Study of Alcohol-related Liver Disease in Europe

Trial statusRecruiting
Trial phaseNot listed
Trial typeObservational
Biological sexAll
Age18-75
SponsorUniversity Hospital, Lille

About this trial

Alcohol-induced liver injury is made up of fatty liver, fibrosis and alcoholic hepatitis (AH), elementary lesions that may occur separately, simultaneously or sequentially in a same patient. Among these histological features, alcoholic hepatitis, a necro-inflammatory process is associated with the fastest fibrosis progression leading to cirrhosis in 40% of cases and a pivotal lesion driving increased risk of liver decompensation.

The non-invasive methods for the diagnosis of fibrosis open new perspectives for a better understanding of the natural history of disease-progression from early injury to the cirrhotic stage, for the identification of subgroup patients at risk of developing cirrhosis at medium term and for proposing a strategy of screening of patients with extensive cirrhosis at risk of liver-threatening events. There is an urgent need to perform studies in asymptomatic heavy drinkers in order to identify cut-offs associated with significant risk of development of cirrhosis at medium term. Such objectives require large-scale screening of heavy drinkers. Each of non-invasive methods have been tested to predict with of extensive fibrosis with a high predictive performance as shown below.

A screening policy cannot be accepted without answering the following questions: a) are the requirements of public health screening fulfilled? b) Is the group of patients undergoing screening defined? c) is there a reliable method for of testing? Indeed, the detection of a disease is subject to certain public health requirements and may be proposed to health authorities only if it modifies the management of subjects screened. In the specific case of mass screening of liver fibrosis in heavy drinkers, only the detection of extensive fibrosis could fulfill this criterion because of the potential survival benefit resulting from the screening of hepatocellular carcinoma (HCC) in patients with extensive fibrosis. Indeed, recent studies have found that the probability of receiving curative treatment of HCC was significantly higher in patients who received a six-month surveillance ultrasound. Therefore, the detection of extensive fibrosis seems reasonable in the light of these studies when considering that the yearly risk of development of HCC in the subgroup of heavy drinkers with extensive fibrosis is approximately 3%.

Taking into account the above scientific arguments, the most recent EASL clinical practical guidelines on ALD recommend longitudinal studies using non-invasive tools to evaluate screening of extensive fibrosis and disease progression in heavy drinkers.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Active alcohol excessive consumption defined as > 210 g per week for men and> 140 g per week for women during the previous year.

Patients with high risk of alcoholic-related liver disease can be included only if the following assessment were available: Abdominal Ultrasound / Ultrasound elastography pulse (FibroScan®) / FibroTest®, AshTest® and LCR1-LCR2® (cost will be supported by Biopredictive) / Non-patented methods: Forns Index; Fib-4, Hepascore®/ Absolute values should be provided for all these methods.

Patients must provide written informed consent and agree to have blood stored for the study and tissue stored for those in whom physicians performed liver biopsy according their clinical practice.

Patients should agree to participate for at least 5-year follow-up.

Disqualifiers

Evidence of other forms of known chronic liver disease including:Positive test result at baseline for hepatitis B surface antigen or positive serology of hepatitis C virus infection (regardless PCR results)/ Autoimmune liver disease / Known or suspected HCC

Any previous episode of decompensated liver disease, including ascites, hepatic encephalopathy, or variceal bleeding before current hospitalization and/or inclusion in the study

Known positivity for human immunodeficiency virus infection.

Terminal extrahepatic illness defined as: All conditions evolved into a clinical stage to limit the patient's functional status (e.g.: heart failure, renal failure, neurological or respiratory diseases, or any other disabling diseases etc. …).

Trial population

This study will be conducted in adults patients with active alcohol excessive consumption defined as \> 210 g per week for men and\> 140 g per week for women during the previous year. Patients with high risk of alcoholic-related liver disease.

Trial design

Design model

Cohort

Time perspective

Prospective

Treatments tested in this trial

Not listed

Trial groups

7,500 Participants
are grouped into 5 trial groups
Group A: 1: Patients with minimal risk of extensive fibrosis
Group B: 2: Patients with intermediate risk of fibrosis
Group C: Patients with high risk of extensive fibrosis
Group D: Patients with compensated cirrhosis biopsy-proven
Group E: Patients with a first decompensation

Trial outcomes

Primary outcomes

1

A first occurrence of clinical diagnosis of cirrhosis and/or its complications(for patients of group 1 and 2)

The primary endpoint is a composite criterion defined as a first occurrence of clinical diagnosis of cirrhosis and/or its complications. The primary endpoint will be held in the presence of any of the following criteria: Clinical cirrhosis Or Hepatocellular carcinoma (HCC) Or Histological diagnosis of cirrhosis on liver biopsy Or Biological features of liver dysfunction: INR≥1.5 in the presence of one of the following features: platelet count \<100 000, albumin \<35g, bilirubin \> 2\* ULN it will assess the risk of clinical diagnosis of cirrhosis and/or its complications in heavy drinkers classified according to non-invasive methods at minimal or intermediate risk of extensive fibrosis (groups 1,2).

Time frame
at five years

Secondary outcomes

1

cumulative incidence of cirrhosis and/or complications by treating death as competing risk.(for patients of group 3)

measure the risk of clinical diagnosis of cirrhosis and/or its complications in heavy drinkers classified according to non-invasive methods at high risk of extensive fibrosis (group 3).

Time frame
at five years
2

All-cause of death

all-cause mortality in groups of heavy drinkers (Groups 1,2,3) and cirrhotic groups (Groups 4 et 5)

Time frame
at five years
3

Biobanking of liver tissue and blood samples for further analyses such as cirrhosis disease studies

A multi-national registry of liver tissue and blood samples (bio-bank collection) to get more insights in risk of development of cirrhosis and disease-progression of cirrhosis

Time frame
at five years
4

LCR1/LCR2 test

Measure the performance of LCR1 and LCR2 to predict risk of development of hepatocellular carcinoma (All Groups) LCR1 test combines (using Cox model) hepatoprotective proteins (apolipoproteinA1, haptoglobin) with known risk factors (gender, age, gamma-glutamyltranspeptidase), and a marker of fibrosis (alpha2-macroglobulin). To increase the specificity, the LCR2 test was developed by combining the components of LCR1 to alpha-fetoprotein. The predetermined cutoffs are \<0.015 for low-LCR1, and \<0.044 for low-LCR2 will be tested as the rule-out values to exclude a risk of hepatocellular carcinoma.

Time frame
at five years

Other outcomes

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