Clinical trial NCT06472973: ADDICTOlogical Intervention in LIVEr Transplantation Recipients
Official title: ADDICTOlogical Intervention in LIVEr Transplantation Recipients
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Alcohol Associated Liver Disease
Liver Transplantation
Keywords: Liver transplantation
Addiction follow-up
Alcohol relapse
Survival
Lead sponsor: University Hospital, Montpellier
Sponsor class: OTHER
First posted: 2024-06-25
Enrollment: 720
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Transplantation for end-stage-liver disease (ESLD) in the context of Alcohol-Associated Liver Disease (AALD) has been increasing and represents the main indication for Liver Transplantation (LT) in the world. Alcohol Use Disorder (AUD) is considered a brain chronic disease and requires a transdisciplinary approach that includes medical treatment and behavioral interventions.

In the context of LT, alcohol relapse occurs in 26 % up to 50% of LT recipients. Among Liver transplant recipients for AALD, severe alcoholic relapse (defined as more than 3 alcoholic drinks per day for women and 4/day for men) after LT leads to impaired longterm survival due to recurrent alcoholic cirrhosis (RAC), cardiovascular events and de novo cancer.

Several strategies have been developed to prevent alcohol relapse. After LT, integrating an addiction team into the LT program has been advocated by the latest guidelines in Europe and the United States, in order to bring the management of alcohol-use disorder (AUD) in transplantation units, through the association of psychosocial and pharmacological interventions previously reported in AALD. However, those guidelines were based on descriptive studies, and the effect of this management needs to be confirmed through a randomized, controlled, multicenter study, involving centers that still do not include an addiction team in their LT programs.

This study will therefore assess prospectively and comparatively the impact of an addiction intervention after LT on return to alcohol use rates. We hypothesize that standardized targeted addiction monitoring of Liver Transplant recipients decreases the rates of alcohol relapse two years post-liver transplantation.

Detailed description: Liver transplantation (LT) is the only curative option for end-stage liver disease and unresectable hepatocellular carcinoma (HCC) without extrahepatic spread. Alcohol Associated Liver Disease (AALD) has become the most common indication for liver transplantation (LT) in many Western countries.In France, AALD accounts for at least 40% of all LT, between decompensated cirrhosis and HCC, which represents more than 500 patients each year.

One, five and 10-year graft rate and patient survival rate after LT for AALD are at least comparable to those of other indications. Nevertheless, long-term survival rates are hampered by frequent and/or excessive relapse in alcohol consumption. Relapse increases the risk of recurrent alcohol-associated cirrhosis but also of de novo alcohol-induced solid malignancies, mainly cancers of the upper aero digestive tract. Graft and patient survival rates, especially long-term, are thus hindered by the occurrence of excessive relapse.

Relapse rates vary immensely between studies and there is a lack of standardization in the definition of its severity, mainly because it is impossible to define the boundaries/thresholds for "safe consumption". However, there is consensus that harm appears for alcohol intake exceeding three portions per day for males and two for females, for at least 100 days with a sense of loss of control. This pattern of relapse, often described as "severe" can be found between 10 and 26% of patients. Most efforts aiming to reduce post-LT relapse rates focus on improving patient selection. Risk-factors of alcohol relapse often found in literature include short duration of pre-LT sobriety (\<6 months), diagnosis of alcohol dependence, family history of alcohol-use disorder, psychiatric comorbidities including other substance abuse, prior alcohol rehabilitation and female gender. Scores such as HRAR (High Risk Alcoholism Relapse) have also attempted to stratify relapse risk based on pre-LT risk factors. Unfortunately, these criteria are not sensitive enough and most patients who finally benefit from the intervention are in the low to medium risk groups.

It is therefore a priority to utilize also resources in the post-LT setting to decrease alcohol relapse since it is a frequent and relatively difficult to predict event, with a high impact on outcomes after LT. We hypothesize that post-transplant addiction specialist interventions in liver transplant patients with AALD as primary or secondary indication will result in decreased regular and/or severe alcohol relapse rate two years post-LT. By extension, this could result in higher graft and patient survival rates, especially in long term.

More recently, our group has performed a retrospective analysis of three centers with different addiction follow-up practices suggesting a benefit on severe relapse rates of addiction specialist intervention after LT for AALD. However, the main limit of this work is the retrospective design with different follow-up periods and duration. We designed a multicenter superiority randomized controlled trial with 2 parallel arms:

* Interventional arm where participants are offered targeted addictology follow-up and participate in addiction consultations
* Control arm where participants have classical follow-up by the transplant specialists of the LT center during the post-transplant follow-up period

The randomization will be elaborated using 1:1 ratio and minimization method. It will be stratified on centers and alcohol consumption history.

According to a French cohort study of patients with liver transplantation for alcohol-related disorders, 25% of them relapsed at 2 years.To account for mortality censoring during follow-up, we will apply a 5% increase of the sample size to reach 720 participants (360 in each arm). The comparison of the primary endpoint between arms will be carried out using intention to treat principle. The time to relapse will be expressed using Kaplan-Meier curves in each arm, and compared using a log-rank test. The effect size will be estimated using Cox proportional.

Eligibility criteria: Inclusion Criteria:

* Aged 18 years or above
* Hospitalized for LT for AALD as primary or secondary indication
* Discharged from intensive care unit to hepatology or surgery wards

Exclusion Criteria:

* Having a longitudinal pre-transplant addiction follow-up defined by at least 3 appointments within the last 6 months or a temporary contraindication to LT due to alcohol consumption while on the waiting list
* Severe alcohol-associated hepatitis as primary indication for liver transplantation
* Impossibility of patient follow up over the next 2 years
* General criteria:

  * Refusal or absence of informed consent,
  * Non-affiliation to the French national health insurance,
  * Persons placed under legal protection, guardianship or curatorship

Primary outcomes:
measure: Time to return to alcohol use
timeFrame: During 2 years after discharge from Liver transplantation hospitalization
Secondary outcomes:
measure: Return to alcohol use of the slip type
timeFrame: During 2 years after discharge from Liver transplantation hospitalization
measure: Tobacco use
timeFrame: During 2 years after discharge from Liver transplantation hospitalization
measure: Other psychoactive substances use
timeFrame: During 2 years after discharge from Liver transplantation hospitalization
measure: Addiction therapies
timeFrame: During 2 years after discharge from Liver transplantation hospitalization
measure: Major significant clinical events
timeFrame: During 2 years after discharge from Liver transplantation hospitalization
measure: Biochemical liver tests
timeFrame: During 2 years after discharge from Liver transplantation hospitalization
measure: Alcohol consumption biomarker ethanol/Peth)
timeFrame: At 1 month, 11 or 13 months and at 24 months after discharge from Liver transplantation hospitalization
measure: Liver fibrosis
timeFrame: 2 years after discharge from Liver transplantation hospitalization
measure: Evolution of cognitive disorders
timeFrame: During 2 years after discharge from Liver transplantation hospitalization
measure: Mortality and alcohol-associated mortality rate
timeFrame: During 2 years after discharge from Liver transplantation hospitalization
Other outcomes:
Locations:
city: Besançon
country: France
facility: Besançon University Hospital
city: Bordeaux
country: France
facility: Bordeaux University Hospital
city: Clermont-Ferrand
country: France
facility: Clermont Ferrand University Hospital
city: Dijon
country: France
facility: Dijon University Hospital
city: Grenoble
country: France
facility: Grenoble University Hospital
city: Lille
country: France
facility: Lille University Hospital
city: Lyon
country: France
facility: Lyon University Hospital
city: Marseille
country: France
facility: Marseille University Hospital
city: Montpellier
country: France
facility: Montpellier University Hospital
city: Nice
country: France
facility: Nice University Hospital
city: Paris
country: France
facility: APHP Mondor
city: Paris
country: France
facility: APHP Paul Brousse
city: Paris
country: France
facility: APHP Salpetrière
city: Rennes
country: France
facility: Rennes University Hospital
city: Strasbourg
country: France
facility: Strasbourg University Hospital
city: Toulouse
country: France
facility: Toulouse University Hospital
city: Tours
country: France
facility: Tours University Hospital
Study officials:
affiliation: University Hospital, Montpellier
name: Hélène DONNADIEU, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: