<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/NCT04492254</url>
  </required_header>
  <id_info>
    <org_study_id>TRI-08892</org_study_id>
    <secondary_id>2020-003125-39</secondary_id>
    <nct_id>NCT04492254</nct_id>
  </id_info>
  <brief_title>Early Prophylactic Low-molecular-weight Heparin (LMWH) in Symptomatic COVID-19 Positive Patients</brief_title>
  <acronym>ETHIC</acronym>
  <official_title>Early Thromboprophylaxis in COVID-19 (ETHIC Trial): an Open Label, Randomized Phase IIIb Trial of Community-based (LMWH) Versus Standard of Care (no Enoxaparin) in COVID-19 Positive Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Thrombosis Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Sanofi</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Thrombosis Research Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Evidence has shown that COVID-19 infections can lead to an increased risk of blood clots.&#xD;
      These blood clots can lead to individuals being admitted to hospital, or, unfortunately in&#xD;
      severe cases, death. Enoxaparin is a blood-thinning drug which has been used by doctors and&#xD;
      nurses in hospitals for many years to prevent the thickening of blood which may lead to a&#xD;
      clot. It is easier for doctors to prevent new blood clots from forming than treating existing&#xD;
      blood clots.&#xD;
&#xD;
      Currently, there are no treatments for COVID-19. There is an urgent need to find a safe and&#xD;
      effective treatment to prevent worsening of the disease that may lead to hospital admission&#xD;
      and/or death. The ETHIC (Early Thromboprophylaxis in COVID-19) study aims to find out if&#xD;
      giving enoxaparin in an early stage of the COVID-19 disease can prevent individuals being&#xD;
      admitted to hospital and/or death. The study will take place in approximately 8 to 10&#xD;
      countries, in approximately 30 to 50 centres.&#xD;
&#xD;
      Patients will be allowed to take part if they have had a confirmed COVID-19 infection, are ≥&#xD;
      55 years of age and have at least two of the following additional risk factors; age ≥ 70&#xD;
      years, body mass index &gt; 25 kg/m2, chronic obstructive pulmonary disease, diabetes,&#xD;
      cardiovascular disease, or corticosteroid use.&#xD;
&#xD;
      Half the patients in the study will receive the blood-thinning drug enoxaparin for three&#xD;
      weeks, and half will receive no treatment. Individuals will be randomly allocated to one of&#xD;
      these groups. After 21 days, the number of patients in each group who were either admitted to&#xD;
      hospital, or died, will be compared. The number of patients in each group who developed a&#xD;
      blood clot (venous thromboembolism) will also be compared. Further comparisons will be made&#xD;
      at both 50 and 90 days after the beginning of the study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an open label randomized controlled trial of symptomatic individuals with confirmed&#xD;
      COVID-19 in a community setting.&#xD;
&#xD;
      Justification: There is currently no standard of care treatment for Covid-19.&#xD;
&#xD;
      Upon enrolment into the study, patients will be randomised to receive either enoxaparin (40&#xD;
      mg once per day if &lt; 100 kg, 40 mg twice per day if ≥ 100 kg) or the current standard of care&#xD;
      (no enoxaparin) for three weeks (21 days). Randomisation must occur within 5 days of the&#xD;
      SARS-CoV-2 test. Data will be collected at baseline and 21 days, with further assessments at&#xD;
      50 and 90 days.&#xD;
&#xD;
      Participants randomised to enoxaparin will receive pre-loaded syringes as part of the study,&#xD;
      and information regarding self-administration will be provided by the sponsor. Participants&#xD;
      in the control arm of this study will receive no treatment (current standard of care).&#xD;
&#xD;
      Screening Phase:&#xD;
&#xD;
      Investigator sites will be selected to represent community care in each country (from general&#xD;
      practice/office based care settings, testing centres and hospitals) and invited to&#xD;
      participate. All individuals satisfying the inclusion/exclusion criteria will be considered&#xD;
      for enrolment and their medical history checked to exclude any patients not suitable.&#xD;
&#xD;
      Participants will be provided with a patient information sheet and consent form (PISCF),&#xD;
      either paper or an electronic version. All participants must provide informed consent by&#xD;
      reviewing and discussing the PISCF and by completing and signing the consent form (paper&#xD;
      version or the electronic version). Once informed consent has been obtained, data related to&#xD;
      baseline will be collected from a review of the participants' medical records and entered&#xD;
      into the electronic data capture system.&#xD;
&#xD;
      Treatment Phase:&#xD;
&#xD;
      Data related to clinical outcomes for both the primary outcome (composite of hospitalisation&#xD;
      and/or death) and secondary safety outcome (major bleeding) will be measured at 21 days. This&#xD;
      time point will be used as a marker for collection of all data from the preceding period.&#xD;
&#xD;
      Safety and Monitoring Phase:&#xD;
&#xD;
      Data related to all outcomes will be again measured at 50 days. This time point will be used&#xD;
      as a marker for collection of all data from the preceding period to evaluate the incidence of&#xD;
      bleeding in all participants.&#xD;
&#xD;
      End of Study and Follow-up Phase:&#xD;
&#xD;
      The outcomes of death and hospitalisation will be further recorded 90 days after&#xD;
      randomisation. This time point will be used as a marker for collection of all information&#xD;
      from the interim period. The end of the trial will occur immediately following the last&#xD;
      visit/data item of the last patient undergoing the trial. The aim of data collection will be&#xD;
      to accurately capture all planned and unplanned visits, interruptions to treatment and&#xD;
      events.&#xD;
&#xD;
      In case no patient data have been recorded in the participant's medical records at the site&#xD;
      during the months following the last data entry, a follow-up phone contact will be made by&#xD;
      the site and documented to verify that all events are being captured and participants are not&#xD;
      lost to follow up.&#xD;
&#xD;
      The schedule of assessments is as follows: Reference: Section 6.5 of the protocol. Pages 27&#xD;
      to 29.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Average event rate (end point) was much lower than expected. A larger sample size would have&#xD;
    been required to maintain same statistical power, which was not achievable in a feasible time&#xD;
    scale. No safety concerns were identified with bleeding.&#xD;
  </why_stopped>
  <start_date type="Actual">October 27, 2020</start_date>
  <completion_date type="Actual">November 29, 2021</completion_date>
  <primary_completion_date type="Actual">November 29, 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>
    <intervention_model_description>Open label, multicentre, multi-national, randomized controlled trial.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Hospital Admission</measure>
    <time_frame>21 days</time_frame>
    <description>Hospital admission including:&#xD;
Pneumonia Acute Respiratory distress syndrome Admission to intensive care unit (ICU) Mechanical ventilation (MV)/intubation requirement Continuous positive airway pressure (CPAP)/Non-invasive ventilation Extracorporeal membrane oxygenation (ECMO)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Hospital Admission</measure>
    <time_frame>50 days</time_frame>
    <description>Hospital admission including:&#xD;
Pneumonia Acute Respiratory distress syndrome Admission to intensive care unit (ICU) Mechanical ventilation (MV)/intubation requirement Continuous positive airway pressure (CPAP)/Non-invasive ventilation Extracorporeal membrane oxygenation (ECMO)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Hospital Admission</measure>
    <time_frame>90 days</time_frame>
    <description>Hospital admission including:&#xD;
Pneumonia Acute Respiratory distress syndrome Admission to intensive care unit (ICU) Mechanical ventilation (MV)/intubation requirement Continuous positive airway pressure (CPAP)/Non-invasive ventilation Extracorporeal membrane oxygenation (ECMO)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Death</measure>
    <time_frame>21 days</time_frame>
    <description>All-cause Cardiovascular Non-Cardiovascular Specific causes Fatal bleed</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Death</measure>
    <time_frame>50 days</time_frame>
    <description>All-cause Cardiovascular Non-Cardiovascular Specific causes Fatal bleed</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Death</measure>
    <time_frame>90 days</time_frame>
    <description>All-cause Cardiovascular Non-Cardiovascular Specific causes Fatal bleed</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Bleeding (as defined by ISTH criteria)</measure>
    <time_frame>21 and 50 days</time_frame>
    <description>Frequency Location Treatment (transfusion and units of blood products transfused) Severity (classified as major, clinically relevant non-major and minor)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Diagnosis of VTE</measure>
    <time_frame>21, 50 and 90 days</time_frame>
    <description>Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">219</enrollment>
  <condition>COVID-19</condition>
  <arm_group>
    <arm_group_label>Enoxaparin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>(40 mg o/d if &lt; 100 kg, 40 mg b/d if ≥ 100 kg)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Current standard of care (no enoxaparin)</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Standard of care</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Enoxaparin</intervention_name>
    <description>The treatment provided will be enoxaparin sodium 40mg/0.4 mL. All doses will be provided in pre-filled, single-dose syringes for subcutaneous injection.</description>
    <arm_group_label>Enoxaparin</arm_group_label>
    <other_name>Lovenox/Clexane</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Signed Informed consent&#xD;
&#xD;
          -  Confirmed COVID-19 (i.e. symptoms + positive test for SARS-CoV-2)&#xD;
&#xD;
          -  Male or female, age ≥ 55 years&#xD;
&#xD;
          -  At least two of the following additional risk factors:&#xD;
&#xD;
        Age ≥ 70 years Body mass index &gt; 25 kg/m2 Chronic obstructive pulmonary disease (COPD)*&#xD;
        Diabetes* Cardiovascular disease* Corticosteroid use&#xD;
&#xD;
        *Defined as any disease requiring medical intervention or treatment.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Contraindications to unfractionated heparin or LMWH&#xD;
&#xD;
          -  Recent (&lt;48 hours) or planned spinal or epidural anesthesia or puncture, PCI or&#xD;
             thrombolytic therapy within the preceding 24 hours&#xD;
&#xD;
          -  Increased risk for bleeding complications&#xD;
&#xD;
          -  Pregnant women&#xD;
&#xD;
          -  Severe renal impairment (GFR &lt; 30 mL/min)&#xD;
&#xD;
          -  Receiving any antiplatelet therapy (with the exception of low dose (≤100mg) aspirin)&#xD;
             or anticoagulant therapy (e.g. VKA, DOAC)&#xD;
&#xD;
          -  Patients participating in an interventional study that is outside the purview of TRI&#xD;
             sponsored studies.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>55 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ajay Kakkar</last_name>
    <role>Study Director</role>
    <affiliation>Thrombosis Research Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Harry Gibbs, National Co-ordinating Investigator, The Alfred Hospital</name>
      <address>
        <city>Melbourne</city>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dr Frank Cools, National Co-ordinating Investigator, AZ Klina</name>
      <address>
        <city>Brasschaat</city>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Prof. Barry Jacobson, National Coordinating Investigator, University of the Witwatersrand</name>
      <address>
        <city>Johannesburg</city>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>Belgium</country>
    <country>South Africa</country>
  </location_countries>
  <reference>
    <citation>Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020 Apr;18(4):844-847. doi: 10.1111/jth.14768. Epub 2020 Mar 13.</citation>
    <PMID>32073213</PMID>
  </reference>
  <reference>
    <citation>Spiezia L, Boscolo A, Poletto F, Cerruti L, Tiberio I, Campello E, Navalesi P, Simioni P. COVID-19-Related Severe Hypercoagulability in Patients Admitted to Intensive Care Unit for Acute Respiratory Failure. Thromb Haemost. 2020 Jun;120(6):998-1000. doi: 10.1055/s-0040-1710018. Epub 2020 Apr 21.</citation>
    <PMID>32316063</PMID>
  </reference>
  <reference>
    <citation>Escher R, Breakey N, Lammle B. Severe COVID-19 infection associated with endothelial activation. Thromb Res. 2020 Jun;190:62. doi: 10.1016/j.thromres.2020.04.014. Epub 2020 Apr 15. No abstract available.</citation>
    <PMID>32305740</PMID>
  </reference>
  <reference>
    <citation>Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020 May;18(5):1094-1099. doi: 10.1111/jth.14817. Epub 2020 Apr 27.</citation>
    <PMID>32220112</PMID>
  </reference>
  <reference>
    <citation>Peng YD, Meng K, Guan HQ, Leng L, Zhu RR, Wang BY, He MA, Cheng LX, Huang K, Zeng QT. [Clinical characteristics and outcomes of 112 cardiovascular disease patients infected by 2019-nCoV]. Zhonghua Xin Xue Guan Bing Za Zhi. 2020 Jun 24;48(6):450-455. doi: 10.3760/cma.j.cn112148-20200220-00105. Chinese.</citation>
    <PMID>32120458</PMID>
  </reference>
  <reference>
    <citation>Lighter J, Phillips M, Hochman S, Sterling S, Johnson D, Francois F, Stachel A. Obesity in Patients Younger Than 60 Years Is a Risk Factor for COVID-19 Hospital Admission. Clin Infect Dis. 2020 Jul 28;71(15):896-897. doi: 10.1093/cid/ciaa415. No abstract available.</citation>
    <PMID>32271368</PMID>
  </reference>
  <reference>
    <citation>Verity R, Okell LC, Dorigatti I, Winskill P, Whittaker C, Imai N, Cuomo-Dannenburg G, Thompson H, Walker PGT, Fu H, Dighe A, Griffin JT, Baguelin M, Bhatia S, Boonyasiri A, Cori A, Cucunuba Z, FitzJohn R, Gaythorpe K, Green W, Hamlet A, Hinsley W, Laydon D, Nedjati-Gilani G, Riley S, van Elsland S, Volz E, Wang H, Wang Y, Xi X, Donnelly CA, Ghani AC, Ferguson NM. Estimates of the severity of coronavirus disease 2019: a model-based analysis. Lancet Infect Dis. 2020 Jun;20(6):669-677. doi: 10.1016/S1473-3099(20)30243-7. Epub 2020 Mar 30. Erratum In: Lancet Infect Dis. 2020 Apr 15;: Lancet Infect Dis. 2020 May 4;:</citation>
    <PMID>32240634</PMID>
  </reference>
  <reference>
    <citation>Banerjee A, Pasea L, Harris S, Gonzalez-Izquierdo A, Torralbo A, Shallcross L, Noursadeghi M, Pillay D, Sebire N, Holmes C, Pagel C, Wong WK, Langenberg C, Williams B, Denaxas S, Hemingway H. Estimating excess 1-year mortality associated with the COVID-19 pandemic according to underlying conditions and age: a population-based cohort study. Lancet. 2020 May 30;395(10238):1715-1725. doi: 10.1016/S0140-6736(20)30854-0. Epub 2020 May 12.</citation>
    <PMID>32405103</PMID>
  </reference>
  <reference>
    <citation>Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005 Apr;3(4):692-4. doi: 10.1111/j.1538-7836.2005.01204.x.</citation>
    <PMID>15842354</PMID>
  </reference>
  <reference>
    <citation>Kaatz S, Ahmad D, Spyropoulos AC, Schulman S; Subcommittee on Control of Anticoagulation. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost. 2015 Nov;13(11):2119-26. doi: 10.1111/jth.13140. No abstract available.</citation>
    <PMID>26764429</PMID>
  </reference>
  <reference>
    <citation>Day M. Covid-19: four fifths of cases are asymptomatic, China figures indicate. BMJ. 2020 Apr 2;369:m1375. doi: 10.1136/bmj.m1375. No abstract available.</citation>
    <PMID>32241884</PMID>
  </reference>
  <reference>
    <citation>Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020 Mar 17;323(11):1061-1069. doi: 10.1001/jama.2020.1585. Erratum In: JAMA. 2021 Mar 16;325(11):1113.</citation>
    <PMID>32031570</PMID>
  </reference>
  <reference>
    <citation>Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24. Erratum In: Lancet. 2020 Jan 30;:</citation>
    <PMID>31986264</PMID>
  </reference>
  <reference>
    <citation>Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 28;395(10229):1033-1034. doi: 10.1016/S0140-6736(20)30628-0. Epub 2020 Mar 16. No abstract available.</citation>
    <PMID>32192578</PMID>
  </reference>
  <reference>
    <citation>Mousavi S, Moradi M, Khorshidahmad T, Motamedi M. Anti-Inflammatory Effects of Heparin and Its Derivatives: A Systematic Review. Adv Pharmacol Sci. 2015;2015:507151. doi: 10.1155/2015/507151. Epub 2015 May 12.</citation>
    <PMID>26064103</PMID>
  </reference>
  <reference>
    <citation>Proschan MA. Two-stage sample size re-estimation based on a nuisance parameter: a review. J Biopharm Stat. 2005;15(4):559-74. doi: 10.1081/BIP-200062852.</citation>
    <PMID>16022163</PMID>
  </reference>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>July 22, 2020</study_first_submitted>
  <study_first_submitted_qc>July 29, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 30, 2020</study_first_posted>
  <last_update_submitted>April 26, 2022</last_update_submitted>
  <last_update_submitted_qc>April 26, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 2, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Low Molecular Weight Heparin</keyword>
  <keyword>Enoxaparin</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>Enoxaparin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>December 2, 2022</submitted>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04492254
org study id: TRI-08892
secondary id: 2020-003125-39
nct id: NCT04492254
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Evidence has shown that COVID-19 infections can lead to an increased risk of blood clots.
      These blood clots can lead to individuals being admitted to hospital, or, unfortunately in
      severe cases, death. Enoxaparin is a blood-thinning drug which has been used by doctors and
      nurses in hospitals for many years to prevent the thickening of blood which may lead to a
      clot. It is easier for doctors to prevent new blood clots from forming than treating existing
      blood clots.

      Currently, there are no treatments for COVID-19. There is an urgent need to find a safe and
      effective treatment to prevent worsening of the disease that may lead to hospital admission
      and/or death. The ETHIC (Early Thromboprophylaxis in COVID-19) study aims to find out if
      giving enoxaparin in an early stage of the COVID-19 disease can prevent individuals being
      admitted to hospital and/or death. The study will take place in approximately 8 to 10
      countries, in approximately 30 to 50 centres.

      Patients will be allowed to take part if they have had a confirmed COVID-19 infection, are ≥
      55 years of age and have at least two of the following additional risk factors; age ≥ 70
      years, body mass index > 25 kg/m2, chronic obstructive pulmonary disease, diabetes,
      cardiovascular disease, or corticosteroid use.

      Half the patients in the study will receive the blood-thinning drug enoxaparin for three
      weeks, and half will receive no treatment. Individuals will be randomly allocated to one of
      these groups. After 21 days, the number of patients in each group who were either admitted to
      hospital, or died, will be compared. The number of patients in each group who developed a
      blood clot (venous thromboembolism) will also be compared. Further comparisons will be made
      at both 50 and 90 days after the beginning of the study.
This is an open label randomized controlled trial of symptomatic individuals with confirmed
      COVID-19 in a community setting.

      Justification: There is currently no standard of care treatment for Covid-19.

      Upon enrolment into the study, patients will be randomised to receive either enoxaparin (40
      mg once per day if < 100 kg, 40 mg twice per day if ≥ 100 kg) or the current standard of care
      (no enoxaparin) for three weeks (21 days). Randomisation must occur within 5 days of the
      SARS-CoV-2 test. Data will be collected at baseline and 21 days, with further assessments at
      50 and 90 days.

      Participants randomised to enoxaparin will receive pre-loaded syringes as part of the study,
      and information regarding self-administration will be provided by the sponsor. Participants
      in the control arm of this study will receive no treatment (current standard of care).

      Screening Phase:

      Investigator sites will be selected to represent community care in each country (from general
      practice/office based care settings, testing centres and hospitals) and invited to
      participate. All individuals satisfying the inclusion/exclusion criteria will be considered
      for enrolment and their medical history checked to exclude any patients not suitable.

      Participants will be provided with a patient information sheet and consent form (PISCF),
      either paper or an electronic version. All participants must provide informed consent by
      reviewing and discussing the PISCF and by completing and signing the consent form (paper
      version or the electronic version). Once informed consent has been obtained, data related to
      baseline will be collected from a review of the participants' medical records and entered
      into the electronic data capture system.

      Treatment Phase:

      Data related to clinical outcomes for both the primary outcome (composite of hospitalisation
      and/or death) and secondary safety outcome (major bleeding) will be measured at 21 days. This
      time point will be used as a marker for collection of all data from the preceding period.

      Safety and Monitoring Phase:

      Data related to all outcomes will be again measured at 50 days. This time point will be used
      as a marker for collection of all data from the preceding period to evaluate the incidence of
      bleeding in all participants.

      End of Study and Follow-up Phase:

      The outcomes of death and hospitalisation will be further recorded 90 days after
      randomisation. This time point will be used as a marker for collection of all information
      from the interim period. The end of the trial will occur immediately following the last
      visit/data item of the last patient undergoing the trial. The aim of data collection will be
      to accurately capture all planned and unplanned visits, interruptions to treatment and
      events.

      In case no patient data have been recorded in the participant's medical records at the site
      during the months following the last data entry, a follow-up phone contact will be made by
      the site and documented to verify that all events are being captured and participants are not
      lost to follow up.

      The schedule of assessments is as follows: Reference: Section 6.5 of the protocol. Pages 27
      to 29.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Open label, multicentre, multi-national, randomized controlled trial.
primary purpose: Treatment
masking: None (Open Label)
measure: Hospital Admission
time frame: 21 days
description: Hospital admission including:
Pneumonia Acute Respiratory distress syndrome Admission to intensive care unit (ICU) Mechanical ventilation (MV)/intubation requirement Continuous positive airway pressure (CPAP)/Non-invasive ventilation Extracorporeal membrane oxygenation (ECMO)
measure: Hospital Admission
time frame: 50 days
description: Hospital admission including:
Pneumonia Acute Respiratory distress syndrome Admission to intensive care unit (ICU) Mechanical ventilation (MV)/intubation requirement Continuous positive airway pressure (CPAP)/Non-invasive ventilation Extracorporeal membrane oxygenation (ECMO)
measure: Hospital Admission
time frame: 90 days
description: Hospital admission including:
Pneumonia Acute Respiratory distress syndrome Admission to intensive care unit (ICU) Mechanical ventilation (MV)/intubation requirement Continuous positive airway pressure (CPAP)/Non-invasive ventilation Extracorporeal membrane oxygenation (ECMO)
measure: Death
time frame: 21 days
description: All-cause Cardiovascular Non-Cardiovascular Specific causes Fatal bleed
measure: Death
time frame: 50 days
description: All-cause Cardiovascular Non-Cardiovascular Specific causes Fatal bleed
measure: Death
time frame: 90 days
description: All-cause Cardiovascular Non-Cardiovascular Specific causes Fatal bleed
measure: Bleeding (as defined by ISTH criteria)
time frame: 21 and 50 days
description: Frequency Location Treatment (transfusion and units of blood products transfused) Severity (classified as major, clinically relevant non-major and minor)
measure: Diagnosis of VTE
time frame: 21, 50 and 90 days
description: Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE)
arm group label: Enoxaparin
arm group type: Experimental
description: (40 mg o/d if < 100 kg, 40 mg b/d if ≥ 100 kg)
arm group label: Current standard of care (no enoxaparin)
arm group type: No Intervention
description: Standard of care
intervention type: Drug
intervention name: Enoxaparin
description: The treatment provided will be enoxaparin sodium 40mg/0.4 mL. All doses will be provided in pre-filled, single-dose syringes for subcutaneous injection.
arm group label: Enoxaparin
other name: Lovenox/Clexane
criteria: 
gender: All
minimum age: 55 Years
maximum age: N/A
healthy volunteers: No
last name: Ajay Kakkar
role: Study Director
affiliation: Thrombosis Research Institute
facility: 
facility: 
facility: 
country: Australia
country: Belgium
country: South Africa
citation: Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020 Apr;18(4):844-847. doi: 10.1111/jth.14768. Epub 2020 Mar 13.
PMID: 32073213
citation: Spiezia L, Boscolo A, Poletto F, Cerruti L, Tiberio I, Campello E, Navalesi P, Simioni P. COVID-19-Related Severe Hypercoagulability in Patients Admitted to Intensive Care Unit for Acute Respiratory Failure. Thromb Haemost. 2020 Jun;120(6):998-1000. doi: 10.1055/s-0040-1710018. Epub 2020 Apr 21.
PMID: 32316063
citation: Escher R, Breakey N, Lammle B. Severe COVID-19 infection associated with endothelial activation. Thromb Res. 2020 Jun;190:62. doi: 10.1016/j.thromres.2020.04.014. Epub 2020 Apr 15. No abstract available.
PMID: 32305740
citation: Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020 May;18(5):1094-1099. doi: 10.1111/jth.14817. Epub 2020 Apr 27.
PMID: 32220112
citation: Peng YD, Meng K, Guan HQ, Leng L, Zhu RR, Wang BY, He MA, Cheng LX, Huang K, Zeng QT. [Clinical characteristics and outcomes of 112 cardiovascular disease patients infected by 2019-nCoV]. Zhonghua Xin Xue Guan Bing Za Zhi. 2020 Jun 24;48(6):450-455. doi: 10.3760/cma.j.cn112148-20200220-00105. Chinese.
PMID: 32120458
citation: Lighter J, Phillips M, Hochman S, Sterling S, Johnson D, Francois F, Stachel A. Obesity in Patients Younger Than 60 Years Is a Risk Factor for COVID-19 Hospital Admission. Clin Infect Dis. 2020 Jul 28;71(15):896-897. doi: 10.1093/cid/ciaa415. No abstract available.
PMID: 32271368
citation: Verity R, Okell LC, Dorigatti I, Winskill P, Whittaker C, Imai N, Cuomo-Dannenburg G, Thompson H, Walker PGT, Fu H, Dighe A, Griffin JT, Baguelin M, Bhatia S, Boonyasiri A, Cori A, Cucunuba Z, FitzJohn R, Gaythorpe K, Green W, Hamlet A, Hinsley W, Laydon D, Nedjati-Gilani G, Riley S, van Elsland S, Volz E, Wang H, Wang Y, Xi X, Donnelly CA, Ghani AC, Ferguson NM. Estimates of the severity of coronavirus disease 2019: a model-based analysis. Lancet Infect Dis. 2020 Jun;20(6):669-677. doi: 10.1016/S1473-3099(20)30243-7. Epub 2020 Mar 30. Erratum In: Lancet Infect Dis. 2020 Apr 15;: Lancet Infect Dis. 2020 May 4;:
PMID: 32240634
citation: Banerjee A, Pasea L, Harris S, Gonzalez-Izquierdo A, Torralbo A, Shallcross L, Noursadeghi M, Pillay D, Sebire N, Holmes C, Pagel C, Wong WK, Langenberg C, Williams B, Denaxas S, Hemingway H. Estimating excess 1-year mortality associated with the COVID-19 pandemic according to underlying conditions and age: a population-based cohort study. Lancet. 2020 May 30;395(10238):1715-1725. doi: 10.1016/S0140-6736(20)30854-0. Epub 2020 May 12.
PMID: 32405103
citation: Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005 Apr;3(4):692-4. doi: 10.1111/j.1538-7836.2005.01204.x.
PMID: 15842354
citation: Kaatz S, Ahmad D, Spyropoulos AC, Schulman S; Subcommittee on Control of Anticoagulation. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost. 2015 Nov;13(11):2119-26. doi: 10.1111/jth.13140. No abstract available.
PMID: 26764429
citation: Day M. Covid-19: four fifths of cases are asymptomatic, China figures indicate. BMJ. 2020 Apr 2;369:m1375. doi: 10.1136/bmj.m1375. No abstract available.
PMID: 32241884
citation: Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020 Mar 17;323(11):1061-1069. doi: 10.1001/jama.2020.1585. Erratum In: JAMA. 2021 Mar 16;325(11):1113.
PMID: 32031570
citation: Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24. Erratum In: Lancet. 2020 Jan 30;:
PMID: 31986264
citation: Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 28;395(10229):1033-1034. doi: 10.1016/S0140-6736(20)30628-0. Epub 2020 Mar 16. No abstract available.
PMID: 32192578
citation: Mousavi S, Moradi M, Khorshidahmad T, Motamedi M. Anti-Inflammatory Effects of Heparin and Its Derivatives: A Systematic Review. Adv Pharmacol Sci. 2015;2015:507151. doi: 10.1155/2015/507151. Epub 2015 May 12.
PMID: 26064103
citation: Proschan MA. Two-stage sample size re-estimation based on a nuisance parameter: a review. J Biopharm Stat. 2005;15(4):559-74. doi: 10.1081/BIP-200062852.
PMID: 16022163
responsible party type: Sponsor
mesh term: COVID-19
mesh term: Enoxaparin
sharing ipd: No
submitted: December 2, 2022