<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/NCT03034148</url>
  </required_header>
  <id_info>
    <org_study_id>cb07012015</org_study_id>
    <nct_id>NCT03034148</nct_id>
  </id_info>
  <brief_title>Platelet Acetyl Coenzyme A Carboxylase Phosphorylation in Coronary Artery Disease</brief_title>
  <acronym>ACCTHEROMA</acronym>
  <official_title>Prospective Evaluation of Acetyl-Coenzyme A Carboxylase Phosphorylation State in Platelets in Atherothrombotic Coronary Artery Disease.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cliniques universitaires Saint-Luc- Université Catholique de Louvain</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Cliniques universitaires Saint-Luc- Université Catholique de Louvain</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      In human purified platelets, only thrombin, and not the other platelet agonists, leads to a&#xD;
      transient activation of the protein kinase activated by AMP (AMPK) and to phosphorylation of&#xD;
      its &quot;bona fide&quot; substrate, ACC on its Ser79. ACC phosphorylation (P-ACC) can be an&#xD;
      interesting marker of thrombin action on platelets. Indeed platelet and coagulation&#xD;
      interplay, though undoubtedly present in atherosclerosis and atherothrombosis, remains&#xD;
      difficult to assess. Our group showed that atherosclerotic mice (SRBI/Apolipoprotein E&#xD;
      knock-out) had higher platelet P-ACC compared to corresponding control mice (C57BL6). In&#xD;
      agreement with these data, preliminary results showed increased platelet P-ACC in a small&#xD;
      cohort of patients admitted for coronary angiogram, with demonstrated coronary artery disease&#xD;
      (CAD).&#xD;
&#xD;
      In the light of our preliminary results, we sought to analyze platelet P-ACC in a large&#xD;
      prospective clinical trial (ACCTHEROMA) in patients admitted for coronary angiogram. The aim&#xD;
      of the study is to compare platelet P-ACC in platelets of patients with CAD and more&#xD;
      particularly in unstable CAD patients to non-CAD patients. This study could potentially&#xD;
      identify patients at high risk of future ischemic cardiovascular events, because of a higher&#xD;
      level of thrombin generation.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Consecutive patients with planned coronary angiogram at the Cliniques Universitaires Saint&#xD;
      Luc, Brussels, whatever the indication, will be included between March 2015 and February&#xD;
      2016. Informed consent will be obtained before angiogram.&#xD;
&#xD;
      A. Blood Sampling Routine veinous blood sample will be done under fasting condition in the&#xD;
      cardiology ward before the angiogram (standard of care for patients undergoing coronary&#xD;
      angiogram).&#xD;
&#xD;
      In order to avoid additional puncture for blood sampling and to limit platelet activation,&#xD;
      blood samples are withdrawn after sheath insertion at the Cath lab before any drug&#xD;
      administration. The following measurements will be done:&#xD;
&#xD;
        -  Routine coagulation tests including international rationalize ratio, activated cephaline&#xD;
           time, thrombin time, prothrombin time, Fibrinogen, DDimers.&#xD;
&#xD;
        -  Platelet reactivity testing by the Multiple Electrode Aggregometer (Multiplate Analysis)&#xD;
&#xD;
        -  Platelet isolation and lysates will be stocked frozen for phospho-protein analysis by&#xD;
           immunoblotting and electrochemiluminescence (ECLIA)&#xD;
&#xD;
        -  Aliquots of poor platelet plasma stocked frozen for inflammation (HsCRP), thrombin&#xD;
           generation tests (thrombin-antithrombin complex, prothrombin fragment F1.2, endogenous&#xD;
           thrombin generation potential-ETP), platelet activation markers (platelet factor 4,&#xD;
           soluble CD40ligand, soluble P-selectin) and circulating micro-RNA extraction.&#xD;
&#xD;
        -  Platelet isolation and further purification for platelet specific micro-RNA extraction.&#xD;
&#xD;
      B. Atherosclerosis evaluation All patients underwent coronary angiogram. Significant coronary&#xD;
      artery lesion is defined as a luminal stenosis above 50%. Syntax score will be calculated for&#xD;
      all patients.&#xD;
&#xD;
      Global atherosclerotic plaque burden on coronary and extracoronary arteries will be evaluated&#xD;
      by measuring calcium score on thoraco-abdominal scanner with prospective ECG-gating in a&#xD;
      randomly selected subgroup of patients. Coronary artery calcification (CAC) is expressed as&#xD;
      Agatston score using calcium scoring software (Philips Healthcare) with a threshold of 130&#xD;
      Hounsfield units. The degree of atherosclerotic burden on coronary arteries is classified as&#xD;
      mild (Agatston score &lt;100), moderate (Agatston score 100-400) or severe (Agatston score&#xD;
      &gt;400). Aortic calcification (AoC score) was measured from aortic arch to iliac arteries in&#xD;
      all patients.&#xD;
&#xD;
      C. Data collection Baseline characteristics of patients will be collected from the medical&#xD;
      database of the Cliniques Universitaires Saint Luc. All coronary angiogram will be reviewed&#xD;
      by 2 different investigators and syntax score will be calculated with the online syntax score&#xD;
      calculator. CAC Agatston and AoC score will also be assessed by 2 different investigators.&#xD;
&#xD;
      D.Patients Classification for platelet P-ACC analysis Platelet ACC phosphorylation (P-ACC)&#xD;
      analysis will be done by immunoblotting with a specific antibody probing for phosphorylated&#xD;
      (Ser 79) ACC. Purified washed platelets stimulated with 0.5 units/ml thrombin will be used as&#xD;
      positive internal controls.&#xD;
&#xD;
      Patients will first be classified in non-CAD and CAD groups based on the results of coronary&#xD;
      angiogram and CAC Agatston score: Non-CAD (absence of lesion on angiogram and/or CAC Agatston&#xD;
      score&lt;100) and CAD (presence of at least 1 lesion on angiogram and/or CAC Agatston&#xD;
      score&gt;100).&#xD;
&#xD;
      In a second analysis, based on clinical presentation, the CAD group will further be divided&#xD;
      into Stable CAD or Unstable CAD [acute coronary syndrome (ACS)]. Platelet P-ACC will be&#xD;
      compared in both subgroups. This detailed classification will outline high-risk patients with&#xD;
      ongoing acute coronary syndrome.&#xD;
&#xD;
      E. Sample size and statistical analysis. Based on our preliminary data, we determined that&#xD;
      enrolment of 102 patients would provide a power of 80% at a significance level of 5% to&#xD;
      detect a difference of 0.15 (A.U.) in the phosphorylation of ACC in atherosclerotic patients,&#xD;
      compared to non CAD patients.&#xD;
&#xD;
      Continuous variables will be expressed as mean +/- one standard deviation, categoric&#xD;
      variables as counts and percentages. Patients will separated in four groups depending on the&#xD;
      level of P-ACC (quartiles). Clinical presentation, thrombin generation markers and calcium&#xD;
      scoring will be compared in all these groups, based on ANOVA analysis. Variables will be&#xD;
      submitted to logistic regression test in order to identify independent predictors of high ACC&#xD;
      phosphorylation state. The role of high platelets P-ACC in assessing the risk of the patients&#xD;
      will be then studied.&#xD;
&#xD;
      F.Follow-up A follow-up period of 3 years is planned. Events recorded during the follow-up&#xD;
      period will be obtained from the medical database and a phone call will be done in case of&#xD;
      missing data.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>March 2015</start_date>
  <completion_date type="Actual">February 2016</completion_date>
  <primary_completion_date type="Actual">February 2016</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Screening</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>an increase in platelet ACC phosphorylation state in patients with coronary artery disease</measure>
    <time_frame>2 years</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>a correlation between thrombin generation markers and platelet P-ACC in overall population.</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>platelet ACC phosphorylation state according clinical severity of CAD (stable versus unstable patients)</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>the role of platelet P-ACC in predicting the risk of the patient for future cardiovascular events (death, myocardial infarction, stroke)</measure>
    <time_frame>3 years</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">188</enrollment>
  <condition>Coronary Artery Disease</condition>
  <condition>Acute Coronary Syndrome</condition>
  <condition>Coronary Thrombosis</condition>
  <arm_group>
    <arm_group_label>Coronary artery disease</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>blood sampling for biomarkers assessment in a population undergoing coronary angiogram</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Platelet Acetyl Coenzyme A Carboxylase analysis in CAD</intervention_name>
    <arm_group_label>Coronary artery disease</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Signed informed consent&#xD;
&#xD;
          -  Planned angiography within the next 3 days, whatever the indication.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Not able to sign informed consent&#xD;
&#xD;
          -  Patients on anticoagulation therapy (oral or parenteral) including heparins,&#xD;
             fondaparinux, vitamin K antagonist, novel oral anticoagulants, for any reasons.&#xD;
&#xD;
          -  Active neoplasia&#xD;
&#xD;
          -  Active inflammatory disease&#xD;
&#xD;
          -  Patients with life expectancy lower than 3 years&#xD;
&#xD;
          -  Haemophilia and other coagulopathy&#xD;
&#xD;
          -  Abnormal platelet count&#xD;
&#xD;
          -  Heart transplanted patients&#xD;
&#xD;
          -  Active hepatitis B or C or HIV patients&#xD;
&#xD;
          -  Any contra-indication for coronary angiography.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Christophe Beauloye, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Cliniques universitaires Saint-Luc- Université Catholique de Louvain</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cliniques Universitaires Saint Luc</name>
      <address>
        <city>Brussels</city>
        <zip>1200</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
  </location_countries>
  <results_reference>
    <citation>Onselaer MB, Oury C, Hunter RW, Eeckhoudt S, Barile N, Lecut C, Morel N, Viollet B, Jacquet LM, Bertrand L, Sakamoto K, Vanoverschelde JL, Beauloye C, Horman S. The Ca(2+) /calmodulin-dependent kinase kinase beta-AMP-activated protein kinase-alpha1 pathway regulates phosphorylation of cytoskeletal targets in thrombin-stimulated human platelets. J Thromb Haemost. 2014 Jun;12(6):973-86. doi: 10.1111/jth.12568.</citation>
    <PMID>24655923</PMID>
  </results_reference>
  <verification_date>February 2017</verification_date>
  <study_first_submitted>January 25, 2017</study_first_submitted>
  <study_first_submitted_qc>January 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 27, 2017</study_first_posted>
  <last_update_submitted>February 15, 2017</last_update_submitted>
  <last_update_submitted_qc>February 15, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">February 17, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Coronary artery disease</keyword>
  <keyword>Atherothrombosis</keyword>
  <keyword>Thrombin generation</keyword>
  <keyword>Platelet Acetyl Coenzyme A carboxylase phosphorylation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Coronary Artery Disease</mesh_term>
    <mesh_term>Myocardial Ischemia</mesh_term>
    <mesh_term>Coronary Disease</mesh_term>
    <mesh_term>Thrombosis</mesh_term>
    <mesh_term>Acute Coronary Syndrome</mesh_term>
    <mesh_term>Coronary Thrombosis</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/NCT03034148
org study id: cb07012015
nct id: NCT03034148
lead sponsor: 
has dmc: No
In human purified platelets, only thrombin, and not the other platelet agonists, leads to a
      transient activation of the protein kinase activated by AMP (AMPK) and to phosphorylation of
      its "bona fide" substrate, ACC on its Ser79. ACC phosphorylation (P-ACC) can be an
      interesting marker of thrombin action on platelets. Indeed platelet and coagulation
      interplay, though undoubtedly present in atherosclerosis and atherothrombosis, remains
      difficult to assess. Our group showed that atherosclerotic mice (SRBI/Apolipoprotein E
      knock-out) had higher platelet P-ACC compared to corresponding control mice (C57BL6). In
      agreement with these data, preliminary results showed increased platelet P-ACC in a small
      cohort of patients admitted for coronary angiogram, with demonstrated coronary artery disease
      (CAD).

      In the light of our preliminary results, we sought to analyze platelet P-ACC in a large
      prospective clinical trial (ACCTHEROMA) in patients admitted for coronary angiogram. The aim
      of the study is to compare platelet P-ACC in platelets of patients with CAD and more
      particularly in unstable CAD patients to non-CAD patients. This study could potentially
      identify patients at high risk of future ischemic cardiovascular events, because of a higher
      level of thrombin generation.
Consecutive patients with planned coronary angiogram at the Cliniques Universitaires Saint
      Luc, Brussels, whatever the indication, will be included between March 2015 and February
      2016. Informed consent will be obtained before angiogram.

      A. Blood Sampling Routine veinous blood sample will be done under fasting condition in the
      cardiology ward before the angiogram (standard of care for patients undergoing coronary
      angiogram).

      In order to avoid additional puncture for blood sampling and to limit platelet activation,
      blood samples are withdrawn after sheath insertion at the Cath lab before any drug
      administration. The following measurements will be done:

        -  Routine coagulation tests including international rationalize ratio, activated cephaline
           time, thrombin time, prothrombin time, Fibrinogen, DDimers.

        -  Platelet reactivity testing by the Multiple Electrode Aggregometer (Multiplate Analysis)

        -  Platelet isolation and lysates will be stocked frozen for phospho-protein analysis by
           immunoblotting and electrochemiluminescence (ECLIA)

        -  Aliquots of poor platelet plasma stocked frozen for inflammation (HsCRP), thrombin
           generation tests (thrombin-antithrombin complex, prothrombin fragment F1.2, endogenous
           thrombin generation potential-ETP), platelet activation markers (platelet factor 4,
           soluble CD40ligand, soluble P-selectin) and circulating micro-RNA extraction.

        -  Platelet isolation and further purification for platelet specific micro-RNA extraction.

      B. Atherosclerosis evaluation All patients underwent coronary angiogram. Significant coronary
      artery lesion is defined as a luminal stenosis above 50%. Syntax score will be calculated for
      all patients.

      Global atherosclerotic plaque burden on coronary and extracoronary arteries will be evaluated
      by measuring calcium score on thoraco-abdominal scanner with prospective ECG-gating in a
      randomly selected subgroup of patients. Coronary artery calcification (CAC) is expressed as
      Agatston score using calcium scoring software (Philips Healthcare) with a threshold of 130
      Hounsfield units. The degree of atherosclerotic burden on coronary arteries is classified as
      mild (Agatston score <100), moderate (Agatston score 100-400) or severe (Agatston score
      >400). Aortic calcification (AoC score) was measured from aortic arch to iliac arteries in
      all patients.

      C. Data collection Baseline characteristics of patients will be collected from the medical
      database of the Cliniques Universitaires Saint Luc. All coronary angiogram will be reviewed
      by 2 different investigators and syntax score will be calculated with the online syntax score
      calculator. CAC Agatston and AoC score will also be assessed by 2 different investigators.

      D.Patients Classification for platelet P-ACC analysis Platelet ACC phosphorylation (P-ACC)
      analysis will be done by immunoblotting with a specific antibody probing for phosphorylated
      (Ser 79) ACC. Purified washed platelets stimulated with 0.5 units/ml thrombin will be used as
      positive internal controls.

      Patients will first be classified in non-CAD and CAD groups based on the results of coronary
      angiogram and CAC Agatston score: Non-CAD (absence of lesion on angiogram and/or CAC Agatston
      score<100) and CAD (presence of at least 1 lesion on angiogram and/or CAC Agatston
      score>100).

      In a second analysis, based on clinical presentation, the CAD group will further be divided
      into Stable CAD or Unstable CAD [acute coronary syndrome (ACS)]. Platelet P-ACC will be
      compared in both subgroups. This detailed classification will outline high-risk patients with
      ongoing acute coronary syndrome.

      E. Sample size and statistical analysis. Based on our preliminary data, we determined that
      enrolment of 102 patients would provide a power of 80% at a significance level of 5% to
      detect a difference of 0.15 (A.U.) in the phosphorylation of ACC in atherosclerotic patients,
      compared to non CAD patients.

      Continuous variables will be expressed as mean +/- one standard deviation, categoric
      variables as counts and percentages. Patients will separated in four groups depending on the
      level of P-ACC (quartiles). Clinical presentation, thrombin generation markers and calcium
      scoring will be compared in all these groups, based on ANOVA analysis. Variables will be
      submitted to logistic regression test in order to identify independent predictors of high ACC
      phosphorylation state. The role of high platelets P-ACC in assessing the risk of the patients
      will be then studied.

      F.Follow-up A follow-up period of 3 years is planned. Events recorded during the follow-up
      period will be obtained from the medical database and a phone call will be done in case of
      missing data.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Screening
masking: None (Open Label)
measure: an increase in platelet ACC phosphorylation state in patients with coronary artery disease
time frame: 2 years
measure: a correlation between thrombin generation markers and platelet P-ACC in overall population.
time frame: 2 years
measure: platelet ACC phosphorylation state according clinical severity of CAD (stable versus unstable patients)
time frame: 2 years
measure: the role of platelet P-ACC in predicting the risk of the patient for future cardiovascular events (death, myocardial infarction, stroke)
time frame: 3 years
arm group label: Coronary artery disease
arm group type: Other
description: blood sampling for biomarkers assessment in a population undergoing coronary angiogram
intervention type: Diagnostic Test
intervention name: Platelet Acetyl Coenzyme A Carboxylase analysis in CAD
arm group label: Coronary artery disease
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Christophe Beauloye, MD, PhD
role: Principal Investigator
affiliation: Cliniques universitaires Saint-Luc- Université Catholique de Louvain
facility: 
country: Belgium
citation: Onselaer MB, Oury C, Hunter RW, Eeckhoudt S, Barile N, Lecut C, Morel N, Viollet B, Jacquet LM, Bertrand L, Sakamoto K, Vanoverschelde JL, Beauloye C, Horman S. The Ca(2+) /calmodulin-dependent kinase kinase beta-AMP-activated protein kinase-alpha1 pathway regulates phosphorylation of cytoskeletal targets in thrombin-stimulated human platelets. J Thromb Haemost. 2014 Jun;12(6):973-86. doi: 10.1111/jth.12568.
PMID: 24655923
responsible party type: Sponsor
mesh term: Coronary Artery Disease
mesh term: Myocardial Ischemia
mesh term: Coronary Disease
mesh term: Thrombosis
mesh term: Acute Coronary Syndrome
mesh term: Coronary Thrombosis
sharing ipd: No