<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/NCT03837925</url>
  </required_header>
  <id_info>
    <org_study_id>2016-02</org_study_id>
    <nct_id>NCT03837925</nct_id>
  </id_info>
  <brief_title>Pharmaco-metabolomic Effects of Statins: METASTATINE</brief_title>
  <acronym>METASTATINE</acronym>
  <official_title>Pharmaco-metabolomic Effects of Statins: METASTATINE</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>French Cardiology Society</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Fondation Coeur et Recherche</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>ICAN Nutrition Education and Research</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Fédération francaise de cardiologie</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>French Cardiology Society</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>
      Statins are effective in cardio-vascular prevention by lowering LDL-Cholesterol levels but&#xD;
      also through other mechanisms poorly understood. Our hypothesis is that some of these effects&#xD;
      are mediated by microbiota alteration, leading to diminution of expression of microbiota&#xD;
      derived pro-atherogenic metabolites.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The aim of this prospective double blind placebo-controlled study is to evaluate the acute&#xD;
      effects of statins on microbiota and its derived metabolites at 2 and 6 weeks.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 13, 2019</start_date>
  <completion_date type="Actual">December 21, 2022</completion_date>
  <primary_completion_date type="Actual">December 21, 2022</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>2 groups of patients having treatment or placebo</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Placebo manufactured as the treatment. Packaging identical.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Rate of trimethylamine N-oxide trimethylamine oxide in blood, measured post-prandially at week-6 in atorvastatin arm and placebo arm.</measure>
    <time_frame>Week-6</time_frame>
    <description>The main objective of the study is to measure the direct effect of Hydroxy-methyl-glutaryl-coenzyme A reductase inhibitors (Atorvastatin) on the production of atherogenic metabolites derived from intestinal microbiota</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Rate of trimethylamine N-oxide trimethylamine oxide in blood, measured post-prandially at week-2 in atorvastatin arm and placebo arm.</measure>
    <time_frame>week-2</time_frame>
    <description>To evaluate the evolution of the whole circulating metabolomic profile linked to the introduction of statins</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of trimethylamine N-oxide trimethylamine oxide in blood, measured pre and post-prandially at week-2 and week-6 in atorvastatin arm.</measure>
    <time_frame>Week-2 and week-6</time_frame>
    <description>To evaluate changes in the microbiome related to the introduction of statins</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Comparison between W0, W2 and W6 after initiation of atorvastatin vs placebo of circulating metabolomic profile (pre- and postprandial)</measure>
    <time_frame>Week 2 and Week 6</time_frame>
    <description>To correlate changes in lipid parameters induced by statins with metabolomic and lipidemic changes and microbiome. Rate of 100 metabolites will be analysed, and gathered as follows:&#xD;
metabolism of acylcarnitine (3), metabolism of bile acids (5), carbohydrate metabolism (1), dietary choline metabolism (3), metabolism of amino acids (34), vitamins and cofactors (7), metabolism of creatine (2), polyamine metabolism (3), purine metabolism (5), pyrimidine metabolism (9), tryptophan / kynurenine metabolism (21), caffeine metabolism (3), Citric Acid cycle (3), urea cycle (1)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Comparison between W0, W2 and W6 after initiation of atorvastatin vs placebo of the microbiome</measure>
    <time_frame>Week 2 and Week 6</time_frame>
    <description>To analyze the influence of the microbiota on the variability of response to atorvastatin.&#xD;
169/5000 The stool will be analyzed by metagenomic sequencing using the &quot;shot gun&quot; technique, a direct sequencing that quantifies the number of bacterial genes and annotates them.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">120</enrollment>
  <condition>Cardiovascular Diseases</condition>
  <arm_group>
    <arm_group_label>ATORVASTATIN</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Atorvastatin 40mg caps: one daily. 3 patient visits: inclusion / week 2 / week 6. At each visit, blood sampling, stool sampling, ECG, to evaluate the pharmaco-metabolomic effects of the Statine</description>
  </arm_group>
  <arm_group>
    <arm_group_label>PLACEBO</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo caps: one daily. 3 patient visits: inclusion / week 2 / week 6. At each visit, blood sampling, stool sampling, ECG to compare the pharmaco-metabolomic effects of the Statine between atorvastatin arm and placebo arm</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Atorvastatin 40mg Tablet</intervention_name>
    <description>Patient participation for 6 weeks of treatment</description>
    <arm_group_label>ATORVASTATIN</arm_group_label>
    <other_name>No other name</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo comparator</intervention_name>
    <description>Patient participation for 6 weeks of treatment</description>
    <arm_group_label>PLACEBO</arm_group_label>
    <other_name>No other name</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patient with cardiovascular risk requiring statins in primary prevention&#xD;
&#xD;
          -  Contraception for women of childbearing age&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Previous antibiotics, proton pomp inhibitors, statins or other hypolipidemic drugs&#xD;
             intake in the previous three months&#xD;
&#xD;
          -  Renal insufficiency with creatinine clearance &lt;40ml/min&#xD;
&#xD;
          -  Contra-indication to statins&#xD;
&#xD;
          -  Previously known conditions affecting muscles, or digestive system&#xD;
&#xD;
          -  Requirement of statins in secondary prevention&#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>Joe Elie SALEM, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>CIC 1421 CHU Pitie Salpetriere</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>CIC La Sapétrière</name>
      <address>
        <city>Paris</city>
        <zip>75013</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CIC HEGP</name>
      <address>
        <city>Paris</city>
        <zip>75015</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>February 7, 2019</study_first_submitted>
  <study_first_submitted_qc>February 11, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 12, 2019</study_first_posted>
  <last_update_submitted>January 17, 2023</last_update_submitted>
  <last_update_submitted_qc>January 17, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">January 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Statins</keyword>
  <keyword>cardiovascular risk</keyword>
  <keyword>primary prevention microbiota</keyword>
  <keyword>metabolomics</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cardiovascular Diseases</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Atorvastatin</mesh_term>
  </intervention_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/NCT03837925
org study id: 2016-02
nct id: NCT03837925
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Statins are effective in cardio-vascular prevention by lowering LDL-Cholesterol levels but
      also through other mechanisms poorly understood. Our hypothesis is that some of these effects
      are mediated by microbiota alteration, leading to diminution of expression of microbiota
      derived pro-atherogenic metabolites.
The aim of this prospective double blind placebo-controlled study is to evaluate the acute
      effects of statins on microbiota and its derived metabolites at 2 and 6 weeks.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: 2 groups of patients having treatment or placebo
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Placebo manufactured as the treatment. Packaging identical.
measure: Rate of trimethylamine N-oxide trimethylamine oxide in blood, measured post-prandially at week-6 in atorvastatin arm and placebo arm.
time frame: Week-6
description: The main objective of the study is to measure the direct effect of Hydroxy-methyl-glutaryl-coenzyme A reductase inhibitors (Atorvastatin) on the production of atherogenic metabolites derived from intestinal microbiota
measure: Rate of trimethylamine N-oxide trimethylamine oxide in blood, measured post-prandially at week-2 in atorvastatin arm and placebo arm.
time frame: week-2
description: To evaluate the evolution of the whole circulating metabolomic profile linked to the introduction of statins
measure: Rate of trimethylamine N-oxide trimethylamine oxide in blood, measured pre and post-prandially at week-2 and week-6 in atorvastatin arm.
time frame: Week-2 and week-6
description: To evaluate changes in the microbiome related to the introduction of statins
measure: Comparison between W0, W2 and W6 after initiation of atorvastatin vs placebo of circulating metabolomic profile (pre- and postprandial)
time frame: Week 2 and Week 6
description: To correlate changes in lipid parameters induced by statins with metabolomic and lipidemic changes and microbiome. Rate of 100 metabolites will be analysed, and gathered as follows:
metabolism of acylcarnitine (3), metabolism of bile acids (5), carbohydrate metabolism (1), dietary choline metabolism (3), metabolism of amino acids (34), vitamins and cofactors (7), metabolism of creatine (2), polyamine metabolism (3), purine metabolism (5), pyrimidine metabolism (9), tryptophan / kynurenine metabolism (21), caffeine metabolism (3), Citric Acid cycle (3), urea cycle (1)
measure: Comparison between W0, W2 and W6 after initiation of atorvastatin vs placebo of the microbiome
time frame: Week 2 and Week 6
description: To analyze the influence of the microbiota on the variability of response to atorvastatin.
169/5000 The stool will be analyzed by metagenomic sequencing using the "shot gun" technique, a direct sequencing that quantifies the number of bacterial genes and annotates them.
arm group label: ATORVASTATIN
arm group type: Experimental
description: Atorvastatin 40mg caps: one daily. 3 patient visits: inclusion / week 2 / week 6. At each visit, blood sampling, stool sampling, ECG, to evaluate the pharmaco-metabolomic effects of the Statine
arm group label: PLACEBO
arm group type: Placebo Comparator
description: Placebo caps: one daily. 3 patient visits: inclusion / week 2 / week 6. At each visit, blood sampling, stool sampling, ECG to compare the pharmaco-metabolomic effects of the Statine between atorvastatin arm and placebo arm
intervention type: Drug
intervention name: Atorvastatin 40mg Tablet
description: Patient participation for 6 weeks of treatment
arm group label: ATORVASTATIN
other name: No other name
intervention type: Drug
intervention name: Placebo comparator
description: Patient participation for 6 weeks of treatment
arm group label: PLACEBO
other name: No other name
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Joe Elie SALEM, MD
role: Principal Investigator
affiliation: CIC 1421 CHU Pitie Salpetriere
facility: 
facility: 
country: France
responsible party type: Sponsor
mesh term: Cardiovascular Diseases
mesh term: Atorvastatin
sharing ipd: No