate tacrolimus bioavailability, which is crucial for optimizing immunosuppressive therapy and minimizing the risk of transplant rejection.

Secondary objectives include:

• Comparing the practicability of the two treatments in terms of ease of dosing and stability of blood trough levels.
• Measuring the efficacy and safety of both treatments.

The clinical trial involves **adult** participants who are recipients of a whole or split liver transplant, either from a deceased or living donor, and are undergoing prophylaxis for transplant rejection. The study population includes both **male** and **female** subjects aged 18 years and older. Participants are required to have an ABO blood type compatible with the organ donor and must be capable of swallowing an oral formulation of tacrolimus in tablet or capsule form. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that participants are suitable for evaluating the bioavailability of two tacrolimus formulations, with the aim of demonstrating the superiority of Envarsus® over Advagraf® in terms of the concentration/dose ratio after 12 weeks of therapy.

The clinical trial is designed as a **randomized**, open-label, two-arm, parallel-group, superiority study aimed at assessing the **bioavailability** and practicability of Envarsus® compared with Advagraf® in de novo liver transplant recipients. The primary objective is to compare the bioavailability of two once-daily **tacrolimus** formulations and demonstrate the superiority of Envarsus® over Advagraf® in terms of the concentration/dose (C/D) ratio after 12 weeks of therapy. The trial is expected to run from December 1, 2020, to December 31, 2026, with a maximum treatment period of 36 months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), liver transplant status, and ability to swallow oral formulations of tacrolimus. Following randomization, participants will attend follow-up visits at 1, 2, 4, and 12 weeks, with additional assessments at 1, 2, and 3 years. These visits will monitor the primary endpoint, which is the dose-normalized trough level (C/D ratio) at 12 weeks, as well as secondary endpoints including the number of dose adjustments, time to reach target trough levels, and incidence of adverse events.

The expected length of participant involvement is up to 36 months, with conditions for early termination including significant adverse events, withdrawal of consent, or non-compliance with study procedures. The trial will also evaluate the incidence of graft failure, acute rejection episodes, and other clinical outcomes over the study duration. The study aims to provide comprehensive data on the efficacy and safety of the tacrolimus formulations in the context of liver transplant rejection prophylaxis.

The clinical trial involves the administration of **Envarsus** 1 mg prolonged-release tablets, which contain the active substance **tacrolimus**. These tablets are formulated for oral administration and are designed to release the active ingredient gradually over time. The maximum daily dose is 0.17 mg/kg, with a total maximum dose of 186.15 mg/kg over a treatment period of up to 36 months. Participant compliance is monitored through regular assessments of drug levels in the bloodstream to ensure adherence to the dosing schedule.

**Advagraf** 0.5 mg, 1 mg, 3 mg, and 5 mg prolonged-release hard capsules are also used in the study. These capsules contain **tacrolimus** as the active ingredient and are administered orally. The maximum daily dose for these formulations is 0.30 mg/kg, with a total maximum dose of 328.50 mg/kg over a 36-month treatment period. The prolonged-release formulation ensures a steady release of the medication, and participant compliance is similarly monitored through blood level assessments.

Additionally, **Envarsus** 0.75 mg and 4 mg prolonged-release tablets are included in the trial. These tablets also contain **tacrolimus** and are administered orally. The dosing regimen is consistent with the 1 mg formulation, with a maximum daily dose of 0.17 mg/kg and a total maximum dose of 186.15 mg/kg over the treatment period. Compliance monitoring is conducted to ensure proper adherence to the dosing schedule.

Non-experimental treatments in the study include the use of **interleukin inhibitors** and **glucocorticoids**. These are categorized under the ATC codes L04AC and H02AB, respectively. The pharmaceutical forms and routes of administration for these treatments are not specified, and they are used as auxiliary treatments within the trial. The role of these treatments is to support the primary objective of comparing the bioavailability of the tacrolimus formulations.

Efficacy in this clinical trial will be assessed by evaluating the bioavailability of two once-daily tacrolimus formulations, Envarsus® and Advagraf®, in de novo liver transplant recipients. The primary endpoint for efficacy is the dose-normalised trough level, or **C/D ratio**, measured at 12 weeks. This parameter serves as an estimate of tacrolimus bioavailability and is crucial for determining the superiority of Envarsus® over Advagraf®.

Secondary endpoints include a variety of measures to further assess efficacy and safety. These include the number of investigational medicinal product (IMP) dose adjustments until 12 weeks, time to reach the first defined range in target trough level, and the number of measurements above and below this range. Additional secondary endpoints involve the mean tacrolimus trough level and inter-patient variability at various time points (1, 2, 4, and 12 weeks), as well as the incidence and severity of clinically-confirmed biopsy-proven acute rejection (BPAR) at 12 weeks and up to 3 years. Other important measures include the incidence of graft failure, death, and treatment failure rates, as well as laboratory measures of liver function, metabolic profile, and renal function at specified intervals.

The trial will also monitor the incidence of adverse events, changes in vital signs, and the occurrence of post-transplant diabetes mellitus and hyperglycemia. The schedule for measuring these parameters includes assessments at 12 weeks and at 1, 2, and 3 years post-transplantation. The data collected will be analyzed to determine the efficacy of the tacrolimus formulations in maintaining appropriate drug levels and preventing transplant-related complications.