<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/NCT04505774</url>
  </required_header>
  <id_info>
    <org_study_id>ACTIV-4 ACUTE</org_study_id>
    <secondary_id>1OT2HL156812-01</secondary_id>
    <nct_id>NCT04505774</nct_id>
    <nct_alias>NCT04359277</nct_alias>
  </id_info>
  <brief_title>Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE</brief_title>
  <acronym>ACTIV-4A</acronym>
  <official_title>A Multicenter, Adaptive, Randomized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic and Additional Strategies in Hospitalized Adults With COVID-19</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Matthew Neal MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Heart, Lung, and Blood Institute (NHLBI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Pittsburgh</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a randomized, open label, adaptive platform trial to compare the effectiveness of&#xD;
      antithrombotic and additional strategies for prevention of adverse outcomes in COVID-19&#xD;
      positive inpatients&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The severe acute respiratory syndrome coronavirus 2, which causes the highly contagious&#xD;
      coronavirus disease 2019 (COVID-19), has resulted in a global pandemic.&#xD;
&#xD;
      The clinical spectrum of COVID-19 infection is broad, encompassing asymptomatic infection,&#xD;
      mild upper respiratory tract illness, and severe viral pneumonia with respiratory failure and&#xD;
      death. The risk of thrombotic complications is increased, even as compared to other viral&#xD;
      respiratory illnesses, such as influenza. A pro-inflammatory cytokine response as well as&#xD;
      induction of procoagulant factors associated with COVID-19 has been proposed to contribute to&#xD;
      thrombosis as well as plaque rupture through local inflammation. Patients with COVID-19 are&#xD;
      at increased risk for arterial and vein thromboembolism, with high rates observed despite&#xD;
      thromboprophylaxis. Autopsy reports have noted micro and macro vascular thrombosis across&#xD;
      multiple organ beds consistent with an early hypercoagulable state.&#xD;
&#xD;
      Notably, in COVID-19, data in the U.K. and U.S. document that infection and outcomes of&#xD;
      infection are worse in African and Hispanic descent persons than in other groups. The reasons&#xD;
      for this are uncertain.&#xD;
&#xD;
      Viral Infection and Thrombosis A large body of literature links inflammation and coagulation;&#xD;
      altered hemostasis is a known complication of respiratory viral infections. Procoagulant&#xD;
      markers are severely elevated in viral infections. Specifically, proinflammatory cytokines in&#xD;
      viral infections upregulate expression of tissue factor, markers of thrombin generation,&#xD;
      platelet activation, and down-regulate natural anticoagulant proteins C and S.&#xD;
&#xD;
      Studies have demonstrated significant risk of deep venous thrombosis (DVT), pulmonary&#xD;
      embolism (PE), and myocardial infarction (MI) associated with viral respiratory infections.&#xD;
      In a series of patients with fatal influenza H1N1, 75% had pulmonary thrombi on autopsy (a&#xD;
      rate considerably higher than reported on autopsy studies among the general intensive care&#xD;
      unit population). Incidence ratio for acute myocardial infarction in the context of Influenza&#xD;
      A is over 10. Severe acute respiratory syndrome coronavirus-1 (SARS CoV-1) and influenza have&#xD;
      been associated with disseminated intravascular coagulation (DIC), endothelial damage, DVT,&#xD;
      PE, and large artery ischemic stroke. Patients with Influenza H1N1 and acute respiratory&#xD;
      distress syndrome (ARDS) had a 23.3-fold higher risk for pulmonary embolism, and a 17.9-fold&#xD;
      increased risk for deep vein thrombosis. Compared to those treated with systemic&#xD;
      anticoagulation, those without treatment were 33 times more likely to suffer a VTE.&#xD;
&#xD;
      Thrombosis, both microvascular and macrovascular, is a prominent feature in multiple organs&#xD;
      at autopsy in fatal cases of COVID-19. Thrombosis may thus contribute to respiratory failure,&#xD;
      renal failure, and hepatic injury in COVID-19. The number of megakaryocytes in tissues is&#xD;
      higher than in other forms of ARDS, and thrombi are platelet-rich based on specific staining.&#xD;
      Thrombotic stroke has been reported in young COVID-19 patients with no cardiovascular risk&#xD;
      factors. Both arterial and venous thrombotic events have been seen in increasing numbers of&#xD;
      hospitalized patients infected with COVID-19. The incidence of thrombosis has ranged from 10&#xD;
      to 30% in hospitalized patients; however, this varies by type of thrombosis captured&#xD;
      (arterial or vein) and severity of illness (ICU level care, requiring mechanical ventilation,&#xD;
      etc.).&#xD;
&#xD;
      Additional treatment strategies Data from the multiplatform randomized controlled trial&#xD;
      (mpRCT) demonstrated that (1) therapeutic dose anticoagulation with heparin was not&#xD;
      beneficial in improving clinical outcomes compared to standard of care prophylactic dose&#xD;
      heparin in severely ill (ICU level of care) patients, and (2) therapeutic dose&#xD;
      anticoagulation with heparin was beneficial in improving organ support free days compared to&#xD;
      standard of care prophylactic dose heparin in moderately ill (hospitalized and not requiring&#xD;
      organ support) patients. However, there remains significant residual risk for adverse&#xD;
      clinical outcomes and excess mortality for severely ill as well as moderately ill patients.&#xD;
&#xD;
      Antithrombotic regimens that are shown to be efficacious will be combined in clinical&#xD;
      practice with other agents to treat COVID-19 hospitalized patients. This adaptive platform&#xD;
      trial will test other promising agents when added to proven therapies, such as heparin. The&#xD;
      rationale and risks for each agent will be included in the arm-specific appendix. Two&#xD;
      specific agents to be added as arms, effective October 2021, include the P-selectin&#xD;
      inhibitor, Crizanlizumab as well as SGLT2 inhibitors. P-selectin may play a proximal role in&#xD;
      the inflammatory and thrombotic cascade in patients with COVID-19 and P-selectin inhibition&#xD;
      may be a effective in preventing downstream sequelae. In addition, SGLT-2 inhibitors have&#xD;
      been shown to decrease capillary leak and may promote vascular integrity in COVID-19.&#xD;
&#xD;
      This platform trial will have multiple arms, which may be dropped or added as the platform&#xD;
      trial progresses. Sample size will be flexible: the trial will be stopped for efficacy or&#xD;
      futility based on pre-determined statistical thresholds as defined in the arm-specific&#xD;
      appendices. Each arm will have an adaptive component for determinations of futility or&#xD;
      success.&#xD;
&#xD;
      Randomization assignments are at the participant level, stratified by enrolling site and by&#xD;
      ICU level of care vs non-ICU level of care and/or other arm-specific criteria.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">September 4, 2020</start_date>
  <completion_date type="Anticipated">November 2023</completion_date>
  <primary_completion_date type="Anticipated">August 31, 2023</primary_completion_date>
  <phase>Phase 4</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>
    <intervention_model_description>This is an adaptive design</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>There will be independent masked adjudicators.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>21 Day Organ Support (respiratory or vasopressor) Free Days</measure>
    <time_frame>21 days from study enrollment</time_frame>
    <description>which is defined as the number of days that a patient is alive and free of organ support through the first 21 days after trial entry. Organ Support is defined as receipt of non-invasive mechanical ventilation, high flow nasal canula oxygen, mechanical ventilation, or vasopressor therapy, with death at any time during the index hospitalization assigned -1 days.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Secondary Endpoint all cause mortality</measure>
    <time_frame>28 days from study enrollment</time_frame>
    <description>Categorization of the primary endpoint into a three-level ordinal outcome (Death, invasive mechanical ventilation without death, neither invasive mechanical ventilation nor death)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Other Platform Secondary Endpoints of Morbidity and Hospitalization</measure>
    <time_frame>28 days from study enrollment</time_frame>
    <description>Categorization of the primary endpoint into a three-level ordinal outcome (Death, organ support (any respiratory or cardiovascular) without death, neither organ support nor death) (for moderate illness severity at enrollment)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Days free of death</measure>
    <time_frame>28 days from enrollment</time_frame>
    <description>Days free of death and respiratory and cardiovascular organ support and renal replacement therapy (RRT) during Index Hospitalization through Day 28.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Death Composite</measure>
    <time_frame>28 days from enrollment</time_frame>
    <description>Composite endpoint of death, pulmonary embolism, systemic arterial thromboembolism, myocardial infarction, or ischemic stroke at hospital discharge or 28 days, whichever occurs first.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Acute kidney injury</measure>
    <time_frame>90 days from enrollment</time_frame>
    <description>Individual endpoints comprising the primary and secondary endpoint components; death during hospitalization, WHO clinical scale and 90 day mortality</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Primary Safety Endpoint of Major Bleeding</measure>
    <time_frame>28 days from study enrollment</time_frame>
    <description>Major bleeding (as defined by the ISTH)</description>
  </other_outcome>
  <other_outcome>
    <measure>Secondary Safety Endpoint of HIT</measure>
    <time_frame>28 days from study enrollment</time_frame>
    <description>Confirmed heparin induced thrombocytopenia (HIT)</description>
  </other_outcome>
  <number_of_arms>6</number_of_arms>
  <enrollment type="Actual">880</enrollment>
  <condition>Covid19</condition>
  <arm_group>
    <arm_group_label>Therapeutic Dose Anticoagulation</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>increased dose of heparin above standard of care.&#xD;
1.0 - This arm was stopped in severe patients in December 2020 and results are published in PMID: 34351722 (NEJM, August, 2021) (see reference section for citation). This arm was stopped for moderate patients in January 2021.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Prophylactic Dose Anticoagulation</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Heparin standard of care&#xD;
1.0 - this arm was stopped for all patients in January, 2021 and results are published in PMID: 34351721 (NEJM, August, 2021) (see reference section for citation)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Therapeutic Dose Anticoagulation + P2Y12 inhibitor</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>increased dose of heparin above standard of care with an added P2Y12 inhibitor&#xD;
This Arm enrolled moderate illness patients only. Enrollment of moderate illness patients in the trial was ended per DSMB on June 19, 2021 and results are published in PMID: PMID: 35040887 (JAMA, January, 2022) (see reference section for citation)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Prophylactic Dose Anticoagulation + P2Y12 inhibitor</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Heparin standard of care with an added P2Y12 inhibitor&#xD;
This Arm enrolled severe illness patients only. Enrollment of severe illness patients in the trial was ended per DSMB in June 2022.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard of Care + Crizanlizumab</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Standard of care plus crizanlizumab infusion&#xD;
This arm will enroll moderate and severe illness patients&#xD;
This arm was ended for all patients per the DSMB in September 2022.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard of Care + SGLT2 inhibitor</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Standard of care plus SGLT2 inhibitor&#xD;
This arm will enroll moderate and severe illness patients&#xD;
This arm was ended in March 2023</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>theraputic heparin</intervention_name>
    <description>increased dose of heparin above standard of care.</description>
    <arm_group_label>Therapeutic Dose Anticoagulation</arm_group_label>
    <arm_group_label>Therapeutic Dose Anticoagulation + P2Y12 inhibitor</arm_group_label>
    <other_name>unfractionated heparin</other_name>
    <other_name>Enoxaparin</other_name>
    <other_name>Dalteparin</other_name>
    <other_name>Tinzaparin</other_name>
    <other_name>Heparin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>prophylactic heparin</intervention_name>
    <description>standard of care dose of heparin</description>
    <arm_group_label>Prophylactic Dose Anticoagulation</arm_group_label>
    <arm_group_label>Prophylactic Dose Anticoagulation + P2Y12 inhibitor</arm_group_label>
    <other_name>enoxaparin</other_name>
    <other_name>dalteparin</other_name>
    <other_name>Tinzaparin</other_name>
    <other_name>Fondparinux</other_name>
    <other_name>Heparin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>P2Y12</intervention_name>
    <description>added P2Y12 inhibitor</description>
    <arm_group_label>Prophylactic Dose Anticoagulation + P2Y12 inhibitor</arm_group_label>
    <arm_group_label>Therapeutic Dose Anticoagulation + P2Y12 inhibitor</arm_group_label>
    <other_name>Ticagrelor</other_name>
    <other_name>Prasugrel</other_name>
    <other_name>Clopidogrel</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Crizanlizumab Injection</intervention_name>
    <description>crizanlizumab injection</description>
    <arm_group_label>Standard of Care + Crizanlizumab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>SGLT2 inhibitor</intervention_name>
    <description>sglt2 inhibitor</description>
    <arm_group_label>Standard of Care + SGLT2 inhibitor</arm_group_label>
    <other_name>dapagliflozin</other_name>
    <other_name>empagliflozin</other_name>
    <other_name>canagliflozin</other_name>
    <other_name>ertugliflozin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  ≥ 18 years of age&#xD;
&#xD;
          -  Hospitalized for COVID-19&#xD;
&#xD;
          -  Enrolled within 72 hours of hospital admittance or 72 hours of positive COVID test&#xD;
&#xD;
          -  Expected to require hospitalization for &gt; 72 hours&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Imminent death&#xD;
&#xD;
          -  Requirement for chronic mechanical ventilation via tracheostomy prior to&#xD;
             hospitalization&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
        Inclusion Criteria for Arm E&#xD;
&#xD;
        Inclusion criteria contained in the master protocol in addition to the following:&#xD;
&#xD;
        Moderate illness severity - defined as non-ICU level of care at the time of randomization&#xD;
        (not receiving high flow nasal oxygen (HFNO), non-invasive ventilation (NIV), invasive&#xD;
        ventilation (IV), vasopressors or inotropes, or extracorporeal membrane oxygenation (ECMO)&#xD;
        OR Severe illness severity - defined as ICU level of care at the time of randomization&#xD;
        (receiving HFNO, NIV, IV, vasopressors or inotropes, or ECMO)&#xD;
&#xD;
        For moderate illness severity, participants are required to meet one or more of the&#xD;
        following risk criteria:&#xD;
&#xD;
          1. Age ≥ 65 years or&#xD;
&#xD;
          2. ≥2 of the following -&#xD;
&#xD;
               -  O2 supplementation &gt; 2 liters per minute&#xD;
&#xD;
               -  BMI ≥ 35&#xD;
&#xD;
               -  GFR ≤ 60&#xD;
&#xD;
               -  History of Type 2 diabetes&#xD;
&#xD;
               -  History of heart failure (regardless of ejection fraction)&#xD;
&#xD;
               -  D dimer ≥ 2x the site's upper limit of normal (ULN)&#xD;
&#xD;
               -  Troponin ≥ 2x the site's ULN&#xD;
&#xD;
               -  BNP≥100 pg/mL or NT-proBNP≥300 pg/mL&#xD;
&#xD;
               -  CRP ≥50 mg/L&#xD;
&#xD;
        Exclusion Criteria for Arm E&#xD;
&#xD;
          -  Exclusion criteria contained in the master protocol, and&#xD;
&#xD;
          -  Any condition that, in the opinion of the investigator, precludes the use of&#xD;
             crizanlizumab such as uncontrolled bleeding or severe anemia (hemoglobin&lt;4 g/dL)&#xD;
&#xD;
          -  Open label treatment with crizanlizumab within the past three months&#xD;
&#xD;
        Inclusion Criteria for Arm F&#xD;
&#xD;
        Inclusion criteria contained in the master protocol in addition to the following:&#xD;
&#xD;
        Moderate illness severity - defined as non-ICU level of care at the time of randomization&#xD;
        (not receiving high flow nasal oxygen (HFNO), non-invasive ventilation (NIV), invasive&#xD;
        ventilation (IV), vasopressors or inotropes, or extracorporeal membrane oxygenation (ECMO))&#xD;
        OR Severe illness severity - defined as ICU level of care at the time of randomization&#xD;
        (receiving HFNO, NIV, IV, vasopressors or inotropes, or ECMO)&#xD;
&#xD;
        For moderate illness severity, participants are required to meet one or more of the&#xD;
        following risk criteria:&#xD;
&#xD;
          1. Age ≥ 65 years or&#xD;
&#xD;
          2. ≥2 of the following-&#xD;
&#xD;
               -  O2 supplementation &gt; 2 liters per minute&#xD;
&#xD;
               -  BMI ≥ 35&#xD;
&#xD;
               -  GFR ≤ 60&#xD;
&#xD;
               -  History of Type 2 diabetes&#xD;
&#xD;
               -  History of heart failure (regardless of ejection fraction)&#xD;
&#xD;
               -  D dimer ≥ 2x the site's upper limit of normal (ULN)&#xD;
&#xD;
               -  Troponin ≥ 2x the site's ULN&#xD;
&#xD;
               -  BNP≥100 pg/mL or NT-proBNP≥300 pg/mL&#xD;
&#xD;
               -  CRP ≥50 mg/L&#xD;
&#xD;
        Exclusion Criteria for Arm F&#xD;
&#xD;
        In addition to the exclusion criteria noted in the master protocol, arm-specific exclusion&#xD;
        criteria are as follows:&#xD;
&#xD;
          -  Known hypersensitivity to any SGLT2 inhibitors&#xD;
&#xD;
          -  Type 1 diabetes&#xD;
&#xD;
          -  History of diabetic ketoacidosis&#xD;
&#xD;
          -  eGFR &lt;20 and/or requirement for renal replacement therapy&#xD;
&#xD;
          -  Open label treatment with any SGLT2 inhibitor&#xD;
&#xD;
               -  Based on a recommendation from the ACTIV4 DSMB on December 19, 2020, enrollment&#xD;
                  of patients requiring ICU level of care into the therapeutic anti-coagulation arm&#xD;
                  was stopped due to meeting a futility threshold and a potential for harm for this&#xD;
                  sub-group could not be excluded. Enrollment continues for moderately ill&#xD;
                  hospitalized COVID-19 patients.&#xD;
&#xD;
               -  Based on a recommendation from the ACTIV4 DSMB on June 18, 2021, enrollment of&#xD;
                  patients not requiring ICU level of care and randomized to P2Y12 or standard care&#xD;
                  was stopped due to meeting a futility threshold. Enrollment continues for&#xD;
                  severely ill (ICU level of care) hospitalized COVID-19 patients.&#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>Judith Hochman, MD</last_name>
    <role>Study Chair</role>
    <affiliation>New York University Grossman School of Medicine</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Scott Solomon, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Brigham and Women's Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Mikhail Kosiborod, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Saint Lukes</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Jeffrey Berger, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>New York University Grossman School of Medicine</affiliation>
  </overall_official>
  <overall_official>
    <last_name>MATTHEW D NEAL, MD</last_name>
    <role>Study Chair</role>
    <affiliation>University of Pittsburgh</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Alabama</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35233</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Arizona</name>
      <address>
        <city>Tucson</city>
        <state>Arizona</state>
        <zip>85719</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Arkansas for Medical Sciences</name>
      <address>
        <city>Little Rock</city>
        <state>Arkansas</state>
        <zip>72205</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kaiser Permanente Fontana</name>
      <address>
        <city>Fontana</city>
        <state>California</state>
        <zip>92335</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kaiser Permanente Los Angeles</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90027</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Smidt Heart Institute at Cedars-Sinai</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90048</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ronald Reagan UCLA Medical Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90095</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UC San Diego Hillcrest</name>
      <address>
        <city>San Diego</city>
        <state>California</state>
        <zip>92103</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Zuckerberg San Francisco General Hospital</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UCSF San Francisco</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94143</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Zuckerberg San Francisco General Hospital</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94410</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stanford University Medical Center</name>
      <address>
        <city>Stanford</city>
        <state>California</state>
        <zip>94305</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center</name>
      <address>
        <city>Torrance</city>
        <state>California</state>
        <zip>90502</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Denver Health and Hospital Authority</name>
      <address>
        <city>Denver</city>
        <state>Colorado</state>
        <zip>80401</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Mary's Hospital &amp; Regional Medical Center</name>
      <address>
        <city>Grand Junction</city>
        <state>Colorado</state>
        <zip>81501</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saint Francis Hospital and Medical Center</name>
      <address>
        <city>Hartford</city>
        <state>Connecticut</state>
        <zip>06105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Florida</name>
      <address>
        <city>Gainesville</city>
        <state>Florida</state>
        <zip>32608</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Hospital</name>
      <address>
        <city>Jacksonville</city>
        <state>Florida</state>
        <zip>32216</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AdventHealth Tampa</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33613</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Emory</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30308</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Morehouse School of Medicine</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30310</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Queens Medical Center</name>
      <address>
        <city>Honolulu</city>
        <state>Hawaii</state>
        <zip>96813</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Hospital</name>
      <address>
        <city>Belleville</city>
        <state>Illinois</state>
        <zip>62226</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cook County Health</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Illinois at Chicago Health (UIH)</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>OSF Little Company of Mary Medical Center (OSF LCM)</name>
      <address>
        <city>Evergreen Park</city>
        <state>Illinois</state>
        <zip>60805</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Indiana University Health Methodist Hospital</name>
      <address>
        <city>Indianapolis</city>
        <state>Iowa</state>
        <zip>46202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kansas University Medical Center</name>
      <address>
        <city>Kansas City</city>
        <state>Kansas</state>
        <zip>66160</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ochsner Clinic Foundation</name>
      <address>
        <city>New Orleans</city>
        <state>Louisiana</state>
        <zip>70121</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Boston University</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02118</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St Elizabeth's Medical Center</name>
      <address>
        <city>Brighton</city>
        <state>Massachusetts</state>
        <zip>02135</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Baystate Medical Center</name>
      <address>
        <city>Springfield</city>
        <state>Massachusetts</state>
        <zip>01199</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Massachusetts</name>
      <address>
        <city>Worcester</city>
        <state>Massachusetts</state>
        <zip>01655</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Michigan</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Wayne State University</name>
      <address>
        <city>Detroit</city>
        <state>Michigan</state>
        <zip>48201</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hennepin County Medical Center</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55415</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Mississippi Medical Center</name>
      <address>
        <city>Jackson</city>
        <state>Mississippi</state>
        <zip>39216</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington University School of Medicine, ACCS Research</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Medical Center of Southern Nevada</name>
      <address>
        <city>Las Vegas</city>
        <state>Nevada</state>
        <zip>89102</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cooper Health</name>
      <address>
        <city>Camden</city>
        <state>New Jersey</state>
        <zip>08103</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Englewood Health</name>
      <address>
        <city>Englewood</city>
        <state>New Jersey</state>
        <zip>07631</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Atlantic Health System</name>
      <address>
        <city>Morristown</city>
        <state>New Jersey</state>
        <zip>07960</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rutgers New Jersey Medical School</name>
      <address>
        <city>Newark</city>
        <state>New Jersey</state>
        <zip>07103</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AtlantiCare Regional Medical Center</name>
      <address>
        <city>Pomona</city>
        <state>New Jersey</state>
        <zip>08240</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Albany Medical College</name>
      <address>
        <city>Albany</city>
        <state>New York</state>
        <zip>12208</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Jacobi Medical Center</name>
      <address>
        <city>Bronx</city>
        <state>New York</state>
        <zip>10461</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Montefiore Medical Center</name>
      <address>
        <city>Bronx</city>
        <state>New York</state>
        <zip>10461</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mercy Hospital Buffalo</name>
      <address>
        <city>Buffalo</city>
        <state>New York</state>
        <zip>14220</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>VA New York Harbor Healthcare System</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10010</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>NYU Langone</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10016</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mt. Sinai Hospital</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10029</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>SUNY Upstate University Hospital</name>
      <address>
        <city>Syracuse</city>
        <state>New York</state>
        <zip>13210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Westchester Medical Center</name>
      <address>
        <city>Valhalla</city>
        <state>New York</state>
        <zip>10595</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Duke University Hospital</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27704</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Wake Forest</name>
      <address>
        <city>Winston-Salem</city>
        <state>North Carolina</state>
        <zip>27157</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cleveland Clinic Akron General</name>
      <address>
        <city>Akron</city>
        <state>Ohio</state>
        <zip>44307</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Cincinnati Medical Center</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45219</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The MetroHealth System</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cleveland Clinic Foundation</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44195</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ohio State Universtiy Wexner Medical Center</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mercy Health St Vincent Medical Center</name>
      <address>
        <city>Toledo</city>
        <state>Ohio</state>
        <zip>43608</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ascension St. John Clinical Research Institute</name>
      <address>
        <city>Tulsa</city>
        <state>Oklahoma</state>
        <zip>74104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oregon Health and Science University</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97239</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Geisinger Research</name>
      <address>
        <city>Danville</city>
        <state>Pennsylvania</state>
        <zip>17822</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Doylestown Cardiology Associates</name>
      <address>
        <city>Doylestown</city>
        <state>Pennsylvania</state>
        <zip>18901</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Penn State Health Milton S. Hershey Medical Center</name>
      <address>
        <city>Hershey</city>
        <state>Pennsylvania</state>
        <zip>17033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital of the University of Pennsylvania</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Temple University</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19141</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UPMC Presbyterian</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15260</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rhode Island Hospital</name>
      <address>
        <city>Providence</city>
        <state>Rhode Island</state>
        <zip>02903</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Miriam Hospital</name>
      <address>
        <city>Providence</city>
        <state>Rhode Island</state>
        <zip>02906</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sarah Cannon and HCA Research Institute</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37203</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Skyline Medical Center</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37207</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Texas at Austin</name>
      <address>
        <city>Austin</city>
        <state>Texas</state>
        <zip>78701</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Texas Southwestern Medical Center</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75390</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical City Ft Worth</name>
      <address>
        <city>Fort Worth</city>
        <state>Texas</state>
        <zip>76104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Baylor Scott and White Medical Center - Temple</name>
      <address>
        <city>Temple</city>
        <state>Texas</state>
        <zip>76508</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HCA Henrico Doctors Hospital</name>
      <address>
        <city>Richmond</city>
        <state>Virginia</state>
        <zip>23229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Swedish Hospital</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98122</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>West Virginia University CTR</name>
      <address>
        <city>Morgantown</city>
        <state>West Virginia</state>
        <zip>26506</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Wisconsin Hospital; Meriter Hospital (UW affiliated)</name>
      <address>
        <city>Madison</city>
        <state>Wisconsin</state>
        <zip>53715</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Sao Francisco de Assis</name>
      <address>
        <city>Braganca Paulista</city>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>União Brasileira de Educação e Assistência - Hospital São Lucas da PUCRS</name>
      <address>
        <city>Porto Alegre</city>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centro de Estudos Clínicos do Hospital Cárdio Pulmonar</name>
      <address>
        <city>Salvador</city>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fundação Faculdade Regional De Medicina De São José Do Rio Preto</name>
      <address>
        <city>São José do Rio Preto</city>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Instituto Dante Pazzanese de Cardiologia</name>
      <address>
        <city>São Paulo</city>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da USP-InCor-HCFMUSP</name>
      <address>
        <city>São Paulo</city>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedaliero Sant Anna e San Sebastiano</name>
      <address>
        <city>Caserta</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Maria Cecilia Hospital , Cotignola, Ravenna</name>
      <address>
        <city>Cotignola</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Università degli Studi di Ferrara, Ferrara</name>
      <address>
        <city>Ferrara</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedaliero -Universitaria Careggi</name>
      <address>
        <city>Firenze</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Policlinico di Napoli, Napoli</name>
      <address>
        <city>Napoli</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AOU Policlinico di Palermo, Palermo</name>
      <address>
        <city>Palermo</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>ASL-1 Imperiese, Sanremo</name>
      <address>
        <city>Sanremo</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario A Coruna</name>
      <address>
        <city>A Coruna</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Virgen del Mar</name>
      <address>
        <city>Almeria</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Arnau de Vilanova</name>
      <address>
        <city>Lleida</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario La Paz</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Ramon Y Cajal</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Clínico Universitario de Salamanca</name>
      <address>
        <city>Salamanca</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Clínico Universitario de Santiago de Compostela</name>
      <address>
        <city>Santiago de Compostela</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Brazil</country>
    <country>Italy</country>
    <country>Spain</country>
    <country>United States</country>
  </location_countries>
  <reference>
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  <verification_date>July 2023</verification_date>
  <study_first_submitted>August 6, 2020</study_first_submitted>
  <study_first_submitted_qc>August 7, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 10, 2020</study_first_posted>
  <last_update_submitted>July 10, 2023</last_update_submitted>
  <last_update_submitted_qc>July 10, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 11, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Pittsburgh</investigator_affiliation>
    <investigator_full_name>Matthew Neal MD</investigator_full_name>
    <investigator_title>MD</investigator_title>
  </responsible_party>
  <keyword>anti-coagulation</keyword>
  <keyword>antithrombosis</keyword>
  <keyword>anticoagulation</keyword>
  <keyword>ACTIV</keyword>
  <keyword>inpatient</keyword>
  <keyword>heparin</keyword>
  <keyword>p2y12</keyword>
  <keyword>endothelial dysfunction</keyword>
  <keyword>vascular integrity</keyword>
  <keyword>P-selectin</keyword>
  <keyword>crizanlizumab</keyword>
  <keyword>SGLT-2 inhibitor</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>Dapagliflozin</mesh_term>
    <mesh_term>Empagliflozin</mesh_term>
    <mesh_term>Canagliflozin</mesh_term>
    <mesh_term>Sodium-Glucose Transporter 2 Inhibitors</mesh_term>
    <mesh_term>Ertugliflozin</mesh_term>
    <mesh_term>Heparin</mesh_term>
    <mesh_term>Calcium heparin</mesh_term>
    <mesh_term>Enoxaparin</mesh_term>
    <mesh_term>Dalteparin</mesh_term>
    <mesh_term>Tinzaparin</mesh_term>
    <mesh_term>Heparin, Low-Molecular-Weight</mesh_term>
    <mesh_term>Enoxaparin sodium</mesh_term>
    <mesh_term>Clopidogrel</mesh_term>
    <mesh_term>Ticagrelor</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Data will be shared as per NIH guidelines.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_info_type>Analytic Code</ipd_info_type>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>October 22, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/74/NCT04505774/ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT04505774
org study id: ACTIV-4 ACUTE
secondary id: 1OT2HL156812-01
nct id: NCT04505774
nct alias: NCT04359277
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This is a randomized, open label, adaptive platform trial to compare the effectiveness of
      antithrombotic and additional strategies for prevention of adverse outcomes in COVID-19
      positive inpatients
The severe acute respiratory syndrome coronavirus 2, which causes the highly contagious
      coronavirus disease 2019 (COVID-19), has resulted in a global pandemic.

      The clinical spectrum of COVID-19 infection is broad, encompassing asymptomatic infection,
      mild upper respiratory tract illness, and severe viral pneumonia with respiratory failure and
      death. The risk of thrombotic complications is increased, even as compared to other viral
      respiratory illnesses, such as influenza. A pro-inflammatory cytokine response as well as
      induction of procoagulant factors associated with COVID-19 has been proposed to contribute to
      thrombosis as well as plaque rupture through local inflammation. Patients with COVID-19 are
      at increased risk for arterial and vein thromboembolism, with high rates observed despite
      thromboprophylaxis. Autopsy reports have noted micro and macro vascular thrombosis across
      multiple organ beds consistent with an early hypercoagulable state.

      Notably, in COVID-19, data in the U.K. and U.S. document that infection and outcomes of
      infection are worse in African and Hispanic descent persons than in other groups. The reasons
      for this are uncertain.

      Viral Infection and Thrombosis A large body of literature links inflammation and coagulation;
      altered hemostasis is a known complication of respiratory viral infections. Procoagulant
      markers are severely elevated in viral infections. Specifically, proinflammatory cytokines in
      viral infections upregulate expression of tissue factor, markers of thrombin generation,
      platelet activation, and down-regulate natural anticoagulant proteins C and S.

      Studies have demonstrated significant risk of deep venous thrombosis (DVT), pulmonary
      embolism (PE), and myocardial infarction (MI) associated with viral respiratory infections.
      In a series of patients with fatal influenza H1N1, 75% had pulmonary thrombi on autopsy (a
      rate considerably higher than reported on autopsy studies among the general intensive care
      unit population). Incidence ratio for acute myocardial infarction in the context of Influenza
      A is over 10. Severe acute respiratory syndrome coronavirus-1 (SARS CoV-1) and influenza have
      been associated with disseminated intravascular coagulation (DIC), endothelial damage, DVT,
      PE, and large artery ischemic stroke. Patients with Influenza H1N1 and acute respiratory
      distress syndrome (ARDS) had a 23.3-fold higher risk for pulmonary embolism, and a 17.9-fold
      increased risk for deep vein thrombosis. Compared to those treated with systemic
      anticoagulation, those without treatment were 33 times more likely to suffer a VTE.

      Thrombosis, both microvascular and macrovascular, is a prominent feature in multiple organs
      at autopsy in fatal cases of COVID-19. Thrombosis may thus contribute to respiratory failure,
      renal failure, and hepatic injury in COVID-19. The number of megakaryocytes in tissues is
      higher than in other forms of ARDS, and thrombi are platelet-rich based on specific staining.
      Thrombotic stroke has been reported in young COVID-19 patients with no cardiovascular risk
      factors. Both arterial and venous thrombotic events have been seen in increasing numbers of
      hospitalized patients infected with COVID-19. The incidence of thrombosis has ranged from 10
      to 30% in hospitalized patients; however, this varies by type of thrombosis captured
      (arterial or vein) and severity of illness (ICU level care, requiring mechanical ventilation,
      etc.).

      Additional treatment strategies Data from the multiplatform randomized controlled trial
      (mpRCT) demonstrated that (1) therapeutic dose anticoagulation with heparin was not
      beneficial in improving clinical outcomes compared to standard of care prophylactic dose
      heparin in severely ill (ICU level of care) patients, and (2) therapeutic dose
      anticoagulation with heparin was beneficial in improving organ support free days compared to
      standard of care prophylactic dose heparin in moderately ill (hospitalized and not requiring
      organ support) patients. However, there remains significant residual risk for adverse
      clinical outcomes and excess mortality for severely ill as well as moderately ill patients.

      Antithrombotic regimens that are shown to be efficacious will be combined in clinical
      practice with other agents to treat COVID-19 hospitalized patients. This adaptive platform
      trial will test other promising agents when added to proven therapies, such as heparin. The
      rationale and risks for each agent will be included in the arm-specific appendix. Two
      specific agents to be added as arms, effective October 2021, include the P-selectin
      inhibitor, Crizanlizumab as well as SGLT2 inhibitors. P-selectin may play a proximal role in
      the inflammatory and thrombotic cascade in patients with COVID-19 and P-selectin inhibition
      may be a effective in preventing downstream sequelae. In addition, SGLT-2 inhibitors have
      been shown to decrease capillary leak and may promote vascular integrity in COVID-19.

      This platform trial will have multiple arms, which may be dropped or added as the platform
      trial progresses. Sample size will be flexible: the trial will be stopped for efficacy or
      futility based on pre-determined statistical thresholds as defined in the arm-specific
      appendices. Each arm will have an adaptive component for determinations of futility or
      success.

      Randomization assignments are at the participant level, stratified by enrolling site and by
      ICU level of care vs non-ICU level of care and/or other arm-specific criteria.
allocation: Randomized
intervention model: Sequential Assignment
intervention model description: This is an adaptive design
primary purpose: Treatment
masking: None (Open Label)
masking description: There will be independent masked adjudicators.
measure: 21 Day Organ Support (respiratory or vasopressor) Free Days
time frame: 21 days from study enrollment
description: which is defined as the number of days that a patient is alive and free of organ support through the first 21 days after trial entry. Organ Support is defined as receipt of non-invasive mechanical ventilation, high flow nasal canula oxygen, mechanical ventilation, or vasopressor therapy, with death at any time during the index hospitalization assigned -1 days.
measure: Secondary Endpoint all cause mortality
time frame: 28 days from study enrollment
description: Categorization of the primary endpoint into a three-level ordinal outcome (Death, invasive mechanical ventilation without death, neither invasive mechanical ventilation nor death)
measure: Other Platform Secondary Endpoints of Morbidity and Hospitalization
time frame: 28 days from study enrollment
description: Categorization of the primary endpoint into a three-level ordinal outcome (Death, organ support (any respiratory or cardiovascular) without death, neither organ support nor death) (for moderate illness severity at enrollment)
measure: Days free of death
time frame: 28 days from enrollment
description: Days free of death and respiratory and cardiovascular organ support and renal replacement therapy (RRT) during Index Hospitalization through Day 28.
measure: Death Composite
time frame: 28 days from enrollment
description: Composite endpoint of death, pulmonary embolism, systemic arterial thromboembolism, myocardial infarction, or ischemic stroke at hospital discharge or 28 days, whichever occurs first.
measure: Acute kidney injury
time frame: 90 days from enrollment
description: Individual endpoints comprising the primary and secondary endpoint components; death during hospitalization, WHO clinical scale and 90 day mortality
measure: Primary Safety Endpoint of Major Bleeding
time frame: 28 days from study enrollment
description: Major bleeding (as defined by the ISTH)
measure: Secondary Safety Endpoint of HIT
time frame: 28 days from study enrollment
description: Confirmed heparin induced thrombocytopenia (HIT)
arm group label: Therapeutic Dose Anticoagulation
arm group type: Other
description: increased dose of heparin above standard of care.
1.0 - This arm was stopped in severe patients in December 2020 and results are published in PMID: 34351722 (NEJM, August, 2021) (see reference section for citation). This arm was stopped for moderate patients in January 2021.
arm group label: Prophylactic Dose Anticoagulation
arm group type: Other
description: Heparin standard of care
1.0 - this arm was stopped for all patients in January, 2021 and results are published in PMID: 34351721 (NEJM, August, 2021) (see reference section for citation)
arm group label: Therapeutic Dose Anticoagulation + P2Y12 inhibitor
arm group type: Other
description: increased dose of heparin above standard of care with an added P2Y12 inhibitor
This Arm enrolled moderate illness patients only. Enrollment of moderate illness patients in the trial was ended per DSMB on June 19, 2021 and results are published in PMID: PMID: 35040887 (JAMA, January, 2022) (see reference section for citation)
arm group label: Prophylactic Dose Anticoagulation + P2Y12 inhibitor
arm group type: Other
description: Heparin standard of care with an added P2Y12 inhibitor
This Arm enrolled severe illness patients only. Enrollment of severe illness patients in the trial was ended per DSMB in June 2022.
arm group label: Standard of Care + Crizanlizumab
arm group type: Other
description: Standard of care plus crizanlizumab infusion
This arm will enroll moderate and severe illness patients
This arm was ended for all patients per the DSMB in September 2022.
arm group label: Standard of Care + SGLT2 inhibitor
arm group type: Other
description: Standard of care plus SGLT2 inhibitor
This arm will enroll moderate and severe illness patients
This arm was ended in March 2023
intervention type: Drug
intervention name: theraputic heparin
description: increased dose of heparin above standard of care.
arm group label: Therapeutic Dose Anticoagulation
arm group label: Therapeutic Dose Anticoagulation + P2Y12 inhibitor
other name: unfractionated heparin
other name: Enoxaparin
other name: Dalteparin
other name: Tinzaparin
other name: Heparin
intervention type: Drug
intervention name: prophylactic heparin
description: standard of care dose of heparin
arm group label: Prophylactic Dose Anticoagulation
arm group label: Prophylactic Dose Anticoagulation + P2Y12 inhibitor
other name: enoxaparin
other name: dalteparin
other name: Tinzaparin
other name: Fondparinux
other name: Heparin
intervention type: Drug
intervention name: P2Y12
description: added P2Y12 inhibitor
arm group label: Prophylactic Dose Anticoagulation + P2Y12 inhibitor
arm group label: Therapeutic Dose Anticoagulation + P2Y12 inhibitor
other name: Ticagrelor
other name: Prasugrel
other name: Clopidogrel
intervention type: Drug
intervention name: Crizanlizumab Injection
description: crizanlizumab injection
arm group label: Standard of Care + Crizanlizumab
intervention type: Drug
intervention name: SGLT2 inhibitor
description: sglt2 inhibitor
arm group label: Standard of Care + SGLT2 inhibitor
other name: dapagliflozin
other name: empagliflozin
other name: canagliflozin
other name: ertugliflozin
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Judith Hochman, MD
role: Study Chair
affiliation: New York University Grossman School of Medicine
last name: Scott Solomon, MD
role: Principal Investigator
affiliation: Brigham and Women's Hospital
last name: Mikhail Kosiborod, MD
role: Principal Investigator
affiliation: Saint Lukes
last name: Jeffrey Berger, MD
role: Principal Investigator
affiliation: New York University Grossman School of Medicine
last name: MATTHEW D NEAL, MD
role: Study Chair
affiliation: University of Pittsburgh
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country: Brazil
country: Italy
country: Spain
country: United States
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citation: REMAP-CAP Investigators; ACTIV-4a Investigators; ATTACC Investigators; Goligher EC, Bradbury CA, McVerry BJ, Lawler PR, Berger JS, Gong MN, Carrier M, Reynolds HR, Kumar A, Turgeon AF, Kornblith LZ, Kahn SR, Marshall JC, Kim KS, Houston BL, Derde LPG, Cushman M, Tritschler T, Angus DC, Godoy LC, McQuilten Z, Kirwan BA, Farkouh ME, Brooks MM, Lewis RJ, Berry LR, Lorenzi E, Gordon AC, Ahuja T, Al-Beidh F, Annane D, Arabi YM, Aryal D, Baumann Kreuziger L, Beane A, Bhimani Z, Bihari S, Billett HH, Bond L, Bonten M, Brunkhorst F, Buxton M, Buzgau A, Castellucci LA, Chekuri S, Chen JT, Cheng AC, Chkhikvadze T, Coiffard B, Contreras A, Costantini TW, de Brouwer S, Detry MA, Duggal A, Dzavik V, Effron MB, Eng HF, Escobedo J, Estcourt LJ, Everett BM, Fergusson DA, Fitzgerald M, Fowler RA, Froess JD, Fu Z, Galanaud JP, Galen BT, Gandotra S, Girard TD, Goodman AL, Goossens H, Green C, Greenstein YY, Gross PL, Haniffa R, Hegde SM, Hendrickson CM, Higgins AM, Hindenburg AA, Hope AA, Horowitz JM, Horvat CM, Huang DT, Hudock K, Hunt BJ, Husain M, Hyzy RC, Jacobson JR, Jayakumar D, Keller NM, Khan A, Kim Y, Kindzelski A, King AJ, Knudson MM, Kornblith AE, Kutcher ME, Laffan MA, Lamontagne F, Le Gal G, Leeper CM, Leifer ES, Lim G, Gallego Lima F, Linstrum K, Litton E, Lopez-Sendon J, Lother SA, Marten N, Saud Marinez A, Martinez M, Mateos Garcia E, Mavromichalis S, McAuley DF, McDonald EG, McGlothlin A, McGuinness SP, Middeldorp S, Montgomery SK, Mouncey PR, Murthy S, Nair GB, Nair R, Nichol AD, Nicolau JC, Nunez-Garcia B, Park JJ, Park PK, Parke RL, Parker JC, Parnia S, Paul JD, Pompilio M, Quigley JG, Rosenson RS, Rost NS, Rowan K, Santos FO, Santos M, Santos MO, Satterwhite L, Saunders CT, Schreiber J, Schutgens REG, Seymour CW, Siegal DM, Silva DG Jr, Singhal AB, Slutsky AS, Solvason D, Stanworth SJ, Turner AM, van Bentum-Puijk W, van de Veerdonk FL, van Diepen S, Vazquez-Grande G, Wahid L, Wareham V, Widmer RJ, Wilson JG, Yuriditsky E, Zhong Y, Berry SM, McArthur CJ, Neal MD, Hochman JS, Webb SA, Zarychanski R. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19. N Engl J Med. 2021 Aug 26;385(9):777-789. doi: 10.1056/NEJMoa2103417. Epub 2021 Aug 4.
PMID: 34351722
citation: Berger JS, Kornblith LZ, Gong MN, Reynolds HR, Cushman M, Cheng Y, McVerry BJ, Kim KS, Lopes RD, Atassi B, Berry S, Bochicchio G, de Oliveira Antunes M, Farkouh ME, Greenstein Y, Hade EM, Hudock K, Hyzy R, Khatri P, Kindzelski A, Kirwan BA, Baumann Kreuziger L, Lawler PR, Leifer E, Lopez-Sendon Moreno J, Lopez-Sendon J, Luther JF, Nigro Maia L, Quigley J, Sherwin R, Wahid L, Wilson J, Hochman JS, Neal MD; ACTIV-4a Investigators. Effect of P2Y12 Inhibitors on Survival Free of Organ Support Among Non-Critically Ill Hospitalized Patients With COVID-19: A Randomized Clinical Trial. JAMA. 2022 Jan 18;327(3):227-236. doi: 10.1001/jama.2021.23605.
PMID: 35040887
responsible party type: Sponsor-Investigator
investigator affiliation: University of Pittsburgh
investigator full name: Matthew Neal MD
investigator title: MD
mesh term: COVID-19
mesh term: Dapagliflozin
mesh term: Empagliflozin
mesh term: Canagliflozin
mesh term: Sodium-Glucose Transporter 2 Inhibitors
mesh term: Ertugliflozin
mesh term: Heparin
mesh term: Calcium heparin
mesh term: Enoxaparin
mesh term: Dalteparin
mesh term: Tinzaparin
mesh term: Heparin, Low-Molecular-Weight
mesh term: Enoxaparin sodium
mesh term: Clopidogrel
mesh term: Ticagrelor
sharing ipd: Yes
ipd description: Data will be shared as per NIH guidelines.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd info type: Analytic Code
provided document: 