<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/NCT04402827</url>
  </required_header>
  <id_info>
    <org_study_id>EC 162/20</org_study_id>
    <nct_id>NCT04402827</nct_id>
  </id_info>
  <brief_title>Different Susceptibility to SARS CoV-2 Infection Among Health Care Workers Highly Exposed to COVID-19.</brief_title>
  <acronym>CoVEX</acronym>
  <official_title>Differences in Susceptibility to SARS CoV-2 Infection According to ACE2 and CD26 Receptors, Specific CD4/CD8 T Cell Response to Viral Peptides, and KIR Receptors Among Health Care Workers Highly Exposed to Patients With COVID-19 Diagnosis.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Asociacion para el Estudio de las Enfermedades Infecciosas</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Asociacion para el Estudio de las Enfermedades Infecciosas</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>
      The primary objective of this study is to establish differences in susceptibility to SARS&#xD;
      CoV-2 infection among health care workers (HCW) highly exposed to patients with COVID-19&#xD;
      diagnosis. To ascertain this issue, we evaluated:&#xD;
&#xD;
        -  Changes in receptor polymorphism (ACE2 and CD26 receptor study.&#xD;
&#xD;
        -  SARS-CoV-2 CD4/CD8 T cell response (CTL)&#xD;
&#xD;
        -  Different KIR phenotypes&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Only 24% of health care workers (HCW) had developed inmunological response to SARS CoV-2&#xD;
      infection in one centre attending thousands of COVID-19 patients, and with shorteness of&#xD;
      personal protective equipments. Our hypothesis is that this relatively low number of infected&#xD;
      HCW could be secondary to:&#xD;
&#xD;
        1. Differences in susceptibility to infection mediated by changes in viral receptors. Thus,&#xD;
           it is important to characterize and genotyping the main receptor for SARS-CoV-2, ACE2,&#xD;
           and other related receptor, such as CD26.&#xD;
&#xD;
        2. Increased cellular immune response, offering cross-immunity against SARS CoV-2 infection&#xD;
           by previous exposure to other coronavirus or respiratory pathogens. A specific CD4/CD8 T&#xD;
           cell response to viral peptides could respond this question&#xD;
&#xD;
        3. Specific KIR phenotypes (Killer Immunoglobulin-like Receptors): Natural killer cells&#xD;
           (NK) response to alterations of class I HLA molecules presented in infected cells. An&#xD;
           increase in class I HLA expression could lead to an increase in NK activation by&#xD;
           increasing its ability to produce IFN-gamma.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 1, 2020</start_date>
  <completion_date type="Actual">September 30, 2021</completion_date>
  <primary_completion_date type="Actual">August 30, 2021</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>Susceptibility to SARS CoV-2 infection according to ACE2 receptor</measure>
    <time_frame>1 month</time_frame>
    <description>ACE2 analysis</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cellular immune response to SARS CoV-2 infection</measure>
    <time_frame>1 month</time_frame>
    <description>Activation of CD4-CD8 by viral peptides</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Susceptibility to infections according to KIR phenoytpes</measure>
    <time_frame>2 months</time_frame>
    <description>Analysis of KIR in NK cells</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Characteristics of exposure in time and intensity of HCW with SARS CoV-2 infection</measure>
    <time_frame>1 month</time_frame>
    <description>Survey</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cellular immune response in HCW with positive IgG against SARS CoV-2</measure>
    <time_frame>1 month</time_frame>
    <description>Activation of CD4-CD8 by viral peptides</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">140</enrollment>
  <condition>Health Care Worker Patient Transmission</condition>
  <condition>Receptor Site Alteration</condition>
  <condition>Susceptibility, Disease</condition>
  <condition>Immune Response</condition>
  <arm_group>
    <arm_group_label>Cases</arm_group_label>
    <description>HCW highly exposed (defined as more than 15 days of continued personal attention in ICU, anaesthesia, or Infectious Diseases wards) to patients with a diagnosis of COVID-19 (PCR confirmed), who remained asymptomatic and with a negative serology (IgM and IgG negative). Transient entry or stay in the zone (kitchen personnel, rehab members,...) will be not included.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Controls</arm_group_label>
    <description>HCW highly exposed to PCR-confirmed patients with a diagnosis of COVID-19, as defined above, matched by age and sex, who had suffered confirmed SARS CoV-2 disease (positive PCR or after, positive IgG)</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Susceptibility to infection</intervention_name>
    <description>ACE2 and CD26 receptor study: After genomic DNA extraction and quantification using a NanoDrop-1000, 14 ACE2 SNPs (rs1978124, rs2048683, rs2074192, rs2106809, rs2285666, rs233575, rs4240157, rs4646142, rs4646155, rs4646156, rs4646188, rs4830542, rs6632677, and rs879922) will be studied. In addition, one CD26 (DPP4) SNP (rs7608798) will be analysed (qualitative measure).&#xD;
SARS-CoV-2 CD4/CD8 T cell response: SARS-CoV-2 peptides (Prot-S, Pros-N and Port-M) will be used to activate CD4 and CD8 T cells. Cytokines released, such as IFNg, TNFa, IL4, IL17A, and IL2, from each cell subset will be measured by flow cytometry (quantitative measure).&#xD;
KIR characterization: Characterization of the presence of 14 genes plus 2 pseudogenes of KIR gene family (qualitative genotyping) by PCR, mRNA expression profiling (quantitative measures) by RT-PCR, and phenotyping of human NK cells analyzing different KIR receptors (quantitative measure) by flow cytometry, will be analyzed.</description>
    <arm_group_label>Cases</arm_group_label>
    <arm_group_label>Controls</arm_group_label>
    <other_name>KIR measurements</other_name>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        -  Cases: HCW highly exposed to COVID-19 diagnosed patients (see definition) who remained&#xD;
             free of symptoms of disease and had a negative serology against SARS-CoV-2 (both IgG&#xD;
             and IgM)&#xD;
&#xD;
          -  Controls: HCW highly exposed to COVID-19 diagnosed patients who had suffered the&#xD;
             infection and/or had presence of antibodies in the serological test, paired by sex and&#xD;
             age (5 year interval)&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion criteria&#xD;
&#xD;
          -  HCW older than 18 years&#xD;
&#xD;
          -  Highly exposed to COVID-19 according to the definition&#xD;
&#xD;
          -  Negative (cases) or positive (controls) serology against SARS-CoV-2 infection&#xD;
             Exclusion criteria&#xD;
&#xD;
          -  Presence of any disease / treatment which could alter the susceptibility (corticoid&#xD;
             therapy, chemotherapy, monoclonal antibodies)&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
        High exposure definition: direct and continued care of COVID-19 diagnosed patients for 2&#xD;
        weeks or more, without aerosol- generating procedures, with inappropriate personal&#xD;
        protective equipment (PPE), or unprotected exposure to patients with COVID-19 during&#xD;
        aerosol-generating procedures.&#xD;
&#xD;
        The definition of appropriate PPE was based on previous recommendations. The absence of any&#xD;
        part of the PPE constituted an unprotected exposure. We defined the following as&#xD;
        aerosol-generating procedures: airway suction, application of a high-flow O2 instrument,&#xD;
        bronchoscopy, endotracheal intubation, tracheostomy, nebulizer treatment, sputum induction,&#xD;
        positive pressure ventilation, manual ventilation and cardiopulmonary resuscitation.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jose L Casado, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Ramon y Cajal Physician</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital Ramon y Cajal</name>
      <address>
        <city>Madrid</city>
        <zip>28034</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <verification_date>October 2021</verification_date>
  <study_first_submitted>May 23, 2020</study_first_submitted>
  <study_first_submitted_qc>May 23, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 27, 2020</study_first_posted>
  <last_update_submitted>October 23, 2021</last_update_submitted>
  <last_update_submitted_qc>October 23, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">October 26, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>coronavirus, susceptibility, transmission, HCW</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
    <mesh_term>Disease Susceptibility</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>Data about receptors could be shared with other investigators about the susceptiblity to SARS CoV-2 However, KIR phenotypes should be shared after ethical comitee approval</ipd_description>
  </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/NCT04402827
org study id: EC 162/20
nct id: NCT04402827
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The primary objective of this study is to establish differences in susceptibility to SARS
      CoV-2 infection among health care workers (HCW) highly exposed to patients with COVID-19
      diagnosis. To ascertain this issue, we evaluated:

        -  Changes in receptor polymorphism (ACE2 and CD26 receptor study.

        -  SARS-CoV-2 CD4/CD8 T cell response (CTL)

        -  Different KIR phenotypes
Only 24% of health care workers (HCW) had developed inmunological response to SARS CoV-2
      infection in one centre attending thousands of COVID-19 patients, and with shorteness of
      personal protective equipments. Our hypothesis is that this relatively low number of infected
      HCW could be secondary to:

        1. Differences in susceptibility to infection mediated by changes in viral receptors. Thus,
           it is important to characterize and genotyping the main receptor for SARS-CoV-2, ACE2,
           and other related receptor, such as CD26.

        2. Increased cellular immune response, offering cross-immunity against SARS CoV-2 infection
           by previous exposure to other coronavirus or respiratory pathogens. A specific CD4/CD8 T
           cell response to viral peptides could respond this question

        3. Specific KIR phenotypes (Killer Immunoglobulin-like Receptors): Natural killer cells
           (NK) response to alterations of class I HLA molecules presented in infected cells. An
           increase in class I HLA expression could lead to an increase in NK activation by
           increasing its ability to produce IFN-gamma.
observational model: Case-Control
time perspective: Prospective
measure: Susceptibility to SARS CoV-2 infection according to ACE2 receptor
time frame: 1 month
description: ACE2 analysis
measure: Cellular immune response to SARS CoV-2 infection
time frame: 1 month
description: Activation of CD4-CD8 by viral peptides
measure: Susceptibility to infections according to KIR phenoytpes
time frame: 2 months
description: Analysis of KIR in NK cells
measure: Characteristics of exposure in time and intensity of HCW with SARS CoV-2 infection
time frame: 1 month
description: Survey
measure: Cellular immune response in HCW with positive IgG against SARS CoV-2
time frame: 1 month
description: Activation of CD4-CD8 by viral peptides
arm group label: Cases
description: HCW highly exposed (defined as more than 15 days of continued personal attention in ICU, anaesthesia, or Infectious Diseases wards) to patients with a diagnosis of COVID-19 (PCR confirmed), who remained asymptomatic and with a negative serology (IgM and IgG negative). Transient entry or stay in the zone (kitchen personnel, rehab members,...) will be not included.
arm group label: Controls
description: HCW highly exposed to PCR-confirmed patients with a diagnosis of COVID-19, as defined above, matched by age and sex, who had suffered confirmed SARS CoV-2 disease (positive PCR or after, positive IgG)
intervention type: Diagnostic Test
intervention name: Susceptibility to infection
description: ACE2 and CD26 receptor study: After genomic DNA extraction and quantification using a NanoDrop-1000, 14 ACE2 SNPs (rs1978124, rs2048683, rs2074192, rs2106809, rs2285666, rs233575, rs4240157, rs4646142, rs4646155, rs4646156, rs4646188, rs4830542, rs6632677, and rs879922) will be studied. In addition, one CD26 (DPP4) SNP (rs7608798) will be analysed (qualitative measure).
SARS-CoV-2 CD4/CD8 T cell response: SARS-CoV-2 peptides (Prot-S, Pros-N and Port-M) will be used to activate CD4 and CD8 T cells. Cytokines released, such as IFNg, TNFa, IL4, IL17A, and IL2, from each cell subset will be measured by flow cytometry (quantitative measure).
KIR characterization: Characterization of the presence of 14 genes plus 2 pseudogenes of KIR gene family (qualitative genotyping) by PCR, mRNA expression profiling (quantitative measures) by RT-PCR, and phenotyping of human NK cells analyzing different KIR receptors (quantitative measure) by flow cytometry, will be analyzed.
arm group label: Cases
arm group label: Controls
other name: KIR measurements
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Jose L Casado, MD, PhD
role: Principal Investigator
affiliation: Ramon y Cajal Physician
facility: 
country: Spain
responsible party type: Sponsor
mesh term: COVID-19
mesh term: Disease Susceptibility
sharing ipd: Undecided
ipd description: Data about receptors could be shared with other investigators about the susceptiblity to SARS CoV-2 However, KIR phenotypes should be shared after ethical comitee approval