<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/NCT04401293</url>
  </required_header>
  <id_info>
    <org_study_id>20-0340</org_study_id>
    <nct_id>NCT04401293</nct_id>
  </id_info>
  <brief_title>Full Dose Heparin Vs. Prophylactic Or Intermediate Dose Heparin in High Risk COVID-19 Patients</brief_title>
  <official_title>Systemic Anticoagulation With Full Dose Low Molecular Weight Heparin (LMWH) Vs. Prophylactic or Intermediate Dose LMWH in High Risk COVID-19 Patients (HEP-COVID Trial)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Northwell Health</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Northwell Health</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>
      The aim of this study is to test the hypothesis that prophylaxis of severe COVID-19 patients&#xD;
      with treatment dose LMWH leads to better thromboembolic-free outcomes and associated&#xD;
      complications during hospitalization than prophylaxis with institutional standard of care&#xD;
      with prophylactic to intermediate-doses of UFH or LMWH&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      There are clinical data to support the observation that hospitalized acutely ill medical&#xD;
      patients with severe viral pneumonitis/Acute Respiratory Distress Syndrome (ARDS), such as&#xD;
      those with influenza H1N1 infection, have an over 23-fold increased risk for venous&#xD;
      thromboembolism (VTE) - especially pulmonary embolism (PE) - with an overall 44% incidence of&#xD;
      VTE in ARDS associated with H1N1 pneumonia. Multicenter studies from China report that key&#xD;
      markers of inflammation and/or coagulopathy are associated with morbidity and increased&#xD;
      mortality in COVID-19 patients. Elevated D-dimer levels (that are sometime greater than 4 or&#xD;
      6 times the upper limit of normal [ULN]) are strongly associated with mortality in patients&#xD;
      with severe COVID-19 illness. Recent data also shows that mortality among COVID-19 patients&#xD;
      is markedly higher in patients with elevated Troponin-T (TnT) levels than in patients with&#xD;
      normal TnT levels. Recently a cohort of 81 patients retrospectively evaluated diagnosed with&#xD;
      severe COVID-19 pneumonia and reported a lower extremity VTE incidence of 25% (20/81) and a&#xD;
      mortality of 40% (8/20) in the presence of VTE. Reported a case of bilateral pulmonary&#xD;
      embolism in a 75 year old woman diagnosed with severe COVID-19, in the absence of&#xD;
      predisposing risk factors and a negative lower extremity US. Lastly the investigated use of&#xD;
      Tissue Plasminogen Activator (tPA) in the treatment of COVID-19 associated ARDS and reported&#xD;
      promising, but transient, results in terms of pulmonary function improvement. It appears that&#xD;
      either the SARS-CoV2 infection itself induces a hypercoagulable state, possibly by&#xD;
      hypofibrinolytic mechanisms, or the cytokine storm in COVID-19 patients with severe disease&#xD;
      induces a prothrombotic state, which leads to clinical deterioration, hypoxia and hemodynamic&#xD;
      instability secondary to thromboembolic phenomena and potentially cardiac ischemia.&#xD;
      Preliminary data from Northwell Health System, which has one of the largest populations of&#xD;
      hospitalized COVID-19 patients in the US, reveals a positivity rate for deep vein thrombosis&#xD;
      (DVT) of 40% of those COVID-19 patients screened by Doppler compression ultrasonography of&#xD;
      the lower extremities.&#xD;
&#xD;
      Heparin has been shown to have anti-inflammatory and immunomodulatory properties in addition&#xD;
      to its anticoagulation effect, which could play a beneficial role in sepsis. In addition,&#xD;
      there is in vitro evidence that the large negatively charged sulfated glycosaminoglycans of&#xD;
      unfractionated heparin may act as an alternate ligand for the SARS-CoV2 receptor irrespective&#xD;
      of ACE2. Whether this in vitro evidence supports the role of a protective or deleterious&#xD;
      mechanism in COVID-19 infection is not known. However, an early report with empiric use of&#xD;
      treatment dose unfractionated heparin (UFH) in ARDS from a different viral family, influenza&#xD;
      H1N1, revealed that H1N1 ARDS patients under systemic anticoagulation had 33-fold fewer VTE&#xD;
      events than those treated given prophylactic doses of UFH/low-molecular weight heparin (LMWH)&#xD;
      thromboprophylaxis. Very recent evidence suggests that therapy with prophylactic to&#xD;
      intermediate doses of the LMWH enoxaparin (30mg to 60mg QD) in severe hospitalized COVID-19&#xD;
      patents with a SIC score ≥ 4 or D-dimer (Dd) &gt; 6 X ULN improves outcomes and prognosis.&#xD;
      All-cause mortality at 28 days was reduced from 64.2% to 40.0% in those patients with a SIC&#xD;
      score ≥ 4 (p=0.029), and from 52.4% to 32.8% in those patients with an elevated Dd &gt; 6 x ULN&#xD;
      (P=0.017). Notably, Klok and colleagues investigated 184 ICU patients infected with COVID-19&#xD;
      and reported a 13% mortality rate, a relatively high incidence of CTPA- or&#xD;
      ultrasonography-confirmed VTE rate (27%), and arterial thrombotic events (3.7%) despite the&#xD;
      use of standard dose thromboprophylaxis. Postulated mechanisms for the improved prognosis&#xD;
      with the use of treatment doses of LMWH in the sick COVID-19 population include the decrease&#xD;
      in the risk of microthrombi, especially in the pulmonary vasculature, which can lead to&#xD;
      hypoxemia, pulmonary vasoconstriction and right ventricular dysfunction as well as the&#xD;
      decrease in the risk of progression to disseminated intravascular coagulopathy as a&#xD;
      contributor to the high mortality seen in these patients.&#xD;
&#xD;
      The optimal dose of heparin (either LMWH or UFH) in hospitalized COVID-19 patients is&#xD;
      unknown, as patients on conventional prophylactic dose heparin (UFH or LMWH) as supported by&#xD;
      international guidance statements on hospitalized COVID-19 patients appear to remain at risk&#xD;
      for thromboembolic events. There is data to support improved efficacy with treatment doses of&#xD;
      twice daily enoxaparin versus once-daily weight-adjusted enoxaparin for the management of&#xD;
      VTE, especially with large thrombus burden. There is also long-standing data to support that&#xD;
      treatment-dose heparin can reduce major cardiovascular events. Our current standard of care&#xD;
      in our 24 hospital Northwell Health System, which has a very large hospitalized COVID-19&#xD;
      patient population, is to use Lovenox 40mg SQ QD for patients with a BMI &lt; 30 and Creatinine&#xD;
      Clearance (CrCl) &gt; 15ml/min, Lovenox 40mg SQ BID for patients with a BMI &gt; 30 and CrCl &gt;&#xD;
      15ml/min, and UFH 5000U SQ BID or TID in patients with a CrCl &lt; 15ml/min and BMI &lt; 30 and UFH&#xD;
      7500U SQ BID or TID with a CrCl &lt; 15ml/min and BMI &gt; 30. Large healthcare institutions in the&#xD;
      US and elsewhere have protocols for in-patient thromboprophylaxis ranging from&#xD;
      prophylactic-to-intermediate dose UFH or LMWH for the management of patients with COVID-19&#xD;
      associated coagulopathy. The aim of this study is to test the hypothesis that prophylaxis of&#xD;
      severe COVID-19 patients with treatment dose LMWH leads to better thromboembolic-free&#xD;
      outcomes and associated complications during hospitalization than prophylaxis with&#xD;
      institutional standard of care with prophylactic to intermediate-doses of UFH or LMWH.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 26, 2020</start_date>
  <completion_date type="Actual">May 14, 2021</completion_date>
  <primary_completion_date type="Actual">May 14, 2021</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
    <masking_description>Due to the pragmatic nature of this study &quot;open-label multi-center randomized active control trial&quot; with pseudo-blinding mechanisms at the time of randomization the study subject and corresponding Site PIs will be blinded (unaware of specific treatment arm the patient is assigned to i.e. Arm 0 or Arm 1). The study pharmacists as well as data extractors and designated randomization personnel (i.e. research coordinators and/or research nurses performing the randomization process) will be un-blinded (aware of specific treatment arm the patient is assigned to i.e. Arm 0 or Arm 1). At the time of subject randomization study subjects will be stratified to either ICU level of care vs. Non-ICU level of care.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Composite Outcome of Arterial Thromboembolic Events, Venous Thromboembolic Events and All-cause Mortality at Day 30 ± 2 Days.</measure>
    <time_frame>Day 30 ± 2 days</time_frame>
    <description>Risk of arterial thromboembolic events (including myocardial infarction, stroke, systemic embolism), venous thromboembolism (including symptomatic deep vein thrombosis (DVT) of the upper or lower extremity, asymptomatic proximal DVT of the lower extremity, non-fatal pulmonary embolism (PE)), and all-cause mortality at Day 30 ± 2 days.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Major Bleeding</measure>
    <time_frame>Day 30 ± 2 days</time_frame>
    <description>Risk of major bleeding defined using the International Society of Thrombosis and Haemostasis (ISTH) criteria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Composite Outcome of Arterial Thromboembolic Events, Venous Thromboembolic Events and All-cause Mortality at Hospital Day 10 + 4</measure>
    <time_frame>Day 10 + 4</time_frame>
    <description>The composite of arterial thromboembolic events (including myocardial infarction, stroke, systemic embolism), venous thromboembolism (including symptomatic deep vein thrombosis (DVT) of the upper or lower extremity, asymptomatic proximal DVT of the lower extremity, non-fatal pulmonary embolism (PE)), and all-cause mortality at Hospital Day 10 + 4</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sepsis-induced Coagulopathy (SIC) Score</measure>
    <time_frame>Day 30 ± 2 days.</time_frame>
    <description>Sepsis-induced coagulopathy (SIC) score predicts likelihood of sepsis-induced coagulopathy based on ISTH guidelines.&#xD;
The score uses the following domains:&#xD;
Platelets, K/uL (thousands per microliter)&#xD;
INR (International Normalized Ratio)&#xD;
D-Dimer Level&#xD;
Fibrinogen&#xD;
Platelet count &gt; 100 cells x 10^9/L is 0 points, platelet count 50 to 100 cells x 10^9/L is 1 point and Platelet count &lt; 50 cells x 10^9/L is 2 points. INR &lt; 1.3 is 0 points, INR 1.3 to 1.7 is 1 point and INR &gt; 1.7 is 2 points. D-Dimer level &lt; 400 ng/mL is 0 points, D-Dimer level 400-4000 ng/mL is 2 points and D-Dimer level &gt; 4000 ng/mL is 3 points. Fibrinogen level &gt; 100 mg/dL is 0 points and fibrinogen level &lt; 100 mg/dL is 1 point.&#xD;
Calculated (SIC) scores yields a possible 0 to 6 points, where ≥4 predicts higher mortality rates within 30 days and greater risk of pulmonary embolism.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression to Acute Respiratory Distress Syndrome (ARDS)</measure>
    <time_frame>Day 30 ± 2 days.</time_frame>
    <description>Progression to Acute Respiratory Distress Syndrome (ARDS) based on monitoring of patient conditions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Need for Intubation</measure>
    <time_frame>Day 30 ± 2 days.</time_frame>
    <description>Need for Intubation will be based on monitoring of patient conditions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Re-hospitalization</measure>
    <time_frame>Day 30 ± 2 days.</time_frame>
    <description>Need for Re-hospitalization will be based on monitoring of patient conditions.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">257</enrollment>
  <condition>Sars-CoV2</condition>
  <condition>COVID</condition>
  <arm_group>
    <arm_group_label>Full Dose LMWH anticoagulation therapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects in this study arm will be treated with therapeutic doses of subcutaneous low-molecular-weight heparin (enoxaparin). Enoxaparin 1mg/kg SQ BID for CrCl ≥ 30ml/min (or Enoxaparin 0.5mg/kg SQ BID for CrCl ≥ 15ml/min and &lt; 30ml/min) during the course of their hospitalization.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Prophylactic/Intermediate Dose LMWH or UFH therapy</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Subjects in this study arm will be treated with Local institutional standard-of-care for prophylactic-dose or intermediate-dose UFH or LMWH. Regimens allowed are UFH up to 22,500 IU daily in BID or TID doses (i.e. UFH 5000 IU SQ BID/TID or 7500 IU BID/TID), enoxaparin 30mg and 40mg SQ QD or BID (the use of weight-based enoxaparin i.e. 0.5mg/kg SQ BID for this arm is acceptable but strongly discouraged), dalteparin 2500IU or 5000IU QD.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Enoxaparin</intervention_name>
    <description>Full Dose LMWH anticoagulation therapy</description>
    <arm_group_label>Full Dose LMWH anticoagulation therapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prophylactic/Intermediate Dose Enoxaparin</intervention_name>
    <description>Prophylactic/Intermediate Dose LMWH or UFH therapy</description>
    <arm_group_label>Prophylactic/Intermediate Dose LMWH or UFH therapy</arm_group_label>
    <other_name>Unfractionated heparin</other_name>
    <other_name>dalteparin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Subject (or legally authorized representative) provides written informed consent prior&#xD;
             to initiation of any study procedures.&#xD;
&#xD;
          2. Understands and agrees to comply with planned study procedures.&#xD;
&#xD;
          3. Male or non-pregnant female adult ≥18 years of age at time of enrollment.&#xD;
&#xD;
          4. Subject consents to randomization within 72 hours of hospital admission or transfer&#xD;
             from another facility within 72 hours of index presentation.&#xD;
&#xD;
          5. Subjects with a positive COVID-19 diagnosis by nasal swab or serologic testing.&#xD;
&#xD;
          6. Hospitalized with a requirement for supplemental oxygen.&#xD;
&#xD;
          7. Have:&#xD;
&#xD;
               -  Either a D- Dimer &gt; 4.0 X ULN, OR&#xD;
&#xD;
               -  Sepsis-induced coagulopathy (SIC) score of ≥4&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Indications for therapeutic anticoagulation&#xD;
&#xD;
          2. Absolute contraindication to anticoagulation including:&#xD;
&#xD;
               1. active bleeding,&#xD;
&#xD;
               2. recent (within 1 month) history of bleed,&#xD;
&#xD;
               3. dual (but not single) antiplatelet therapy,&#xD;
&#xD;
               4. active gastrointestinal and intracranial cancer,&#xD;
&#xD;
               5. a history of bronchiectasis or pulmonary cavitation,&#xD;
&#xD;
               6. Hepatic failure with a baseline INR &gt; 1.5,&#xD;
&#xD;
               7. CrCl &lt; 15ml/min,&#xD;
&#xD;
               8. a platelet count &lt; 25,000,&#xD;
&#xD;
               9. a history of heparin-induced thrombocytopenia (HIT) within the past 100 days or&#xD;
                  in the presence of circulating antibodies,&#xD;
&#xD;
              10. contraindications to enoxaparin including a hypersensitivity to enoxaparin&#xD;
                  sodium, hypersensitivity to heparin or pork products, hypersensitivity to benzyl&#xD;
                  alcohol,&#xD;
&#xD;
              11. pregnant female,&#xD;
&#xD;
              12. inability to give or designate to give informed consent,&#xD;
&#xD;
              13. participation in another blinded trial of investigational drug therapy for&#xD;
                  COVID-19&#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>Alex C Spyropoulos, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Northwell Health</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Beth Israel Newark</name>
      <address>
        <city>Newark</city>
        <state>New Jersey</state>
        <zip>07112</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Southside Hospital</name>
      <address>
        <city>Bay Shore</city>
        <state>New York</state>
        <zip>11706</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Huntington Hospital</name>
      <address>
        <city>Huntington</city>
        <state>New York</state>
        <zip>11743</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lenox Hill Hospital</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10075</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Long Island Jewish Medical Center</name>
      <address>
        <city>Queens</city>
        <state>New York</state>
        <zip>11040</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Staten Island University Hospital</name>
      <address>
        <city>Staten Island</city>
        <state>New York</state>
        <zip>10309</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://doi.org/10.1016/j.jacc.2020.03.031</url>
    <description>Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the Coronavirus Disease 2019 (COVID-19) Pandemic</description>
  </link>
  <link>
    <url>https://doi.org/10.1016/j.jvsv.2018.08.010</url>
    <description>Empirical systemic anticoagulation is associated with decreased venous thromboembolism in critically ill influenza A H1N1 acute respiratory distress syndrome patients</description>
  </link>
  <link>
    <url>https://doi.org/10.1111/jth.14768</url>
    <description>Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia</description>
  </link>
  <link>
    <url>https://doi.org/10.1111/jth.14817</url>
    <description>Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy</description>
  </link>
  <link>
    <url>https://doi.org/10.1001/jamacardio.2020.1017</url>
    <description>Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19)</description>
  </link>
  <link>
    <url>https://doi.org/10.1111/jth.14830</url>
    <description>Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia</description>
  </link>
  <link>
    <url>https://doi.org/10.1093/eurheartj/ehaa254</url>
    <description>Acute pulmonary embolism and COVID-19 pneumonia: a random association</description>
  </link>
  <link>
    <url>https://doi.org/10.1111/jth.14828</url>
    <description>Tissue Plasminogen Activator (tPA) Treatment for COVID-19 Associated Acute Respiratory Distress Syndrome (ARDS): A Case Series</description>
  </link>
  <link>
    <url>https://doi.org/10.1124/pr.115.011247</url>
    <description>Pharmacology of Heparin and Related Drugs</description>
  </link>
  <link>
    <url>https://doi.org/10.1016/j.thromres.2020.04.013</url>
    <description>Incidence of thrombotic complications in critically ill ICU patients with COVID-19</description>
  </link>
  <link>
    <url>https://doi.org/10.1016/j.jacc.2018.01.033</url>
    <description>Bivalirudin or Heparin in Patients Undergoing Invasive Management of Acute Coronary Syndromes</description>
  </link>
  <link>
    <url>https://doi.org/10.1002/rth2.12358</url>
    <description>Emergence of Institutional Antithrombotic Protocols for Coronavirus 2019</description>
  </link>
  <verification_date>November 2021</verification_date>
  <study_first_submitted>May 20, 2020</study_first_submitted>
  <study_first_submitted_qc>May 21, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 26, 2020</study_first_posted>
  <results_first_submitted>October 29, 2021</results_first_submitted>
  <results_first_submitted_qc>November 17, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">November 22, 2021</results_first_posted>
  <last_update_submitted>November 17, 2021</last_update_submitted>
  <last_update_submitted_qc>November 17, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">November 22, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Northwell Health</investigator_affiliation>
    <investigator_full_name>Alex Spyropoulos</investigator_full_name>
    <investigator_title>System Director - Anticoagulation and Clinical Thrombosis Services Northwell Health at Lenox Hill Hospital</investigator_title>
  </responsible_party>
  <keyword>COVID-19</keyword>
  <keyword>Anticoagulation</keyword>
  <keyword>Heparin</keyword>
  <keyword>Coronavirus</keyword>
  <keyword>Thrombosis</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>Heparin</mesh_term>
    <mesh_term>Enoxaparin</mesh_term>
    <mesh_term>Calcium heparin</mesh_term>
    <mesh_term>Dalteparin</mesh_term>
    <mesh_term>Enoxaparin sodium</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>March 23, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/93/NCT04401293/Prot_SAP_003.pdf</document_url>
    </provided_document>
    <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>December 3, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/93/NCT04401293/ICF_004.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Full Dose LMWH Anticoagulation Therapy</title>
          <description>Subjects in this study arm will be treated with therapeutic doses of subcutaneous low-molecular-weight heparin (enoxaparin). Enoxaparin 1mg/kg SQ BID for CrCl ≥ 30ml/min (or Enoxaparin 0.5mg/kg SQ BID for CrCl ≥ 15ml/min and &lt; 30ml/min) during the course of their hospitalization.&#xD;
Enoxaparin: Full Dose LMWH anticoagulation therapy</description>
        </group>
        <group group_id="P2">
          <title>Prophylactic/Intermediate Dose LMWH or UFH Therapy</title>
          <description>Subjects in this study arm will be treated with Local institutional standard-of-care for prophylactic-dose or intermediate-dose UFH or LMWH. Regimens allowed are UFH up to 22,500 IU daily in BID or TID doses (i.e. UFH 5000 IU SQ BID/TID or 7500 IU BID/TID), enoxaparin 30mg and 40mg SQ QD or BID (the use of weight-based enoxaparin i.e. 0.5mg/kg SQ BID for this arm is acceptable but strongly discouraged), dalteparin 2500IU or 5000IU QD.&#xD;
Prophylactic/Intermediate Dose Enoxaparin: Prophylactic/Intermediate Dose LMWH or UFH therapy</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="130"/>
                <participants group_id="P2" count="127"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="129"/>
                <participants group_id="P2" count="124"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Full Dose LMWH Anticoagulation Therapy</title>
          <description>Subjects in this study arm will be treated with therapeutic doses of subcutaneous low-molecular-weight heparin (enoxaparin). Enoxaparin 1mg/kg SQ BID for CrCl ≥ 30ml/min (or Enoxaparin 0.5mg/kg SQ BID for CrCl ≥ 15ml/min and &lt; 30ml/min) during the course of their hospitalization.&#xD;
Enoxaparin: Full Dose LMWH anticoagulation therapy</description>
        </group>
        <group group_id="B2">
          <title>Prophylactic/Intermediate Dose LMWH or UFH Therapy</title>
          <description>Subjects in this study arm will be treated with Local institutional standard-of-care for prophylactic-dose or intermediate-dose UFH or LMWH. Regimens allowed are UFH up to 22,500 IU daily in BID or TID doses (i.e. UFH 5000 IU SQ BID/TID or 7500 IU BID/TID), enoxaparin 30mg and 40mg SQ QD or BID (the use of weight-based enoxaparin i.e. 0.5mg/kg SQ BID for this arm is acceptable but strongly discouraged), dalteparin 2500IU or 5000IU QD.&#xD;
Prophylactic/Intermediate Dose Enoxaparin: Prophylactic/Intermediate Dose LMWH or UFH therapy</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="129"/>
            <count group_id="B2" value="124"/>
            <count group_id="B3" value="253"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age, Customized</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <title>Age in Years</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="65.8" spread="13.9"/>
                    <measurement group_id="B2" value="67.7" spread="14.1"/>
                    <measurement group_id="B3" value="66.7" spread="14.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex/Gender, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Male</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="68"/>
                    <measurement group_id="B2" value="68"/>
                    <measurement group_id="B3" value="136"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Female</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="61"/>
                    <measurement group_id="B2" value="56"/>
                    <measurement group_id="B3" value="117"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="25"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="33"/>
                    <measurement group_id="B2" value="37"/>
                    <measurement group_id="B3" value="70"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="56"/>
                    <measurement group_id="B2" value="46"/>
                    <measurement group_id="B3" value="102"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="29"/>
                    <measurement group_id="B2" value="27"/>
                    <measurement group_id="B3" value="56"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Composite Outcome of Arterial Thromboembolic Events, Venous Thromboembolic Events and All-cause Mortality at Day 30 ± 2 Days.</title>
        <description>Risk of arterial thromboembolic events (including myocardial infarction, stroke, systemic embolism), venous thromboembolism (including symptomatic deep vein thrombosis (DVT) of the upper or lower extremity, asymptomatic proximal DVT of the lower extremity, non-fatal pulmonary embolism (PE)), and all-cause mortality at Day 30 ± 2 days.</description>
        <time_frame>Day 30 ± 2 days</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Full Dose LMWH Anticoagulation Therapy</title>
            <description>Subjects in this study arm will be treated with therapeutic doses of subcutaneous low-molecular-weight heparin (enoxaparin). Enoxaparin 1mg/kg SQ BID for CrCl ≥ 30ml/min (or Enoxaparin 0.5mg/kg SQ BID for CrCl ≥ 15ml/min and &lt; 30ml/min) during the course of their hospitalization.&#xD;
Enoxaparin: Full Dose LMWH anticoagulation therapy</description>
          </group>
          <group group_id="O2">
            <title>Prophylactic/Intermediate Dose LMWH or UFH Therapy</title>
            <description>Subjects in this study arm will be treated with Local institutional standard-of-care for prophylactic-dose or intermediate-dose UFH or LMWH. Regimens allowed are UFH up to 22,500 IU daily in BID or TID doses (i.e. UFH 5000 IU SQ BID/TID or 7500 IU BID/TID), enoxaparin 30mg and 40mg SQ QD or BID (the use of weight-based enoxaparin i.e. 0.5mg/kg SQ BID for this arm is acceptable but strongly discouraged), dalteparin 2500IU or 5000IU QD.&#xD;
Prophylactic/Intermediate Dose Enoxaparin: Prophylactic/Intermediate Dose LMWH or UFH therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Composite Outcome of Arterial Thromboembolic Events, Venous Thromboembolic Events and All-cause Mortality at Day 30 ± 2 Days.</title>
          <description>Risk of arterial thromboembolic events (including myocardial infarction, stroke, systemic embolism), venous thromboembolism (including symptomatic deep vein thrombosis (DVT) of the upper or lower extremity, asymptomatic proximal DVT of the lower extremity, non-fatal pulmonary embolism (PE)), and all-cause mortality at Day 30 ± 2 days.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="129"/>
                <count group_id="O2" value="124"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="25"/>
                    <measurement group_id="O2" value="31"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Major Bleeding</title>
        <description>Risk of major bleeding defined using the International Society of Thrombosis and Haemostasis (ISTH) criteria</description>
        <time_frame>Day 30 ± 2 days</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Full Dose LMWH Anticoagulation Therapy</title>
            <description>Subjects in this study arm will be treated with therapeutic doses of subcutaneous low-molecular-weight heparin (enoxaparin). Enoxaparin 1mg/kg SQ BID for CrCl ≥ 30ml/min (or Enoxaparin 0.5mg/kg SQ BID for CrCl ≥ 15ml/min and &lt; 30ml/min) during the course of their hospitalization.&#xD;
Enoxaparin: Full Dose LMWH anticoagulation therapy</description>
          </group>
          <group group_id="O2">
            <title>Prophylactic/Intermediate Dose LMWH or UFH Therapy</title>
            <description>Subjects in this study arm will be treated with Local institutional standard-of-care for prophylactic-dose or intermediate-dose UFH or LMWH. Regimens allowed are UFH up to 22,500 IU daily in BID or TID doses (i.e. UFH 5000 IU SQ BID/TID or 7500 IU BID/TID), enoxaparin 30mg and 40mg SQ QD or BID (the use of weight-based enoxaparin i.e. 0.5mg/kg SQ BID for this arm is acceptable but strongly discouraged), dalteparin 2500IU or 5000IU QD.&#xD;
Prophylactic/Intermediate Dose Enoxaparin: Prophylactic/Intermediate Dose LMWH or UFH therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Major Bleeding</title>
          <description>Risk of major bleeding defined using the International Society of Thrombosis and Haemostasis (ISTH) criteria</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="129"/>
                <count group_id="O2" value="124"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Composite Outcome of Arterial Thromboembolic Events, Venous Thromboembolic Events and All-cause Mortality at Hospital Day 10 + 4</title>
        <description>The composite of arterial thromboembolic events (including myocardial infarction, stroke, systemic embolism), venous thromboembolism (including symptomatic deep vein thrombosis (DVT) of the upper or lower extremity, asymptomatic proximal DVT of the lower extremity, non-fatal pulmonary embolism (PE)), and all-cause mortality at Hospital Day 10 + 4</description>
        <time_frame>Day 10 + 4</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Full Dose LMWH Anticoagulation Therapy</title>
            <description>Subjects in this study arm will be treated with therapeutic doses of subcutaneous low-molecular-weight heparin (enoxaparin). Enoxaparin 1mg/kg SQ BID for CrCl ≥ 30ml/min (or Enoxaparin 0.5mg/kg SQ BID for CrCl ≥ 15ml/min and &lt; 30ml/min) during the course of their hospitalization.&#xD;
Enoxaparin: Full Dose LMWH anticoagulation therapy</description>
          </group>
          <group group_id="O2">
            <title>Prophylactic/Intermediate Dose LMWH or UFH Therapy</title>
            <description>Subjects in this study arm will be treated with Local institutional standard-of-care for prophylactic-dose or intermediate-dose UFH or LMWH. Regimens allowed are UFH up to 22,500 IU daily in BID or TID doses (i.e. UFH 5000 IU SQ BID/TID or 7500 IU BID/TID), enoxaparin 30mg and 40mg SQ QD or BID (the use of weight-based enoxaparin i.e. 0.5mg/kg SQ BID for this arm is acceptable but strongly discouraged), dalteparin 2500IU or 5000IU QD.&#xD;
Prophylactic/Intermediate Dose Enoxaparin: Prophylactic/Intermediate Dose LMWH or UFH therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Composite Outcome of Arterial Thromboembolic Events, Venous Thromboembolic Events and All-cause Mortality at Hospital Day 10 + 4</title>
          <description>The composite of arterial thromboembolic events (including myocardial infarction, stroke, systemic embolism), venous thromboembolism (including symptomatic deep vein thrombosis (DVT) of the upper or lower extremity, asymptomatic proximal DVT of the lower extremity, non-fatal pulmonary embolism (PE)), and all-cause mortality at Hospital Day 10 + 4</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="129"/>
                <count group_id="O2" value="124"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Sepsis-induced Coagulopathy (SIC) Score</title>
        <description>Sepsis-induced coagulopathy (SIC) score predicts likelihood of sepsis-induced coagulopathy based on ISTH guidelines.&#xD;
The score uses the following domains:&#xD;
Platelets, K/uL (thousands per microliter)&#xD;
INR (International Normalized Ratio)&#xD;
D-Dimer Level&#xD;
Fibrinogen&#xD;
Platelet count &gt; 100 cells x 10^9/L is 0 points, platelet count 50 to 100 cells x 10^9/L is 1 point and Platelet count &lt; 50 cells x 10^9/L is 2 points. INR &lt; 1.3 is 0 points, INR 1.3 to 1.7 is 1 point and INR &gt; 1.7 is 2 points. D-Dimer level &lt; 400 ng/mL is 0 points, D-Dimer level 400-4000 ng/mL is 2 points and D-Dimer level &gt; 4000 ng/mL is 3 points. Fibrinogen level &gt; 100 mg/dL is 0 points and fibrinogen level &lt; 100 mg/dL is 1 point.&#xD;
Calculated (SIC) scores yields a possible 0 to 6 points, where ≥4 predicts higher mortality rates within 30 days and greater risk of pulmonary embolism.</description>
        <time_frame>Day 30 ± 2 days.</time_frame>
        <population>COVID-19 patients have been noted to have significantly elevated markers of hypercoagulability including d-dimer (Dd), fibrinogen levels, FVIII levels, short activated partial thromboplastin time (aPTT) and Sepsis-Induced Coagulopathy (SIC) scores with an increase in venous thromboembolic disease as well as cardiac injury.</population>
        <group_list>
          <group group_id="O1">
            <title>Full Dose LMWH Anticoagulation Therapy</title>
            <description>Subjects in this study arm will be treated with therapeutic doses of subcutaneous low-molecular-weight heparin (enoxaparin). Enoxaparin 1mg/kg SQ BID for CrCl ≥ 30ml/min (or Enoxaparin 0.5mg/kg SQ BID for CrCl ≥ 15ml/min and &lt; 30ml/min) during the course of their hospitalization.&#xD;
Enoxaparin: Full Dose LMWH anticoagulation therapy</description>
          </group>
          <group group_id="O2">
            <title>Prophylactic/Intermediate Dose LMWH or UFH Therapy</title>
            <description>Subjects in this study arm will be treated with Local institutional standard-of-care for prophylactic-dose or intermediate-dose UFH or LMWH. Regimens allowed are UFH up to 22,500 IU daily in BID or TID doses (i.e. UFH 5000 IU SQ BID/TID or 7500 IU BID/TID), enoxaparin 30mg and 40mg SQ QD or BID (the use of weight-based enoxaparin i.e. 0.5mg/kg SQ BID for this arm is acceptable but strongly discouraged), dalteparin 2500IU or 5000IU QD.&#xD;
Prophylactic/Intermediate Dose Enoxaparin: Prophylactic/Intermediate Dose LMWH or UFH therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Sepsis-induced Coagulopathy (SIC) Score</title>
          <description>Sepsis-induced coagulopathy (SIC) score predicts likelihood of sepsis-induced coagulopathy based on ISTH guidelines.&#xD;
The score uses the following domains:&#xD;
Platelets, K/uL (thousands per microliter)&#xD;
INR (International Normalized Ratio)&#xD;
D-Dimer Level&#xD;
Fibrinogen&#xD;
Platelet count &gt; 100 cells x 10^9/L is 0 points, platelet count 50 to 100 cells x 10^9/L is 1 point and Platelet count &lt; 50 cells x 10^9/L is 2 points. INR &lt; 1.3 is 0 points, INR 1.3 to 1.7 is 1 point and INR &gt; 1.7 is 2 points. D-Dimer level &lt; 400 ng/mL is 0 points, D-Dimer level 400-4000 ng/mL is 2 points and D-Dimer level &gt; 4000 ng/mL is 3 points. Fibrinogen level &gt; 100 mg/dL is 0 points and fibrinogen level &lt; 100 mg/dL is 1 point.&#xD;
Calculated (SIC) scores yields a possible 0 to 6 points, where ≥4 predicts higher mortality rates within 30 days and greater risk of pulmonary embolism.</description>
          <population>COVID-19 patients have been noted to have significantly elevated markers of hypercoagulability including d-dimer (Dd), fibrinogen levels, FVIII levels, short activated partial thromboplastin time (aPTT) and Sepsis-Induced Coagulopathy (SIC) scores with an increase in venous thromboembolic disease as well as cardiac injury.</population>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="129"/>
                <count group_id="O2" value="124"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.35" spread="0.73"/>
                    <measurement group_id="O2" value="2.31" spread="0.85"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression to Acute Respiratory Distress Syndrome (ARDS)</title>
        <description>Progression to Acute Respiratory Distress Syndrome (ARDS) based on monitoring of patient conditions.</description>
        <time_frame>Day 30 ± 2 days.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Full Dose LMWH Anticoagulation Therapy</title>
            <description>Subjects in this study arm will be treated with therapeutic doses of subcutaneous low-molecular-weight heparin (enoxaparin). Enoxaparin 1mg/kg SQ BID for CrCl ≥ 30ml/min (or Enoxaparin 0.5mg/kg SQ BID for CrCl ≥ 15ml/min and &lt; 30ml/min) during the course of their hospitalization.&#xD;
Enoxaparin: Full Dose LMWH anticoagulation therapy</description>
          </group>
          <group group_id="O2">
            <title>Prophylactic/Intermediate Dose LMWH or UFH Therapy</title>
            <description>Subjects in this study arm will be treated with Local institutional standard-of-care for prophylactic-dose or intermediate-dose UFH or LMWH. Regimens allowed are UFH up to 22,500 IU daily in BID or TID doses (i.e. UFH 5000 IU SQ BID/TID or 7500 IU BID/TID), enoxaparin 30mg and 40mg SQ QD or BID (the use of weight-based enoxaparin i.e. 0.5mg/kg SQ BID for this arm is acceptable but strongly discouraged), dalteparin 2500IU or 5000IU QD.&#xD;
Prophylactic/Intermediate Dose Enoxaparin: Prophylactic/Intermediate Dose LMWH or UFH therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Progression to Acute Respiratory Distress Syndrome (ARDS)</title>
          <description>Progression to Acute Respiratory Distress Syndrome (ARDS) based on monitoring of patient conditions.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="127"/>
                <count group_id="O2" value="121"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11"/>
                    <measurement group_id="O2" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Need for Intubation</title>
        <description>Need for Intubation will be based on monitoring of patient conditions.</description>
        <time_frame>Day 30 ± 2 days.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Full Dose LMWH Anticoagulation Therapy</title>
            <description>Subjects in this study arm will be treated with therapeutic doses of subcutaneous low-molecular-weight heparin (enoxaparin). Enoxaparin 1mg/kg SQ BID for CrCl ≥ 30ml/min (or Enoxaparin 0.5mg/kg SQ BID for CrCl ≥ 15ml/min and &lt; 30ml/min) during the course of their hospitalization.&#xD;
Enoxaparin: Full Dose LMWH anticoagulation therapy</description>
          </group>
          <group group_id="O2">
            <title>Prophylactic/Intermediate Dose LMWH or UFH Therapy</title>
            <description>Subjects in this study arm will be treated with Local institutional standard-of-care for prophylactic-dose or intermediate-dose UFH or LMWH. Regimens allowed are UFH up to 22,500 IU daily in BID or TID doses (i.e. UFH 5000 IU SQ BID/TID or 7500 IU BID/TID), enoxaparin 30mg and 40mg SQ QD or BID (the use of weight-based enoxaparin i.e. 0.5mg/kg SQ BID for this arm is acceptable but strongly discouraged), dalteparin 2500IU or 5000IU QD.&#xD;
Prophylactic/Intermediate Dose Enoxaparin: Prophylactic/Intermediate Dose LMWH or UFH therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Need for Intubation</title>
          <description>Need for Intubation will be based on monitoring of patient conditions.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="122"/>
                <count group_id="O2" value="121"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="17"/>
                    <measurement group_id="O2" value="21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Re-hospitalization</title>
        <description>Need for Re-hospitalization will be based on monitoring of patient conditions.</description>
        <time_frame>Day 30 ± 2 days.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Full Dose LMWH Anticoagulation Therapy</title>
            <description>Subjects in this study arm will be treated with therapeutic doses of subcutaneous low-molecular-weight heparin (enoxaparin). Enoxaparin 1mg/kg SQ BID for CrCl ≥ 30ml/min (or Enoxaparin 0.5mg/kg SQ BID for CrCl ≥ 15ml/min and &lt; 30ml/min) during the course of their hospitalization.&#xD;
Enoxaparin: Full Dose LMWH anticoagulation therapy</description>
          </group>
          <group group_id="O2">
            <title>Prophylactic/Intermediate Dose LMWH or UFH Therapy</title>
            <description>Subjects in this study arm will be treated with Local institutional standard-of-care for prophylactic-dose or intermediate-dose UFH or LMWH. Regimens allowed are UFH up to 22,500 IU daily in BID or TID doses (i.e. UFH 5000 IU SQ BID/TID or 7500 IU BID/TID), enoxaparin 30mg and 40mg SQ QD or BID (the use of weight-based enoxaparin i.e. 0.5mg/kg SQ BID for this arm is acceptable but strongly discouraged), dalteparin 2500IU or 5000IU QD.&#xD;
Prophylactic/Intermediate Dose Enoxaparin: Prophylactic/Intermediate Dose LMWH or UFH therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Re-hospitalization</title>
          <description>Need for Re-hospitalization will be based on monitoring of patient conditions.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="129"/>
                <count group_id="O2" value="124"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From screening/randomization, adverse event data was monitored and collected for each participant for 30 days (± 2 days), which was their duration in the study.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Full Dose LMWH Anticoagulation Therapy</title>
          <description>Subjects in this study arm will be treated with therapeutic doses of subcutaneous low-molecular-weight heparin (enoxaparin). Enoxaparin 1mg/kg SQ BID for CrCl ≥ 30ml/min (or Enoxaparin 0.5mg/kg SQ BID for CrCl ≥ 15ml/min and &lt; 30ml/min) during the course of their hospitalization.&#xD;
Enoxaparin: Full Dose LMWH anticoagulation therapy</description>
        </group>
        <group group_id="E2">
          <title>Prophylactic/Intermediate Dose LMWH or UFH Therapy</title>
          <description>Subjects in this study arm will be treated with Local institutional standard-of-care for prophylactic-dose or intermediate-dose UFH or LMWH. Regimens allowed are UFH up to 22,500 IU daily in BID or TID doses (i.e. UFH 5000 IU SQ BID/TID or 7500 IU BID/TID), enoxaparin 30mg and 40mg SQ QD or BID (the use of weight-based enoxaparin i.e. 0.5mg/kg SQ BID for this arm is acceptable but strongly discouraged), dalteparin 2500IU or 5000IU QD.&#xD;
Prophylactic/Intermediate Dose Enoxaparin: Prophylactic/Intermediate Dose LMWH or UFH therapy</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (10.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="25" subjects_at_risk="129"/>
                <counts group_id="E2" subjects_affected="31" subjects_at_risk="124"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="129"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="124"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Thrombocytopenia</sub_title>
                <description>Patient was found to have low platelets during this admission. Low platelets were probably due to the blood thinner she was taking (lovenox). Excessive bruising and ecchymosis.</description>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="129"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="124"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="129"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="124"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Alex Spyropoulos, MD</name_or_title>
      <organization>System Director - Anticoagulation and Clinical Thrombosis Services Northwell Health at Lenox Hill Hospital Affiliation: Northwell Health</organization>
      <phone>(212) 434-6776</phone>
      <email>aspyropoul@northwell.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT04401293
org study id: 20-0340
nct id: NCT04401293
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
The aim of this study is to test the hypothesis that prophylaxis of severe COVID-19 patients
      with treatment dose LMWH leads to better thromboembolic-free outcomes and associated
      complications during hospitalization than prophylaxis with institutional standard of care
      with prophylactic to intermediate-doses of UFH or LMWH
There are clinical data to support the observation that hospitalized acutely ill medical
      patients with severe viral pneumonitis/Acute Respiratory Distress Syndrome (ARDS), such as
      those with influenza H1N1 infection, have an over 23-fold increased risk for venous
      thromboembolism (VTE) - especially pulmonary embolism (PE) - with an overall 44% incidence of
      VTE in ARDS associated with H1N1 pneumonia. Multicenter studies from China report that key
      markers of inflammation and/or coagulopathy are associated with morbidity and increased
      mortality in COVID-19 patients. Elevated D-dimer levels (that are sometime greater than 4 or
      6 times the upper limit of normal [ULN]) are strongly associated with mortality in patients
      with severe COVID-19 illness. Recent data also shows that mortality among COVID-19 patients
      is markedly higher in patients with elevated Troponin-T (TnT) levels than in patients with
      normal TnT levels. Recently a cohort of 81 patients retrospectively evaluated diagnosed with
      severe COVID-19 pneumonia and reported a lower extremity VTE incidence of 25% (20/81) and a
      mortality of 40% (8/20) in the presence of VTE. Reported a case of bilateral pulmonary
      embolism in a 75 year old woman diagnosed with severe COVID-19, in the absence of
      predisposing risk factors and a negative lower extremity US. Lastly the investigated use of
      Tissue Plasminogen Activator (tPA) in the treatment of COVID-19 associated ARDS and reported
      promising, but transient, results in terms of pulmonary function improvement. It appears that
      either the SARS-CoV2 infection itself induces a hypercoagulable state, possibly by
      hypofibrinolytic mechanisms, or the cytokine storm in COVID-19 patients with severe disease
      induces a prothrombotic state, which leads to clinical deterioration, hypoxia and hemodynamic
      instability secondary to thromboembolic phenomena and potentially cardiac ischemia.
      Preliminary data from Northwell Health System, which has one of the largest populations of
      hospitalized COVID-19 patients in the US, reveals a positivity rate for deep vein thrombosis
      (DVT) of 40% of those COVID-19 patients screened by Doppler compression ultrasonography of
      the lower extremities.

      Heparin has been shown to have anti-inflammatory and immunomodulatory properties in addition
      to its anticoagulation effect, which could play a beneficial role in sepsis. In addition,
      there is in vitro evidence that the large negatively charged sulfated glycosaminoglycans of
      unfractionated heparin may act as an alternate ligand for the SARS-CoV2 receptor irrespective
      of ACE2. Whether this in vitro evidence supports the role of a protective or deleterious
      mechanism in COVID-19 infection is not known. However, an early report with empiric use of
      treatment dose unfractionated heparin (UFH) in ARDS from a different viral family, influenza
      H1N1, revealed that H1N1 ARDS patients under systemic anticoagulation had 33-fold fewer VTE
      events than those treated given prophylactic doses of UFH/low-molecular weight heparin (LMWH)
      thromboprophylaxis. Very recent evidence suggests that therapy with prophylactic to
      intermediate doses of the LMWH enoxaparin (30mg to 60mg QD) in severe hospitalized COVID-19
      patents with a SIC score ≥ 4 or D-dimer (Dd) > 6 X ULN improves outcomes and prognosis.
      All-cause mortality at 28 days was reduced from 64.2% to 40.0% in those patients with a SIC
      score ≥ 4 (p=0.029), and from 52.4% to 32.8% in those patients with an elevated Dd > 6 x ULN
      (P=0.017). Notably, Klok and colleagues investigated 184 ICU patients infected with COVID-19
      and reported a 13% mortality rate, a relatively high incidence of CTPA- or
      ultrasonography-confirmed VTE rate (27%), and arterial thrombotic events (3.7%) despite the
      use of standard dose thromboprophylaxis. Postulated mechanisms for the improved prognosis
      with the use of treatment doses of LMWH in the sick COVID-19 population include the decrease
      in the risk of microthrombi, especially in the pulmonary vasculature, which can lead to
      hypoxemia, pulmonary vasoconstriction and right ventricular dysfunction as well as the
      decrease in the risk of progression to disseminated intravascular coagulopathy as a
      contributor to the high mortality seen in these patients.

      The optimal dose of heparin (either LMWH or UFH) in hospitalized COVID-19 patients is
      unknown, as patients on conventional prophylactic dose heparin (UFH or LMWH) as supported by
      international guidance statements on hospitalized COVID-19 patients appear to remain at risk
      for thromboembolic events. There is data to support improved efficacy with treatment doses of
      twice daily enoxaparin versus once-daily weight-adjusted enoxaparin for the management of
      VTE, especially with large thrombus burden. There is also long-standing data to support that
      treatment-dose heparin can reduce major cardiovascular events. Our current standard of care
      in our 24 hospital Northwell Health System, which has a very large hospitalized COVID-19
      patient population, is to use Lovenox 40mg SQ QD for patients with a BMI < 30 and Creatinine
      Clearance (CrCl) > 15ml/min, Lovenox 40mg SQ BID for patients with a BMI > 30 and CrCl >
      15ml/min, and UFH 5000U SQ BID or TID in patients with a CrCl < 15ml/min and BMI < 30 and UFH
      7500U SQ BID or TID with a CrCl < 15ml/min and BMI > 30. Large healthcare institutions in the
      US and elsewhere have protocols for in-patient thromboprophylaxis ranging from
      prophylactic-to-intermediate dose UFH or LMWH for the management of patients with COVID-19
      associated coagulopathy. The aim of this study is to test the hypothesis that prophylaxis of
      severe COVID-19 patients with treatment dose LMWH leads to better thromboembolic-free
      outcomes and associated complications during hospitalization than prophylaxis with
      institutional standard of care with prophylactic to intermediate-doses of UFH or LMWH.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
masking description: Due to the pragmatic nature of this study "open-label multi-center randomized active control trial" with pseudo-blinding mechanisms at the time of randomization the study subject and corresponding Site PIs will be blinded (unaware of specific treatment arm the patient is assigned to i.e. Arm 0 or Arm 1). The study pharmacists as well as data extractors and designated randomization personnel (i.e. research coordinators and/or research nurses performing the randomization process) will be un-blinded (aware of specific treatment arm the patient is assigned to i.e. Arm 0 or Arm 1). At the time of subject randomization study subjects will be stratified to either ICU level of care vs. Non-ICU level of care.
measure: Composite Outcome of Arterial Thromboembolic Events, Venous Thromboembolic Events and All-cause Mortality at Day 30 ± 2 Days.
time frame: Day 30 ± 2 days
description: Risk of arterial thromboembolic events (including myocardial infarction, stroke, systemic embolism), venous thromboembolism (including symptomatic deep vein thrombosis (DVT) of the upper or lower extremity, asymptomatic proximal DVT of the lower extremity, non-fatal pulmonary embolism (PE)), and all-cause mortality at Day 30 ± 2 days.
measure: Major Bleeding
time frame: Day 30 ± 2 days
description: Risk of major bleeding defined using the International Society of Thrombosis and Haemostasis (ISTH) criteria
measure: Composite Outcome of Arterial Thromboembolic Events, Venous Thromboembolic Events and All-cause Mortality at Hospital Day 10 + 4
time frame: Day 10 + 4
description: The composite of arterial thromboembolic events (including myocardial infarction, stroke, systemic embolism), venous thromboembolism (including symptomatic deep vein thrombosis (DVT) of the upper or lower extremity, asymptomatic proximal DVT of the lower extremity, non-fatal pulmonary embolism (PE)), and all-cause mortality at Hospital Day 10 + 4
measure: Sepsis-induced Coagulopathy (SIC) Score
time frame: Day 30 ± 2 days.
description: Sepsis-induced coagulopathy (SIC) score predicts likelihood of sepsis-induced coagulopathy based on ISTH guidelines.
The score uses the following domains:
Platelets, K/uL (thousands per microliter)
INR (International Normalized Ratio)
D-Dimer Level
Fibrinogen
Platelet count > 100 cells x 10^9/L is 0 points, platelet count 50 to 100 cells x 10^9/L is 1 point and Platelet count < 50 cells x 10^9/L is 2 points. INR < 1.3 is 0 points, INR 1.3 to 1.7 is 1 point and INR > 1.7 is 2 points. D-Dimer level < 400 ng/mL is 0 points, D-Dimer level 400-4000 ng/mL is 2 points and D-Dimer level > 4000 ng/mL is 3 points. Fibrinogen level > 100 mg/dL is 0 points and fibrinogen level < 100 mg/dL is 1 point.
Calculated (SIC) scores yields a possible 0 to 6 points, where ≥4 predicts higher mortality rates within 30 days and greater risk of pulmonary embolism.
measure: Progression to Acute Respiratory Distress Syndrome (ARDS)
time frame: Day 30 ± 2 days.
description: Progression to Acute Respiratory Distress Syndrome (ARDS) based on monitoring of patient conditions.
measure: Need for Intubation
time frame: Day 30 ± 2 days.
description: Need for Intubation will be based on monitoring of patient conditions.
measure: Re-hospitalization
time frame: Day 30 ± 2 days.
description: Need for Re-hospitalization will be based on monitoring of patient conditions.
arm group label: Full Dose LMWH anticoagulation therapy
arm group type: Experimental
description: Subjects in this study arm will be treated with therapeutic doses of subcutaneous low-molecular-weight heparin (enoxaparin). Enoxaparin 1mg/kg SQ BID for CrCl ≥ 30ml/min (or Enoxaparin 0.5mg/kg SQ BID for CrCl ≥ 15ml/min and < 30ml/min) during the course of their hospitalization.
arm group label: Prophylactic/Intermediate Dose LMWH or UFH therapy
arm group type: Active Comparator
description: Subjects in this study arm will be treated with Local institutional standard-of-care for prophylactic-dose or intermediate-dose UFH or LMWH. Regimens allowed are UFH up to 22,500 IU daily in BID or TID doses (i.e. UFH 5000 IU SQ BID/TID or 7500 IU BID/TID), enoxaparin 30mg and 40mg SQ QD or BID (the use of weight-based enoxaparin i.e. 0.5mg/kg SQ BID for this arm is acceptable but strongly discouraged), dalteparin 2500IU or 5000IU QD.
intervention type: Drug
intervention name: Enoxaparin
description: Full Dose LMWH anticoagulation therapy
arm group label: Full Dose LMWH anticoagulation therapy
intervention type: Drug
intervention name: Prophylactic/Intermediate Dose Enoxaparin
description: Prophylactic/Intermediate Dose LMWH or UFH therapy
arm group label: Prophylactic/Intermediate Dose LMWH or UFH therapy
other name: Unfractionated heparin
other name: dalteparin
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Alex C Spyropoulos, MD
role: Principal Investigator
affiliation: Northwell Health
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
url: https://doi.org/10.1016/j.jacc.2020.03.031
description: Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the Coronavirus Disease 2019 (COVID-19) Pandemic
url: https://doi.org/10.1016/j.jvsv.2018.08.010
description: Empirical systemic anticoagulation is associated with decreased venous thromboembolism in critically ill influenza A H1N1 acute respiratory distress syndrome patients
url: https://doi.org/10.1111/jth.14768
description: Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia
url: https://doi.org/10.1111/jth.14817
description: Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy
url: https://doi.org/10.1001/jamacardio.2020.1017
description: Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19)
url: https://doi.org/10.1111/jth.14830
description: Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia
url: https://doi.org/10.1093/eurheartj/ehaa254
description: Acute pulmonary embolism and COVID-19 pneumonia: a random association
url: https://doi.org/10.1111/jth.14828
description: Tissue Plasminogen Activator (tPA) Treatment for COVID-19 Associated Acute Respiratory Distress Syndrome (ARDS): A Case Series
url: https://doi.org/10.1124/pr.115.011247
description: Pharmacology of Heparin and Related Drugs
url: https://doi.org/10.1016/j.thromres.2020.04.013
description: Incidence of thrombotic complications in critically ill ICU patients with COVID-19
url: https://doi.org/10.1016/j.jacc.2018.01.033
description: Bivalirudin or Heparin in Patients Undergoing Invasive Management of Acute Coronary Syndromes
url: https://doi.org/10.1002/rth2.12358
description: Emergence of Institutional Antithrombotic Protocols for Coronavirus 2019
responsible party type: Principal Investigator
investigator affiliation: Northwell Health
investigator full name: Alex Spyropoulos
investigator title: System Director - Anticoagulation and Clinical Thrombosis Services Northwell Health at Lenox Hill Hospital
mesh term: COVID-19
mesh term: Heparin
mesh term: Enoxaparin
mesh term: Calcium heparin
mesh term: Dalteparin
mesh term: Enoxaparin sodium
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 