<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/NCT04413864</url>
  </required_header>
  <id_info>
    <org_study_id>APHP200413</org_study_id>
    <secondary_id>2020-A00799-30</secondary_id>
    <nct_id>NCT04413864</nct_id>
  </id_info>
  <brief_title>Immunomodulatory Profile of Dexmedetomidine Sedation in Patients Recovering After ARDS Covid-19</brief_title>
  <acronym>DEXDO-COVID</acronym>
  <official_title>Immunomodulatory Profile of Dexmedetomidine Sedation in Patients Recovering After ARDS Covid-19</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assistance Publique - Hôpitaux de Paris</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assistance Publique - Hôpitaux de Paris</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>
      Covid-19 infection is due to SARS-CoV-2 member of the Coronavirus family represented by SARS-&#xD;
      and MERS-CoVwith neuronal tropism capacity for the brainstem and thalami. Dexmedetomidine&#xD;
      has(i) central antihypertensive (ii) sedative and (iii) neuroprotective properties and is&#xD;
      often used during patient recovering after mechanical ventilation withdrawal.&#xD;
&#xD;
      Dexmedetomidine administration could change the immunomodulatory profile of Covid-19 patients&#xD;
      and reduce inflammatory response.CAM-ICU scores and Blood samples from Covid-19 ICU patients&#xD;
      will be collected at 4 different timepoints (before Dexmedetomidine administration, at D2, D7&#xD;
      and M6) to analyse the inflammatory profile with different approaches:i) chromatin&#xD;
      accessibility, ii) transcriptome analysis, iii) inflammatory cytokines and chemokines levels.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Coronaviruses (CoV) cause enteric and respiratory diseases. Most human CoVs, such as hCoV -&#xD;
      229E, OC43, NL63 and HKU1, cause mild respiratory disease, but the global spread of two&#xD;
      previously well-knownCoVs: Severe Acute Respiratory Syndrome (SARS-CoV) and Middle East&#xD;
      respiratory syndrome (MERS-CoV) has proven the lethal potential of human CoV.&#xD;
&#xD;
      While MERS-CoV is still not eliminated from the world, another highly pathogenic CoV,&#xD;
      currently named SARS- CoV-2, started in December 2019 in Wuhan, in China. This new CoV caused&#xD;
      a Chinese outbreak of severe pneumonia (coronavirus 2019 [COVID - 19]), and quickly spread to&#xD;
      other countries.&#xD;
&#xD;
      Genomic analyzes show that SARS-CoV-2 shares a highly homological sequence with other&#xD;
      beta-coronavirus (βCoV) as MERS-CoV and SARS-CoV.&#xD;
&#xD;
      Some work published in the 2000s has shown the presence of SARS-CoV viruses in neurons.&#xD;
      Similarly, some experimental work has demonstrate that the MERS-COV5 and SARS-CoV6 viruses&#xD;
      detected in the intra-nasal airways have an affinity for several brain regions such as&#xD;
      brainstem or thalami. MERS-Cov viral particles have been found in several organs, including&#xD;
      brain after injection of an inoculum in mice.&#xD;
&#xD;
      Several studies indicate that the brain region involved in this context is the brainstem.&#xD;
&#xD;
      The path taken by the virus is not yet clear, but several arguments in the literature&#xD;
      indicate the hematogenous or lymphatic pathway, in particular during the acute phase of the&#xD;
      infection. In addition, a viral invasion of the peripheral nerves could occur, followed by a&#xD;
      secondary cerebral invasion with synaptic transmission already shown for other viruses.&#xD;
      Epidemiological data for SARS-CoV-2 (COVID-19 infection) showing median time between first&#xD;
      symptoms and dyspnea of 5 days, and hospitalization of 7 days10. This delayed period seems&#xD;
      sufficient to allow the virus to invade the central nervous system. A recent work shows that&#xD;
      patients infected with COVID-19 have neurological symptoms (headache, nausea, vomiting).&#xD;
&#xD;
      Large doses of sedation could be required to control a phase of severe delirium found in&#xD;
      Covid-19 positive patients during the recovering phase in ICU. This delirium could be&#xD;
      explained by the manifestation of septic encephalopathy, or even direct spread of the virus&#xD;
      in the central nervous system. Study of neuroinflammation biomarkers in bleed could&#xD;
      understand the progression of the disease and propose therapeutic strategies according to the&#xD;
      patient phenotype. In this context, the idea of finding a neuroprotective treatment to limit&#xD;
      the toxic effect of this virus on the brain is promising.&#xD;
&#xD;
      Dexmedetomidine is a selective adrenergic receptor agonist with antihypertensive, hypnotic&#xD;
      and analgesic properties. This molecule has an important capacity of diffusion in the central&#xD;
      nervous system with a central action in the locus cœruleus involved in vigilance thus&#xD;
      explaining its sedative action; it also acts on the posterior grey column also providing&#xD;
      analgesia via hyperpolarization of nerve fibers type C. Its distribution and its elimination&#xD;
      are done according to a bicompartmental model. It is strongly linked to plasma proteins (94%)&#xD;
      and is metabolized by the liver by glucuronidation, with an elimination half-life of two&#xD;
      hours, 90% eliminated by the kidney and 10% in the stool. Dexmedetomidine is a powerful&#xD;
      sympatholytic and should never be administered as a bolus or as a loading dose, it should be&#xD;
      administered as a continuous infusion at a start dose of 0.7 µg / kg / min and then adjusted&#xD;
      to sedation scores between 0,4 and 1,1 µg/kg/h.&#xD;
&#xD;
      Dexmedetomidine has neuroprotective effects. In experimental models such as the&#xD;
      intraperitoneal injection of LPS, spinal cord lesions and ischemia-reperfusion,&#xD;
      dexmedetomidine lower the cerebral inflammation directly on the microglial phenotype. The&#xD;
      molecular pathway involved is not clear yet, however several studies show an action of&#xD;
      Dexmedetomidine on the MAP kinase pathway.&#xD;
&#xD;
      Dexmedetomidine could be a direct neuroprotective agent by decreasing the brain inflammation&#xD;
      induced by Covid-19 infection. Adapted utilisation of Dexmedetomidine for each patient&#xD;
      profile could facilitate recovery and shorten the stay of patients in intensive care.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">April 24, 2020</start_date>
  <completion_date type="Anticipated">October 24, 2022</completion_date>
  <primary_completion_date type="Anticipated">October 24, 2022</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>open-label monocentric cohort study, with intervention added</intervention_model_description>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change of inflammatory cytokines concentration (mmol / L) in Covid19 + patients from Baseline at 6 months</measure>
    <time_frame>Month6</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change of interrelationship between inflammation (cytokines levels) and ICU delirium in Covid19 + patient from Baseline at 6 months</measure>
    <time_frame>Month6</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Modification in inflammatory genes expressed (expressed / non expressed) in PBMC between Baseline and M6</measure>
    <time_frame>Month6</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in quantity of chromatine's openings (chromatin accessibility profiles) in ICU patient recovering from covid19 infection</measure>
    <time_frame>Day2, Month6</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in genes expression in Covid-19 patient with delirium in ICU between Day2 and Month6</measure>
    <time_frame>Day2, Month6</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">50</enrollment>
  <condition>SARS-CoV 2</condition>
  <arm_group>
    <arm_group_label>SARS-CoV-2 (Covid-19 positive)</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Patients hospitalized in intensive care unit (ICU), infected with SARS-CoV-2</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Inflammatory cytokines and chemokines profiles of patients with dexmedetomidine administration</intervention_name>
    <description>Assigned Interventions:&#xD;
Blood samples collection at inclusion (D0) and follow-up visits (D2, D7 and M6)&#xD;
CAM-ICU scores during ICU hospitalisation, neurological questionnaires at M6 (GOAT, GOSE, MOCA, Barthel Index, PTSD, GDS, Rankin score, HADS)</description>
    <arm_group_label>SARS-CoV-2 (Covid-19 positive)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patient ≥ 18 years at time of inclusion&#xD;
&#xD;
          -  Hospitalized in intensive care unit (ICU)&#xD;
&#xD;
          -  Administration of dexmedetomidine scheduled for 7 days&#xD;
&#xD;
          -  Intubated/ventilated patient infected with SARS-CoV-2 (Covid-19 positive patient)&#xD;
&#xD;
          -  Patient affiliated to a social security system (French State medical aid excluded)&#xD;
&#xD;
          -  Hemoglobin level ≥ 9 g /dL&#xD;
&#xD;
          -  Patient or parent / close / trusted person having been informed about the study and&#xD;
             having given informed consent (or inclusion procedure in an emergency situation)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Protected major (under safeguardship, curatorship or guardianship)&#xD;
&#xD;
          -  Pregnancy or breastfeeding&#xD;
&#xD;
          -  Contra-indication to dexmedetomidine administration&#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>Vincent DEGOS, Pr</last_name>
    <role>Study Director</role>
    <affiliation>Assistance Publique - Hôpitaux de Paris</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Vincent DEGOS, Pr</last_name>
    <phone>142163761</phone>
    <phone_ext>+33</phone_ext>
    <email>vincent.degos@aphp.fr</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Alice JACQUENS</last_name>
    <phone>688652473</phone>
    <phone_ext>+33</phone_ext>
    <email>alice.jacquens@gmail.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Intensive Care Unit and Respiratory division ; Groupe hospitalier Pitie-Salpetriere and Universite Pierre et Marie Curie Paris 6</name>
      <address>
        <city>Paris</city>
        <zip>75013</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Alexandre Demoule, Md, PhD</last_name>
      <phone>+ 33 1 42 16 77 61</phone>
    </contact>
    <investigator>
      <last_name>Alexandre Demoule, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>May 2021</verification_date>
  <study_first_submitted>April 21, 2020</study_first_submitted>
  <study_first_submitted_qc>June 2, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 4, 2020</study_first_posted>
  <last_update_submitted>June 18, 2021</last_update_submitted>
  <last_update_submitted_qc>June 18, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">June 21, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>SARS-CoV-2</keyword>
  <keyword>Covid-19</keyword>
  <keyword>Dexmedetomidine</keyword>
  <keyword>Neuroinflammation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dexmedetomidine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT04413864
org study id: APHP200413
secondary id: 2020-A00799-30
nct id: NCT04413864
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Covid-19 infection is due to SARS-CoV-2 member of the Coronavirus family represented by SARS-
      and MERS-CoVwith neuronal tropism capacity for the brainstem and thalami. Dexmedetomidine
      has(i) central antihypertensive (ii) sedative and (iii) neuroprotective properties and is
      often used during patient recovering after mechanical ventilation withdrawal.

      Dexmedetomidine administration could change the immunomodulatory profile of Covid-19 patients
      and reduce inflammatory response.CAM-ICU scores and Blood samples from Covid-19 ICU patients
      will be collected at 4 different timepoints (before Dexmedetomidine administration, at D2, D7
      and M6) to analyse the inflammatory profile with different approaches:i) chromatin
      accessibility, ii) transcriptome analysis, iii) inflammatory cytokines and chemokines levels.
Coronaviruses (CoV) cause enteric and respiratory diseases. Most human CoVs, such as hCoV -
      229E, OC43, NL63 and HKU1, cause mild respiratory disease, but the global spread of two
      previously well-knownCoVs: Severe Acute Respiratory Syndrome (SARS-CoV) and Middle East
      respiratory syndrome (MERS-CoV) has proven the lethal potential of human CoV.

      While MERS-CoV is still not eliminated from the world, another highly pathogenic CoV,
      currently named SARS- CoV-2, started in December 2019 in Wuhan, in China. This new CoV caused
      a Chinese outbreak of severe pneumonia (coronavirus 2019 [COVID - 19]), and quickly spread to
      other countries.

      Genomic analyzes show that SARS-CoV-2 shares a highly homological sequence with other
      beta-coronavirus (βCoV) as MERS-CoV and SARS-CoV.

      Some work published in the 2000s has shown the presence of SARS-CoV viruses in neurons.
      Similarly, some experimental work has demonstrate that the MERS-COV5 and SARS-CoV6 viruses
      detected in the intra-nasal airways have an affinity for several brain regions such as
      brainstem or thalami. MERS-Cov viral particles have been found in several organs, including
      brain after injection of an inoculum in mice.

      Several studies indicate that the brain region involved in this context is the brainstem.

      The path taken by the virus is not yet clear, but several arguments in the literature
      indicate the hematogenous or lymphatic pathway, in particular during the acute phase of the
      infection. In addition, a viral invasion of the peripheral nerves could occur, followed by a
      secondary cerebral invasion with synaptic transmission already shown for other viruses.
      Epidemiological data for SARS-CoV-2 (COVID-19 infection) showing median time between first
      symptoms and dyspnea of 5 days, and hospitalization of 7 days10. This delayed period seems
      sufficient to allow the virus to invade the central nervous system. A recent work shows that
      patients infected with COVID-19 have neurological symptoms (headache, nausea, vomiting).

      Large doses of sedation could be required to control a phase of severe delirium found in
      Covid-19 positive patients during the recovering phase in ICU. This delirium could be
      explained by the manifestation of septic encephalopathy, or even direct spread of the virus
      in the central nervous system. Study of neuroinflammation biomarkers in bleed could
      understand the progression of the disease and propose therapeutic strategies according to the
      patient phenotype. In this context, the idea of finding a neuroprotective treatment to limit
      the toxic effect of this virus on the brain is promising.

      Dexmedetomidine is a selective adrenergic receptor agonist with antihypertensive, hypnotic
      and analgesic properties. This molecule has an important capacity of diffusion in the central
      nervous system with a central action in the locus cœruleus involved in vigilance thus
      explaining its sedative action; it also acts on the posterior grey column also providing
      analgesia via hyperpolarization of nerve fibers type C. Its distribution and its elimination
      are done according to a bicompartmental model. It is strongly linked to plasma proteins (94%)
      and is metabolized by the liver by glucuronidation, with an elimination half-life of two
      hours, 90% eliminated by the kidney and 10% in the stool. Dexmedetomidine is a powerful
      sympatholytic and should never be administered as a bolus or as a loading dose, it should be
      administered as a continuous infusion at a start dose of 0.7 µg / kg / min and then adjusted
      to sedation scores between 0,4 and 1,1 µg/kg/h.

      Dexmedetomidine has neuroprotective effects. In experimental models such as the
      intraperitoneal injection of LPS, spinal cord lesions and ischemia-reperfusion,
      dexmedetomidine lower the cerebral inflammation directly on the microglial phenotype. The
      molecular pathway involved is not clear yet, however several studies show an action of
      Dexmedetomidine on the MAP kinase pathway.

      Dexmedetomidine could be a direct neuroprotective agent by decreasing the brain inflammation
      induced by Covid-19 infection. Adapted utilisation of Dexmedetomidine for each patient
      profile could facilitate recovery and shorten the stay of patients in intensive care.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: open-label monocentric cohort study, with intervention added
primary purpose: Other
masking: None (Open Label)
measure: Change of inflammatory cytokines concentration (mmol / L) in Covid19 + patients from Baseline at 6 months
time frame: Month6
measure: Change of interrelationship between inflammation (cytokines levels) and ICU delirium in Covid19 + patient from Baseline at 6 months
time frame: Month6
measure: Modification in inflammatory genes expressed (expressed / non expressed) in PBMC between Baseline and M6
time frame: Month6
measure: Change in quantity of chromatine's openings (chromatin accessibility profiles) in ICU patient recovering from covid19 infection
time frame: Day2, Month6
measure: Change in genes expression in Covid-19 patient with delirium in ICU between Day2 and Month6
time frame: Day2, Month6
arm group label: SARS-CoV-2 (Covid-19 positive)
arm group type: Other
description: Patients hospitalized in intensive care unit (ICU), infected with SARS-CoV-2
intervention type: Other
intervention name: Inflammatory cytokines and chemokines profiles of patients with dexmedetomidine administration
description: Assigned Interventions:
Blood samples collection at inclusion (D0) and follow-up visits (D2, D7 and M6)
CAM-ICU scores during ICU hospitalisation, neurological questionnaires at M6 (GOAT, GOSE, MOCA, Barthel Index, PTSD, GDS, Rankin score, HADS)
arm group label: SARS-CoV-2 (Covid-19 positive)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Vincent DEGOS, Pr
role: Study Director
affiliation: Assistance Publique - Hôpitaux de Paris
last name: Vincent DEGOS, Pr
phone: 142163761
phone ext: +33
email: vincent.degos@aphp.fr
last name: Alice JACQUENS
phone: 688652473
phone ext: +33
email: alice.jacquens@gmail.com
facility: 
status: Recruiting
contact: 
investigator: 
country: France
responsible party type: Sponsor
mesh term: COVID-19
mesh term: Dexmedetomidine
sharing ipd: Undecided