<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/NCT04419610</url>
  </required_header>
  <id_info>
    <org_study_id>283093</org_study_id>
    <nct_id>NCT04419610</nct_id>
  </id_info>
  <brief_title>RAS and Coagulopathy in COVID19</brief_title>
  <official_title>Investigating the Relationship Between the Renin Angiotensin System and the Coagulopathy Associated With COVID-19</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Imperial College London</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Imperial College London</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      To determine whether the coagulopathy associated with COVID-19 infection is driven by&#xD;
      overactivation of the renin angiotensin system (RAS)&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The proposed study will be run as a double-blind, randomized controlled experimental medicine&#xD;
      study in male and female hospitalised (n=60) aged 18 or over, with confirmed COVID-19&#xD;
      infection. Patients who are admitted due to confirmed COVID-19 infection will be screened&#xD;
      with a routine medical assessment (see Table 1) and enrolled if they meet the eligibility&#xD;
      criteria. Subjects will be block randomised based on age to continuous intravenous infusion&#xD;
      of placebo or TRV027 for 7 days.&#xD;
&#xD;
      Day 1 procedures can occur on the same day of screening and include a venous blood test prior&#xD;
      to commencing an intravenous infusion of either placebo or TRV027 at 12mg/hr. The infusions&#xD;
      will continue for 7 days. Venous blood tests will be repeated at days 3, 5 and 8, amounting&#xD;
      to approximately 120mLs of blood in total over the 8-day period.&#xD;
&#xD;
      Once the infusion has finished, the subjects will remain in hospital for a further 24 hours&#xD;
      for vital signs and adverse event monitoring. If a subject exits the trial before the 7-day&#xD;
      infusion finishes, they will be advised to remain in hospital for a 24 hour period for&#xD;
      monitoring. Subjects will be followed up on Day 30 either via telephone or via medical&#xD;
      records.&#xD;
&#xD;
      . The role of the renin angiotensin system (RAS) in COVID-19 infection has been widely&#xD;
      discussed for two reasons. First, SARS-COV-2, the virus causing COVID-19, invades type II&#xD;
      pneumocytes in the lung by binding to an enzyme called angiotensin converting enzyme 2&#xD;
      (ACE2). As the virus enters the cell, via one of its receptors, ACE2, it is thought that this&#xD;
      is internalised and is hence unable to perform its physiological action of converting&#xD;
      Angiotensin II (AngII) to Ang(1-7). Second, it has been noted that severe COVID-19 infection&#xD;
      has many features which are strikingly similar to the effects of overactivation of the RAS.&#xD;
      Indeed, these features are apparent in preclinical models using AngII infusions and include&#xD;
      lung injury, lung inflammation, myocardial microinfarcts, characteristic glomerular&#xD;
      thrombosis and coagulopathy. The coagulopathy is particularly noteworthy given an early&#xD;
      increase in D-Dimer has very high positive predictor value for death in COVID-19, and D-dimer&#xD;
      concentrations are unusually high in COVID-19, over and above what would be expected for an&#xD;
      acute phase response or a pneumonia caused by a respiratory virus such as influenza.&#xD;
&#xD;
      AngII and Ang(1-7) affect various aspects of the coagulation system including platelets and&#xD;
      endothelial cells, and we therefore hypothesise that overaction of RAS is partly responsible&#xD;
      for the coagulopathy present in COVID-19 infection. Because the over activation of the RAS in&#xD;
      COVID-19 infection is due to both Angiotensin II excess and Ang(1-7) depletion, standard&#xD;
      tools to modulate RAS (angiotensin converting enzyme inhibitors and angiotensin receptor&#xD;
      blockers) cannot be used to test this hypothesis as they address the Angiotensin II excess,&#xD;
      but not the Ang(1-7) depletion. TRV027 is a similar peptide to Ang(1-7) but is a much more&#xD;
      potent biased agonist at AT1R than Ang(1-7) and would be expected to oppose the effects of&#xD;
      AngII accumulation, and functionally correct the Ang(1-7) deficiency. Hence it is an&#xD;
      appropriate tool to examine the link between RAS activation and coagulopathy in the context&#xD;
      of COVID-19 infection.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 9, 2020</start_date>
  <completion_date type="Actual">May 12, 2021</completion_date>
  <primary_completion_date type="Actual">May 12, 2021</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Health Services Research</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Coagulopathy associated with COVID-19</measure>
    <time_frame>Day 1 and Day 8</time_frame>
    <description>Mean change from baseline D-dimer at day 1 to day 3 post randomisation following administration of TRV027 or placebo.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Markers of dysregulation of coagulation system</measure>
    <time_frame>Day 1, 3, 5 and Day 8</time_frame>
    <description>Absolute D-Dimer - (Fibrin Equivalent units)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Markers of dysregulation of coagulation system</measure>
    <time_frame>Day 1, 3, Day 5 and Day 8</time_frame>
    <description>platelet count (E9 /L)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Markers of dysregulation of coagulation system</measure>
    <time_frame>Day 1, 3, Day 5 and Day 8</time_frame>
    <description>aPTT (Activated Partial Thromboplastin time) - seconds</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Markers of dysregulation of coagulation system</measure>
    <time_frame>Day 1, 3, Day 5 and Day 8</time_frame>
    <description>INR - (calculated as a ratio from aPTT)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Markers of dysregulation of coagulation system</measure>
    <time_frame>Day 1, 3, Day 5 and Day 8</time_frame>
    <description>fibrinogen (g/L)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Markers of dysregulation of coagulation system</measure>
    <time_frame>Day 1, 3, Day 5 and Day 8</time_frame>
    <description>Ferritin Ug/mL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Markers of dysregulation of RAS</measure>
    <time_frame>Day 1</time_frame>
    <description>Plasma Renin Mass and activity (nmol/L/h)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Markers of Haemolysis/inflammation</measure>
    <time_frame>Day 1, 3, Day 5 and Day 8</time_frame>
    <description>Total bilirubin (umol/L)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Markers of Haemolysis/Inflammation</measure>
    <time_frame>Day 3, Day 5 and Day 8</time_frame>
    <description>LDH u/L</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Markers of Haemolysis/inflammation</measure>
    <time_frame>Day 1, 3, Day 5 and Day 8</time_frame>
    <description>Haptoglobin g/L</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Markers of Inflammation (bacterial sepsis)</measure>
    <time_frame>day 1, 3, 5 and 8</time_frame>
    <description>Pro-calcitonin ug/L</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Markers of organ dysregulation - kidney</measure>
    <time_frame>Day 1, 3, Day 5 and Day 8</time_frame>
    <description>Creatinine (umol/L)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Markers of dysregulation of cardiovascular system</measure>
    <time_frame>Day 1, 3, Day 5 and Day 8</time_frame>
    <description>BNP (B-type natriuetic Peptide) ng/L</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Markers of dysregulation of cardiovascular system</measure>
    <time_frame>Day 1, 3, Day 5 and Day 8</time_frame>
    <description>Troponin ng/L</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>marker of dysregulation of endocrine system</measure>
    <time_frame>Day 1, 3, Day 5 and Day 8</time_frame>
    <description>glucose mmol/L</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>COVID</condition>
  <arm_group>
    <arm_group_label>Patients with confirmed/suspected C19 given intervention</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Intravenous infusion of either placebo or TRV027 at 12mg/hr. Treatment will continue until discharge or for 7 days (whichever is sooner).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Patients with confirmed/suspected C19 given no intervention</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Saline infusion.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>TRV027</intervention_name>
    <description>peptide for infusion</description>
    <arm_group_label>Patients with confirmed/suspected C19 given intervention</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>sodium chloride 0.9%</intervention_name>
    <description>placebo comparator for infusion</description>
    <arm_group_label>Patients with confirmed/suspected C19 given no intervention</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        INCLUSION CRITERIA&#xD;
&#xD;
        A subject will be eligible for inclusion in this study only if all of the following&#xD;
        criteria apply at the time of screening:&#xD;
&#xD;
          1. Hospitalised with confirmed COVID-19 infection.&#xD;
&#xD;
          2. Screened within 96hrs of SARS-COV-2 positive PCR.&#xD;
&#xD;
          3. Age 18 or over&#xD;
&#xD;
          4. Capable of giving written informed consent, which includes compliance with the&#xD;
             requirements and restrictions listed in the consent form.&#xD;
&#xD;
          5. Systolic blood pressure between 100 and 180&#xD;
&#xD;
        EXCLUSION CRITERIA&#xD;
&#xD;
        A subject will not be eligible for inclusion in this study if any of the following criteria&#xD;
        apply at the time of screening:&#xD;
&#xD;
          1. Any unrelated clinical condition, which, in the opinion of the investigator, may&#xD;
             affect D-dimer during the course of the study, independent of COVID-19 infection, e.g.&#xD;
             subsets of cancers and coagulopathies.&#xD;
&#xD;
          2. Concomitant medication which inhibit the action of TRV027 (ARB's).&#xD;
&#xD;
          3. Any clinically significant medical conditions that in the opinion of the investigator&#xD;
             would compromise subjects' safety or compliance with study procedures.&#xD;
&#xD;
          4. Any clinical condition which in the opinion of the principal investigator would&#xD;
             compromise the scientific integrity of the study&#xD;
&#xD;
          5. Unwillingness or inability to follow the procedures outlined in the protocol.&#xD;
&#xD;
          6. Subject is pregnant or breastfeeding&#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>DAVID OWEN</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Health Service, United Kingdom</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Katrina Pollock</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Health Service, United Kingdom</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Imperial College NHS Trust</name>
      <address>
        <city>London</city>
        <zip>W12 0HS</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>May 2021</verification_date>
  <study_first_submitted>April 16, 2020</study_first_submitted>
  <study_first_submitted_qc>June 4, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 5, 2020</study_first_posted>
  <last_update_submitted>May 25, 2021</last_update_submitted>
  <last_update_submitted_qc>May 25, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">May 27, 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>Hemostatic Disorders</mesh_term>
    <mesh_term>Blood Coagulation Disorders</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>March 12, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/10/NCT04419610/Prot_002.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <pending_results>
    <submitted>September 27, 2022</submitted>
    <returned>August 18, 2023</returned>
  </pending_results>
  <!-- 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/NCT04419610
org study id: 283093
nct id: NCT04419610
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
To determine whether the coagulopathy associated with COVID-19 infection is driven by
      overactivation of the renin angiotensin system (RAS)
The proposed study will be run as a double-blind, randomized controlled experimental medicine
      study in male and female hospitalised (n=60) aged 18 or over, with confirmed COVID-19
      infection. Patients who are admitted due to confirmed COVID-19 infection will be screened
      with a routine medical assessment (see Table 1) and enrolled if they meet the eligibility
      criteria. Subjects will be block randomised based on age to continuous intravenous infusion
      of placebo or TRV027 for 7 days.

      Day 1 procedures can occur on the same day of screening and include a venous blood test prior
      to commencing an intravenous infusion of either placebo or TRV027 at 12mg/hr. The infusions
      will continue for 7 days. Venous blood tests will be repeated at days 3, 5 and 8, amounting
      to approximately 120mLs of blood in total over the 8-day period.

      Once the infusion has finished, the subjects will remain in hospital for a further 24 hours
      for vital signs and adverse event monitoring. If a subject exits the trial before the 7-day
      infusion finishes, they will be advised to remain in hospital for a 24 hour period for
      monitoring. Subjects will be followed up on Day 30 either via telephone or via medical
      records.

      . The role of the renin angiotensin system (RAS) in COVID-19 infection has been widely
      discussed for two reasons. First, SARS-COV-2, the virus causing COVID-19, invades type II
      pneumocytes in the lung by binding to an enzyme called angiotensin converting enzyme 2
      (ACE2). As the virus enters the cell, via one of its receptors, ACE2, it is thought that this
      is internalised and is hence unable to perform its physiological action of converting
      Angiotensin II (AngII) to Ang(1-7). Second, it has been noted that severe COVID-19 infection
      has many features which are strikingly similar to the effects of overactivation of the RAS.
      Indeed, these features are apparent in preclinical models using AngII infusions and include
      lung injury, lung inflammation, myocardial microinfarcts, characteristic glomerular
      thrombosis and coagulopathy. The coagulopathy is particularly noteworthy given an early
      increase in D-Dimer has very high positive predictor value for death in COVID-19, and D-dimer
      concentrations are unusually high in COVID-19, over and above what would be expected for an
      acute phase response or a pneumonia caused by a respiratory virus such as influenza.

      AngII and Ang(1-7) affect various aspects of the coagulation system including platelets and
      endothelial cells, and we therefore hypothesise that overaction of RAS is partly responsible
      for the coagulopathy present in COVID-19 infection. Because the over activation of the RAS in
      COVID-19 infection is due to both Angiotensin II excess and Ang(1-7) depletion, standard
      tools to modulate RAS (angiotensin converting enzyme inhibitors and angiotensin receptor
      blockers) cannot be used to test this hypothesis as they address the Angiotensin II excess,
      but not the Ang(1-7) depletion. TRV027 is a similar peptide to Ang(1-7) but is a much more
      potent biased agonist at AT1R than Ang(1-7) and would be expected to oppose the effects of
      AngII accumulation, and functionally correct the Ang(1-7) deficiency. Hence it is an
      appropriate tool to examine the link between RAS activation and coagulopathy in the context
      of COVID-19 infection.
allocation: Randomized
intervention model: Single Group Assignment
primary purpose: Health Services Research
masking: Double (Participant, Investigator)
measure: Coagulopathy associated with COVID-19
time frame: Day 1 and Day 8
description: Mean change from baseline D-dimer at day 1 to day 3 post randomisation following administration of TRV027 or placebo.
measure: Markers of dysregulation of coagulation system
time frame: Day 1, 3, 5 and Day 8
description: Absolute D-Dimer - (Fibrin Equivalent units)
measure: Markers of dysregulation of coagulation system
time frame: Day 1, 3, Day 5 and Day 8
description: platelet count (E9 /L)
measure: Markers of dysregulation of coagulation system
time frame: Day 1, 3, Day 5 and Day 8
description: aPTT (Activated Partial Thromboplastin time) - seconds
measure: Markers of dysregulation of coagulation system
time frame: Day 1, 3, Day 5 and Day 8
description: INR - (calculated as a ratio from aPTT)
measure: Markers of dysregulation of coagulation system
time frame: Day 1, 3, Day 5 and Day 8
description: fibrinogen (g/L)
measure: Markers of dysregulation of coagulation system
time frame: Day 1, 3, Day 5 and Day 8
description: Ferritin Ug/mL
measure: Markers of dysregulation of RAS
time frame: Day 1
description: Plasma Renin Mass and activity (nmol/L/h)
measure: Markers of Haemolysis/inflammation
time frame: Day 1, 3, Day 5 and Day 8
description: Total bilirubin (umol/L)
measure: Markers of Haemolysis/Inflammation
time frame: Day 3, Day 5 and Day 8
description: LDH u/L
measure: Markers of Haemolysis/inflammation
time frame: Day 1, 3, Day 5 and Day 8
description: Haptoglobin g/L
measure: Markers of Inflammation (bacterial sepsis)
time frame: day 1, 3, 5 and 8
description: Pro-calcitonin ug/L
measure: Markers of organ dysregulation - kidney
time frame: Day 1, 3, Day 5 and Day 8
description: Creatinine (umol/L)
measure: Markers of dysregulation of cardiovascular system
time frame: Day 1, 3, Day 5 and Day 8
description: BNP (B-type natriuetic Peptide) ng/L
measure: Markers of dysregulation of cardiovascular system
time frame: Day 1, 3, Day 5 and Day 8
description: Troponin ng/L
measure: marker of dysregulation of endocrine system
time frame: Day 1, 3, Day 5 and Day 8
description: glucose mmol/L
arm group label: Patients with confirmed/suspected C19 given intervention
arm group type: Experimental
description: Intravenous infusion of either placebo or TRV027 at 12mg/hr. Treatment will continue until discharge or for 7 days (whichever is sooner).
arm group label: Patients with confirmed/suspected C19 given no intervention
arm group type: Placebo Comparator
description: Saline infusion.
intervention type: Biological
intervention name: TRV027
description: peptide for infusion
arm group label: Patients with confirmed/suspected C19 given intervention
intervention type: Other
intervention name: sodium chloride 0.9%
description: placebo comparator for infusion
arm group label: Patients with confirmed/suspected C19 given no intervention
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: DAVID OWEN
role: Principal Investigator
affiliation: National Health Service, United Kingdom
last name: Katrina Pollock
role: Principal Investigator
affiliation: National Health Service, United Kingdom
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Hemostatic Disorders
mesh term: Blood Coagulation Disorders
sharing ipd: No
provided document: 
submitted: September 27, 2022
returned: August 18, 2023