Evaluation of the Benefits of Administering Immunosuppressive Drugs as Single Daily Doses Over the First Year After Liver Transplantation (EASY)
EASY
1 other identifier
interventional
162
1 country
18
Brief Summary
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®.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_4
Started Apr 2025
Typical duration for phase_4
18 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
April 3, 2024
CompletedFirst Posted
Study publicly available on registry
April 9, 2024
CompletedStudy Start
First participant enrolled
April 15, 2025
CompletedPrimary Completion
Last participant's last visit for primary outcome
April 15, 2028
ExpectedStudy Completion
Last participant's last visit for all outcomes
April 15, 2028
March 19, 2026
March 1, 2026
3 years
April 3, 2024
March 16, 2026
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
Treatment failure
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 Outcomes (11)
Adherence to treatment
Month 18
measuring of quality of life
Month 18
Adherence to treatment
Month 18
measuring of quality of life
Month 18
Appearance Adverse events
month 18
- +6 more secondary outcomes
Study Arms (4)
Standard of care 1
ACTIVE COMPARATORTest 1
EXPERIMENTALTest 2
EXPERIMENTALStandard of care 2
ACTIVE COMPARATORInterventions
Patients receive LCP-tacrolimus once daily (QD) and MMF twice daily (BID) as per the usual care.
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
Patients receive XR-tacrolimus once daily (QD) and MMF twice daily (BID) as per the usual care.
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
Eligibility Criteria
You may qualify if:
- 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
You may not qualify if:
- 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.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (18)
CHU de Besançon - Hôpital Jean Minjoz
Besançon, 25000, France
Beaujon hospital - APHP
Clichy, 92110, France
CHU de Dijon Bourgogne
Dijon, 21000, France
CHu de Grenoble
Grenoble, 38043, France
Lille university hospital
Lille, 59000, France
Limoges university hospital
Limoges, 87042, France
Lyon university hospital
Lyon, 69000, France
APHP
Marseille, 13000, France
Montpellier university hospital
Montpellier, 34000, France
Nice university hospital
Nice, 06202, France
Pitie Salpetriere hospital - APHP
Paris, 75013, France
Bordeaux university hospital
Pessac, 33604, France
Poitiers university hospital
Poitiers, 86000, France
Rennes university hospital
Rennes, 35033, France
Strasbourg university hospital
Strasbourg, 67000, France
Toulouse university hospital
Toulouse, 31000, France
Tours university Hospital
Tours, 37000, France
Paul Brousse Hospital - APHP
Villejuif, 94800, France
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 4
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
April 3, 2024
First Posted
April 9, 2024
Study Start
April 15, 2025
Primary Completion (Estimated)
April 15, 2028
Study Completion (Estimated)
April 15, 2028
Last Updated
March 19, 2026
Record last verified: 2026-03
Data Sharing
- IPD Sharing
- Will not share