Evaluation of Tacrolimus and Mycophenolate Mofetil in Immunosuppressive Regimens for Liver Transplant Recipients: A Comparative Study

The primary objective of this study is to demonstrate that in liver transplant recipients, an immunosuppressive strategy based on mycophenolate mofetil (MMF) administered once daily (QD) starting at six months post-transplantation is not inferior to MMF administered twice daily (BID) in terms of the incidence of treatment failure at 18 months post-transplantation. If this is demonstrated, the study will further aim to show that LCP-tacrolimus (ENVARSUS®) is equivalent to XR-tacrolimus (ADVAGRAF®) QD in terms of treatment failure incidence at six months post-transplantation. The clinical relevance of these objectives lies in optimizing immunosuppressive regimens to potentially improve patient adherence, reduce adverse effects, and maintain graft function.

Secondary objectives include: - Evaluating the equivalence of LCP-tacrolimus to XR-tacrolimus in terms of treatment failure incidence at 18 months post-transplantation. - Comparing the incidence of death, graft loss, and biopsy-proven acute rejection between the four study arms at 6 and 18 months post-transplantation. - Assessing the impact of LCP-tacrolimus versus XR-tacrolimus on adherence and health-related quality of life at 18 months post-transplantation. - Comparing the incidence of adverse events such as gastrointestinal disorders, CMV infections, neutropenia, sepsis, renal function impairment, new onset post-transplant diabetes mellitus, hypertension, hyperlipidemia, and tremor over 18 months. - Evaluating the benefits of switching from MMF BID to MMF QD in terms of adherence, health-related quality of life, and adverse events. - Comparing the average daily exposure to tacrolimus and mycophenolic acid, as well as tacrolimus and MPA dose metrics, between the study arms at each post-transplantation period.

The clinical trial involves **liver transplantation** recipients, specifically targeting male and female patients aged 18 and older. Participants are recipients of a first liver allograft from a deceased donor and must have been transplanted for less than four weeks at the time of enrollment. The study population is required to be free from any inter-current progressive life-threatening or graft-threatening diseases. All participants have provided written informed consent and are affiliated with or beneficiaries of a social security regimen. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of administering **immunosuppressive** drugs as single daily doses in liver transplant recipients. This is a randomized, double-blind, controlled trial with a primary objective to demonstrate that an immunosuppressive strategy based on mycophenolate mofetil (MMF) once daily (QD) is not inferior to MMF administered twice daily (BID) in terms of treatment failure incidence at 18 months post-transplantation. The trial will also assess the equivalence of LCP-tacrolimus (ENVARSUS®) to XR-tacrolimus (ADVAGRAF®) in terms of treatment failure incidence at six months post-transplantation. The trial is expected to commence recruitment on September 2, 2024, and conclude by September 2, 2027, with a maximum treatment period of 18 months for participants.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, recent liver transplantation, and absence of life-threatening conditions. Follow-up visits will occur at regular intervals to monitor treatment adherence, adverse events, and primary and secondary endpoints, including patient death, graft loss, and biopsy-proven acute rejection. The end-of-study visit will assess the final outcomes and gather data on the long-term effects of the treatment regimens. Participant involvement is expected to last up to 18 months, with conditions for early termination including significant adverse events or withdrawal of consent.

The trial will include male and female patients aged 18 and older who have received a first liver allograft from a deceased donor and have been transplanted for less than four weeks at enrollment. Participants must have signed a written informed consent and be affiliated with a social security regimen. The primary endpoint is a composite measure of treatment failure, defined by events such as patient death, graft loss, or acute rejection with a rejection activity index score of 4 or higher. Secondary endpoints will compare various outcomes between different treatment arms, including the proportion of deaths, graft losses, and non-adherence rates, as well as quality of life measures and adverse event incidences.

The clinical trial involves the administration of several **immunosuppressant** medications, primarily focusing on the active substance **tacrolimus**. The experimental medications include Advagraf and Envarsus, both of which are prolonged-release formulations designed for oral use. Advagraf is available in hard capsule form with dosages of 0.5 mg, 1 mg, 3 mg, and 5 mg. The maximum daily dose for Advagraf is 100 mg, with a total maximum dose of 54,750 mg over a treatment period of up to 18 months. Envarsus is provided in tablet form with dosages of 0.75 mg, 1 mg, and 4 mg, sharing the same maximum daily and total dose limits as Advagraf. Both medications are administered once daily.

In addition to the experimental medications, the trial includes the use of CellCept, which contains the active substance **mycophenolate mofetil**. CellCept is available in two pharmaceutical forms: 250 mg hard capsules and 500 mg film-coated tablets. The maximum daily dose for CellCept is 4000 mg, with a total maximum dose of 2190 g over the same 18-month treatment period. CellCept is also administered orally, and its dosing schedule is determined based on the specific requirements of the trial protocol.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial aims to evaluate the efficacy and safety of these immunosuppressive strategies in liver transplant recipients, with a focus on the incidence of treatment failure as defined by a composite endpoint. The trial's objective is to demonstrate the non-inferiority and equivalence of the experimental medications compared to standard treatment regimens.

Efficacy in this clinical trial will be assessed using a composite endpoint termed "treatment failure." This endpoint is defined by the occurrence of any of the following events: patient death, graft loss, or biopsy-proven acute rejection with a rejection activity index score of 4 or higher according to the Banff criteria. The primary objective is to evaluate the incidence of treatment failure at 18 months post-transplantation for patients on Envarsus® compared to those on MMF administered twice daily (BID). If non-inferiority is demonstrated, the secondary objective will assess the equivalence of LCP-tacrolimus (Envarsus®) to XR-tacrolimus (Advagraf®) in terms of treatment failure incidence at six months post-transplantation.

Secondary endpoints include comparisons between patients on XR-tacrolimus and LCP-tacrolimus at 18 months post-transplantation regarding the proportion of deaths, graft losses, and biopsy-proven acute rejection with an activity score of 4 or higher. Additional comparisons will be made between the four study arms at six and 18 months post-transplantation, focusing on the same parameters. Other secondary endpoints involve evaluating the proportion of non-adherent patients, mean Physical Component Summary (PCS-QOL) and Mental Component Summary (MCS-QOL) scores, and the incidence of adverse events of interest. Furthermore, pharmacokinetic parameters such as mean tacrolimus and MPA AUC0-24h, mean tacrolimus C0/dose, and AUC0-24h/dose will be compared across the four arms at each post-transplantation period.