<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/NCT04408365</url>
  </required_header>
  <id_info>
    <org_study_id>282930</org_study_id>
    <nct_id>NCT04408365</nct_id>
  </id_info>
  <brief_title>Endothelial Function, Inflammation and Organ Dysfunction in COVID-19</brief_title>
  <official_title>Endothelial Function, Inflammation, and Organ Dysfunction in Critically Ill Patients With COVID-19</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Guy's and St Thomas' NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>King's College Hospital NHS Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Guy's and St Thomas' NHS Foundation Trust</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 is a rapidly evolving pandemic with approximately 5% of all patients which require&#xD;
      intensive care unit admission. In critically ill patients infected with COVID-19,&#xD;
      approximately 15% had severe shock requiring medications to increase blood pressure. It&#xD;
      appears that blood vessel tone is altered and microcirculation is not well regulated in&#xD;
      patients with COVID-19. The underlying pathophysiology and contributing factors are unknown.&#xD;
      The association with subsequent organ dysfunction and outcome is also unclear. Therefore, the&#xD;
      investigators aim to investigate serial changes of relevant biomarkers in this population to&#xD;
      improve the understanding of this disease, to investigate the association with clinically&#xD;
      important outcomes and to find out how best to treat patients. The data will serve to develop&#xD;
      strategies for individualised management of this high-risk group.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      COVID-19 is a rapidly evolving pandemic with approximately 5% of all patients requiring&#xD;
      admission to an intensive care unit. In critically ill patients infected with COVID-19, acute&#xD;
      respiratory distress syndrome (ARDS) is found in 40%, 11.9% required continuous renal&#xD;
      replacement therapy (RRT), and 13.4% had vasodilatory shock.&#xD;
&#xD;
      Currently, supportive treatment is the mainstay treatment, with fluid administration and&#xD;
      vasopressors for haemodynamic support and lung-protective ventilation in patients with severe&#xD;
      respiratory failure.3 Targeted drugs, antiviral therapies, and vaccines are still currently&#xD;
      being developed, but there is currently insufficient evidence to recommend any drug over&#xD;
      another.&#xD;
&#xD;
      Dysregulation of vasomotor tone and alteration of microcirculatory function are common in&#xD;
      patients infected with COVID-19. The underlying pathophysiology and contributing factors are&#xD;
      unknown. The association with subsequent organ dysfunction and outcome is also unclear.&#xD;
&#xD;
      Circulating bio-adrenomedullin regulates vascular tone and endothelial permeability during&#xD;
      sepsis, and has been shown to associate with 28-day mortality, vasopressor requirement, RRT,&#xD;
      and positive fluid balance. Proenkephalin is a biomarker of glomerular function, and was&#xD;
      shown to elevate in patients with acute kidney injury (AKI), especially in those with&#xD;
      persistent AKI, and major adverse kidney events. Dipeptidyl peptidase 3 (DPP-3) is a&#xD;
      myocardial depressant factor, which is involved in angiotensin II cleavage. High DPP-3 levels&#xD;
      were associated with severe organ dysfunction and short-term mortality. In critically ill&#xD;
      patients, COVID-19 has been reported to be associated with cardiovascular dysfunction and&#xD;
      high mortality.&#xD;
&#xD;
      The renin-angiotensin-aldosterone system (RAAS) may be linked to the pathogenesis of&#xD;
      COVID-19. The coronavirus receptor utilizes angiotensin converting enzyme 2 (ACE2) to enter&#xD;
      target cells. Endogenous angiotensin II is hypothesized to prevent binding of coronavirus to&#xD;
      ACE2, causing internalization and downregulation of ACE2, and causing lysosome-mediated&#xD;
      destruction of ACE2. There are no human studies in COVID-19 patients to confirm this&#xD;
      hypothesis yet.&#xD;
&#xD;
      There is very little knowledge of underlying pathogenesis in patients with COVID-19 and&#xD;
      vasodilatory shock. Therefore, the investigators aim to investigate serial changes of&#xD;
      relevant biomarkers in this population to give further understanding of this disease and to&#xD;
      investigate the association with clinically important outcomes. The data will serve to&#xD;
      develop strategies for individualized management of this high-risk group.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">August 5, 2020</start_date>
  <completion_date type="Anticipated">December 31, 2022</completion_date>
  <primary_completion_date type="Anticipated">July 31, 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>Change of plasma bio-adrenomedullin</measure>
    <time_frame>Day 1-7 after intensive care unit admission</time_frame>
    <description>Change of plasma bio-adrenomedullin</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change of plasma proenkephalin</measure>
    <time_frame>Day 1-7 after intensive care unit admission</time_frame>
    <description>Change of plasma proenkephalin</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change of plasma dipeptidyl peptidase-3</measure>
    <time_frame>Day 1-7 after intensive care unit admission</time_frame>
    <description>Change of plasma dipeptidyl peptidase-3</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change of plasma renin</measure>
    <time_frame>Day 1-7 after intensive care unit admission</time_frame>
    <description>Change of plasma renin</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change of plasma angiotensin II</measure>
    <time_frame>Day 1-7 after intensive care unit admission</time_frame>
    <description>Change of plasma angiotensin II</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Duration of vasodilatory shock</measure>
    <time_frame>7 and 28 days</time_frame>
    <description>Duration of vasodilatory shock</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Acute kidney injury</measure>
    <time_frame>7 and 28 days</time_frame>
    <description>As defined by the Kidney Disease: Improving Global Outcomes criteria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Need for renal replacement therapy</measure>
    <time_frame>7 and 28 days</time_frame>
    <description>Need for renal replacement therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of ventilation</measure>
    <time_frame>7 and 28 days</time_frame>
    <description>Duration of ventilation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of extracorporeal membrane oxygenation</measure>
    <time_frame>7 and 28 days</time_frame>
    <description>Duration of extracorporeal membrane oxygenation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>28 days</time_frame>
    <description>ICU and hospital</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">82</enrollment>
  <condition>COVID</condition>
  <condition>Shock</condition>
  <arm_group>
    <arm_group_label>COVID-19 patients</arm_group_label>
    <description>Adult COVID-19 patients admitted to intensive care units</description>
  </arm_group>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Daily blood samples from ICU admission until day 7 and around the onset of vasodilatory shock&#xD;
      Daily urine and RRT effluent fluid samples (if available) from ICU admission until day 7&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Adult COVID-19 patients who are admitted in intensive care units&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Adult patients (≥ 18 years old) admitted to intensive care units&#xD;
&#xD;
          2. Confirmed or suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV2)&#xD;
             infection resulting in coronavirus disease 2019 (COVID-19)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        None&#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>Nuttha Lumlertgul, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Guy's &amp; St Thomas' Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Marlies Ostermann, MD, PhD</last_name>
    <phone>0044 207 188 3038</phone>
    <phone_ext>83036</phone_ext>
    <email>Marlies.Ostermann@gstt.nhs.uk</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Nuttha Lumlertgul, MD, PhD</last_name>
    <phone>0044 207 188 3038</phone>
    <phone_ext>83036</phone_ext>
    <email>Nuttha.Lumlertgul@gstt.nhs.uk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Guy's &amp; St Thomas' Hospital</name>
      <address>
        <city>London</city>
        <zip>SE1 7EH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Marlies Ostermann, MD, PhD</last_name>
      <phone>020 71883038</phone>
      <email>Marlies.Ostermann@gstt.nhs.uk</email>
    </contact>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>May 27, 2020</study_first_submitted>
  <study_first_submitted_qc>May 27, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 29, 2020</study_first_posted>
  <last_update_submitted>August 6, 2021</last_update_submitted>
  <last_update_submitted_qc>August 6, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">August 9, 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>Inflammation</mesh_term>
  </condition_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/NCT04408365
org study id: 282930
nct id: NCT04408365
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
COVID-19 is a rapidly evolving pandemic with approximately 5% of all patients which require
      intensive care unit admission. In critically ill patients infected with COVID-19,
      approximately 15% had severe shock requiring medications to increase blood pressure. It
      appears that blood vessel tone is altered and microcirculation is not well regulated in
      patients with COVID-19. The underlying pathophysiology and contributing factors are unknown.
      The association with subsequent organ dysfunction and outcome is also unclear. Therefore, the
      investigators aim to investigate serial changes of relevant biomarkers in this population to
      improve the understanding of this disease, to investigate the association with clinically
      important outcomes and to find out how best to treat patients. The data will serve to develop
      strategies for individualised management of this high-risk group.
COVID-19 is a rapidly evolving pandemic with approximately 5% of all patients requiring
      admission to an intensive care unit. In critically ill patients infected with COVID-19, acute
      respiratory distress syndrome (ARDS) is found in 40%, 11.9% required continuous renal
      replacement therapy (RRT), and 13.4% had vasodilatory shock.

      Currently, supportive treatment is the mainstay treatment, with fluid administration and
      vasopressors for haemodynamic support and lung-protective ventilation in patients with severe
      respiratory failure.3 Targeted drugs, antiviral therapies, and vaccines are still currently
      being developed, but there is currently insufficient evidence to recommend any drug over
      another.

      Dysregulation of vasomotor tone and alteration of microcirculatory function are common in
      patients infected with COVID-19. The underlying pathophysiology and contributing factors are
      unknown. The association with subsequent organ dysfunction and outcome is also unclear.

      Circulating bio-adrenomedullin regulates vascular tone and endothelial permeability during
      sepsis, and has been shown to associate with 28-day mortality, vasopressor requirement, RRT,
      and positive fluid balance. Proenkephalin is a biomarker of glomerular function, and was
      shown to elevate in patients with acute kidney injury (AKI), especially in those with
      persistent AKI, and major adverse kidney events. Dipeptidyl peptidase 3 (DPP-3) is a
      myocardial depressant factor, which is involved in angiotensin II cleavage. High DPP-3 levels
      were associated with severe organ dysfunction and short-term mortality. In critically ill
      patients, COVID-19 has been reported to be associated with cardiovascular dysfunction and
      high mortality.

      The renin-angiotensin-aldosterone system (RAAS) may be linked to the pathogenesis of
      COVID-19. The coronavirus receptor utilizes angiotensin converting enzyme 2 (ACE2) to enter
      target cells. Endogenous angiotensin II is hypothesized to prevent binding of coronavirus to
      ACE2, causing internalization and downregulation of ACE2, and causing lysosome-mediated
      destruction of ACE2. There are no human studies in COVID-19 patients to confirm this
      hypothesis yet.

      There is very little knowledge of underlying pathogenesis in patients with COVID-19 and
      vasodilatory shock. Therefore, the investigators aim to investigate serial changes of
      relevant biomarkers in this population to give further understanding of this disease and to
      investigate the association with clinically important outcomes. The data will serve to
      develop strategies for individualized management of this high-risk group.
observational model: Cohort
time perspective: Prospective
measure: Change of plasma bio-adrenomedullin
time frame: Day 1-7 after intensive care unit admission
description: Change of plasma bio-adrenomedullin
measure: Change of plasma proenkephalin
time frame: Day 1-7 after intensive care unit admission
description: Change of plasma proenkephalin
measure: Change of plasma dipeptidyl peptidase-3
time frame: Day 1-7 after intensive care unit admission
description: Change of plasma dipeptidyl peptidase-3
measure: Change of plasma renin
time frame: Day 1-7 after intensive care unit admission
description: Change of plasma renin
measure: Change of plasma angiotensin II
time frame: Day 1-7 after intensive care unit admission
description: Change of plasma angiotensin II
measure: Duration of vasodilatory shock
time frame: 7 and 28 days
description: Duration of vasodilatory shock
measure: Acute kidney injury
time frame: 7 and 28 days
description: As defined by the Kidney Disease: Improving Global Outcomes criteria
measure: Need for renal replacement therapy
time frame: 7 and 28 days
description: Need for renal replacement therapy
measure: Duration of ventilation
time frame: 7 and 28 days
description: Duration of ventilation
measure: Duration of extracorporeal membrane oxygenation
time frame: 7 and 28 days
description: Duration of extracorporeal membrane oxygenation
measure: Mortality
time frame: 28 days
description: ICU and hospital
arm group label: COVID-19 patients
description: Adult COVID-19 patients admitted to intensive care units
Daily blood samples from ICU admission until day 7 and around the onset of vasodilatory shock
      Daily urine and RRT effluent fluid samples (if available) from ICU admission until day 7
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Nuttha Lumlertgul, MD, PhD
role: Principal Investigator
affiliation: Guy's & St Thomas' Hospital
last name: Marlies Ostermann, MD, PhD
phone: 0044 207 188 3038
phone ext: 83036
email: Marlies.Ostermann@gstt.nhs.uk
last name: Nuttha Lumlertgul, MD, PhD
phone: 0044 207 188 3038
phone ext: 83036
email: Nuttha.Lumlertgul@gstt.nhs.uk
facility: 
status: Recruiting
contact: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Inflammation
sharing ipd: Undecided