<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/NCT03822195</url>
  </required_header>
  <id_info>
    <org_study_id>2124</org_study_id>
    <nct_id>NCT03822195</nct_id>
  </id_info>
  <brief_title>Lectine Pathway in Unstable Carotid Plaque</brief_title>
  <official_title>Evaluation of Lectine Pathway in Assessment of Unstable Carotid Plaque</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fondazione Policlinico Universitario Agostino Gemelli IRCCS</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Fondazione Policlinico Universitario Agostino Gemelli IRCCS</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>
      The study is aimed to investigate the possible role of lectin pathway - an alternative&#xD;
      pathway of complement activation - in affecting stability of carotid atherosclerotic plaques&#xD;
      and the possible correlations with clinical neurologic features.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In addition to the known hemodynamic criteria, instable carotid plaques can be responsible&#xD;
      for brain ischemia, therefore is paramount to identify preoperatively possible markers of&#xD;
      plaque instability. The study is aimed to investigate the possible role of lectin pathway -&#xD;
      an alternative pathway of complement activation - in affecting stability of carotid&#xD;
      atherosclerotic plaques and the possible correlations with clinical neurologic features.&#xD;
      Study population will include 40 patients with internal carotid artery stenosis &gt;=70%&#xD;
      (assessed by echocolordoppler), symptomatic or asymptomatic, surgically treated by&#xD;
      endoarterectomy. Removed plaques will be evaluated by histologic exam and immunofluorescence&#xD;
      for ficolins 1-2-3 and Mannose Binding Lectin (MBL). Plasma samples will be used for ELISA&#xD;
      test of lectin pathway complement activation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    PI changed Institution&#xD;
  </why_stopped>
  <start_date type="Anticipated">April 1, 2019</start_date>
  <completion_date type="Anticipated">February 28, 2021</completion_date>
  <primary_completion_date type="Anticipated">January 31, 2021</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>lectine pathway of complement activation in carotid plaques</measure>
    <time_frame>preoperative</time_frame>
    <description>assessment of association between plasmatic levels of complement activators and plaque instability (histologic index). Protein plasma levels will be assessed as optical density. Plaque instability will be quantified by a vulnerability score that combines four different histological parameters according to their quartile distribution (Fumagalli et al., Frontiers Immunology 2017). Their association will be analyzed as odds ratio (95%-CI) by a Fisher test.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>focal neurologic symptoms and plasmatic levels of complement activators</measure>
    <time_frame>preoperative, postoperative day 3, 3 months after surgery</time_frame>
    <description>Correlation of onset of focal neurologic symptoms (TIA, any stroke) due to carotid stenosis and peripheral plasma levels of complement activators. Neurological exam + CT or MNR will be used as clinical measurement tool</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>focal neurologic symptoms and histologic index of plaque instability</measure>
    <time_frame>through study completion (average 1 year)</time_frame>
    <description>correlation of onset of focal neurologic symptoms (TIA, any stroke) due to carotid stenosis and histologic index for plaque instability. Protein plasma levels will be assessed as optical density. Plaque instability will be quantified by a vulnerability score that combines four different histological parameters according to their quartile distribution (Fumagalli et al., Frontiers Immunology 2017).</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">0</enrollment>
  <condition>Carotid Artery Plaque</condition>
  <condition>Mannose-Binding Lectin Complement Pathway</condition>
  <arm_group>
    <arm_group_label>asymptomatic</arm_group_label>
    <description>asymptomatic patients undergoing carotid endoarterectomy for stenosis &gt;70% (velocimetric criteria at echodoppler)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>symptomatic</arm_group_label>
    <description>symptomatic (TIA, crescendo TIA, minor stroke) patients undergoing carotid endoarterectomy, independently from stenosis evaluated by echodoppler</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Carotid endoarterectomy</intervention_name>
    <description>Surgical removal of carotid bifurcation plaque and arterial repair (direct suture or patch)</description>
    <arm_group_label>asymptomatic</arm_group_label>
    <arm_group_label>symptomatic</arm_group_label>
    <other_name>CEA</other_name>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Atherosclerotic plaque surgically removed from the carotid bifurcation Peripheral blood&#xD;
      sample&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Study population will include 40 patients with symptomatic or asymptomatic internal carotid&#xD;
        artery stenosis &gt;=70% (measured by echocolordoppler) treated by elective or urgent&#xD;
        endoarterectomy.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  patients undergone elective or urgent carotid endoarterectomy (CEA) for internal&#xD;
             carotid stenosis &gt;70% (assessed by velocimetric criteria) with or without neurologic&#xD;
             symptoms&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  recent (&lt;20 days) major/minor stroke with positive CT scan&#xD;
&#xD;
          -  absolute contraindications to surgery (cardiac, respiratory, anesthesiologic risk)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Angela MR Ferrante, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Fondazione Policlinico Universitario A.Gemelli IRCCS Roma</affiliation>
  </overall_official>
  <reference>
    <citation>Verhoeven B, Hellings WE, Moll FL, de Vries JP, de Kleijn DP, de Bruin P, Busser E, Schoneveld AH, Pasterkamp G. Carotid atherosclerotic plaques in patients with transient ischemic attacks and stroke have unstable characteristics compared with plaques in asymptomatic and amaurosis fugax patients. J Vasc Surg. 2005 Dec;42(6):1075-81. doi: 10.1016/j.jvs.2005.08.009.</citation>
    <PMID>16376194</PMID>
  </reference>
  <reference>
    <citation>Longhi L, Orsini F, De Blasio D, Fumagalli S, Ortolano F, Locatelli M, Stocchetti N, De Simoni MG. Mannose-binding lectin is expressed after clinical and experimental traumatic brain injury and its deletion is protective. Crit Care Med. 2014 Aug;42(8):1910-8. doi: 10.1097/CCM.0000000000000399.</citation>
    <PMID>24810526</PMID>
  </reference>
  <reference>
    <citation>Fust G, Munthe-Fog L, Illes Z, Szeplaki G, Molnar T, Pusch G, Hirschberg K, Szegedi R, Szeplaki Z, Prohaszka Z, Skjoedt MO, Garred P. Low ficolin-3 levels in early follow-up serum samples are associated with the severity and unfavorable outcome of acute ischemic stroke. J Neuroinflammation. 2011 Dec 29;8:185. doi: 10.1186/1742-2094-8-185.</citation>
    <PMID>22206485</PMID>
  </reference>
  <reference>
    <citation>Osthoff M, Katan M, Fluri F, Schuetz P, Bingisser R, Kappos L, Steck AJ, Engelter ST, Mueller B, Christ-Crain M, Trendelenburg M. Mannose-binding lectin deficiency is associated with smaller infarction size and favorable outcome in ischemic stroke patients. PLoS One. 2011;6(6):e21338. doi: 10.1371/journal.pone.0021338. Epub 2011 Jun 21.</citation>
    <PMID>21712986</PMID>
  </reference>
  <reference>
    <citation>Zangari R, Zanier ER, Torgano G, Bersano A, Beretta S, Beghi E, Casolla B, Checcarelli N, Lanfranconi S, Maino A, Mandelli C, Micieli G, Orzi F, Picetti E, Silvestrini M, Stocchetti N, Zecca B, Garred P, De Simoni MG; LEPAS group. Early ficolin-1 is a sensitive prognostic marker for functional outcome in ischemic stroke. J Neuroinflammation. 2016 Jan 20;13:16. doi: 10.1186/s12974-016-0481-2.</citation>
    <PMID>26792363</PMID>
  </reference>
  <reference>
    <citation>Pilely K, Fumagalli S, Rosbjerg A, Genster N, Skjoedt MO, Perego C, Ferrante AMR, De Simoni MG, Garred P. C-Reactive Protein Binds to Cholesterol Crystals and Co-Localizes with the Terminal Complement Complex in Human Atherosclerotic Plaques. Front Immunol. 2017 Aug 29;8:1040. doi: 10.3389/fimmu.2017.01040. eCollection 2017.</citation>
    <PMID>28900428</PMID>
  </reference>
  <reference>
    <citation>Hellings WE, Pasterkamp G, Vollebregt A, Seldenrijk CA, De Vries JP, Velema E, De Kleijn DP, Moll FL. Intraobserver and interobserver variability and spatial differences in histologic examination of carotid endarterectomy specimens. J Vasc Surg. 2007 Dec;46(6):1147-54. doi: 10.1016/j.jvs.2007.08.018. Epub 2007 Oct 22.</citation>
    <PMID>17950565</PMID>
  </reference>
  <results_reference>
    <citation>Fumagalli S, Perego C, Zangari R, De Blasio D, Oggioni M, De Nigris F, Snider F, Garred P, Ferrante AM, De Simoni MG. Lectin Pathway of Complement Activation Is Associated with Vulnerability of Atherosclerotic Plaques. Front Immunol. 2017 Mar 16;8:288. doi: 10.3389/fimmu.2017.00288. eCollection 2017.</citation>
    <PMID>28360913</PMID>
  </results_reference>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>January 7, 2019</study_first_submitted>
  <study_first_submitted_qc>January 26, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 30, 2019</study_first_posted>
  <last_update_submitted>July 22, 2020</last_update_submitted>
  <last_update_submitted_qc>July 22, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 24, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Fondazione Policlinico Universitario Agostino Gemelli IRCCS</investigator_affiliation>
    <investigator_full_name>Angela M.R. Ferrante</investigator_full_name>
    <investigator_title>Angela M.R. Ferrante MD PhD</investigator_title>
  </responsible_party>
  <keyword>carotid artery atherosclerosis</keyword>
  <keyword>alternative complement pathway</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carotid Stenosis</mesh_term>
  </condition_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/NCT03822195
org study id: 2124
nct id: NCT03822195
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The study is aimed to investigate the possible role of lectin pathway - an alternative
      pathway of complement activation - in affecting stability of carotid atherosclerotic plaques
      and the possible correlations with clinical neurologic features.
In addition to the known hemodynamic criteria, instable carotid plaques can be responsible
      for brain ischemia, therefore is paramount to identify preoperatively possible markers of
      plaque instability. The study is aimed to investigate the possible role of lectin pathway -
      an alternative pathway of complement activation - in affecting stability of carotid
      atherosclerotic plaques and the possible correlations with clinical neurologic features.
      Study population will include 40 patients with internal carotid artery stenosis >=70%
      (assessed by echocolordoppler), symptomatic or asymptomatic, surgically treated by
      endoarterectomy. Removed plaques will be evaluated by histologic exam and immunofluorescence
      for ficolins 1-2-3 and Mannose Binding Lectin (MBL). Plasma samples will be used for ELISA
      test of lectin pathway complement activation.
observational model: Cohort
time perspective: Prospective
measure: lectine pathway of complement activation in carotid plaques
time frame: preoperative
description: assessment of association between plasmatic levels of complement activators and plaque instability (histologic index). Protein plasma levels will be assessed as optical density. Plaque instability will be quantified by a vulnerability score that combines four different histological parameters according to their quartile distribution (Fumagalli et al., Frontiers Immunology 2017). Their association will be analyzed as odds ratio (95%-CI) by a Fisher test.
measure: focal neurologic symptoms and plasmatic levels of complement activators
time frame: preoperative, postoperative day 3, 3 months after surgery
description: Correlation of onset of focal neurologic symptoms (TIA, any stroke) due to carotid stenosis and peripheral plasma levels of complement activators. Neurological exam + CT or MNR will be used as clinical measurement tool
measure: focal neurologic symptoms and histologic index of plaque instability
time frame: through study completion (average 1 year)
description: correlation of onset of focal neurologic symptoms (TIA, any stroke) due to carotid stenosis and histologic index for plaque instability. Protein plasma levels will be assessed as optical density. Plaque instability will be quantified by a vulnerability score that combines four different histological parameters according to their quartile distribution (Fumagalli et al., Frontiers Immunology 2017).
arm group label: asymptomatic
description: asymptomatic patients undergoing carotid endoarterectomy for stenosis >70% (velocimetric criteria at echodoppler)
arm group label: symptomatic
description: symptomatic (TIA, crescendo TIA, minor stroke) patients undergoing carotid endoarterectomy, independently from stenosis evaluated by echodoppler
intervention type: Procedure
intervention name: Carotid endoarterectomy
description: Surgical removal of carotid bifurcation plaque and arterial repair (direct suture or patch)
arm group label: asymptomatic
arm group label: symptomatic
other name: CEA
Atherosclerotic plaque surgically removed from the carotid bifurcation Peripheral blood
      sample
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 40 Years
maximum age: 80 Years
healthy volunteers: No
last name: Angela MR Ferrante, MD
role: Principal Investigator
affiliation: Fondazione Policlinico Universitario A.Gemelli IRCCS Roma
citation: Verhoeven B, Hellings WE, Moll FL, de Vries JP, de Kleijn DP, de Bruin P, Busser E, Schoneveld AH, Pasterkamp G. Carotid atherosclerotic plaques in patients with transient ischemic attacks and stroke have unstable characteristics compared with plaques in asymptomatic and amaurosis fugax patients. J Vasc Surg. 2005 Dec;42(6):1075-81. doi: 10.1016/j.jvs.2005.08.009.
PMID: 16376194
citation: Longhi L, Orsini F, De Blasio D, Fumagalli S, Ortolano F, Locatelli M, Stocchetti N, De Simoni MG. Mannose-binding lectin is expressed after clinical and experimental traumatic brain injury and its deletion is protective. Crit Care Med. 2014 Aug;42(8):1910-8. doi: 10.1097/CCM.0000000000000399.
PMID: 24810526
citation: Fust G, Munthe-Fog L, Illes Z, Szeplaki G, Molnar T, Pusch G, Hirschberg K, Szegedi R, Szeplaki Z, Prohaszka Z, Skjoedt MO, Garred P. Low ficolin-3 levels in early follow-up serum samples are associated with the severity and unfavorable outcome of acute ischemic stroke. J Neuroinflammation. 2011 Dec 29;8:185. doi: 10.1186/1742-2094-8-185.
PMID: 22206485
citation: Osthoff M, Katan M, Fluri F, Schuetz P, Bingisser R, Kappos L, Steck AJ, Engelter ST, Mueller B, Christ-Crain M, Trendelenburg M. Mannose-binding lectin deficiency is associated with smaller infarction size and favorable outcome in ischemic stroke patients. PLoS One. 2011;6(6):e21338. doi: 10.1371/journal.pone.0021338. Epub 2011 Jun 21.
PMID: 21712986
citation: Zangari R, Zanier ER, Torgano G, Bersano A, Beretta S, Beghi E, Casolla B, Checcarelli N, Lanfranconi S, Maino A, Mandelli C, Micieli G, Orzi F, Picetti E, Silvestrini M, Stocchetti N, Zecca B, Garred P, De Simoni MG; LEPAS group. Early ficolin-1 is a sensitive prognostic marker for functional outcome in ischemic stroke. J Neuroinflammation. 2016 Jan 20;13:16. doi: 10.1186/s12974-016-0481-2.
PMID: 26792363
citation: Pilely K, Fumagalli S, Rosbjerg A, Genster N, Skjoedt MO, Perego C, Ferrante AMR, De Simoni MG, Garred P. C-Reactive Protein Binds to Cholesterol Crystals and Co-Localizes with the Terminal Complement Complex in Human Atherosclerotic Plaques. Front Immunol. 2017 Aug 29;8:1040. doi: 10.3389/fimmu.2017.01040. eCollection 2017.
PMID: 28900428
citation: Hellings WE, Pasterkamp G, Vollebregt A, Seldenrijk CA, De Vries JP, Velema E, De Kleijn DP, Moll FL. Intraobserver and interobserver variability and spatial differences in histologic examination of carotid endarterectomy specimens. J Vasc Surg. 2007 Dec;46(6):1147-54. doi: 10.1016/j.jvs.2007.08.018. Epub 2007 Oct 22.
PMID: 17950565
citation: Fumagalli S, Perego C, Zangari R, De Blasio D, Oggioni M, De Nigris F, Snider F, Garred P, Ferrante AM, De Simoni MG. Lectin Pathway of Complement Activation Is Associated with Vulnerability of Atherosclerotic Plaques. Front Immunol. 2017 Mar 16;8:288. doi: 10.3389/fimmu.2017.00288. eCollection 2017.
PMID: 28360913
responsible party type: Principal Investigator
investigator affiliation: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
investigator full name: Angela M.R. Ferrante
investigator title: Angela M.R. Ferrante MD PhD
mesh term: Carotid Stenosis