Evaluation of the Benefits of Administering Immunosuppressive Drugs as Single Daily Doses Over the First Year After Liver Transplantation (EASY) (EASY)

March 16, 2026 updated by: University Hospital, Limoges

Evaluation of the Benefits of Administering Immunosuppressive Drugs as Single Daily Doses Over the First Year After Liver Transplantation

World Health Organization considers non-adherence has a strong negative impact on the health of patients with chronic diseases. In transplantation, adherence to immunosuppressive drug regimens associates with late rejection and graft loss making it a critical determinant of patient outcome. The prevalence of non-adherence in transplant patients, including liver transplant patients, can be as high as 40%. Among others, life-long intake and complexity of immunosuppressive regimen make patients prone to non-adherence. For instance, non-adherence is more prevalent among patients with higher numbers of immunosuppressive drugs. One of the most commonly cited causes of non-adherence is forgetfulness and disruptions in routine, with the evening dose of twice daily regimens being the most likely to be affected6. Besides non-adherence, the constraints generated in everyday life by immunosuppression (including timely and regular drug intake) and the complexity of the immunosuppressive regimens represent a burden for the patients and are probably associated with a health-related quality of life deterioration. Therefore, long-term adherence and quality of life after liver transplantation might be improved by using a well-tolerated and easy-to-handle immunosuppressive regimen.

The immunosuppressive regimen after liver transplantation is in most cases based on different combinations of tacrolimus, mycophenolate mofetil and corticosteroids. While corticosteroids are administered once daily, tacrolimus can be administered either twice-daily (BID) as an immediate-release, or once-daily (QD) as an extended-release formulation. Among once-daily tacrolimus formulations, LCP-tacrolimus (ENVARSUS XR®) is approved for the prevention of transplant rejection in adult liver allograft recipients. It has demonstrated similar outcomes compared to immediate-release tacrolimus BID, in both kidney and liver transplantation. Mycophenolate has only been approved for BID administration, preventing from taking all immunosuppressive drugs once daily. Yet, single daily dosing would probably contribute to better adherence and quality of life in patients receiving a life-long treatment.

Although the half-life of mycophenolic acid (MPA), the active moiety of mycophenolate mofetil (MMF) is compatible with once-daily administration, no published randomized clinical study has ever evaluated the efficacy and safety of MMF administered QD.

The narrow therapeutic index and wide pharmacokinetic variability of tacrolimus and mycophenolate justify individual dose adjustment by means of therapeutic drug monitoring (TDM), in order to minimize the risk of acute rejection and the occurrence of adverse events. For tacrolimus, TDM is generally based on the trough concentration (C0) and sometimes on the area under the concentration-time curve (AUC), while for mycophenolate it should be based on the AUC of MPA. However, the dose adjustment of MMF in liver transplant patients is most of the time performed a posteriori, based on clinical signs of inefficacy of toxicity.

Limited sampling strategies with maximum a posteriori Bayesian estimation have been developed by our team for both molecules in adult liver transplant patients to estimate their AUC, which is considered the best marker of exposure for both. Therefore, tacrolimus AUC0-24h can be estimated by Bayesian estimation using samples collected before administration (C0), 8 (C8h) and 12 (C12h) hours after the administration of ENVARSUS XR®, or 1 and 3 hours after the administration of PROGRAF® and ADVAGRAF®. For mycophenolate, the MPA AUC can be estimated using samples collected 20 min, 1 and 3 hours after MMF administration, by Bayesian estimation.

Even if limited to 2 or 3 blood samples, tacrolimus TDM for ENVARSUS® requires late sampling (12h post-dose). To overcome the necessity of a longer hospital stay, microsampling devices (MSD) such as the Volumetric absorptive microsampling (VAMS®) device (Mitra®) can be used by the patients to take samples themselves, at home. Moreover, they are less invasive than venipuncture and collect low but accurate volumes of blood for analysis.

In this context, we propose a randomized controlled non-inferiority study to demonstrate that in liver transplant recipients, an immunosuppressive strategy based on single daily doses of LCP-tacrolimus (ENVARSUS XR®) and mycophenolate mofetil (CELLCEPT®) started at M6 post-transplantation is not inferior to XR-tacrolimus (ADVAGRAF®) and MMF administered BID, in terms of incidence of treatment failure (see below) at the end of the first year after transplantation, and to obtain adherence, quality of life and safety data. In order to compare solely MMF QD to MMF BID, patients on ENVARSUS XR® and MMF QD will be compared to a third group of patients receiving ENVARSUS XR® and MMF BID. A direct comparison of efficacy and safety, quality of life, adherence and exposure indices will be performed between ENVARSUS XR® and ADVAGRAF®.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

162

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • France
      • Besançon, France, 25000
        • Recruiting
        • CHU de Besançon - Hôpital Jean Minjoz
        • Contact:
        • Principal Investigator:
          • carine RICHOU, MD
      • Clichy, France, 92110
        • Recruiting
        • Beaujon Hospital - APHP
        • Principal Investigator:
          • Francois DURAND, MD
        • Contact:
      • Dijon, France, 21000
        • Recruiting
        • CHU de Dijon Bourgogne
        • Contact:
        • Principal Investigator:
          • Marianne LATOURNERIE, MD
      • Grenoble, France, 38043
        • Not yet recruiting
        • CHU de Grenoble
        • Contact:
        • Principal Investigator:
          • Claire BERTHAULT, MD
      • Lille, France, 59000
      • Limoges, France, 87042
        • Recruiting
        • Limoges University Hospital
        • Principal Investigator:
          • Marilyne DEBETTE-GRATIEN, MD
        • Contact:
      • Lyon, France, 69000
        • Recruiting
        • Lyon University Hospital
        • Principal Investigator:
          • Teresa ANTONINI, MD
        • Contact:
      • Marseille, France, 13000
        • Recruiting
        • APHP
        • Contact:
        • Principal Investigator:
          • Sophie CHOPINET, MD
      • Montpellier, France, 34000
        • Recruiting
        • Montpellier University Hospital
        • Contact:
        • Principal Investigator:
          • Stéphanie FAURE, MD
      • Nice, France, 06202
        • Recruiting
        • Nice University Hospital
        • Principal Investigator:
          • Rodolphe ANTY, MD
        • Contact:
      • Paris, France, 75013
        • Recruiting
        • Pitie Salpetriere hospital - APHP
        • Principal Investigator:
          • Filomena CONTI, MD
        • Contact:
      • Pessac, France, 33604
      • Poitiers, France, 86000
        • Recruiting
        • Poitiers University Hospital
        • Principal Investigator:
          • Christine SILVAIN, MD
        • Contact:
      • Rennes, France, 35033
      • Strasbourg, France, 67000
      • Toulouse, France, 31000
        • Recruiting
        • Toulouse University Hospital
        • Principal Investigator:
          • Nassim KAMAR, MD
        • Contact:
      • Tours, France, 37000
        • Recruiting
        • Tours University Hospital
        • Principal Investigator:
          • Ephrem SALAME, MD
        • Contact:
      • Villejuif, France, 94800
        • Recruiting
        • Paul Brousse Hospital - APHP
        • Principal Investigator:
          • Faouzi SALIBA, MD
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Recipients of a first liver allograft from a deceased donor
  • Transplanted for less than four weeks at enrolment.
  • Without inter-current progressive life-threatening or graft-threatening disease.
  • Having signed a written informed consent for their participation in the study.
  • Affiliated to, or beneficiary of, a social security regimen

Exclusion Criteria:

  • Recipients of a split-liver transplantation.
  • Recipients of any transplanted organ other than the liver
  • Patient who has undergone colon resection
  • Patients under legal protection (guardianship, curatorship).
  • Patient presenting any contra-indication to tacrolimus or to MMF according to the summary of product characteristics (SmPC) of ENVARSUS®, ADVAGRAF® and CELLCEPT®.
  • Patients in whom everolimus-based calcineurin inhibitors (CNI) minimization is anticipated
  • Patients treated with HIV or HCV protease inhibitors.
  • Pregnant or lactating women.
  • Women of childbearing potential without any effective contraceptive method (according to the guidelines of CTFG, Clinical Trial Facilitation Group, related to contraception and pregnancy test in clinical trials) or not practicing sexual abstinence.
  • Sexually active men having a female partner, without any effective contraception.
  • Patients incapable of understanding the purposes and risks of the study, who cannot give written informed consent, or who are unwilling to comply with the study protocol.
  • Patients enrolled in another clinical study evaluating drugs or therapeutic strategies potentially interfering with the objectives of the EASY study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Test 1
Drug: XR-tacrolimus QD + MMF BID then MMF QD
Patients start on XR-Tacrolimus once daily (QD) and MMF twice daily (BID) as per the usual care. At 6 months post-transplantation (±1 month) MMF administration frequency will be switched from BID to QD, in the morning, at the same daily dose
Experimental: Test 2
Drug: LCP-tacrolimus QD + MMF QD then MMF QD
Patients start on LCP-Tacrolimus once daily (QD) and MMF twice daily (BID) as per usual care. At 6 months post-transplantation (±1 month), MMF administration frequency will be switched from BID to QD, in the morning, at the same daily dose
Active Comparator: Standard of care 1
Drug: XR-tacrolimus QD + MMF BID
Patients receive XR-tacrolimus once daily (QD) and MMF twice daily (BID) as per the usual care.
Active Comparator: Standard of care 2
Drug: LCP-tacrolimus QD + MMF BID
Patients receive LCP-tacrolimus once daily (QD) and MMF twice daily (BID) as per the usual care.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Treatment failure
Time Frame: month 12
Treatment failure, defined by the occurrence of any of the following events: Patient death, Graft loss, Biopsy-proven acute rejection, rejection activity index score ≥4 according to the Banff criteria
month 12

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Adherence to treatment
Time Frame: Month 18
Adherence evaluated using the BAASIS questionnaire and patient diaries. Arm LCP-tacrolimus vs. Arm XR-tacrolimus
Month 18
measuring of quality of life
Time Frame: Month 18
Health-related quality of life composite scores evaluated using the SF-36 questionnaire. Arm LCP-tacrolimus vs. Arm XR-tacrolimus
Month 18
Adherence to treatment
Time Frame: Month 18
Adherence evaluated using the BAASIS questionnaire and patient diaries. Benefits of switching from Arm MMF BID to Arm MMF QD
Month 18
measuring of quality of life
Time Frame: Month 18
Health-related quality of life composite scores evaluated using the SF-36 questionnaire. Benefits of switching from Arm MMF BID to Arm MMF QD
Month 18
Appearance Adverse events
Time Frame: month 18
Adverse events and their severity whenever applicable during the first year after transplantation ( Gastro-intestinal, Cytomegalovirus (CMV) infection or reactivation, Neutropenia, Sepsis, Renal function impairment, post-transplant diabetes mellitus, Hypertension, Hyperlipidemia, Tremor). Arm LCP-tacrolimus vs. Arm XR-tacrolimus
month 18
Appearance Adverse events
Time Frame: month 18
Adverse events and their severity whenever applicable during the first year after transplantation ( Gastro-intestinal, CMV infection or reactivation, Neutropenia, Sepsis, Renal function impairment, post-transplant diabetes mellitus, Hypertension, Hyperlipidemia, Tremor). Arm MMF BID to Arm MMF QD
month 18
Comparison tacrolimus daily exposure
Time Frame: month 18
average daily exposure of tacrolimus by AUC 0-24h determined by Bayesian estimation compare between the 3 arms
month 18
Comparison of MPA daily exposure
Time Frame: month 18
average daily exposure of MPA AUC 0-24h determined by Bayesian estimation compare between the 3 arms
month 18
Comparison of Tacrolimus AUC 0-24h
Time Frame: month 18
measurement of Tacrolimus AUC 0-24h to comparison between the 3 arms
month 18
Comparison of MPA AUC 0-24h
Time Frame: month 18
measurement of MPA AUC 0-24h to comparison between the 3 arms
month 18
Comparison of Tacrolimus dose
Time Frame: month 18
measurement of Tacrolimus dose at C0 to comparison between the 3 arms
month 18

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Limoges

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 15, 2025

Primary Completion (Estimated)

April 15, 2028

Study Completion (Estimated)

April 15, 2028

Study Registration Dates

First Submitted

April 3, 2024

First Submitted That Met QC Criteria

April 3, 2024

First Posted (Actual)

April 9, 2024

Study Record Updates

Last Update Posted (Actual)

March 19, 2026

Last Update Submitted That Met QC Criteria

March 16, 2026

Last Verified

March 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 87RI23_0031 (EASY)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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