<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/NCT03841383</url>
  </required_header>
  <id_info>
    <org_study_id>CFRBH4_IT1</org_study_id>
    <nct_id>NCT03841383</nct_id>
  </id_info>
  <brief_title>Association Between Coronary Flow Reserve and BH4 Levels in High CV Risk</brief_title>
  <official_title>Study to Investigate the Association Between Coronary Flow Reserve and BH4 Levels in Patients With High Cardiovascular Risk</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>IRCCS San Raffaele</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Servier</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>IRCCS San Raffaele</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>
      To determine if there is a relationship between coronary flow reserve (CFR) and&#xD;
      platelet/plasma BH2 and BH4 levels in patients with high cardiovascular risk .&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Primary parameter :&#xD;
&#xD;
      relationship between coronary flow reserve (CFR) and platelet/plasma BH2 and BH4 levels in&#xD;
      patients with hypertension and concomitant cardiovascular risk factors.&#xD;
&#xD;
      Secondary parameter:&#xD;
&#xD;
      Levels of cGMP in platelets.&#xD;
&#xD;
      4. Study design&#xD;
&#xD;
      Three parallel groups of patients (n=15 per group):&#xD;
&#xD;
        -  Group 1 with normal coronary flow reserve (CFR ≥2.5)&#xD;
&#xD;
        -  Group 2 with reduced coronary flow reserve (CFR≤2.0)&#xD;
&#xD;
           o Group 3 control subjects (without a high risk profile according to ESC score chart&#xD;
           http://www.heartscore.org. ) matched for age (between 40 and 80 years of age)&#xD;
&#xD;
        -  and gender. 1/3 enrolled patients must be diabetic (Type2 diabetes)&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 6, 2017</start_date>
  <completion_date type="Actual">July 10, 2019</completion_date>
  <primary_completion_date type="Actual">May 31, 2019</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>BH2 and BH4 levels (ng/ml) in plasma and platelets</measure>
    <time_frame>1 week</time_frame>
    <description>Blood samples will be withdrawn and subsequently analyzed to assess biopterins BH4 and BH2 ng/mL concentration in plasma and platelets Each will be determined separately from the same sample, by high-performance liquid chromatography followed by serial electrochemical and fluorescent detection.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Coronary Flow Reserve (CFR) Trans Thoracic Doppler Echocardiography</measure>
    <time_frame>1 week</time_frame>
    <description>Measurement of coronary flow reserve of the left anterior descending coronary artery will be carried out with transthoracic Doppler Echocardiography (TDE) and dipyridamole stress. CFR will be calculated as the ratio between stress and resting flow velocity (cm/sec)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Relationship between coronary flow reserve (CFR) and platelet/plasma BH2 and BH4 levels.</measure>
    <time_frame>1 week</time_frame>
    <description>Simple regression analysis or logistic regression will be used to test the relationship between CFR and biopterins values in plasma and platelets.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Levels of cGMP in platelets</measure>
    <time_frame>1 week</time_frame>
    <description>Comparison of levels of cGMP in platelets among normals, patients with normal CFR and patients with reduced CFR</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">55</enrollment>
  <condition>Hypertension,Essential</condition>
  <arm_group>
    <arm_group_label>Healthy controls</arm_group_label>
  </arm_group>
  <arm_group>
    <arm_group_label>Hypertensive patients</arm_group_label>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Echo stress dipyridamole</intervention_name>
    <description>Echo stress dipyridamole</description>
    <arm_group_label>Healthy controls</arm_group_label>
    <arm_group_label>Hypertensive patients</arm_group_label>
    <other_name>Blood sample</other_name>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Symptomatic (angina symptoms both typical and atypical ) patients referred to the hospital&#xD;
        with hypertension plus risk factors: diabetes, hypercholesterolemia, smoking, chronic renal&#xD;
        failure&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  o men and women (females of childbearing potential must be using highly effective&#xD;
             contraceptive precautions such as implants, injectables, combined oral contraceptives,&#xD;
             intrauterine devices, sexual abstinence or vasectomised partner)&#xD;
&#xD;
               -  Females of childbearing potential or within two years from the menopause must&#xD;
                  have a negative urine pregnancy test&#xD;
&#xD;
               -  between 40 and 80 years of age&#xD;
&#xD;
               -  documented history of hypertension&#xD;
&#xD;
               -  smokers/non smokers R&#xD;
&#xD;
               -  type 2 diabetes R&#xD;
&#xD;
               -  Moderate to severe kidney disease (GFR &gt;30 and &lt;60 ml/min/1.73m2 (estimated MDRD)&#xD;
                  R&#xD;
&#xD;
               -  Hypercholesterolemia R&#xD;
&#xD;
               -  Receiving an optimal standard antihypertensive treatment for at least 6 months,&#xD;
                  stable for at least 15 days&#xD;
&#xD;
               -  All other concomitant treatments stabilized at least for the preceding 15 days&#xD;
&#xD;
               -  Able to give written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  o Females of childbearing potential not using highly effective contraceptive&#xD;
             precautions&#xD;
&#xD;
               -  Patients with obstructive (&gt;50% diameter reduction) CAD on the LAD (based on&#xD;
                  invasive angiography or coronary CTA) or with evidence of previous myocardial&#xD;
                  infarction or history of revascularization in the LAD territory.&#xD;
&#xD;
               -  CAD on the RCA or CX with diameter reduction &gt; 50% (based on invasive angiography&#xD;
                  or coronary CTA) , either native or revascularized (stent)&#xD;
&#xD;
               -  Patients with infectious disease and/or chronic inflammatory diseases&#xD;
&#xD;
               -  Epicardial coronary arteries spasm&#xD;
&#xD;
               -  Patients with severe valve disease and/or significant left ventricular wall&#xD;
                  motion abnormalities&#xD;
&#xD;
               -  Patients under treatment with non-selective beta blockers including propranolol,&#xD;
                  nadolol, pindolol, labetalol, penbutolol, sotalol, carvedilol, and timolol.&#xD;
&#xD;
               -  Contraindications to dipyridamole infusion: asthma, bronchospasm, previous &lt; 24&#xD;
                  hours ingestion of phylline derivatives (tea, coffee, cola, xanthines and&#xD;
                  chocolate) sick sinus syndrome, advanced AV block (second and third degree),&#xD;
                  systolic blood pressure &lt; 90 mmHg, cerebral ischemia, severe sinus bradycardia&#xD;
                  (heart rate &lt;40/min), use of dipyridamole during the last 24 h, severe&#xD;
                  atherosclerotic lesions of extracranial artery &gt;75%.&#xD;
&#xD;
               -  Acute treatment or treatment for acute diseases&#xD;
&#xD;
               -  Patients receiving steroidal anti-inflammatory drugs, dietary supplements of&#xD;
                  folic acid, or antioxidant vitamins.&#xD;
&#xD;
               -  Any condition that may prevent the pt to give informed consent , enter the study&#xD;
                  or bias the results.&#xD;
&#xD;
               -  Participating into other studies&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
  </eligibility>
  <overall_official>
    <last_name>Paolo G Camici, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>IRCCS Ospedale San Raffaele</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>ASST Papa Giovanni XXIII</name>
      <address>
        <city>Bergamo</city>
        <zip>24127</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>IRCCS Ospedale San Raffaele</name>
      <address>
        <city>Milan</city>
        <zip>20132</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>July 2019</verification_date>
  <study_first_submitted>January 25, 2019</study_first_submitted>
  <study_first_submitted_qc>February 13, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 15, 2019</study_first_posted>
  <last_update_submitted>July 11, 2019</last_update_submitted>
  <last_update_submitted_qc>July 11, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">July 12, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>IRCCS San Raffaele</investigator_affiliation>
    <investigator_full_name>Prof. Paolo G Camici MD FACC</investigator_full_name>
    <investigator_title>Professor of Cardiology</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Essential Hypertension</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dipyridamole</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03841383
org study id: CFRBH4_IT1
nct id: NCT03841383
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
To determine if there is a relationship between coronary flow reserve (CFR) and
      platelet/plasma BH2 and BH4 levels in patients with high cardiovascular risk .
Primary parameter :

      relationship between coronary flow reserve (CFR) and platelet/plasma BH2 and BH4 levels in
      patients with hypertension and concomitant cardiovascular risk factors.

      Secondary parameter:

      Levels of cGMP in platelets.

      4. Study design

      Three parallel groups of patients (n=15 per group):

        -  Group 1 with normal coronary flow reserve (CFR ≥2.5)

        -  Group 2 with reduced coronary flow reserve (CFR≤2.0)

           o Group 3 control subjects (without a high risk profile according to ESC score chart
           http://www.heartscore.org. ) matched for age (between 40 and 80 years of age)

        -  and gender. 1/3 enrolled patients must be diabetic (Type2 diabetes)
observational model: Case-Control
time perspective: Prospective
measure: BH2 and BH4 levels (ng/ml) in plasma and platelets
time frame: 1 week
description: Blood samples will be withdrawn and subsequently analyzed to assess biopterins BH4 and BH2 ng/mL concentration in plasma and platelets Each will be determined separately from the same sample, by high-performance liquid chromatography followed by serial electrochemical and fluorescent detection.
measure: Coronary Flow Reserve (CFR) Trans Thoracic Doppler Echocardiography
time frame: 1 week
description: Measurement of coronary flow reserve of the left anterior descending coronary artery will be carried out with transthoracic Doppler Echocardiography (TDE) and dipyridamole stress. CFR will be calculated as the ratio between stress and resting flow velocity (cm/sec)
measure: Relationship between coronary flow reserve (CFR) and platelet/plasma BH2 and BH4 levels.
time frame: 1 week
description: Simple regression analysis or logistic regression will be used to test the relationship between CFR and biopterins values in plasma and platelets.
measure: Levels of cGMP in platelets
time frame: 1 week
description: Comparison of levels of cGMP in platelets among normals, patients with normal CFR and patients with reduced CFR
arm group label: Healthy controls
arm group label: Hypertensive patients
intervention type: Diagnostic Test
intervention name: Echo stress dipyridamole
description: Echo stress dipyridamole
arm group label: Healthy controls
arm group label: Hypertensive patients
other name: Blood sample
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
last name: Paolo G Camici, MD
role: Principal Investigator
affiliation: IRCCS Ospedale San Raffaele
facility: 
facility: 
country: Italy
responsible party type: Principal Investigator
investigator affiliation: IRCCS San Raffaele
investigator full name: Prof. Paolo G Camici MD FACC
investigator title: Professor of Cardiology
mesh term: Essential Hypertension
mesh term: Dipyridamole
sharing ipd: Undecided