<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/NCT04502849</url>
  </required_header>
  <id_info>
    <org_study_id>25.07</org_study_id>
    <nct_id>NCT04502849</nct_id>
  </id_info>
  <brief_title>Apoptosis Proteins and Endothelial Dysfunction in Patients With Atherosclerosis of Peripheral Arteries</brief_title>
  <official_title>Comprehensive Assessment of Indices of Apoptosis and Endothelial Dysfunction and Methods of Their Correction in Patients With Atherosclerosis of Peripheral Arteries</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Ryazan State Medical University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Ryazan State Medical University</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>
      Modern vascular surgery has various options for open and endovascular surgical methods aimed&#xD;
      at treating patients with peripheral arterial diseases. Despite the achievements of vascular&#xD;
      surgery, the occurrence of postoperative complications levels out the success of surgical&#xD;
      interventions and requires repeated surgical interventions. The most common complication is&#xD;
      stenosis of the reconstruction zone, which develops in approximately 50% of operated&#xD;
      patients.&#xD;
&#xD;
      At present, the apoptosis system plays an equally important role in the development of&#xD;
      restenosis of the intervention zone. It has been recognized as a central component in the&#xD;
      pathogenesis of atherosclerosis, in which the Bcl-2 family of proteins is activated. It is a&#xD;
      group of cellular proteins that are important regulators of the apoptosis system in cells&#xD;
      located in the mitochondrial membrane. In experimental animal models, it was shown that&#xD;
      apoptosis after angioplasty of the coronary arteries proceeds in the form of two waves. After&#xD;
      injury to the vascular wall, during the first hours, it is activated in the smooth muscle&#xD;
      cells (SMC) of media, and after two weeks in the cells of the neointima, by the 28th day it&#xD;
      almost completely stops. A decrease in the apoptosis index in the postoperative period may&#xD;
      cause the development of restenosis of the reconstruction zone. The use of antioxidants, for&#xD;
      example, alpha-tocopherol acetate, in the first month of the postoperative period, at the&#xD;
      time of activation of apoptosis, inhibits the latter and reduces the proliferative activity&#xD;
      of the SMC media and neointima. One month after surgery, delayed apoptosis of vascular wall&#xD;
      cells can lead to the development of neointima and restenosis. In this case, the use of drugs&#xD;
      that enhance apoptosis, for example, lipophilic statins, calcium channel blockers, will be&#xD;
      relevant.&#xD;
&#xD;
      Nitric oxide metabolites, depending on the concentration, can act as both an inducer and an&#xD;
      inhibitor of apoptosis. The mechanism of NO-induced apoptosis in SMC includes an increase in&#xD;
      the Bax / Bcl-2 expression ratio, which leads to the release of cytochrome C from&#xD;
      mitochondria, activation of caspase-3 and -9. In patients with atherosclerosis of the&#xD;
      peripheral arteries, proteins of the Bcl-2 family and their relationship with markers of&#xD;
      endothelial dysfunction have not been sufficiently studied, the results obtained are&#xD;
      contradictory.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      250 patients will be divided into 5 groups with follow-up period of 2 years. Blood sampling&#xD;
      for apoptosis and proliferation (Bcl-2, Bax, Fas, p53, PDGF-BB (platelet derived growth&#xD;
      factor BB), VEGF (vascular endothelial growth factor) and endothelial dysfunction (NO&#xD;
      metabolites) markers will be performed before,1 day after, 1 and 6 month after surgery for&#xD;
      groups A-C and for groups D, E when included into study.&#xD;
&#xD;
      Arterial wall sampling for apoptosis and proliferation (Bcl-2, Bax, Fas, p53, PDGF-BB, VEGF)&#xD;
      during surgery in group A-C patients.&#xD;
&#xD;
      Duplex ultrasound of lower limbs arteries will be performed before,1, 6, 12, 18 and 24 month&#xD;
      after surgery for groups A-D and for group E when included into study.&#xD;
&#xD;
      100 mg per os of Vitamin E 1 per day during 1 month after surgery will be prescribed to half&#xD;
      of groups A-C patients.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 1, 2020</start_date>
  <completion_date type="Anticipated">January 1, 2025</completion_date>
  <primary_completion_date type="Actual">January 1, 2023</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Restenosis of the reconstruction zone after surgery (detection of narrowing of the lumen of an artery or prosthesis in the reconstruction area using instrumental methods (ultrasound, angiography)).</measure>
    <time_frame>Up to 2 years after enrollment.</time_frame>
    <description>Revealing restenosis after surgery.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Thrombosis of the reconstruction zone after surgery (detection of thrombosis in arteries or prosthesis in the reconstruction area using instrumental methods (ultrasound, angiography)).</measure>
    <time_frame>Up to 2 years after enrollment.</time_frame>
    <description>Revealing thrombosis after surgery.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Progression of atherosclerosis (detection of narrowing of the lumen of an arteries by atherosclerotic plaque using instrumental methods (ultrasound, angiography)).</measure>
    <time_frame>Up to 2 years after enrollment.</time_frame>
    <description>Increasing the stage of atherosclerosis (Fontaine classification).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Deviations of apoptosis markers in blood and tissue homogenate (Bcl-2, Bax, Fas, VEGF, P53, PDGF-BB) from reference values.</measure>
    <time_frame>Up to 2 years after enrollment.</time_frame>
    <description>Deviation of apoptosis markers from reference values.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Deviations of endothelial dysfunction markers in blood (NO metabolites) from reference values..</measure>
    <time_frame>Up to 2 years after enrollment.</time_frame>
    <description>Deviation of endothelial dysfunction markers from reference values.</description>
  </secondary_outcome>
  <number_of_groups>5</number_of_groups>
  <enrollment type="Anticipated">250</enrollment>
  <condition>Atherosclerosis</condition>
  <condition>Endothelial Dysfunction</condition>
  <arm_group>
    <arm_group_label>Group &quot;Bypass&quot; (A)</arm_group_label>
    <description>50 patients with indications for bypass surgery (chronic lower limb ischemia, stage 2b-4 Fontaine).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group &quot;Endovascular&quot; (B)</arm_group_label>
    <description>50 patients with indications for endovascular angioplasty and stenting (chronic lower limb ischemia, stage 2b-4 Fontaine).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group &quot;Hybrid&quot; (C)</arm_group_label>
    <description>50 patients with indications for hybrid surgery (endovascular angioplasty/stenting and bypass surgery; chronic lower limb ischemia, stage 2b-4 Fontaine).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group &quot;Conservative&quot; (D)</arm_group_label>
    <description>50 patients without indications surgery (conservative treatment, chronic lower limb ischemia, stage 2b-4 Fontaine).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group &quot;Healthy volunteers&quot; (E)</arm_group_label>
    <description>50 healthy subjects.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Bypass surgery</intervention_name>
    <description>Creating a bypass with graft or vein.</description>
    <arm_group_label>Group &quot;Bypass&quot; (A)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Endovascular angioplasty/stenting</intervention_name>
    <description>Performing an angioplasty with or without stenting in stenosis.</description>
    <arm_group_label>Group &quot;Endovascular&quot; (B)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Hybrid surgery</intervention_name>
    <description>Performing an angioplasty with or without stenting in stenosis and creating a bypass with graft or vein.</description>
    <arm_group_label>Group &quot;Hybrid&quot; (C)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vitamin E</intervention_name>
    <description>100 mg Vitamin E per os 1 per day (1 month).</description>
    <arm_group_label>Group &quot;Bypass&quot; (A)</arm_group_label>
    <arm_group_label>Group &quot;Endovascular&quot; (B)</arm_group_label>
    <arm_group_label>Group &quot;Hybrid&quot; (C)</arm_group_label>
    <other_name>Tocopherol acetate</other_name>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Duplex ultrasound</intervention_name>
    <description>Duplex ultrasound of lower limbs arteries.</description>
    <arm_group_label>Group &quot;Bypass&quot; (A)</arm_group_label>
    <arm_group_label>Group &quot;Conservative&quot; (D)</arm_group_label>
    <arm_group_label>Group &quot;Endovascular&quot; (B)</arm_group_label>
    <arm_group_label>Group &quot;Healthy volunteers&quot; (E)</arm_group_label>
    <arm_group_label>Group &quot;Hybrid&quot; (C)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Blood sampling</intervention_name>
    <description>Blood sampling for apoptosis and endothelial dysfunction markers.</description>
    <arm_group_label>Group &quot;Bypass&quot; (A)</arm_group_label>
    <arm_group_label>Group &quot;Conservative&quot; (D)</arm_group_label>
    <arm_group_label>Group &quot;Endovascular&quot; (B)</arm_group_label>
    <arm_group_label>Group &quot;Healthy volunteers&quot; (E)</arm_group_label>
    <arm_group_label>Group &quot;Hybrid&quot; (C)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Arterial wall sampling</intervention_name>
    <description>Arterial wall sampling for apoptosis markers.</description>
    <arm_group_label>Group &quot;Bypass&quot; (A)</arm_group_label>
    <arm_group_label>Group &quot;Hybrid&quot; (C)</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Patients with atherosclerotic peripheral arterial disease.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  men or women over 40 years of age;&#xD;
&#xD;
          -  presence of atherosclerotic peripheral artery disease.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  men or women under 40 years of age;&#xD;
&#xD;
          -  chronic lower limb ischemia of a different etiology (disease Burger, aortoarteritis,&#xD;
             etc.),&#xD;
&#xD;
          -  active cancer or remission period less than 5 years;&#xD;
&#xD;
          -  decompensated diabetes mellitus;&#xD;
&#xD;
          -  pregnancy or breastfeeding in women&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Igor A Suchkov, Sc.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Ryazan State Medical University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Ryazan State Medical University</name>
      <address>
        <city>Ryazan'</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Russian Federation</country>
  </location_countries>
  <verification_date>August 2022</verification_date>
  <study_first_submitted>July 28, 2020</study_first_submitted>
  <study_first_submitted_qc>August 4, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 6, 2020</study_first_posted>
  <last_update_submitted>July 20, 2023</last_update_submitted>
  <last_update_submitted_qc>July 20, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 21, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>atherosclerosis</keyword>
  <keyword>endothelial dysfunction</keyword>
  <keyword>apoptosis</keyword>
  <keyword>restenosis</keyword>
  <keyword>atherosclerotic plaque</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Atherosclerosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vitamin E</mesh_term>
    <mesh_term>Tocopherols</mesh_term>
    <mesh_term>alpha-Tocopherol</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/NCT04502849
org study id: 25.07
nct id: NCT04502849
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Modern vascular surgery has various options for open and endovascular surgical methods aimed
      at treating patients with peripheral arterial diseases. Despite the achievements of vascular
      surgery, the occurrence of postoperative complications levels out the success of surgical
      interventions and requires repeated surgical interventions. The most common complication is
      stenosis of the reconstruction zone, which develops in approximately 50% of operated
      patients.

      At present, the apoptosis system plays an equally important role in the development of
      restenosis of the intervention zone. It has been recognized as a central component in the
      pathogenesis of atherosclerosis, in which the Bcl-2 family of proteins is activated. It is a
      group of cellular proteins that are important regulators of the apoptosis system in cells
      located in the mitochondrial membrane. In experimental animal models, it was shown that
      apoptosis after angioplasty of the coronary arteries proceeds in the form of two waves. After
      injury to the vascular wall, during the first hours, it is activated in the smooth muscle
      cells (SMC) of media, and after two weeks in the cells of the neointima, by the 28th day it
      almost completely stops. A decrease in the apoptosis index in the postoperative period may
      cause the development of restenosis of the reconstruction zone. The use of antioxidants, for
      example, alpha-tocopherol acetate, in the first month of the postoperative period, at the
      time of activation of apoptosis, inhibits the latter and reduces the proliferative activity
      of the SMC media and neointima. One month after surgery, delayed apoptosis of vascular wall
      cells can lead to the development of neointima and restenosis. In this case, the use of drugs
      that enhance apoptosis, for example, lipophilic statins, calcium channel blockers, will be
      relevant.

      Nitric oxide metabolites, depending on the concentration, can act as both an inducer and an
      inhibitor of apoptosis. The mechanism of NO-induced apoptosis in SMC includes an increase in
      the Bax / Bcl-2 expression ratio, which leads to the release of cytochrome C from
      mitochondria, activation of caspase-3 and -9. In patients with atherosclerosis of the
      peripheral arteries, proteins of the Bcl-2 family and their relationship with markers of
      endothelial dysfunction have not been sufficiently studied, the results obtained are
      contradictory.
250 patients will be divided into 5 groups with follow-up period of 2 years. Blood sampling
      for apoptosis and proliferation (Bcl-2, Bax, Fas, p53, PDGF-BB (platelet derived growth
      factor BB), VEGF (vascular endothelial growth factor) and endothelial dysfunction (NO
      metabolites) markers will be performed before,1 day after, 1 and 6 month after surgery for
      groups A-C and for groups D, E when included into study.

      Arterial wall sampling for apoptosis and proliferation (Bcl-2, Bax, Fas, p53, PDGF-BB, VEGF)
      during surgery in group A-C patients.

      Duplex ultrasound of lower limbs arteries will be performed before,1, 6, 12, 18 and 24 month
      after surgery for groups A-D and for group E when included into study.

      100 mg per os of Vitamin E 1 per day during 1 month after surgery will be prescribed to half
      of groups A-C patients.
observational model: Cohort
time perspective: Prospective
measure: Restenosis of the reconstruction zone after surgery (detection of narrowing of the lumen of an artery or prosthesis in the reconstruction area using instrumental methods (ultrasound, angiography)).
time frame: Up to 2 years after enrollment.
description: Revealing restenosis after surgery.
measure: Thrombosis of the reconstruction zone after surgery (detection of thrombosis in arteries or prosthesis in the reconstruction area using instrumental methods (ultrasound, angiography)).
time frame: Up to 2 years after enrollment.
description: Revealing thrombosis after surgery.
measure: Progression of atherosclerosis (detection of narrowing of the lumen of an arteries by atherosclerotic plaque using instrumental methods (ultrasound, angiography)).
time frame: Up to 2 years after enrollment.
description: Increasing the stage of atherosclerosis (Fontaine classification).
measure: Deviations of apoptosis markers in blood and tissue homogenate (Bcl-2, Bax, Fas, VEGF, P53, PDGF-BB) from reference values.
time frame: Up to 2 years after enrollment.
description: Deviation of apoptosis markers from reference values.
measure: Deviations of endothelial dysfunction markers in blood (NO metabolites) from reference values..
time frame: Up to 2 years after enrollment.
description: Deviation of endothelial dysfunction markers from reference values.
arm group label: Group "Bypass" (A)
description: 50 patients with indications for bypass surgery (chronic lower limb ischemia, stage 2b-4 Fontaine).
arm group label: Group "Endovascular" (B)
description: 50 patients with indications for endovascular angioplasty and stenting (chronic lower limb ischemia, stage 2b-4 Fontaine).
arm group label: Group "Hybrid" (C)
description: 50 patients with indications for hybrid surgery (endovascular angioplasty/stenting and bypass surgery; chronic lower limb ischemia, stage 2b-4 Fontaine).
arm group label: Group "Conservative" (D)
description: 50 patients without indications surgery (conservative treatment, chronic lower limb ischemia, stage 2b-4 Fontaine).
arm group label: Group "Healthy volunteers" (E)
description: 50 healthy subjects.
intervention type: Procedure
intervention name: Bypass surgery
description: Creating a bypass with graft or vein.
arm group label: Group "Bypass" (A)
intervention type: Procedure
intervention name: Endovascular angioplasty/stenting
description: Performing an angioplasty with or without stenting in stenosis.
arm group label: Group "Endovascular" (B)
intervention type: Procedure
intervention name: Hybrid surgery
description: Performing an angioplasty with or without stenting in stenosis and creating a bypass with graft or vein.
arm group label: Group "Hybrid" (C)
intervention type: Drug
intervention name: Vitamin E
description: 100 mg Vitamin E per os 1 per day (1 month).
arm group label: Group "Bypass" (A)
arm group label: Group "Endovascular" (B)
arm group label: Group "Hybrid" (C)
other name: Tocopherol acetate
intervention type: Diagnostic Test
intervention name: Duplex ultrasound
description: Duplex ultrasound of lower limbs arteries.
arm group label: Group "Bypass" (A)
arm group label: Group "Conservative" (D)
arm group label: Group "Endovascular" (B)
arm group label: Group "Healthy volunteers" (E)
arm group label: Group "Hybrid" (C)
intervention type: Diagnostic Test
intervention name: Blood sampling
description: Blood sampling for apoptosis and endothelial dysfunction markers.
arm group label: Group "Bypass" (A)
arm group label: Group "Conservative" (D)
arm group label: Group "Endovascular" (B)
arm group label: Group "Healthy volunteers" (E)
arm group label: Group "Hybrid" (C)
intervention type: Diagnostic Test
intervention name: Arterial wall sampling
description: Arterial wall sampling for apoptosis markers.
arm group label: Group "Bypass" (A)
arm group label: Group "Hybrid" (C)
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 40 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Igor A Suchkov, Sc.D.
role: Principal Investigator
affiliation: Ryazan State Medical University
facility: 
country: Russian Federation
responsible party type: Sponsor
mesh term: Atherosclerosis
mesh term: Vitamin E
mesh term: Tocopherols
mesh term: alpha-Tocopherol
sharing ipd: Undecided