<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/NCT04466670</url>
  </required_header>
  <id_info>
    <org_study_id>33788820.9.0000.0068</org_study_id>
    <nct_id>NCT04466670</nct_id>
  </id_info>
  <brief_title>Hemostasis in COVID-19: an Adaptive Clinical Trial</brief_title>
  <official_title>Dynamics of Hemostatic Parameters in COVID-19 and Comparison of Intervention Strategies Through Adaptive Clinical Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Sao Paulo General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Sao Paulo General Hospital</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>
      Hypercoagulability has been demonstrated in COVID-19, leading to respiratory distress and&#xD;
      increased mortality. This is an adaptive clinical trial to compare the efficacy and safety of&#xD;
      two experimental strategies in patients with COVID-19: ASA or inhaled UFH associated with&#xD;
      standard VTE prophylaxis.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">July 11, 2020</start_date>
  <completion_date type="Anticipated">May 30, 2022</completion_date>
  <primary_completion_date type="Anticipated">December 30, 2021</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Hospital discharge - alive / death</measure>
    <time_frame>30 days</time_frame>
    <description>Number of COVID-19 positive patients who are alive within 30 days of symptoms onset</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Length of mechanical ventilation free days</measure>
    <time_frame>30 days</time_frame>
    <description>Comparison of length of mechanical ventilation free days between each treatment arm</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of renal replacement therapy free days</measure>
    <time_frame>30 days</time_frame>
    <description>Comparison of length of renal replacement therapy free days between each treatment arm</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of documented venous thromboembolism or arterial thrombosis</measure>
    <time_frame>3 months</time_frame>
    <description>Comparison of number of thrombosis events between each treatment arm.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">379</enrollment>
  <condition>COVID-19</condition>
  <arm_group>
    <arm_group_label>phase 1</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Observational arm</description>
  </arm_group>
  <arm_group>
    <arm_group_label>phase 2A</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Acetylsalicylic acid</description>
  </arm_group>
  <arm_group>
    <arm_group_label>phase 2B</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>inhaled unfractionated heparin</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo arm for Phase 2A</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>acetylsalicylic acid</intervention_name>
    <description>acetylsalicylic acid (ASA) 100 mg daily PO up to 14 days OR arterial oxygen saturation greater than or equal to 92% on room air OR PaO2 to FiO2 ratio greater than 200 for 2 consecutive days, whichever is first.</description>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_label>phase 2A</arm_group_label>
    <other_name>aspirin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Unfractionated heparin nebulized</intervention_name>
    <description>unfractionated heparin - 25,000 U/ 5 ml nebulized inhalation every 6 hours up to 14 days OR arterial oxygen saturation greater than or equal to 92% on room air OR PaO2 to FiO2 ratio greater than 200 for 2 consecutive days, whichever is first.</description>
    <arm_group_label>phase 2B</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adult ≥18 years of age at time of enrollment&#xD;
&#xD;
          -  Subjects with a positive COVID-19 diagnosis by RT-PCR or serologic testing&#xD;
&#xD;
          -  Subject (or legally authorized representative) must be willing, understanding and able&#xD;
             to provide written informed consent.&#xD;
&#xD;
          -  Only at phase 2:&#xD;
&#xD;
               -  onset of symptoms must not exceed 4 weeks&#xD;
&#xD;
               -  ICU patients&#xD;
&#xD;
               -  PaO2 to FiO2 ratio &lt; 200&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. General&#xD;
&#xD;
               -  Indications for therapeutic anticoagulation&#xD;
&#xD;
               -  History of chronic lung disease oxygen dependent&#xD;
&#xD;
               -  Pregnancy&#xD;
&#xD;
               -  Death considered imminent and inevitable within 24 hours&#xD;
&#xD;
               -  Patients under exclusive palliative care&#xD;
&#xD;
               -  Participation in another trial of investigational drug&#xD;
&#xD;
               -  Body weight &lt; 40 Kg&#xD;
&#xD;
               -  Total bilirubin &gt; 20 mg/dL&#xD;
&#xD;
               -  Severe active bleeding&#xD;
&#xD;
               -  Persistent GI bleeding&#xD;
&#xD;
               -  Known allergy to UFH or LMWH&#xD;
&#xD;
               -  History of heparin-induced thrombocytopenia (HIT) within the past 6 months&#xD;
&#xD;
          2. Exclusion criteria at phase 1&#xD;
&#xD;
               -  Platelet count &lt; 25,000/mm3&#xD;
&#xD;
               -  Bacterial endocarditis&#xD;
&#xD;
          3. Exclusion criteria at phase 2&#xD;
&#xD;
               -  Platelet count &lt; 50,000/mm3&#xD;
&#xD;
               -  History of surgery in the last 30 days&#xD;
&#xD;
               -  Intervention A: allergy to ASA and long-term use of antiplatelet drug&#xD;
&#xD;
               -  Intervention B: inhaled nitric oxide use&#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>Vanderson Rocha</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Sao Paulo General Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Vanderson Rocha</name>
      <address>
        <city>Sao Paulo</city>
        <zip>05403-000</zip>
        <country>Brazil</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Vanderson Rocha, MD.PhD</last_name>
      <phone>+55-11-26617575</phone>
      <email>vanderson.rocha@hc.fm.usp.br</email>
    </contact>
    <contact_backup>
      <last_name>Yeh-Li Ho, MD.PhD</last_name>
      <phone>+55-11-26616045</phone>
      <email>ho.yeh@hc.fm.usp.br</email>
    </contact_backup>
    <investigator>
      <last_name>Yeh-Li Ho, MD.PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Elbio A D'Amico, MD.PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Paula R Villaca, MD.PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Cynthia Rotschild, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Erica Okazaki, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Tania RF Rocha, MPharm</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Giancarlo Fatobene, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Brazil</country>
  </location_countries>
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  <results_reference>
    <citation>Dixon B, Schultz MJ, Smith R, Fink JB, Santamaria JD, Campbell DJ. Nebulized heparin is associated with fewer days of mechanical ventilation in critically ill patients: a randomized controlled trial. Crit Care. 2010;14(5):R180. doi: 10.1186/cc9286. Epub 2010 Oct 11.</citation>
    <PMID>20937093</PMID>
  </results_reference>
  <results_reference>
    <citation>Viecca M, Radovanovic D, Forleo GB, Santus P. Enhanced platelet inhibition treatment improves hypoxemia in patients with severe Covid-19 and hypercoagulability. A case control, proof of concept study. Pharmacol Res. 2020 Aug;158:104950. doi: 10.1016/j.phrs.2020.104950. Epub 2020 May 23.</citation>
    <PMID>32450344</PMID>
  </results_reference>
  <results_reference>
    <citation>Connor JT, Elm JJ, Broglio KR; ESETT and ADAPT-IT Investigators. Bayesian adaptive trials offer advantages in comparative effectiveness trials: an example in status epilepticus. J Clin Epidemiol. 2013 Aug;66(8 Suppl):S130-7. doi: 10.1016/j.jclinepi.2013.02.015.</citation>
    <PMID>23849147</PMID>
  </results_reference>
  <results_reference>
    <citation>Gsponer T, Gerber F, Bornkamp B, Ohlssen D, Vandemeulebroecke M, Schmidli H. A practical guide to Bayesian group sequential designs. Pharm Stat. 2014 Jan-Feb;13(1):71-80. doi: 10.1002/pst.1593. Epub 2013 Aug 24.</citation>
    <PMID>24038922</PMID>
  </results_reference>
  <verification_date>June 2021</verification_date>
  <study_first_submitted>July 8, 2020</study_first_submitted>
  <study_first_submitted_qc>July 8, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 10, 2020</study_first_posted>
  <last_update_submitted>June 4, 2021</last_update_submitted>
  <last_update_submitted_qc>June 4, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">June 9, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Sao Paulo General Hospital</investigator_affiliation>
    <investigator_full_name>Vanderson Geraldo Rocha</investigator_full_name>
    <investigator_title>Full professor</investigator_title>
  </responsible_party>
  <keyword>SARS-CoV-2</keyword>
  <keyword>Thrombosis</keyword>
  <keyword>Coagulopathy</keyword>
  <keyword>Anticoagulation</keyword>
  <keyword>Respiratory failure</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>Aspirin</mesh_term>
    <mesh_term>Heparin</mesh_term>
    <mesh_term>Calcium heparin</mesh_term>
  </intervention_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/NCT04466670
org study id: 33788820.9.0000.0068
nct id: NCT04466670
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Hypercoagulability has been demonstrated in COVID-19, leading to respiratory distress and
      increased mortality. This is an adaptive clinical trial to compare the efficacy and safety of
      two experimental strategies in patients with COVID-19: ASA or inhaled UFH associated with
      standard VTE prophylaxis.
allocation: Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Hospital discharge - alive / death
time frame: 30 days
description: Number of COVID-19 positive patients who are alive within 30 days of symptoms onset
measure: Length of mechanical ventilation free days
time frame: 30 days
description: Comparison of length of mechanical ventilation free days between each treatment arm
measure: Length of renal replacement therapy free days
time frame: 30 days
description: Comparison of length of renal replacement therapy free days between each treatment arm
measure: Number of documented venous thromboembolism or arterial thrombosis
time frame: 3 months
description: Comparison of number of thrombosis events between each treatment arm.
arm group label: phase 1
arm group type: No Intervention
description: Observational arm
arm group label: phase 2A
arm group type: Experimental
description: Acetylsalicylic acid
arm group label: phase 2B
arm group type: Experimental
description: inhaled unfractionated heparin
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo arm for Phase 2A
intervention type: Drug
intervention name: acetylsalicylic acid
description: acetylsalicylic acid (ASA) 100 mg daily PO up to 14 days OR arterial oxygen saturation greater than or equal to 92% on room air OR PaO2 to FiO2 ratio greater than 200 for 2 consecutive days, whichever is first.
arm group label: Placebo
arm group label: phase 2A
other name: aspirin
intervention type: Drug
intervention name: Unfractionated heparin nebulized
description: unfractionated heparin - 25,000 U/ 5 ml nebulized inhalation every 6 hours up to 14 days OR arterial oxygen saturation greater than or equal to 92% on room air OR PaO2 to FiO2 ratio greater than 200 for 2 consecutive days, whichever is first.
arm group label: phase 2B
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Vanderson Rocha
role: Principal Investigator
affiliation: University of Sao Paulo General Hospital
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
country: Brazil
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PMID: 20937093
citation: Viecca M, Radovanovic D, Forleo GB, Santus P. Enhanced platelet inhibition treatment improves hypoxemia in patients with severe Covid-19 and hypercoagulability. A case control, proof of concept study. Pharmacol Res. 2020 Aug;158:104950. doi: 10.1016/j.phrs.2020.104950. Epub 2020 May 23.
PMID: 32450344
citation: Connor JT, Elm JJ, Broglio KR; ESETT and ADAPT-IT Investigators. Bayesian adaptive trials offer advantages in comparative effectiveness trials: an example in status epilepticus. J Clin Epidemiol. 2013 Aug;66(8 Suppl):S130-7. doi: 10.1016/j.jclinepi.2013.02.015.
PMID: 23849147
citation: Gsponer T, Gerber F, Bornkamp B, Ohlssen D, Vandemeulebroecke M, Schmidli H. A practical guide to Bayesian group sequential designs. Pharm Stat. 2014 Jan-Feb;13(1):71-80. doi: 10.1002/pst.1593. Epub 2013 Aug 24.
PMID: 24038922
responsible party type: Principal Investigator
investigator affiliation: University of Sao Paulo General Hospital
investigator full name: Vanderson Geraldo Rocha
investigator title: Full professor
mesh term: COVID-19
mesh term: Aspirin
mesh term: Heparin
mesh term: Calcium heparin