<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/NCT03836443</url>
  </required_header>
  <id_info>
    <org_study_id>D20180507</org_study_id>
    <nct_id>NCT03836443</nct_id>
  </id_info>
  <brief_title>Postprandial Lipotoxicity and Nonalcoholic Fatty Liver Disease</brief_title>
  <acronym>LITONAS</acronym>
  <official_title>Lipid Metabolism, Lipotoxicity and Nonalcoholic Fatty Liver Disease: Implication of Postprandial Cytotoxic Lipids</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assistance Publique - Hôpitaux de Paris</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assistance Publique - Hôpitaux de Paris</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>
      Nonalcoholic fatty liver disease (NAFLD) is mainly considered a nutrition-related disease and&#xD;
      life-style/diet interventions showed some promising results. But in spite of this, there are&#xD;
      no available markers to efficiently guide interventions. the hypothesize put farth by the&#xD;
      investigators is that NAFLD patients develop postprandial abnormalities of plasma lipids upon&#xD;
      &quot;western diet&quot; challenge, more severe in steatohepatitis (NASH) than in pure steatosis&#xD;
      (NAFL), promoting liver injury. Our study aims to evaluate the presence of toxic lipids (such&#xD;
      as free-fatty acids, ceramides, diacylglycerols, sphingolipids) in postprandial state after&#xD;
      ingestion of a &quot;western diet&quot; in NAFLD patients. Consecutive patients (group 1: NAFL&#xD;
      patients; group 2: NASH patients) with biopsy-proven NAFLD (liver biopsy &lt; 6 months) will be&#xD;
      recruited during a period of 12 month. Blood samples will be drawn at fasting, 2hours,&#xD;
      4hours, 6hours and 8hours after ingestion of a &quot;western diet&quot; meal. Plasma lipid profiles&#xD;
      using lipidomics, circulating markers of liver injury and inflammation will be analyzed. the&#xD;
      investigators will also assess the hepatotoxicity of plasma from NAFL or NASH patients&#xD;
      in-vitro.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Factors driving progression from steatosis (NAFL) to steatohepatitis (NASH) in patients with&#xD;
      non-alcoholic fatty liver disease (NAFLD) remain largely unknown. Considerable data now&#xD;
      indicate that steatosis per se is not a hepatotoxic event and may represent in fact a&#xD;
      protective mechanism against free fatty acid (FFA)-induced toxicity. the investigators&#xD;
      previously showed that Kupffer cells from NASH mice accumulate more toxic lipids (ceramides,&#xD;
      diacylglycerols, sphingolipids) enhancing their proinflammatory polarization. Therefore,&#xD;
      &quot;quality&quot; of accumulating lipids rather than &quot;quantity&quot; may play a central role in NAFLD&#xD;
      progression. This is a pilot comparative study aiming to evaluate the presence of toxic&#xD;
      lipids (such as free-fatty acids, ceramides, diacylglycerols, sphingolipids) in postprandial&#xD;
      state after ingestion of a &quot;western diet&quot; in NAFL and NASH patients. The secondary outcomes&#xD;
      were: to evaluate the relationship between postprandial circulating lipids and markers of&#xD;
      liver injury and proinflammatory cytokines; to evaluate hepatotoxicity of postprandial lipids&#xD;
      in vitro. A total of 24 consecutive patients (group 1: 12 NAFL patients; group 2: 12 NASH&#xD;
      patients) with biopsy-proven NAFLD (liver biopsy &lt; 6 months) will be recruited. A dietary&#xD;
      evaluation covering the 2 previous weeks will be performed. Detailed anthropometric data will&#xD;
      be collected (body mass index, waist and hip circumferences, abdominal height, cutaneous&#xD;
      skinfolds) and serum metabolic parameters (standard lipid profile, lipoprotein levels,&#xD;
      fasting plasma glucose, insulin levels, C-peptide levels, hemoglobin A1c) will be evaluated.&#xD;
      After a 12hours overnight fast, patients will undergo an oral &quot;western diet&quot; test consisting&#xD;
      in the ingestion of a high saturated fat, high refined sugar, high fructose-meal called&#xD;
      &quot;western diet&quot; (800 kcal/meal). Blood samples will be drawn at fasting and then 2, 4, 6 and&#xD;
      8hours after ingestion of the standard meal. Each time plasma and serum samples will be&#xD;
      stored at -80°C for subsequent analysis. Lipidomics will be used to quantify each plasma&#xD;
      lipid class (neutral lipids, phospholipids and fatty acid methyl esters). Serum levels of&#xD;
      cytokines will be assessed using multiple assay technology. Markers of liver injury will be&#xD;
      assessed (aminotransferases, Keratin 18 fragments, microRNA-122) in the serum. Hepatocytes&#xD;
      will be cultured with plasma from NAFL or NASH patients, and incubated overnight. In vitro&#xD;
      hepatotoxicity will be evaluated using TUNEL assay, MTT assay and LDH release assay. the&#xD;
      investigators anticipate that inflammation together with hepatocyte death will occur in NAFLD&#xD;
      patients who develop specific postprandial plasma lipid changes with an increase in toxic&#xD;
      lipid levels. Such patients may develop more severe liver lesions (inflammation,&#xD;
      fibrosis/cirrhosis) and benefit of interventions. Identification of a toxic plasma lipid&#xD;
      profile may help choosing the adequate diet in order to prevent deleterious lipid formation.&#xD;
      Identification of a toxic postprandial plasma lipid signature specific to hepatotoxicity may&#xD;
      also serve to develop a discrimination index to be further validated in clinical practice.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">February 2019</start_date>
  <completion_date type="Anticipated">March 2020</completion_date>
  <primary_completion_date type="Anticipated">March 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>A &quot;western diet&quot; meal (high saturated fat, high refined sugar, high fructose) will be administered in each group (800 kcal/meal) after an overnight fast.</intervention_model_description>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Postprandial changes of plasma lipid fractions measured by lipidomic analysis and expressed as nmolof lipid/ml</measure>
    <time_frame>Plasma samples will be collected at 2hours, 4hours, 6hours and 8hours after ingestion of the &quot;western diet&quot; meal to assess postprandial lipid fraction changes</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Circulating markers of liver injury (AST, ALT, cytokeratin 18 fragments, microRNA-122) and serum cytokines (TNF-α, IL-6, IL-1β, IL-8).</measure>
    <time_frame>After a 12hours overnight fast and then at 2, 4, 6 and 8hours after ingestion of the &quot;western diet&quot; meal.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cytotoxic effect of postprandial plasma on hepatocytes in-vitro</measure>
    <time_frame>Plasma samples at 2hours, 4hours, 6hours and 8hours after ingestion of the &quot;western diet&quot; meal.</time_frame>
    <description>Hepatocytes will be cultured with postprandial plasma from NAFL or NASH patients, and incubated overnight. In-vitro hepatotoxicity will be evaluated using TUNEL assay, MTT assay and LDH release assay.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">25</enrollment>
  <condition>Nonalcoholic Fatty Liver Disease (NAFLD)</condition>
  <arm_group>
    <arm_group_label>NAFL patients (group 1)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>A &quot;western diet&quot; meal (high saturated fat, high refined sugar, high fructose) will be administered in each group (800 kcal/meal).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>NASH patients (group 2)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>A &quot;western diet&quot; meal (high saturated fat, high refined sugar, high fructose) will be administered in each group (800 kcal/meal).</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>western diet&quot; meal</intervention_name>
    <description>A &quot;western diet&quot; meal (high saturated fat, high refined sugar, high fructose) will be administered in each group (800 kcal/meal) after an overnight fast.</description>
    <arm_group_label>NAFL patients (group 1)</arm_group_label>
    <arm_group_label>NASH patients (group 2)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        - histological proven NAFLD (liver biopsy &lt;6 months); hospitalised or outpatients followed&#xD;
        up for NAFLD; patients giving their consent for the study; patients covered by health&#xD;
        insurance.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  history of excessive alcohol consumption (&gt;20 g/day for males and &gt;10 g/day for&#xD;
             females) or other cause of liver injury (viral hepatitis, autoimmune hepatitis,&#xD;
             Wilson's disease, hemochromatosis, drug-induced hepatitis, or others); cirrhosis;&#xD;
             ongoing hypolipemiant treatment; diabetes; severe associated disease.&#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>Cosmin VOICAN</last_name>
    <role>Principal Investigator</role>
    <affiliation>AP-HP, Beclere Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Cosmin VOICAN</last_name>
    <phone>01 45 37 47 75</phone>
    <email>cosmin.voican@aphp.fr</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Gabriel Perlemuter</last_name>
    <email>gabriel.perlemuter@aphp.fr</email>
  </overall_contact_backup>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>January 17, 2019</study_first_submitted>
  <study_first_submitted_qc>February 8, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 11, 2019</study_first_posted>
  <last_update_submitted>February 8, 2019</last_update_submitted>
  <last_update_submitted_qc>February 8, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">February 11, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>NAFLD, toxic lipids, postprandial lipotoxicity</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liver Diseases</mesh_term>
    <mesh_term>Fatty Liver</mesh_term>
    <mesh_term>Non-alcoholic Fatty Liver Disease</mesh_term>
  </condition_browse>
  <!-- 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/NCT03836443
org study id: D20180507
nct id: NCT03836443
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Nonalcoholic fatty liver disease (NAFLD) is mainly considered a nutrition-related disease and
      life-style/diet interventions showed some promising results. But in spite of this, there are
      no available markers to efficiently guide interventions. the hypothesize put farth by the
      investigators is that NAFLD patients develop postprandial abnormalities of plasma lipids upon
      "western diet" challenge, more severe in steatohepatitis (NASH) than in pure steatosis
      (NAFL), promoting liver injury. Our study aims to evaluate the presence of toxic lipids (such
      as free-fatty acids, ceramides, diacylglycerols, sphingolipids) in postprandial state after
      ingestion of a "western diet" in NAFLD patients. Consecutive patients (group 1: NAFL
      patients; group 2: NASH patients) with biopsy-proven NAFLD (liver biopsy < 6 months) will be
      recruited during a period of 12 month. Blood samples will be drawn at fasting, 2hours,
      4hours, 6hours and 8hours after ingestion of a "western diet" meal. Plasma lipid profiles
      using lipidomics, circulating markers of liver injury and inflammation will be analyzed. the
      investigators will also assess the hepatotoxicity of plasma from NAFL or NASH patients
      in-vitro.
Factors driving progression from steatosis (NAFL) to steatohepatitis (NASH) in patients with
      non-alcoholic fatty liver disease (NAFLD) remain largely unknown. Considerable data now
      indicate that steatosis per se is not a hepatotoxic event and may represent in fact a
      protective mechanism against free fatty acid (FFA)-induced toxicity. the investigators
      previously showed that Kupffer cells from NASH mice accumulate more toxic lipids (ceramides,
      diacylglycerols, sphingolipids) enhancing their proinflammatory polarization. Therefore,
      "quality" of accumulating lipids rather than "quantity" may play a central role in NAFLD
      progression. This is a pilot comparative study aiming to evaluate the presence of toxic
      lipids (such as free-fatty acids, ceramides, diacylglycerols, sphingolipids) in postprandial
      state after ingestion of a "western diet" in NAFL and NASH patients. The secondary outcomes
      were: to evaluate the relationship between postprandial circulating lipids and markers of
      liver injury and proinflammatory cytokines; to evaluate hepatotoxicity of postprandial lipids
      in vitro. A total of 24 consecutive patients (group 1: 12 NAFL patients; group 2: 12 NASH
      patients) with biopsy-proven NAFLD (liver biopsy < 6 months) will be recruited. A dietary
      evaluation covering the 2 previous weeks will be performed. Detailed anthropometric data will
      be collected (body mass index, waist and hip circumferences, abdominal height, cutaneous
      skinfolds) and serum metabolic parameters (standard lipid profile, lipoprotein levels,
      fasting plasma glucose, insulin levels, C-peptide levels, hemoglobin A1c) will be evaluated.
      After a 12hours overnight fast, patients will undergo an oral "western diet" test consisting
      in the ingestion of a high saturated fat, high refined sugar, high fructose-meal called
      "western diet" (800 kcal/meal). Blood samples will be drawn at fasting and then 2, 4, 6 and
      8hours after ingestion of the standard meal. Each time plasma and serum samples will be
      stored at -80°C for subsequent analysis. Lipidomics will be used to quantify each plasma
      lipid class (neutral lipids, phospholipids and fatty acid methyl esters). Serum levels of
      cytokines will be assessed using multiple assay technology. Markers of liver injury will be
      assessed (aminotransferases, Keratin 18 fragments, microRNA-122) in the serum. Hepatocytes
      will be cultured with plasma from NAFL or NASH patients, and incubated overnight. In vitro
      hepatotoxicity will be evaluated using TUNEL assay, MTT assay and LDH release assay. the
      investigators anticipate that inflammation together with hepatocyte death will occur in NAFLD
      patients who develop specific postprandial plasma lipid changes with an increase in toxic
      lipid levels. Such patients may develop more severe liver lesions (inflammation,
      fibrosis/cirrhosis) and benefit of interventions. Identification of a toxic plasma lipid
      profile may help choosing the adequate diet in order to prevent deleterious lipid formation.
      Identification of a toxic postprandial plasma lipid signature specific to hepatotoxicity may
      also serve to develop a discrimination index to be further validated in clinical practice.
allocation: Non-Randomized
intervention model: Parallel Assignment
intervention model description: A "western diet" meal (high saturated fat, high refined sugar, high fructose) will be administered in each group (800 kcal/meal) after an overnight fast.
primary purpose: Other
masking: None (Open Label)
measure: Postprandial changes of plasma lipid fractions measured by lipidomic analysis and expressed as nmolof lipid/ml
time frame: Plasma samples will be collected at 2hours, 4hours, 6hours and 8hours after ingestion of the "western diet" meal to assess postprandial lipid fraction changes
measure: Circulating markers of liver injury (AST, ALT, cytokeratin 18 fragments, microRNA-122) and serum cytokines (TNF-α, IL-6, IL-1β, IL-8).
time frame: After a 12hours overnight fast and then at 2, 4, 6 and 8hours after ingestion of the "western diet" meal.
measure: Cytotoxic effect of postprandial plasma on hepatocytes in-vitro
time frame: Plasma samples at 2hours, 4hours, 6hours and 8hours after ingestion of the "western diet" meal.
description: Hepatocytes will be cultured with postprandial plasma from NAFL or NASH patients, and incubated overnight. In-vitro hepatotoxicity will be evaluated using TUNEL assay, MTT assay and LDH release assay.
arm group label: NAFL patients (group 1)
arm group type: Active Comparator
description: A "western diet" meal (high saturated fat, high refined sugar, high fructose) will be administered in each group (800 kcal/meal).
arm group label: NASH patients (group 2)
arm group type: Active Comparator
description: A "western diet" meal (high saturated fat, high refined sugar, high fructose) will be administered in each group (800 kcal/meal).
intervention type: Other
intervention name: western diet" meal
description: A "western diet" meal (high saturated fat, high refined sugar, high fructose) will be administered in each group (800 kcal/meal) after an overnight fast.
arm group label: NAFL patients (group 1)
arm group label: NASH patients (group 2)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Cosmin VOICAN
role: Principal Investigator
affiliation: AP-HP, Beclere Hospital
last name: Cosmin VOICAN
phone: 01 45 37 47 75
email: cosmin.voican@aphp.fr
last name: Gabriel Perlemuter
email: gabriel.perlemuter@aphp.fr
responsible party type: Sponsor
mesh term: Liver Diseases
mesh term: Fatty Liver
mesh term: Non-alcoholic Fatty Liver Disease