<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/NCT04436549</url>
  </required_header>
  <id_info>
    <org_study_id>ER.ALL.2018.11</org_study_id>
    <nct_id>NCT04436549</nct_id>
  </id_info>
  <brief_title>Pathology, Venous Disease, and Clinical Correlations</brief_title>
  <acronym>PAVEDI</acronym>
  <official_title>Clinical and Pathological Correlations in Chronic Venous Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Catanzaro</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Catanzaro</source>
  <oversight_info>
    <has_dmc>Yes</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>
      Chronic Venous Disease (CVD) has a high prevalence in the general population of the western&#xD;
      world. Varicose veins are the main signs of this disease that are characterized by important&#xD;
      pathological vessel wall changes. There are also several symptoms that affect the quality of&#xD;
      life of affected patients. The aim of this study is to correlate the main histopathological&#xD;
      abnormalities with the type and the intensity of the symptoms.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Chronic Venous Disease (CVD) of the lower limbs is a widespread chronic condition of the&#xD;
      western world. There are several signs and symptoms that affect quality of life of patients&#xD;
      with CVD. One of the main signs of this disease are varicose veins that are enlarged,&#xD;
      swollen, and twisting superficial veins. Vessel wall of varicose veins shows a significant&#xD;
      histopathological phenotype, characterized by a distortion of structural architecture:&#xD;
      endothelial damage, disorganization of muscle bundles and alteration of the composition of&#xD;
      the extracellular matrix (ECM). Symptoms may be different, according to disease state,&#xD;
      progression and local inflammatory processes. To date, there is no study that correlate the&#xD;
      type and the intensity of symptoms with histopathological phenotype.&#xD;
&#xD;
      Aim of this study is to correlate histopathological phenotype with clinical manifestations.&#xD;
&#xD;
      A cohort of patients with varicose veins scheduled for open surgical treatment that will&#xD;
      undergo to stab avulsion of varicose veins will be recruited. Subsequently, venous tissue&#xD;
      from stab avulsion will collected in order to evaluate the following biomarkers: VEGF&#xD;
      (Vascular -Endothelial Growth Factor), PGP 9.5 (Protein Gene Product 9.5), Fibronectin and&#xD;
      Matrix Metalloproteinase- 9 (MMP-9).&#xD;
&#xD;
      VEGF has a key role as a regulator of angiogenesis; its expression is highly regulated by&#xD;
      hypoxia, in this case induced by venous hypertension. In addition to being a marker of&#xD;
      neoangiogenesis, it increases vascular permeability in inflammatory disorders. PGP 9.5 is a&#xD;
      marker of the innervation of the vessel wall that plays an important role in the regulation&#xD;
      of venous tone. Fibronectin and MMP-9 are direct markers of ECM remodeling and impairment and&#xD;
      they have also a role in chronic inflammation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">December 1, 2019</start_date>
  <completion_date type="Anticipated">October 1, 2020</completion_date>
  <primary_completion_date type="Anticipated">September 1, 2020</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>Cross-Sectional</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Expression of Matrix Metalloproteinase-9 (MMP-9)</measure>
    <time_frame>at 10 month</time_frame>
    <description>EnVision staining system (Dako EnVision™) will be used. A synthetic peptide from the middle region of human MMP9 will be used with dilutions 1:50 with Ethylenediaminetetraacetic acid (EDTA).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Expression of Vascular Endothelial Growth Factor (VEGF)</measure>
    <time_frame>at 10 month</time_frame>
    <description>EnVision staining system (Dako EnVision™) will be used. Monoclonal mouse Anti-Human vascular endothelial growth factor, code No. M7273 will be used with dilution 1:50 with Ethylenediaminetetraacetic acid (EDTA).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Expression of Fibronectin</measure>
    <time_frame>at 10 month</time_frame>
    <description>EnVision staining system (Dako EnVision™) will be used. A synthetic peptide made toward the C-terminal region of the human Fibronectin protein (within residues 2250-2300) will be used with dilution 1:400 citrate buffer.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Expression of Protein Gene Product 9.5 (PGP 9.5)</measure>
    <time_frame>at 10 month</time_frame>
    <description>EnVision staining system (Dako EnVision™) will be used. Purified PGP 9.5 isolated from bovine brain will be used with dilution 1:200 citrate buffer</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Correlation of the biomarkers expression with signs and symptoms</measure>
    <time_frame>At 11 month.</time_frame>
    <description>The expression of the biomarkers that will be studied on venous tissue samples will be correlated with the type of signs and symptoms complained by the patients.</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Varicose Veins</condition>
  <condition>Pathology</condition>
  <condition>Symptoms and Signs</condition>
  <arm_group>
    <arm_group_label>Patients with varicose veins</arm_group_label>
    <description>Patients with varicose veins and eligible to receive open surgery (stab avulsion of varicose veins) as routinely care.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Stab Avulsion of varicose veins</intervention_name>
    <description>Stab avulsion is a technique to remove varicose veins. In this procedure, several tiny cuts (incisions) are made in the skin through which the varicosed vein is removed. Removed varicose veins will be collected and analyzed.</description>
    <arm_group_label>Patients with varicose veins</arm_group_label>
    <other_name>Phlebectomy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Histopathologic evaluation of varicose veins</intervention_name>
    <description>Sample obtained from varicose veins of lower limbs of patients will be collected and immediately fixed in formalin. The tissue fragments will be taken from varicose veins. Subsequently the tissue will be embedded in paraffin and 3-to-4 mm thick sections will be prepared by a microtome. The tissue sections will be processed for histological and immunohistochemical studies of VEGF, MM9, PGP 9.5 AND FRIBRONECTIN. For antibodies the EnVision staining system (Dako EnVision™) will be used. For the analysis of the positive structures detected by immunohistochemistry, a semiquantitative evaluation method will be used.</description>
    <arm_group_label>Patients with varicose veins</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Patients with varicose veins that are scheduled to undergo surgery for varicose veins&#xD;
        removal.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with varicose veins scheduled for surgery&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Peripheral artery disease&#xD;
&#xD;
          -  Malignancy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Raffaele Serra, M.D., Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Magna Graecia of Catanzaro</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Raffaele Serra, M.D., Ph.D.</last_name>
    <phone>+3909613647380</phone>
    <email>rserra@unicz.it</email>
  </overall_contact>
  <location>
    <facility>
      <name>CIFL- Interuniversity Center of Phlebolymphology</name>
      <address>
        <city>Catanzaro</city>
        <zip>88100</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Raffaele Serra, MD</last_name>
      <phone>+393387078043</phone>
      <email>rserra@unicz.it</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>University Magna Graecia of Catanzaro</name>
      <address>
        <city>Catanzaro</city>
        <zip>88100</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Raffaele Serra, M.D., Ph.D.</last_name>
      <phone>+3909613647380</phone>
      <email>rserra@unicz.it</email>
    </contact>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>Birdina J, Pilmane M, Ligers A. The Morphofunctional Changes in the Wall of Varicose Veins. Ann Vasc Surg. 2017 Jul;42:274-284. doi: 10.1016/j.avsg.2016.10.064. Epub 2017 Mar 11.</citation>
    <PMID>28300675</PMID>
  </reference>
  <reference>
    <citation>Kucukguven A, Khalil RA. Matrix metalloproteinases as potential targets in the venous dilation associated with varicose veins. Curr Drug Targets. 2013 Mar;14(3):287-324.</citation>
    <PMID>23316963</PMID>
  </reference>
  <reference>
    <citation>Kolano P, Bednarski IA, Lesiak A, Skibinska M, Stasikowska-Kanicka O, Danilewicz M, Narbutt J. Overexpression of cathepsin K and vascular endothelial growth factor in chronic venous ulcerations. Postepy Dermatol Alergol. 2020 Apr;37(2):234-239. doi: 10.5114/ada.2020.94840. Epub 2020 May 6.</citation>
    <PMID>32489360</PMID>
  </reference>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>June 15, 2020</study_first_submitted>
  <study_first_submitted_qc>June 15, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 18, 2020</study_first_posted>
  <last_update_submitted>June 15, 2020</last_update_submitted>
  <last_update_submitted_qc>June 15, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 18, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Catanzaro</investigator_affiliation>
    <investigator_full_name>Prof. Raffaele Serra, MD, Ph.D.</investigator_full_name>
    <investigator_title>Associate Professor of Vascular Surgery</investigator_title>
  </responsible_party>
  <keyword>pathology</keyword>
  <keyword>varicose veins</keyword>
  <keyword>chronic venous disease</keyword>
  <keyword>symptoms</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Varicose Veins</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/NCT04436549
org study id: ER.ALL.2018.11
nct id: NCT04436549
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Chronic Venous Disease (CVD) has a high prevalence in the general population of the western
      world. Varicose veins are the main signs of this disease that are characterized by important
      pathological vessel wall changes. There are also several symptoms that affect the quality of
      life of affected patients. The aim of this study is to correlate the main histopathological
      abnormalities with the type and the intensity of the symptoms.
Chronic Venous Disease (CVD) of the lower limbs is a widespread chronic condition of the
      western world. There are several signs and symptoms that affect quality of life of patients
      with CVD. One of the main signs of this disease are varicose veins that are enlarged,
      swollen, and twisting superficial veins. Vessel wall of varicose veins shows a significant
      histopathological phenotype, characterized by a distortion of structural architecture:
      endothelial damage, disorganization of muscle bundles and alteration of the composition of
      the extracellular matrix (ECM). Symptoms may be different, according to disease state,
      progression and local inflammatory processes. To date, there is no study that correlate the
      type and the intensity of symptoms with histopathological phenotype.

      Aim of this study is to correlate histopathological phenotype with clinical manifestations.

      A cohort of patients with varicose veins scheduled for open surgical treatment that will
      undergo to stab avulsion of varicose veins will be recruited. Subsequently, venous tissue
      from stab avulsion will collected in order to evaluate the following biomarkers: VEGF
      (Vascular -Endothelial Growth Factor), PGP 9.5 (Protein Gene Product 9.5), Fibronectin and
      Matrix Metalloproteinase- 9 (MMP-9).

      VEGF has a key role as a regulator of angiogenesis; its expression is highly regulated by
      hypoxia, in this case induced by venous hypertension. In addition to being a marker of
      neoangiogenesis, it increases vascular permeability in inflammatory disorders. PGP 9.5 is a
      marker of the innervation of the vessel wall that plays an important role in the regulation
      of venous tone. Fibronectin and MMP-9 are direct markers of ECM remodeling and impairment and
      they have also a role in chronic inflammation.
observational model: Cohort
time perspective: Cross-Sectional
measure: Expression of Matrix Metalloproteinase-9 (MMP-9)
time frame: at 10 month
description: EnVision staining system (Dako EnVision™) will be used. A synthetic peptide from the middle region of human MMP9 will be used with dilutions 1:50 with Ethylenediaminetetraacetic acid (EDTA).
measure: Expression of Vascular Endothelial Growth Factor (VEGF)
time frame: at 10 month
description: EnVision staining system (Dako EnVision™) will be used. Monoclonal mouse Anti-Human vascular endothelial growth factor, code No. M7273 will be used with dilution 1:50 with Ethylenediaminetetraacetic acid (EDTA).
measure: Expression of Fibronectin
time frame: at 10 month
description: EnVision staining system (Dako EnVision™) will be used. A synthetic peptide made toward the C-terminal region of the human Fibronectin protein (within residues 2250-2300) will be used with dilution 1:400 citrate buffer.
measure: Expression of Protein Gene Product 9.5 (PGP 9.5)
time frame: at 10 month
description: EnVision staining system (Dako EnVision™) will be used. Purified PGP 9.5 isolated from bovine brain will be used with dilution 1:200 citrate buffer
measure: Correlation of the biomarkers expression with signs and symptoms
time frame: At 11 month.
description: The expression of the biomarkers that will be studied on venous tissue samples will be correlated with the type of signs and symptoms complained by the patients.
arm group label: Patients with varicose veins
description: Patients with varicose veins and eligible to receive open surgery (stab avulsion of varicose veins) as routinely care.
intervention type: Procedure
intervention name: Stab Avulsion of varicose veins
description: Stab avulsion is a technique to remove varicose veins. In this procedure, several tiny cuts (incisions) are made in the skin through which the varicosed vein is removed. Removed varicose veins will be collected and analyzed.
arm group label: Patients with varicose veins
other name: Phlebectomy
intervention type: Diagnostic Test
intervention name: Histopathologic evaluation of varicose veins
description: Sample obtained from varicose veins of lower limbs of patients will be collected and immediately fixed in formalin. The tissue fragments will be taken from varicose veins. Subsequently the tissue will be embedded in paraffin and 3-to-4 mm thick sections will be prepared by a microtome. The tissue sections will be processed for histological and immunohistochemical studies of VEGF, MM9, PGP 9.5 AND FRIBRONECTIN. For antibodies the EnVision staining system (Dako EnVision™) will be used. For the analysis of the positive structures detected by immunohistochemistry, a semiquantitative evaluation method will be used.
arm group label: Patients with varicose veins
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Raffaele Serra, M.D., Ph.D.
role: Principal Investigator
affiliation: University Magna Graecia of Catanzaro
last name: Raffaele Serra, M.D., Ph.D.
phone: +3909613647380
email: rserra@unicz.it
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
country: Italy
citation: Birdina J, Pilmane M, Ligers A. The Morphofunctional Changes in the Wall of Varicose Veins. Ann Vasc Surg. 2017 Jul;42:274-284. doi: 10.1016/j.avsg.2016.10.064. Epub 2017 Mar 11.
PMID: 28300675
citation: Kucukguven A, Khalil RA. Matrix metalloproteinases as potential targets in the venous dilation associated with varicose veins. Curr Drug Targets. 2013 Mar;14(3):287-324.
PMID: 23316963
citation: Kolano P, Bednarski IA, Lesiak A, Skibinska M, Stasikowska-Kanicka O, Danilewicz M, Narbutt J. Overexpression of cathepsin K and vascular endothelial growth factor in chronic venous ulcerations. Postepy Dermatol Alergol. 2020 Apr;37(2):234-239. doi: 10.5114/ada.2020.94840. Epub 2020 May 6.
PMID: 32489360
responsible party type: Principal Investigator
investigator affiliation: University of Catanzaro
investigator full name: Prof. Raffaele Serra, MD, Ph.D.
investigator title: Associate Professor of Vascular Surgery
mesh term: Varicose Veins
sharing ipd: No