<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/NCT04403061</url>
  </required_header>
  <id_info>
    <org_study_id>EC128/20</org_study_id>
    <nct_id>NCT04403061</nct_id>
  </id_info>
  <brief_title>Th1/Th2/Th17/TREG and TLRs Activation/KIR for COVID 19 Prediction of Outcome</brief_title>
  <acronym>Resistir</acronym>
  <official_title>Th1/Th2/Th17/TREG Response and TLRs Activation/KIR Receptors for Predicting the Evolution of the SARS Cov-2 Infected Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Asociacion para el Estudio de las Enfermedades Infecciosas</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </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>
      To ascertain globally the changes in the cytokines involved and TLRs/KIR activation in&#xD;
      patients admitted to the hospital with a COVID-19 diagnosis, and the changes after initiation&#xD;
      of the different therapies&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      COVID-19 is a disease with an initial viral phase followed, usually at the 7th day, of an&#xD;
      inflammatory state (cytokine storm) leading to respiratory distress, ICU admission and risk&#xD;
      of death. Thus, several biological agents, antagonists of the different cytokines (IL-6,&#xD;
      IL-1) have been used for patients with severe disease. However, there are no data about the&#xD;
      cytokine changes, at admission and after therapy, and its predictive value, a fundamental&#xD;
      knowledge to establish the best therapeutic strategy.&#xD;
&#xD;
      The first line of immune defense is the interaction of the virus with innate immunity cell&#xD;
      members. The toll like receptors (TLRs) family is a group of pattern recognition receptors&#xD;
      that include many different molecules (21-23). These bindings can activate dendritic cells,&#xD;
      monocytes, macrophages. There is an important RNA and DNA connection, activation of TLRs, the&#xD;
      production of type I interferons, and the development of some autoimmune diseases. TLR7 and&#xD;
      TLR8 specifically recognize simple-chain RNA of viruses and are expressed in endosomal&#xD;
      membranes. TLR8 is expressed in regulatory cells (Treg) and its activation results in&#xD;
      inhibition of its regulatory functions. Natural killer cells (NK) respond to alterations of&#xD;
      class I HLA molecules present in infected cells (24-26). An increase in class I HLA&#xD;
      expression could lead to an increase in NK activation by increasing its ability to produce&#xD;
      IFN-gamma. Therefore, the reasons for KIR binding are often variable between individuals and&#xD;
      between populations.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 22, 2020</start_date>
  <completion_date type="Actual">January 10, 2021</completion_date>
  <primary_completion_date type="Actual">December 22, 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>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Changes in cytokines associated with SARS CoV-2 infection</measure>
    <time_frame>1 month</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Evaluation of cellular response</measure>
    <time_frame>1 month</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>TLRs activation</measure>
    <time_frame>1 month</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>KIR phenotype determination</measure>
    <time_frame>1 month</time_frame>
  </primary_outcome>
  <enrollment type="Actual">106</enrollment>
  <condition>Disease, Viral</condition>
  <condition>Cytokine Release Syndrome</condition>
  <condition>TLRs</condition>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Cytokines measurement</intervention_name>
    <description>Quantification of plasma cytokine levels of human GM-CSF, IFN-α, IFN-γ, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p70, IL-17A, and TNF-α using multiplex technol-ogy (quantitative measure).</description>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Cellular response</intervention_name>
    <description>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).</description>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>TLRs activation measurement</intervention_name>
    <description>After specific cell activation through TLR7/8 receptors, such as resiquimod, ORN R-0002, ORN R-0006, ORN R-1263, ORN R-2336, and controls as Poly (I:C), the release of IFNa, IFNg, TNFa, IL12, and IL6 will be analyzed (quantitative measure).</description>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>KIR phenotype evaluation</intervention_name>
    <description>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>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Patients with a diagnosis of COVID-19&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with a diagnosis of COVID-19 (PCR confirmed)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  No informed consent&#xD;
&#xD;
          -  Presence of chronic therapy with immunomodulators, corticoids or antineoplastic&#xD;
             agents.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>100 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <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>January 2021</verification_date>
  <study_first_submitted>May 23, 2020</study_first_submitted>
  <study_first_submitted_qc>May 26, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 27, 2020</study_first_posted>
  <last_update_submitted>January 11, 2021</last_update_submitted>
  <last_update_submitted_qc>January 11, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">January 12, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Virus Diseases</mesh_term>
    <mesh_term>Cytokine Release Syndrome</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>Pending to establish collaboration to share cytokine measurements</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/NCT04403061
org study id: EC128/20
nct id: NCT04403061
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
To ascertain globally the changes in the cytokines involved and TLRs/KIR activation in
      patients admitted to the hospital with a COVID-19 diagnosis, and the changes after initiation
      of the different therapies
COVID-19 is a disease with an initial viral phase followed, usually at the 7th day, of an
      inflammatory state (cytokine storm) leading to respiratory distress, ICU admission and risk
      of death. Thus, several biological agents, antagonists of the different cytokines (IL-6,
      IL-1) have been used for patients with severe disease. However, there are no data about the
      cytokine changes, at admission and after therapy, and its predictive value, a fundamental
      knowledge to establish the best therapeutic strategy.

      The first line of immune defense is the interaction of the virus with innate immunity cell
      members. The toll like receptors (TLRs) family is a group of pattern recognition receptors
      that include many different molecules (21-23). These bindings can activate dendritic cells,
      monocytes, macrophages. There is an important RNA and DNA connection, activation of TLRs, the
      production of type I interferons, and the development of some autoimmune diseases. TLR7 and
      TLR8 specifically recognize simple-chain RNA of viruses and are expressed in endosomal
      membranes. TLR8 is expressed in regulatory cells (Treg) and its activation results in
      inhibition of its regulatory functions. Natural killer cells (NK) respond to alterations of
      class I HLA molecules present in infected cells (24-26). An increase in class I HLA
      expression could lead to an increase in NK activation by increasing its ability to produce
      IFN-gamma. Therefore, the reasons for KIR binding are often variable between individuals and
      between populations.
observational model: Cohort
time perspective: Prospective
measure: Changes in cytokines associated with SARS CoV-2 infection
time frame: 1 month
measure: Evaluation of cellular response
time frame: 1 month
measure: TLRs activation
time frame: 1 month
measure: KIR phenotype determination
time frame: 1 month
intervention type: Diagnostic Test
intervention name: Cytokines measurement
description: Quantification of plasma cytokine levels of human GM-CSF, IFN-α, IFN-γ, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p70, IL-17A, and TNF-α using multiplex technol-ogy (quantitative measure).
intervention type: Diagnostic Test
intervention name: Cellular response
description: 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).
intervention type: Diagnostic Test
intervention name: TLRs activation measurement
description: After specific cell activation through TLR7/8 receptors, such as resiquimod, ORN R-0002, ORN R-0006, ORN R-1263, ORN R-2336, and controls as Poly (I:C), the release of IFNa, IFNg, TNFa, IL12, and IL6 will be analyzed (quantitative measure).
intervention type: Diagnostic Test
intervention name: KIR phenotype evaluation
description: 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.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 100 Years
healthy volunteers: No
facility: 
country: Spain
responsible party type: Sponsor
mesh term: Virus Diseases
mesh term: Cytokine Release Syndrome
sharing ipd: Undecided
ipd description: Pending to establish collaboration to share cytokine measurements