<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/NCT03228238</url>
  </required_header>
  <id_info>
    <org_study_id>ANOVA</org_study_id>
    <nct_id>NCT03228238</nct_id>
  </id_info>
  <brief_title>ANti-Oxidant in Variant Angina (ANOVA) Trial</brief_title>
  <official_title>Effects of Long-term Vitamin C+E and Statin Therapy on Vasospasm Improvement and Regression of Atheroma in Patients With Variant Angina</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Seoul National University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Seoul National University Hospital</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Purpose Objectives&#xD;
&#xD;
        1. To evaluate the anti-oxidant effect of long-term Vitamin C+E therapy on coronary&#xD;
           vasospasm improvement.&#xD;
&#xD;
        2. To evaluate the anti-oxidant effect of long-term statin therapy on coronary vasospasm&#xD;
           improvement.&#xD;
&#xD;
        3. To evaluate the effect of long-term Vitamin C+E and statin therapy on regression of&#xD;
           atheroma in target coronary vessels via intravascular ultrasound.&#xD;
&#xD;
        4. To find out the role of vascular endothelium in variant angina via evaluating long-term&#xD;
           Vitamin C+E and statin therapy on improvement in vascular endothelial function by&#xD;
           assessing brachial arterial expansion capability.&#xD;
&#xD;
        5. To find out the role of vascular endothelium in variant angina via evaluating long-term&#xD;
           Vitamin C+E and statin therapy on improvement in arterial stiffness by assessing pulse&#xD;
           wave velocity(PWV)&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study Design: Prospective, open label, Four-arm, randomized single-center trial to test the&#xD;
      effect long-term Vitamin C+E and Statin therapy on vasospasm improvement and regression of&#xD;
      atheroma in patients with variant angina.&#xD;
&#xD;
      After provocation test, patients will be classified into three groups.(See below)&#xD;
&#xD;
        1. Negative group : Patients who have symptoms that are consistent with vasospastic angina&#xD;
           but only show luminal narrowing less than 50% on coronary angiography during provocation&#xD;
           test.&#xD;
&#xD;
        2. Mild Spastic group : Patients who have symptoms that are consistent with vasospastic&#xD;
           angina and show luminal narrowing over 50% to less than 90% on coronary angiography&#xD;
           during provocation test.&#xD;
&#xD;
        3. Severe Spastic group : Patients who have symptoms that are consistent with vasospastic&#xD;
           angina and show luminal narrowing over 90% on coronary angiography during provocation&#xD;
           test.&#xD;
&#xD;
      In each group (except for patient in Negative group), patients will be randomized in a two by&#xD;
      two factorial manner according to the study drug therapy (Vitamin C+E vs. no Vitamin C+E)&#xD;
      (Statin vs. no Statin) As a result, patients in each group(except for patient in Negative&#xD;
      group) will be randomized to 4 treatment subgroups, which are&#xD;
&#xD;
        1. Control subgroup : Standard medication for Variant angina only&#xD;
&#xD;
        2. Vitamin subgroup : Standard medication + Vitamin C+E&#xD;
&#xD;
        3. Statin subgroup : Standard medication + Statin&#xD;
&#xD;
        4. Dual subgroup : Standard medication + Vitamin C+E + Statin&#xD;
&#xD;
      Patients in Negative group will be prescribed only for standard medication for variant&#xD;
      angina.&#xD;
&#xD;
      Patient Enrollment: Recruiting 300 patients(100 patients for each group, as 25 patients for&#xD;
      each subgroups) from September 2014 through February 2021 at single center in Korea(Seoul&#xD;
      National University Hospital)&#xD;
&#xD;
      Patient Follow-Up: Clinical follow-up will occur at 1, and 6 months, and at 2, 4, and 6&#xD;
      years. Investigator or designee may conduct follow-up as telephone contacts or office visits.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">September 1, 2014</start_date>
  <completion_date type="Anticipated">February 28, 2021</completion_date>
  <primary_completion_date type="Anticipated">September 1, 2020</primary_completion_date>
  <phase>Phase 4</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Vasospasm at 6months</measure>
    <time_frame>at 6 months</time_frame>
    <description>Severity of vasospasm in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to control subgroup.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Vasospasm at 2 years</measure>
    <time_frame>at 2 years</time_frame>
    <description>Severity of vasospasm in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to control subgroup.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Vasospasm at 4 years</measure>
    <time_frame>at 4 years</time_frame>
    <description>Severity of vasospasm in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to control subgroup.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Vasospasm at 6 years</measure>
    <time_frame>at 6 years</time_frame>
    <description>Severity of vasospasm in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to control subgroup.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes from baseline in Vasospasm</measure>
    <time_frame>at 6 months, and at 2, 4, and 6 years follow up period</time_frame>
    <description>Changes of Vasospasm in Control subgroup, Vitamin subgroup, Statin subgroup, and Dual subgroup compared to baseline vasospasm assessed by provocation test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Composed improvement of Vascular endothelial function(Brachial arterial expansion capability)</measure>
    <time_frame>at 6 months, and at 2, 4, and 6 years follow up period</time_frame>
    <description>in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to control subgroup</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Improvement of Vascular endothelial function(Brachial arterial expansion capability)</measure>
    <time_frame>at 6 months, and at 2, 4, and 6 years follow up period</time_frame>
    <description>in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to baseline endothelial function test results</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Comparative analysis of improvement of Vascular endothelial function(Brachial arterial expansion capability)</measure>
    <time_frame>at 6 months, and at 2, 4, and 6 years follow up period</time_frame>
    <description>in Vitamin subgroup, Statin subgroup, and Dual subgroup</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Composed improvement of Arterial stiffness(Pulse wave velocity(PWV))</measure>
    <time_frame>at 6 months, and at 2, 4, and 6 years follow up period</time_frame>
    <description>in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to control subgroup</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Improvement of Arterial stiffness(Pulse wave velocity(PWV))</measure>
    <time_frame>at 6 months, and at 2, 4, and 6 years follow up period</time_frame>
    <description>in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to baseline endothelial function test results</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Comparative analysis of improvement of Arterial stiffness(Pulse wave velocity(PWV))</measure>
    <time_frame>at 6 months, and at 2, 4, and 6 years follow up period</time_frame>
    <description>in Vitamin subgroup, Statin subgroup, and Dual subgroup</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">300</enrollment>
  <condition>Variant Angina</condition>
  <arm_group>
    <arm_group_label>Dual subgroup</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Standard medication for variant angina plus Vitamin C+E plus Statin Vitamin C and Vitamin E : Ascorbic acid Tablet 1g / Tocopherol Capsule 400IU Statin : Atorvastatin calcium 10mg</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Statin subgroup</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Standard medication for variant angina plus Statin Statin : Atorvastatin calcium 10mg</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Vitamin subgroup</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Standard medication for variant angina plus Vitamin C+E Vitamin C and Vitamin E : Ascorbic acid Tablet 1g / Tocopherol Capsule 400IU</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Control subgroup : Standard medication for Variant angina only</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vitamin C and Vitamin E</intervention_name>
    <description>Ascorbic acid Tablet 1g and Tocopherol Capsule 400IU</description>
    <arm_group_label>Dual subgroup</arm_group_label>
    <arm_group_label>Vitamin subgroup</arm_group_label>
    <other_name>Ascorbic acid and Tocopherol</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Statin</intervention_name>
    <description>Atorvastatin calcium 10mg</description>
    <arm_group_label>Dual subgroup</arm_group_label>
    <arm_group_label>Statin subgroup</arm_group_label>
    <other_name>Atorvastatin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Standard medication for variant angina</intervention_name>
    <description>Calcium Channel blocker or NG</description>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_label>Dual subgroup</arm_group_label>
    <arm_group_label>Statin subgroup</arm_group_label>
    <arm_group_label>Vitamin subgroup</arm_group_label>
    <other_name>Calcium Channel blocker or NG</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Subject must be at least 30 years of age.&#xD;
&#xD;
          2. Subject is able to verbally confirm understandings of risks, benefits and treatment&#xD;
             alternatives of receiving the Vitamin C+E or Statin or Dual, and he/she or his/her&#xD;
             legally authorized representative provides written informed consent prior to any study&#xD;
             related procedure.&#xD;
&#xD;
          3. Subject must have symptoms that are consistent with vasospastic angina with planned&#xD;
             Coronary angiography and Provocation test.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patient who has organic coronary stenosis in main coronary branch at least 50% luminal&#xD;
             narrowing after intracoronary nitroglycerin injection&#xD;
&#xD;
          2. Patient who has continuously taken Vitamin C or Vitamin E or Statin within 3months&#xD;
             before Admission&#xD;
&#xD;
          3. Creatinine level ≥ 2.0mg/dL or dependence on dialysis.&#xD;
&#xD;
          4. Severe hepatic dysfunction (AST and ALT: 3 times upper normal reference values).&#xD;
&#xD;
          5. Active Myopathy or elevated Creatine kinase enzyme level (3 times upper normal&#xD;
             reference values).&#xD;
&#xD;
          6. History of Severe hepatic dysfunction or Rhabdomyolysis due to statin side effect&#xD;
&#xD;
          7. Female of childbearing potential, unless a recent pregnancy test is negative, who&#xD;
             possibly plan to become pregnant any time after enrollment into this study.&#xD;
&#xD;
          8. History of Urolithiasis&#xD;
&#xD;
          9. Non-cardiac co-morbid conditions are present with life expectancy &lt;1 year or that may&#xD;
             result in protocol non-compliance (per site investigator's medical judgment).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>30 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Hyo-Soo Kim, Kim</last_name>
    <role>Principal Investigator</role>
    <affiliation>Seoul National University Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Hyo-Soo Kim, MD, PhD</last_name>
    <phone>82-2-2072-2226</phone>
    <email>hyosoo@snu.ac.kr</email>
  </overall_contact>
  <location>
    <facility>
      <name>Seoul National University Hospital</name>
      <address>
        <city>Seoul</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Hyo-Soo Kim, M.D., PhD</last_name>
      <phone>82-2-2072-2226</phone>
      <email>hyosoo@snu.ac.kr</email>
    </contact>
  </location>
  <location_countries>
    <country>Korea, Republic of</country>
  </location_countries>
  <verification_date>July 2017</verification_date>
  <study_first_submitted>July 19, 2017</study_first_submitted>
  <study_first_submitted_qc>July 20, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 24, 2017</study_first_posted>
  <last_update_submitted>July 20, 2017</last_update_submitted>
  <last_update_submitted_qc>July 20, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">July 24, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Seoul National University Hospital</investigator_affiliation>
    <investigator_full_name>Hyo-Soo Kim</investigator_full_name>
    <investigator_title>Director of Cardiac Catheterization Laboratory &amp; Coronary Intervention</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Angina Pectoris</mesh_term>
    <mesh_term>Angina Pectoris, Variant</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vitamins</mesh_term>
    <mesh_term>Ascorbic Acid</mesh_term>
    <mesh_term>Vitamin E</mesh_term>
    <mesh_term>Tocopherols</mesh_term>
    <mesh_term>Calcium Channel Blockers</mesh_term>
    <mesh_term>Atorvastatin</mesh_term>
  </intervention_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/NCT03228238
org study id: ANOVA
nct id: NCT03228238
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
Purpose Objectives

        1. To evaluate the anti-oxidant effect of long-term Vitamin C+E therapy on coronary
           vasospasm improvement.

        2. To evaluate the anti-oxidant effect of long-term statin therapy on coronary vasospasm
           improvement.

        3. To evaluate the effect of long-term Vitamin C+E and statin therapy on regression of
           atheroma in target coronary vessels via intravascular ultrasound.

        4. To find out the role of vascular endothelium in variant angina via evaluating long-term
           Vitamin C+E and statin therapy on improvement in vascular endothelial function by
           assessing brachial arterial expansion capability.

        5. To find out the role of vascular endothelium in variant angina via evaluating long-term
           Vitamin C+E and statin therapy on improvement in arterial stiffness by assessing pulse
           wave velocity(PWV)
Study Design: Prospective, open label, Four-arm, randomized single-center trial to test the
      effect long-term Vitamin C+E and Statin therapy on vasospasm improvement and regression of
      atheroma in patients with variant angina.

      After provocation test, patients will be classified into three groups.(See below)

        1. Negative group : Patients who have symptoms that are consistent with vasospastic angina
           but only show luminal narrowing less than 50% on coronary angiography during provocation
           test.

        2. Mild Spastic group : Patients who have symptoms that are consistent with vasospastic
           angina and show luminal narrowing over 50% to less than 90% on coronary angiography
           during provocation test.

        3. Severe Spastic group : Patients who have symptoms that are consistent with vasospastic
           angina and show luminal narrowing over 90% on coronary angiography during provocation
           test.

      In each group (except for patient in Negative group), patients will be randomized in a two by
      two factorial manner according to the study drug therapy (Vitamin C+E vs. no Vitamin C+E)
      (Statin vs. no Statin) As a result, patients in each group(except for patient in Negative
      group) will be randomized to 4 treatment subgroups, which are

        1. Control subgroup : Standard medication for Variant angina only

        2. Vitamin subgroup : Standard medication + Vitamin C+E

        3. Statin subgroup : Standard medication + Statin

        4. Dual subgroup : Standard medication + Vitamin C+E + Statin

      Patients in Negative group will be prescribed only for standard medication for variant
      angina.

      Patient Enrollment: Recruiting 300 patients(100 patients for each group, as 25 patients for
      each subgroups) from September 2014 through February 2021 at single center in Korea(Seoul
      National University Hospital)

      Patient Follow-Up: Clinical follow-up will occur at 1, and 6 months, and at 2, 4, and 6
      years. Investigator or designee may conduct follow-up as telephone contacts or office visits.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Vasospasm at 6months
time frame: at 6 months
description: Severity of vasospasm in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to control subgroup.
measure: Vasospasm at 2 years
time frame: at 2 years
description: Severity of vasospasm in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to control subgroup.
measure: Vasospasm at 4 years
time frame: at 4 years
description: Severity of vasospasm in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to control subgroup.
measure: Vasospasm at 6 years
time frame: at 6 years
description: Severity of vasospasm in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to control subgroup.
measure: Changes from baseline in Vasospasm
time frame: at 6 months, and at 2, 4, and 6 years follow up period
description: Changes of Vasospasm in Control subgroup, Vitamin subgroup, Statin subgroup, and Dual subgroup compared to baseline vasospasm assessed by provocation test.
measure: Composed improvement of Vascular endothelial function(Brachial arterial expansion capability)
time frame: at 6 months, and at 2, 4, and 6 years follow up period
description: in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to control subgroup
measure: Improvement of Vascular endothelial function(Brachial arterial expansion capability)
time frame: at 6 months, and at 2, 4, and 6 years follow up period
description: in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to baseline endothelial function test results
measure: Comparative analysis of improvement of Vascular endothelial function(Brachial arterial expansion capability)
time frame: at 6 months, and at 2, 4, and 6 years follow up period
description: in Vitamin subgroup, Statin subgroup, and Dual subgroup
measure: Composed improvement of Arterial stiffness(Pulse wave velocity(PWV))
time frame: at 6 months, and at 2, 4, and 6 years follow up period
description: in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to control subgroup
measure: Improvement of Arterial stiffness(Pulse wave velocity(PWV))
time frame: at 6 months, and at 2, 4, and 6 years follow up period
description: in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to baseline endothelial function test results
measure: Comparative analysis of improvement of Arterial stiffness(Pulse wave velocity(PWV))
time frame: at 6 months, and at 2, 4, and 6 years follow up period
description: in Vitamin subgroup, Statin subgroup, and Dual subgroup
arm group label: Dual subgroup
arm group type: Experimental
description: Standard medication for variant angina plus Vitamin C+E plus Statin Vitamin C and Vitamin E : Ascorbic acid Tablet 1g / Tocopherol Capsule 400IU Statin : Atorvastatin calcium 10mg
arm group label: Statin subgroup
arm group type: Experimental
description: Standard medication for variant angina plus Statin Statin : Atorvastatin calcium 10mg
arm group label: Vitamin subgroup
arm group type: Experimental
description: Standard medication for variant angina plus Vitamin C+E Vitamin C and Vitamin E : Ascorbic acid Tablet 1g / Tocopherol Capsule 400IU
arm group label: Control group
arm group type: Active Comparator
description: Control subgroup : Standard medication for Variant angina only
intervention type: Drug
intervention name: Vitamin C and Vitamin E
description: Ascorbic acid Tablet 1g and Tocopherol Capsule 400IU
arm group label: Dual subgroup
arm group label: Vitamin subgroup
other name: Ascorbic acid and Tocopherol
intervention type: Drug
intervention name: Statin
description: Atorvastatin calcium 10mg
arm group label: Dual subgroup
arm group label: Statin subgroup
other name: Atorvastatin
intervention type: Drug
intervention name: Standard medication for variant angina
description: Calcium Channel blocker or NG
arm group label: Control group
arm group label: Dual subgroup
arm group label: Statin subgroup
arm group label: Vitamin subgroup
other name: Calcium Channel blocker or NG
criteria: 
gender: All
minimum age: 30 Years
maximum age: N/A
healthy volunteers: No
last name: Hyo-Soo Kim, Kim
role: Principal Investigator
affiliation: Seoul National University Hospital
last name: Hyo-Soo Kim, MD, PhD
phone: 82-2-2072-2226
email: hyosoo@snu.ac.kr
facility: 
status: Recruiting
contact: 
country: Korea, Republic of
responsible party type: Principal Investigator
investigator affiliation: Seoul National University Hospital
investigator full name: Hyo-Soo Kim
investigator title: Director of Cardiac Catheterization Laboratory & Coronary Intervention
mesh term: Angina Pectoris
mesh term: Angina Pectoris, Variant
mesh term: Vitamins
mesh term: Ascorbic Acid
mesh term: Vitamin E
mesh term: Tocopherols
mesh term: Calcium Channel Blockers
mesh term: Atorvastatin