<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/NCT04472013</url>
  </required_header>
  <id_info>
    <org_study_id>2020-01503; ch20Hutter</org_study_id>
    <nct_id>NCT04472013</nct_id>
  </id_info>
  <brief_title>Systematic Assessment of SARS-CoV-2 Neurotropic Capacity in Modestly and Critically Ill Patients, and Patients Who Died From COVID-19</brief_title>
  <official_title>Systematic Assessment of SARS-CoV-2 Neurotropic Capacity in Modestly and Critically Ill Patients, and Patients Who Died From COVID-19</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital, Basel, Switzerland</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Botnar Research Centre for Child Health</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospital, Basel, Switzerland</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>
      This study is to analyze the microglia reaction or direct neurotropic effects of CNS COVID-19&#xD;
      in pathogenesis and brain stem dysfunction in critically ill patients. A microglia-focused,&#xD;
      brain-specific 50+ marker CODEX panel is used to assess the neuroinflammatory&#xD;
      microenvironment in specific brain regions of deceased COVID-19 patients. The peripheral&#xD;
      (cerebrospinal fluid and peripheral blood) cytokine response to SARS-CoV-2 is investigated in&#xD;
      regard to CNS affection and consecutive blood brain barrier disruption leading to&#xD;
      braininherent neuroinflammatory reactions&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study is to analyze the microglia reaction or direct neurotropic effects of CNS COVID-19&#xD;
      in pathogenesis and brain stem dysfunction in critically ill patients. A microglia-focused,&#xD;
      brain-specific 50+ marker CODEX panel is used to assess the neuroinflammatory&#xD;
      microenvironment in specific brain regions of deceased COVID-19 patients. The peripheral&#xD;
      (cerebrospinal fluid and peripheral blood) cytokine response to SARS-CoV-2 is investigated in&#xD;
      regard to CNS affection and consecutive blood brain barrier disruption leading to&#xD;
      braininherent neuroinflammatory reactions. Primary endpoints of this project are the&#xD;
      multidimensional integration of the analysis from the procedures described above and&#xD;
      assessment of the correlation between the gained clinical data (MRI, mental/neurological&#xD;
      state), the body fluid proteomic and mass-cytometric analysis (CSF and Plasma proteomics,&#xD;
      peripheral blood mass cytometry) and the CODEX analysis of defined brain regions on autopsy&#xD;
      specimens.&#xD;
&#xD;
      Non-critically ill COVID-19 patients and critically ill COVID-19 patients needing mechanical&#xD;
      ventilation at the ICU are included. Autopsy specimens from medulla oblongata, cortex,&#xD;
      cerebellum and olfactory bulb are investigated, including only tissue samples, which have&#xD;
      been submitted to the Institute of Pathology, University Hospital Basel.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 12, 2020</start_date>
  <completion_date type="Actual">November 9, 2022</completion_date>
  <primary_completion_date type="Actual">November 9, 2022</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>MRI imaging data</measure>
    <time_frame>Project duration for each patient takes 1 hour for the MRI at baseline</time_frame>
    <description>Comparison of lesions from patients that are neurologically affected to non-affected individuals in terms of CNS involvement to describe encephalitic changes due to COVID-19 infection.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Proteomic analysis</measure>
    <time_frame>10 minutes for blood draw at baseline</time_frame>
    <description>Description of proteomic biomarkers (CSF and Plasma) in comparison with control reference sample.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Peripheral blood leukocyte Cytof Mass Cytometry Analysis for cell population frequency</measure>
    <time_frame>10 minutes for blood draw at baseline</time_frame>
    <description>Mass cytometry will be performed form peripheral blood mononuclear cells to count cell population frequency.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>CODEX (high dimensional microscopy) workflow analysis of defined regions on brain autopsy specimens</measure>
    <time_frame>at baseline</time_frame>
    <description>In situ distribution assessment of marker expression (CD147 protein, ACE2 protein, Transmembrane protease serine subtype 2 (TMPRSS2))</description>
  </primary_outcome>
  <enrollment type="Actual">40</enrollment>
  <condition>COVID-19 Disease</condition>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Data collection from lumbar puncture</intervention_name>
    <description>Cerebro spinal fluid (CSF) will be acquired by lumbar puncture and sent for routine analysis including CSF chemistry, cytology and microbiology. Targeted CSF proteomics using OLINK Proximity Extension Assay (PEA) technology to assess a potential CNS-contribution of the disease will be performed.</description>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Data collection from blood draw</intervention_name>
    <description>Plasma samples will be acquired for plasma cytokine proteomics using CyTOF (mass cytometry analysis) technology.</description>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>CNS magnetic resonance imaging (MRI) imaging</intervention_name>
    <description>3Tesla magnetic resonance imaging (MRI) will be performed to document early/manifest encephalitic changes in COVID-19 patients.</description>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Microscopy of defined brain regions on autopsy specimens</intervention_name>
    <description>High dimensional, microglia-centric CODEX fluorescent microscopy of defined brain regions on autopsy specimens will be acquired from medulla oblongata, cortex, cerebellum, and olfactory bulb. A brain-specific CODEX panel for the assessment of the immune microenvironment was implemented, with inclusion of a wide array of myeloid/microglia markers, T-cell markers, and a few neuronal markers. All the antibodies have been validated and tested in formalin-fixed tissues of different zones of glioblastoma tumors including invading tumor periphery. The Panel will be modified to include the viral entry receptors, CD147, ACE2 and TMPRSS2. Presence of SARS-CoV-2 virus particles will be assessed by qPCR, andMultiplexed Ion Beam Imaging (MIBI) technology will be used to visualize tropism of virus to specific cellular brain compartments.</description>
  </intervention>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Biological material is appropriately stored in a restricted area only accessible to&#xD;
      authorized personnel. The acquired fluids of lumbar puncture, blood withdrawal and autopsy&#xD;
      (in case of death) are going to be frozen at -80° C and stored at Department of Biomedicine,&#xD;
      University Hospital of Basel. Biological material in this project is not identified by&#xD;
      participant name but by a unique participant number.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        20 non-critically ill COVID-19 patients from the inpatient ward, and 20 critically ill&#xD;
        COVID-19 patients needing mechanical ventilation at the ICU. Recruitment takes places at&#xD;
        University Hospital of Basel and the Kantonsspital Baselland Liestal.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  COVID-19 positive tested&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  COVID-19 negative tested&#xD;
&#xD;
          -  pregnant women&#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>Gregor Hutter, Prof. Dr. med.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Neurosurgery, University Hospital Basel</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Neurosurgery, University Hospital Basel</name>
      <address>
        <city>Basel</city>
        <zip>4031</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Switzerland</country>
  </location_countries>
  <link>
    <url>http://doi.org/10.1038/s41467-022-34068-0</url>
    <description>Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study</description>
  </link>
  <reference>
    <citation>Etter MM, Martins TA, Kulsvehagen L, Possnecker E, Duchemin W, Hogan S, Sanabria-Diaz G, Muller J, Chiappini A, Rychen J, Eberhard N, Guzman R, Mariani L, Melie-Garcia L, Keller E, Jelcic I, Pargger H, Siegemund M, Kuhle J, Oechtering J, Eich C, Tzankov A, Matter MS, Uzun S, Yaldizli O, Lieb JM, Psychogios MN, Leuzinger K, Hirsch HH, Granziera C, Probstel AK, Hutter G. Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study. Nat Commun. 2022 Nov 9;13(1):6777. doi: 10.1038/s41467-022-34068-0.</citation>
    <PMID>36351919</PMID>
  </reference>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>July 14, 2020</study_first_submitted>
  <study_first_submitted_qc>July 14, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 15, 2020</study_first_posted>
  <last_update_submitted>November 15, 2022</last_update_submitted>
  <last_update_submitted_qc>November 15, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 18, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>SARS-CoV-2</keyword>
  <keyword>neurotropism of SARS-CoV-2</keyword>
  <keyword>microglia</keyword>
  <keyword>CODEX (high dimensional microscopy) analysis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</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/NCT04472013
org study id: 2020-01503; ch20Hutter
nct id: NCT04472013
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This study is to analyze the microglia reaction or direct neurotropic effects of CNS COVID-19
      in pathogenesis and brain stem dysfunction in critically ill patients. A microglia-focused,
      brain-specific 50+ marker CODEX panel is used to assess the neuroinflammatory
      microenvironment in specific brain regions of deceased COVID-19 patients. The peripheral
      (cerebrospinal fluid and peripheral blood) cytokine response to SARS-CoV-2 is investigated in
      regard to CNS affection and consecutive blood brain barrier disruption leading to
      braininherent neuroinflammatory reactions
This study is to analyze the microglia reaction or direct neurotropic effects of CNS COVID-19
      in pathogenesis and brain stem dysfunction in critically ill patients. A microglia-focused,
      brain-specific 50+ marker CODEX panel is used to assess the neuroinflammatory
      microenvironment in specific brain regions of deceased COVID-19 patients. The peripheral
      (cerebrospinal fluid and peripheral blood) cytokine response to SARS-CoV-2 is investigated in
      regard to CNS affection and consecutive blood brain barrier disruption leading to
      braininherent neuroinflammatory reactions. Primary endpoints of this project are the
      multidimensional integration of the analysis from the procedures described above and
      assessment of the correlation between the gained clinical data (MRI, mental/neurological
      state), the body fluid proteomic and mass-cytometric analysis (CSF and Plasma proteomics,
      peripheral blood mass cytometry) and the CODEX analysis of defined brain regions on autopsy
      specimens.

      Non-critically ill COVID-19 patients and critically ill COVID-19 patients needing mechanical
      ventilation at the ICU are included. Autopsy specimens from medulla oblongata, cortex,
      cerebellum and olfactory bulb are investigated, including only tissue samples, which have
      been submitted to the Institute of Pathology, University Hospital Basel.
observational model: Cohort
time perspective: Prospective
measure: MRI imaging data
time frame: Project duration for each patient takes 1 hour for the MRI at baseline
description: Comparison of lesions from patients that are neurologically affected to non-affected individuals in terms of CNS involvement to describe encephalitic changes due to COVID-19 infection.
measure: Proteomic analysis
time frame: 10 minutes for blood draw at baseline
description: Description of proteomic biomarkers (CSF and Plasma) in comparison with control reference sample.
measure: Peripheral blood leukocyte Cytof Mass Cytometry Analysis for cell population frequency
time frame: 10 minutes for blood draw at baseline
description: Mass cytometry will be performed form peripheral blood mononuclear cells to count cell population frequency.
measure: CODEX (high dimensional microscopy) workflow analysis of defined regions on brain autopsy specimens
time frame: at baseline
description: In situ distribution assessment of marker expression (CD147 protein, ACE2 protein, Transmembrane protease serine subtype 2 (TMPRSS2))
intervention type: Other
intervention name: Data collection from lumbar puncture
description: Cerebro spinal fluid (CSF) will be acquired by lumbar puncture and sent for routine analysis including CSF chemistry, cytology and microbiology. Targeted CSF proteomics using OLINK Proximity Extension Assay (PEA) technology to assess a potential CNS-contribution of the disease will be performed.
intervention type: Other
intervention name: Data collection from blood draw
description: Plasma samples will be acquired for plasma cytokine proteomics using CyTOF (mass cytometry analysis) technology.
intervention type: Other
intervention name: CNS magnetic resonance imaging (MRI) imaging
description: 3Tesla magnetic resonance imaging (MRI) will be performed to document early/manifest encephalitic changes in COVID-19 patients.
intervention type: Other
intervention name: Microscopy of defined brain regions on autopsy specimens
description: High dimensional, microglia-centric CODEX fluorescent microscopy of defined brain regions on autopsy specimens will be acquired from medulla oblongata, cortex, cerebellum, and olfactory bulb. A brain-specific CODEX panel for the assessment of the immune microenvironment was implemented, with inclusion of a wide array of myeloid/microglia markers, T-cell markers, and a few neuronal markers. All the antibodies have been validated and tested in formalin-fixed tissues of different zones of glioblastoma tumors including invading tumor periphery. The Panel will be modified to include the viral entry receptors, CD147, ACE2 and TMPRSS2. Presence of SARS-CoV-2 virus particles will be assessed by qPCR, andMultiplexed Ion Beam Imaging (MIBI) technology will be used to visualize tropism of virus to specific cellular brain compartments.
Biological material is appropriately stored in a restricted area only accessible to
      authorized personnel. The acquired fluids of lumbar puncture, blood withdrawal and autopsy
      (in case of death) are going to be frozen at -80° C and stored at Department of Biomedicine,
      University Hospital of Basel. Biological material in this project is not identified by
      participant name but by a unique participant number.
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Gregor Hutter, Prof. Dr. med.
role: Principal Investigator
affiliation: Neurosurgery, University Hospital Basel
facility: 
country: Switzerland
url: http://doi.org/10.1038/s41467-022-34068-0
description: Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study
citation: Etter MM, Martins TA, Kulsvehagen L, Possnecker E, Duchemin W, Hogan S, Sanabria-Diaz G, Muller J, Chiappini A, Rychen J, Eberhard N, Guzman R, Mariani L, Melie-Garcia L, Keller E, Jelcic I, Pargger H, Siegemund M, Kuhle J, Oechtering J, Eich C, Tzankov A, Matter MS, Uzun S, Yaldizli O, Lieb JM, Psychogios MN, Leuzinger K, Hirsch HH, Granziera C, Probstel AK, Hutter G. Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study. Nat Commun. 2022 Nov 9;13(1):6777. doi: 10.1038/s41467-022-34068-0.
PMID: 36351919
responsible party type: Sponsor
mesh term: COVID-19