<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04400604</url>
  </required_header>
  <id_info>
    <org_study_id>2019_04</org_study_id>
    <secondary_id>2020-A00527-32</secondary_id>
    <nct_id>NCT04400604</nct_id>
  </id_info>
  <brief_title>Study of Alcohol-related Liver Disease in Europe</brief_title>
  <acronym>SALVE</acronym>
  <official_title>Evaluation of the Natural History of Alcoholic Liver Disease According to Baseline Severity</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital, Lille</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Hospital, Lille</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Alcohol-induced liver injury is made up of fatty liver, fibrosis and alcoholic hepatitis&#xD;
      (AH), elementary lesions that may occur separately, simultaneously or sequentially in a same&#xD;
      patient. Among these histological features, alcoholic hepatitis, a necro-inflammatory process&#xD;
      is associated with the fastest fibrosis progression leading to cirrhosis in 40% of cases and&#xD;
      a pivotal lesion driving increased risk of liver decompensation.&#xD;
&#xD;
      The non-invasive methods for the diagnosis of fibrosis open new perspectives for a better&#xD;
      understanding of the natural history of disease-progression from early injury to the&#xD;
      cirrhotic stage, for the identification of subgroup patients at risk of developing cirrhosis&#xD;
      at medium term and for proposing a strategy of screening of patients with extensive cirrhosis&#xD;
      at risk of liver-threatening events. There is an urgent need to perform studies in&#xD;
      asymptomatic heavy drinkers in order to identify cut-offs associated with significant risk of&#xD;
      development of cirrhosis at medium term. Such objectives require large-scale screening of&#xD;
      heavy drinkers. Each of non-invasive methods have been tested to predict with of extensive&#xD;
      fibrosis with a high predictive performance as shown below.&#xD;
&#xD;
      A screening policy cannot be accepted without answering the following questions: a) are the&#xD;
      requirements of public health screening fulfilled? b) Is the group of patients undergoing&#xD;
      screening defined? c) is there a reliable method for of testing? Indeed, the detection of a&#xD;
      disease is subject to certain public health requirements and may be proposed to health&#xD;
      authorities only if it modifies the management of subjects screened. In the specific case of&#xD;
      mass screening of liver fibrosis in heavy drinkers, only the detection of extensive fibrosis&#xD;
      could fulfill this criterion because of the potential survival benefit resulting from the&#xD;
      screening of hepatocellular carcinoma (HCC) in patients with extensive fibrosis. Indeed,&#xD;
      recent studies have found that the probability of receiving curative treatment of HCC was&#xD;
      significantly higher in patients who received a six-month surveillance ultrasound. Therefore,&#xD;
      the detection of extensive fibrosis seems reasonable in the light of these studies when&#xD;
      considering that the yearly risk of development of HCC in the subgroup of heavy drinkers with&#xD;
      extensive fibrosis is approximately 3%.&#xD;
&#xD;
      Taking into account the above scientific arguments, the most recent EASL clinical practical&#xD;
      guidelines on ALD recommend longitudinal studies using non-invasive tools to evaluate&#xD;
      screening of extensive fibrosis and disease progression in heavy drinkers.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">March 3, 2021</start_date>
  <completion_date type="Anticipated">March 2032</completion_date>
  <primary_completion_date type="Anticipated">March 2032</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>A first occurrence of clinical diagnosis of cirrhosis and/or its complications(for patients of group 1 and 2)</measure>
    <time_frame>at five years</time_frame>
    <description>The primary endpoint is a composite criterion defined as a first occurrence of clinical diagnosis of cirrhosis and/or its complications.&#xD;
The primary endpoint will be held in the presence of any of the following criteria:&#xD;
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 &lt;100 000, albumin &lt;35g, bilirubin &gt; 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).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>cumulative incidence of cirrhosis and/or complications by treating death as competing risk.(for patients of group 3)</measure>
    <time_frame>at five years</time_frame>
    <description>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).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All-cause of death</measure>
    <time_frame>at five years</time_frame>
    <description>all-cause mortality in groups of heavy drinkers (Groups 1,2,3) and cirrhotic groups (Groups 4 et 5)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biobanking of liver tissue and blood samples for further analyses such as cirrhosis disease studies</measure>
    <time_frame>at five years</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>LCR1/LCR2 test</measure>
    <time_frame>at five years</time_frame>
    <description>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 &lt;0.015 for low-LCR1, and &lt;0.044 for low-LCR2 will be tested as the rule-out values to exclude a risk of hepatocellular carcinoma.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Brief Drinking Questionnaire (Audit-C)</measure>
    <time_frame>at five years</time_frame>
    <description>The AUDIT-C (Alcohol Use Disorder Identification Test) quantifies alcohol misuse, based on 3 questions posed to patients about their consumption habits. It was adapted from the first three questions of the AUDIT.&#xD;
The AUDIT-C is scored on a scale of 0-12 (scores of 0 reflect no alcohol use). Each question has 5 answer choice.&#xD;
In men, a score of 4 or more is considered positive; in women, a score of 3 or more is considered positive. Generally, the higher the AUDIT-C score, the more likely it is that the patient's drinking is affecting his/her health and safety.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Alcohol consumption according to the WHO category</measure>
    <time_frame>at five years</time_frame>
    <description>Patterns of alcohol consumption will be classified according the 5 risks levels (Abstinence, Low risk, Medium risk, high risk, very high risk).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The occurrence of decompensation of cirrhosis</measure>
    <time_frame>at five years</time_frame>
    <description>To determine the 5-year risk of first decompensation in patients with biopsy-proven compensated cirrhosis at inclusion (Group 4)</description>
  </secondary_outcome>
  <number_of_groups>5</number_of_groups>
  <enrollment type="Anticipated">7500</enrollment>
  <condition>Alcoholic Liver Disease</condition>
  <arm_group>
    <arm_group_label>1: Patients with minimal risk of extensive fibrosis</arm_group_label>
    <description>TE &lt; 5.8kPa; rule out cut-off value)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>2: Patients with intermediate risk of fibrosis</arm_group_label>
  </arm_group>
  <arm_group>
    <arm_group_label>Patients with high risk of extensive fibrosis</arm_group_label>
  </arm_group>
  <arm_group>
    <arm_group_label>Patients with compensated cirrhosis biopsy-proven</arm_group_label>
  </arm_group>
  <arm_group>
    <arm_group_label>Patients with a first decompensation</arm_group_label>
    <description>patients with a first decompensation event of cirrhosis after exclusion of HCC.</description>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      a genetic sample (DNA, 1 EDTA tube) serum sample (2 dry 7 ml tubes) plasma (2 heparin 7 ml&#xD;
      tubes)&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        This study will be conducted in adults patients with active alcohol excessive consumption&#xD;
        defined as &gt; 210 g per week for men and&gt; 140 g per week for women during the previous year.&#xD;
&#xD;
        Patients with high risk of alcoholic-related liver disease.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Active alcohol excessive consumption defined as &gt; 210 g per week for men and&gt; 140 g&#xD;
             per week for women during the previous year.&#xD;
&#xD;
          -  Patients with high risk of alcoholic-related liver disease can be included only if the&#xD;
             following assessment were available: Abdominal Ultrasound / Ultrasound elastography&#xD;
             pulse (FibroScan®) / FibroTest®, AshTest® and LCR1-LCR2® (cost will be supported by&#xD;
             Biopredictive) / Non-patented methods: Forns Index; Fib-4, Hepascore®/ Absolute values&#xD;
             should be provided for all these methods.&#xD;
&#xD;
        For patient in whom liver stiffness measurements were uninterpretable (unavailable results)&#xD;
        only those with FibroTest® and LCR1 and LCR2 measurements can be included.&#xD;
&#xD;
        Results of FibroScan® were considered unavailable based on following criteria: When no&#xD;
        value was obtained after at least 10 shots (valid shot=0) OR If SR (Success Rate), the&#xD;
        ratio of valid shots to the total number of shots at least 60% OR IQR (InterQuartil Range&#xD;
        reflecting variability of measurements) less than 30% of the median LSM (Liver Stiffness&#xD;
        Measure) value (IQR≤LSM≤30%).&#xD;
&#xD;
          -  Patients must provide written informed consent and agree to have blood stored for the&#xD;
             study and tissue stored for those in whom physicians performed liver biopsy according&#xD;
             their clinical practice.&#xD;
&#xD;
          -  Patients should agree to participate for at least 5-year follow-up.&#xD;
&#xD;
          -  Patients with social insurance&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        For all study groups, the following exclusion criteria will be applied:&#xD;
&#xD;
          -  Evidence of other forms of known chronic liver disease including:Positive test result&#xD;
             at baseline for hepatitis B surface antigen or positive serology of hepatitis C virus&#xD;
             infection (regardless PCR results)/ Autoimmune liver disease / Known or suspected HCC&#xD;
&#xD;
          -  Any previous episode of decompensated liver disease, including ascites, hepatic&#xD;
             encephalopathy, or variceal bleeding before current hospitalization and/or inclusion&#xD;
             in the study&#xD;
&#xD;
          -  Known positivity for human immunodeficiency virus infection.&#xD;
&#xD;
          -  Terminal extrahepatic illness defined as: All conditions evolved into a clinical stage&#xD;
             to limit the patient's functional status (e.g.: heart failure, renal failure,&#xD;
             neurological or respiratory diseases, or any other disabling diseases etc. …).&#xD;
&#xD;
          -  Other medical conditions that may diminish life expectancy to &lt;2 years.&#xD;
&#xD;
          -  Known extra-hepatic cancers with the exception of basal cell skin cancer.&#xD;
&#xD;
          -  Any other condition that, in the opinion of the Investigator, would impede completion&#xD;
             of the study (eg: Homeless, non-compliant patients…).&#xD;
&#xD;
          -  Mental instability or incompetence, such that the validity of informed consent is&#xD;
             uncertain.&#xD;
&#xD;
          -  Lack of informed consent or refusal to participate for follow up evaluation.&#xD;
&#xD;
          -  A condition in which repeated blood draws pose more than minimal risk for the subject&#xD;
             such as hemophilia, other severe coagulation disorders or significantly impaired&#xD;
             venous access.&#xD;
&#xD;
          -  Pregnant or lactating women&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Philippe Mathurin, MD,PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Hospital, Lille</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Philippe Mathurin, MD,PhD</last_name>
    <phone>3 20 44 55 97</phone>
    <phone_ext>+33</phone_ext>
    <email>philippe.mathurin@chru-lille.fr</email>
  </overall_contact>
  <location>
    <facility>
      <name>Hop Claude Huriez Chu Lille</name>
      <address>
        <city>Lille</city>
        <zip>59037</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <phone>0320445962</phone>
    </contact>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>March 2022</verification_date>
  <study_first_submitted>May 14, 2020</study_first_submitted>
  <study_first_submitted_qc>May 20, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 22, 2020</study_first_posted>
  <last_update_submitted>March 14, 2022</last_update_submitted>
  <last_update_submitted_qc>March 14, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 17, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liver Diseases</mesh_term>
    <mesh_term>Liver Diseases, Alcoholic</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04400604
org study id: 2019_04
secondary id: 2020-A00527-32
nct id: NCT04400604
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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.
observational model: Cohort
time perspective: Prospective
measure: A first occurrence of clinical diagnosis of cirrhosis and/or its complications(for patients of group 1 and 2)
time frame: at five years
description: 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).
measure: cumulative incidence of cirrhosis and/or complications by treating death as competing risk.(for patients of group 3)
time frame: at five years
description: 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).
measure: All-cause of death
time frame: at five years
description: all-cause mortality in groups of heavy drinkers (Groups 1,2,3) and cirrhotic groups (Groups 4 et 5)
measure: Biobanking of liver tissue and blood samples for further analyses such as cirrhosis disease studies
time frame: at five years
description: 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
measure: LCR1/LCR2 test
time frame: at five years
description: 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.
measure: Brief Drinking Questionnaire (Audit-C)
time frame: at five years
description: The AUDIT-C (Alcohol Use Disorder Identification Test) quantifies alcohol misuse, based on 3 questions posed to patients about their consumption habits. It was adapted from the first three questions of the AUDIT.
The AUDIT-C is scored on a scale of 0-12 (scores of 0 reflect no alcohol use). Each question has 5 answer choice.
In men, a score of 4 or more is considered positive; in women, a score of 3 or more is considered positive. Generally, the higher the AUDIT-C score, the more likely it is that the patient's drinking is affecting his/her health and safety.
measure: Alcohol consumption according to the WHO category
time frame: at five years
description: Patterns of alcohol consumption will be classified according the 5 risks levels (Abstinence, Low risk, Medium risk, high risk, very high risk).
measure: The occurrence of decompensation of cirrhosis
time frame: at five years
description: To determine the 5-year risk of first decompensation in patients with biopsy-proven compensated cirrhosis at inclusion (Group 4)
arm group label: 1: Patients with minimal risk of extensive fibrosis
description: TE < 5.8kPa; rule out cut-off value)
arm group label: 2: Patients with intermediate risk of fibrosis
arm group label: Patients with high risk of extensive fibrosis
arm group label: Patients with compensated cirrhosis biopsy-proven
arm group label: Patients with a first decompensation
description: patients with a first decompensation event of cirrhosis after exclusion of HCC.
a genetic sample (DNA, 1 EDTA tube) serum sample (2 dry 7 ml tubes) plasma (2 heparin 7 ml
      tubes)
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Philippe Mathurin, MD,PhD
role: Principal Investigator
affiliation: University Hospital, Lille
last name: Philippe Mathurin, MD,PhD
phone: 3 20 44 55 97
phone ext: +33
email: philippe.mathurin@chru-lille.fr
facility: 
status: Recruiting
contact: 
country: France
responsible party type: Sponsor
mesh term: Liver Diseases
mesh term: Liver Diseases, Alcoholic
sharing ipd: No