## Protocol Section
### Identification Module
**NCT ID:** NCT06354179

**Acronym:** EASY

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

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

#### Organization Study ID Info
**ID:** 87RI23_0031 (EASY)
#### Organization
**Class:** OTHER
**Full Name:** University Hospital, Limoges
### Status Module
#### Completion Date
**Date:** 2027-07-01

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-04-11

**Type:** ACTUAL

**Last Update Submit Date:** 2024-04-09

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2027-07-01

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-07-01

**Type:** ESTIMATED

**Status Verified Date:** 2024-04

#### Study First Post Date
**Date:** 2024-04-09
**Type:** ACTUAL
**Study First Submit Date:** 2024-04-03
**Study First Submit QC Date:** 2024-04-03
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** University Hospital, Limoges

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** False

### Description Module

**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®.

### Conditions Module

**Conditions:**

- Liver Transplantation

- Immunosuppression

**Keywords:**

- liver transplantation

- immunosuppression

- tacrolimus

- mycophenolate

- adherence

- once-daily intake

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 162

**Type:** ESTIMATED

**Phases:**

- PHASE4

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Intervention Names:**

- Drug: XR-tacrolimus QD + MMF BID

**Label:** Standard of care

**Type:** ACTIVE_COMPARATOR

#### Arm Group 2

**Intervention Names:**

- Drug: LCP-tacrolimus QD + MMF BID

**Label:** Test 1

**Type:** EXPERIMENTAL

#### Arm Group 3

**Intervention Names:**

- Drug: LCP-tacrolimus QD + MMF QD

**Label:** Test 2

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Standard of care

**Description:** Patients receive tacrolimus once daily (QD) and MMF twice daily (BID) as per the usual care.

**Name:** XR-tacrolimus QD + MMF BID

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- Test 1

**Description:** Patients start on LCP-Tacrolimus once daily (QD) and MMF twice daily (BID) as per the usual care. The MMF dose may be decreased at any time during the study according to the investigator's decision.

**Name:** LCP-tacrolimus QD + MMF BID

**Type:** DRUG

#### Intervention 3

**Arm Group Labels:**

- Test 2

**Description:** 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

**Name:** LCP-tacrolimus QD + MMF QD

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** 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

**Measure:** Treatment failure

**Time Frame:** month 12

#### Secondary Outcomes

**Description:** Adherence evaluated using the BAASIS questionnaire and patient diaries. Arm LCP-tacrolimus vs. Arm XR-tacrolimus

**Measure:** Adherence to treatment

**Time Frame:** Month 18

**Description:** Health-related quality of life composite scores evaluated using the SF-36 questionnaire. Arm LCP-tacrolimus vs. Arm XR-tacrolimus

**Measure:** measuring of quality of life

**Time Frame:** Month 18

**Description:** Adherence evaluated using the BAASIS questionnaire and patient diaries. Benefits of switching from Arm MMF BID to Arm MMF QD

**Measure:** Adherence to treatment

**Time Frame:** Month 18

**Description:** Health-related quality of life composite scores evaluated using the SF-36 questionnaire. Benefits of switching from Arm MMF BID to Arm MMF QD

**Measure:** measuring of quality of life

**Time Frame:** Month 18

**Description:** 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

**Measure:** Appearance Adverse events

**Time Frame:** month 18

**Description:** 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

**Measure:** Appearance Adverse events

**Time Frame:** month 18

**Description:** average daily exposure of tacrolimus by AUC 0-24h determined by Bayesian estimation compare between the 3 arms

**Measure:** Comparison tacrolimus daily exposure

**Time Frame:** month 18

**Description:** average daily exposure of MPA AUC 0-24h determined by Bayesian estimation compare between the 3 arms

**Measure:** Comparison of MPA daily exposure

**Time Frame:** month 18

**Description:** measurement of Tacrolimus dose at C0 to comparison between the 3 arms

**Measure:** Comparison of Tacrolimus dose

**Time Frame:** month 18

**Description:** measurement of Tacrolimus AUC 0-24h to comparison between the 3 arms

**Measure:** Comparison of Tacrolimus AUC 0-24h

**Time Frame:** month 18

**Description:** measurement of MPA AUC 0-24h to comparison between the 3 arms

**Measure:** Comparison of MPA AUC 0-24h

**Time Frame:** month 18

### Eligibility Module

**Eligibility Criteria:** 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 already enrolled in another clinical study evaluating drugs or therapeutic strategies.

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** caroline.monchaud@inserm.fr

**Name:** Caroline MONCHAUD, Pharm D

**Phone:** 555056140

**Phone Ext:** +33

**Role:** CONTACT

**Contact 2:**

**Email:** helene.roussel@chu-limoges.fr

**Name:** Hélène ROUSSEL

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Clichy

**Country:** France

**Facility:** Beaujon hospital - APHP

**Zip:** 92110

**Location 2:**

**City:** Lille

**Contacts:**

***Contact 1:***

- **Email:** sebastien.dharancy@chru-lille.fr

- **Name:** Sébastien DHARANCY, MD

- **Role:** CONTACT

***Contact 2:***

- **Name:** Sébastien DHARANCY, MD

- **Role:** PRINCIPAL_INVESTIGATOR

**Country:** France

**Facility:** Lille university hospital

**Zip:** 59000

**Location 3:**

**City:** Limoges

**Contacts:**

***Contact 1:***

- **Email:** MARILYNE.GRATIEN@chu-limoges.fr

- **Name:** Marilyne DEBETTE-GRATIEN, MD

- **Role:** CONTACT

***Contact 2:***

- **Name:** Marilyne DEBETTE-GRATIEN, MD

- **Role:** PRINCIPAL_INVESTIGATOR

**Country:** France

**Facility:** Limoges university hospital

**Zip:** 87042

**Location 4:**

**City:** Lyon

**Contacts:**

***Contact 1:***

- **Email:** teresa.antonini@chu-lyon.fr

- **Name:** Teresa ANTONINI, MD

- **Role:** CONTACT

***Contact 2:***

- **Name:** Teresa ANTONINI, MD

- **Role:** PRINCIPAL_INVESTIGATOR

**Country:** France

**Facility:** Lyon university hospital

**Zip:** 69000

**Location 5:**

**City:** Montpellier

**Contacts:**

***Contact 1:***

- **Email:** gp-pageaux@chu-montpellier.fr

- **Name:** Georges-Philippe PAGEAUX, MD

- **Role:** CONTACT

***Contact 2:***

- **Name:** Georges-Philippe PAGEAUX, MD

- **Role:** PRINCIPAL_INVESTIGATOR

**Country:** France

**Facility:** Montpellier university hospital

**Zip:** 34000

**Location 6:**

**City:** Nice

**Contacts:**

***Contact 1:***

- **Email:** anty.r@chu-nice.fr

- **Name:** Rodolphe ANTY, MD

- **Role:** CONTACT

***Contact 2:***

- **Name:** Rodolphe ANTY, MD

- **Role:** PRINCIPAL_INVESTIGATOR

**Country:** France

**Facility:** Nice university hospital

**Zip:** 06202

**Location 7:**

**City:** Paris

**Country:** France

**Facility:** Pitie Salpetriere hospital - APHP

**Zip:** 75013

**Location 8:**

**City:** Pessac

**Contacts:**

***Contact 1:***

- **Email:** jean-baptiste.hiriart@chu-bordeaux.fr

- **Name:** Jean-Baptiste HIRIART, MD

- **Role:** CONTACT

***Contact 2:***

- **Name:** Jean-Baptiste HIRIART, MD

- **Role:** PRINCIPAL_INVESTIGATOR

**Country:** France

**Facility:** Bordeaux university hospital

**Zip:** 33604

**Location 9:**

**City:** Poitiers

**Contacts:**

***Contact 1:***

- **Email:** c.silvain@chu-poitiers.fr

- **Name:** Christine SILVAIN, MD

- **Role:** CONTACT

***Contact 2:***

- **Name:** Christine SILVAIN, MD

- **Role:** PRINCIPAL_INVESTIGATOR

**Country:** France

**Facility:** Poitiers university hospital

**Zip:** 86000

**Location 10:**

**City:** Rennes

**Contacts:**

***Contact 1:***

- **Email:** pauline.houssel-debry@chu-rennes.fr

- **Name:** Pauline HOUSSEL-DEBRY, MD

- **Role:** CONTACT

***Contact 2:***

- **Name:** Pauline HOUSSEL-DEBRY, MD

- **Role:** PRINCIPAL_INVESTIGATOR

**Country:** France

**Facility:** Rennes university hospital

**Zip:** 35033

**Location 11:**

**City:** Strasbourg

**Contacts:**

***Contact 1:***

- **Email:** camille.besch@chru-strasbourg.fr

- **Name:** Camille BESCH, MD

- **Role:** CONTACT

***Contact 2:***

- **Name:** Camille BESCH, MD

- **Role:** PRINCIPAL_INVESTIGATOR

**Country:** France

**Facility:** Strasbourg university hospital

**Zip:** 67000

**Location 12:**

**City:** Tours

**Country:** France

**Facility:** Tours university Hospital

**Zip:** 37000

**Location 13:**

**City:** Villejuif

**Country:** France

**Facility:** Paul Brousse Hospital - APHP

**Zip:** 94800

### IPD Sharing Statement Module

**IPD Sharing:** NO

## Derived Section

### Intervention Browse Module - Ancestors

- ID: D000007166

- Term: Immunosuppressive Agents

- ID: D000007155

- Term: Immunologic Factors

- ID: D000045505

- Term: Physiological Effects of Drugs

- ID: D000065095

- Term: Calcineurin Inhibitors

- ID: D000004791

- Term: Enzyme Inhibitors

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

### Intervention Browse Module - Browse Branches

- Abbrev: Infe

- Name: Anti-Infective Agents

- Abbrev: ANeo

- Name: Antineoplastic Agents

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: Hemat

- Name: Hematinics

### Intervention Browse Module - Browse Leaves

- ID: M12128

- Name: Mycophenolic Acid

- Relevance: LOW

- As Found: Unknown

- ID: M18950

- Name: Tacrolimus

- Relevance: HIGH

- As Found: 3 weeks

- ID: M11110

- Name: Liver Extracts

- Relevance: LOW

- As Found: Unknown

- ID: M10212

- Name: Immunosuppressive Agents

- Relevance: LOW

- As Found: Unknown

- ID: M10201

- Name: Immunologic Factors

- Relevance: LOW

- As Found: Unknown

- ID: M30452

- Name: Calcineurin Inhibitors

- Relevance: LOW

- As Found: Unknown

- ID: M7951

- Name: Enzyme Inhibitors

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000016559

- Term: Tacrolimus

### Misc Info Module

- Version Holder: 2024-05-24
