<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/NCT04445623</url>
  </required_header>
  <id_info>
    <org_study_id>MGI-COVID-19-prasugrel</org_study_id>
    <nct_id>NCT04445623</nct_id>
  </id_info>
  <brief_title>Prasugrel in Severe COVID-19 Pneumonia</brief_title>
  <acronym>PARTISAN</acronym>
  <official_title>Prasugrel in the Prevention of Severe SARS-CoV2 Pneumonia in Hospitalised Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Azienda Ospedaliera Universitaria Integrata Verona</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Milan</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Azienda Ospedaliera Universitaria Integrata Verona</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>
      Inflammatory diseases favour the onset of venous thromboembolic events in hospitalized&#xD;
      patients. Thromboprophylaxis with a fixed dose of heparin/low molecular weight heparin (LMWH)&#xD;
      is recommended if concomitant inflammatory disease. In severe acute respiratory syndrome&#xD;
      coronavirus 2 (SARS-CoV2) pneumonia an inflammation-dependent thrombotic process occurs and&#xD;
      platelet activation may promote thrombosis and amplify inflammation, as indicated by previous&#xD;
      experimental evidence , and the similarities with atherothrombosis and thrombotic&#xD;
      microangiopathies. Antiplatelet agents represent the cornerstone in the prevention and&#xD;
      treatment of atherosclerotic arterial thromboembolism, with limited efficacy in the context&#xD;
      of venous thromboembolism. The use of purinergic receptor P2Y12 inhibitors in pneumococcal&#xD;
      pneumonia may improve inflammation and respiratory function in humans. There are no validated&#xD;
      protocols for thrombosis prevention in Covid-19. There is scientific rationale to consider a&#xD;
      P2Y12 inhibitor for the prevention of thrombosis in the pulmonary circulation and attenuation&#xD;
      of inflammation. This is supported by numerous demonstrations of the anti-inflammatory&#xD;
      activity of P2Y12 inhibitors and the evidence of improvement in respiratory function both in&#xD;
      human and experimental pathology. Prasugrel could be considered as an ideal candidate drug&#xD;
      for Covid-19 patients because of higher efficacy and limited Interactions with drugs used in&#xD;
      the treatment of Sars-CoV2. The hypothesis underlying the present study project is that in&#xD;
      Covid-19 platelet activation occurs through an inflammation-dependent mechanism and that&#xD;
      early antithrombotic prophylaxis in non-critical patients could reduce the incidence of&#xD;
      pulmonary thrombosis and respiratory and multi-organ failure improving clinical outcome in&#xD;
      patients with SARS-CoV2 pneumonia. The prevention of thrombogenic platelet activity with a&#xD;
      P2Y12 inhibitor could be superior to fixed dose enoxaparin alone. The proposed treatment is&#xD;
      feasible in all coronavirus disease 2019 (COVID-19) patients, regardless of the treatment&#xD;
      regimen (antivirals, anti-inflammatory drugs, antibiotics), except for specific&#xD;
      contraindications.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Severe respiratory failure and multi-organ damage in coronavirus disease 2019 (COVID-19)&#xD;
      patients have not a unitary pathophysiological interpretation. There is evidence of an&#xD;
      association between the clinical entity of the disease and its severity with the plasma&#xD;
      levels of D-dimer and inflammatory indexes. On the basis of retrospective investigations&#xD;
      there is accumulating evidence of alterations in the haemostatic parameters that with&#xD;
      increased D-dimer values, increased coagulation time and platelets may be predictors of worse&#xD;
      prognosis. A systematic survey conducted in the coronavirus disease 2019 (COVID-19) Centre of&#xD;
      the AOUI Verona, as part of the Database and Study on the role of platelets in the clinical&#xD;
      manifestations of COVID-19 (Ethics Committee CESC Verona and Rovigo approved) revealed by&#xD;
      means of computerized tomography (CT) angiograph in patients with a persistent respiratory&#xD;
      deficit and very high D-dimer values mainly multiple, bilateral vascular occlusions involving&#xD;
      the segmental and subsegmental branches of the pulmonary arteries. This finding is suggestive&#xD;
      of a frequent and clinically relevant thrombotic process in a appreciable number&#xD;
      (approximately 20%) of patients with COVID-19 pneumonia hospitalized in medical wards. It is&#xD;
      a well-established clinical notion that acute and chronic inflammatory diseases may favour&#xD;
      the onset of venous thromboembolic events in hospitalized patients. Thromboprophylaxis with a&#xD;
      fixed dose of heparin/low molecular weight heparin (LMWH) is recommended for medical patient&#xD;
      with concomitant neoplasia or inflammatory disease. It is conceivable that under conditions,&#xD;
      such as SARS-CoV2 pneumonia, an inflammation-dependent thrombotic process takes place and&#xD;
      that platelet activation may play a pathogenic role both in the thrombotic process and in the&#xD;
      amplification of the inflammatory process. In fact, there is experimental evidence that&#xD;
      platelet activation in inflammation would lead to accelerated coagulation and a thrombotic&#xD;
      vascular occlusion, with similarities to what is widely documented in atherothrombosis and&#xD;
      thrombotic microangiopathies. The administration of antiplatelet drugs represents the&#xD;
      cornerstone for the prevention and treatment of arterial thromboembolism in atherosclerotic&#xD;
      disease and has also shown some limited efficacy also in the context of venous and arterial&#xD;
      thromboembolism associated with atrial fibrillation. Preliminary observations indicate that&#xD;
      the use of purinergic receptor P2Y12 inhibitors during pneumococcal pneumonia may improve the&#xD;
      inflammatory process and respiratory function in humans. There are currently no validated&#xD;
      protocols for thrombosis prevention in the field of pulmonary viral diseases, in particular&#xD;
      COVID-19. There is adequate scientific rationale to consider the use of a P2Y12 inhibitor&#xD;
      antiplatelet drug for the prevention of thrombosis in the pulmonary circulation and the&#xD;
      attenuation of pulmonary inflammation. The use of a P2Y12 inhibitor is motivated by numerous&#xD;
      experimental demonstrations of the anti-inflammatory activity of P2Y12 inhibitors and by the&#xD;
      evidence of improvement of respiratory function parameters both in humans and experimental&#xD;
      models. Prasugrel could be considered as an ideal candidate drug for administration in&#xD;
      Covid-19 patients because of its higher efficacy in acute coronary syndrome compared to&#xD;
      clopidogrel. Interactions of prasugrel with drugs used for the treatment of SARS-CoV2 are&#xD;
      limited. The hypothesis underlying the present study project is that in Covid-19 platelet&#xD;
      activation occurs via an inflammation-dependent mechanism and that early antithrombotic&#xD;
      prophylaxis in non-critical patients, like those admitted to medical wards, could reduce the&#xD;
      incidence of pulmonary thrombosis as well as respiratory and multi-organ failure,&#xD;
      contributing to improve clinical outcome of the patients with pneumonia caused by SARS-CoV2&#xD;
      viruses. The anticoagulant activity exerted by a fixed dose of enoxaparin (4000U/day),&#xD;
      recommended in patients with the clinical features described, according to a note of the&#xD;
      &quot;Italian Medicines Agency&quot; (AIFA), together with the prevention of thrombogenic activity of&#xD;
      platelets by means of a P2Y12 inhibitor could prevent aggravation of COVID-19 patients to a&#xD;
      greater extent than enoxaparin alone given at the same dose. Early initiation of treatment&#xD;
      should mitigate the presentation of pneumonia. The proposed treatment is feasible in all&#xD;
      COVID-19 patients, regardless of the treatment regimen used for their condition (antivirals,&#xD;
      anti-inflammatory drugs, antibiotics), except for specific contraindications to the use of&#xD;
      prasugrel, or placebo if patients are treated with antiplatelet drugs.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">July 2020</start_date>
  <completion_date type="Anticipated">January 2021</completion_date>
  <primary_completion_date type="Anticipated">October 2020</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>Experimental phase 3 drug trial, randomized 1:1, double-blind, multicentre in patients treated with prasugrel vs placebo.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Care Provider)</masking>
    <masking_description>use of placebo tablets of the same shape, colour of the investigational drug. Identical time and route of administration.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>P/F ratio at day 7</measure>
    <time_frame>day 7</time_frame>
    <description>PaO2/FiO2 ratio (arterial oxygen tension divided by the fraction of inspired oxygen) detected after 7 days of treatment</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Daily P/F ratio</measure>
    <time_frame>15 days</time_frame>
    <description>PaO2/FiO2 ratio (arterial oxygen tension divided by the fraction of inspired oxygen) detected daily for 15 days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Daily need for oxygen supply</measure>
    <time_frame>15 days</time_frame>
    <description>daily need for oxygen supply for 15 days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Need for ICU</measure>
    <time_frame>day 15 and day 30</time_frame>
    <description>Number of patients requiring transfer to the intensive care unit (ICU) by treatment arm</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Death</measure>
    <time_frame>15 day and day 30</time_frame>
    <description>death by day 15 and day 30 by treatment arm</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MOF</measure>
    <time_frame>day 15 and day 30</time_frame>
    <description>Multi-organ failure (MOF) by day 15 and day 30 assessed using sequential organ failure assessment score (SOFA) score (Units 0-4 better outcome, over 30 worse outcome) by treatment arm</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Discharge</measure>
    <time_frame>day 15 and day 30</time_frame>
    <description>Number of patients discharged after improvement by day 15 and day 30 by treatment arm</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical progression of the disease SOFA score</measure>
    <time_frame>day 15 and day 30</time_frame>
    <description>Clinical progression of the disease evaluated by SOFA score (Units 0-6 better outcome, 15-24 worse outcome) by day 15 and day 30</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical progression of the disease APACHE II</measure>
    <time_frame>day 15 and day 30</time_frame>
    <description>Clinical progression of the disease evaluated by Acute Physiology And Chronic Health Evaluation (APACHE II) score (Units 1-5 better outcome, over 30 worse outcome) by day 15 and day 30</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Venous thrombosis/ pulmonary embolism/thrombosis</measure>
    <time_frame>day 15 and day 30</time_frame>
    <description>Number of patients with venous thrombosis/ pulmonary embolism/thrombosis by day 15 and day 30</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Need for CT imaging</measure>
    <time_frame>day 15</time_frame>
    <description>Number of patients requiring computerized tomography (CT) imaging due to worsening of respiratory function by treatment arm</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Daily Temperature</measure>
    <time_frame>15 days</time_frame>
    <description>Body temperature measured twice daily for 15 days, C°</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Daily blood pressure</measure>
    <time_frame>15 days</time_frame>
    <description>Blood pressure measured twice daily for 15 days, mmHg</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Daily total blood count Hemoglobin</measure>
    <time_frame>15 days</time_frame>
    <description>Total blood count measured in venous blood for 15 days, Hemoglobin, g/L (cell/mcL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Daily total blood count Red Blood Cells</measure>
    <time_frame>15 days</time_frame>
    <description>Total blood count measured in venous blood for 15 days, Red Blood cells (cell/mcL)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Daily total blood count Leukocytes</measure>
    <time_frame>15 days</time_frame>
    <description>Total blood count measured in venous blood for 15 days, Leukocytes (cell/mcL)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Daily total blood count Platelets</measure>
    <time_frame>15 days</time_frame>
    <description>Total blood count measured in venous blood for 15 days, platelets (cell/mcL)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Daily indices of organ damage Liver</measure>
    <time_frame>15 days</time_frame>
    <description>ALT U/L in venous blood</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Indices of inflammation C-reactive protein</measure>
    <time_frame>day 1, 2, 7, 15</time_frame>
    <description>C-reactive protein microg/L in venous blood</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Indices of haemostasis PT</measure>
    <time_frame>day 1, 2, 7,15</time_frame>
    <description>PT ratio in venous blood by treatment arm</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Daily progression at imaging (chest-X-ray)</measure>
    <time_frame>15 days</time_frame>
    <description>progression of lung infiltrates as detected by chest-X-ray by treatment arm</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Major bleeding</measure>
    <time_frame>day 1, 2, 7, 15, 30</time_frame>
    <description>Major and/or clinically relevant bleeding according to International Society of Thrombosis and Haemostasis (ISTH) bleeding scale (Unit 0 better outcome, 4 worse outcome, 11 items) during treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total bleeding</measure>
    <time_frame>day 1, 2, 7, 15, 30</time_frame>
    <description>Total bleeding according to International Society of Thrombosis and Haemostasis (ISTH bleeding) scale (Unit 0 better outcome, 4 worse outcome, 11 items) during treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Unexpected clinical or laboratory findings</measure>
    <time_frame>day 1, 2, 7, 15</time_frame>
    <description>Number of unexpected changes in clinical or laboratory findings not included in the predefined list of outcomes during treatment. .</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Indices of inflammation D-dimer</measure>
    <time_frame>day 1, 2, 7, 15</time_frame>
    <description>D-dimer microg/L in venous blood</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Indices of inflammation Fibrinogen</measure>
    <time_frame>day 1, 2, 7, 15</time_frame>
    <description>Fibrinogen g/L in venous blood</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Indices of inflammation IL-6</measure>
    <time_frame>day 1, 2, 7, 15</time_frame>
    <description>Interleukin (IL)-6 pg/mL in venous blood by treatment arm</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Indices of inflammation IL-1</measure>
    <time_frame>day 1, 2, 7, 15</time_frame>
    <description>Interleukin (IL)-1 pg/mL in venous blood by treatment arm</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Daily indices of organ damage kidney</measure>
    <time_frame>15 days</time_frame>
    <description>serum creatinine micromol/L by treatment arm</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Daily indices of organ damage heart</measure>
    <time_frame>15 days</time_frame>
    <description>troponin t ng/L by treatment arm</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Haemostasis aPTT</measure>
    <time_frame>day 1, 2, 7,15</time_frame>
    <description>aPTT ratio by treatment arm</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Haemostasis VASP PRI</measure>
    <time_frame>day 1, 2, 7,15</time_frame>
    <description>Vasodilator stimulated phosphoprotein (VASP) phosphorylation (PRI) % by treatment arm</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Haemostasis platelet-leukocytes aggregates</measure>
    <time_frame>day 1, 2, 7,15</time_frame>
    <description>Platelet-leukocytes aggregates % in peripheral by treatment arm</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">128</enrollment>
  <condition>COVID19</condition>
  <condition>Thrombosis</condition>
  <arm_group>
    <arm_group_label>prasugrel hydrochloride</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>film-coated tablets of prasugrel hydrochloride (10 mg daily dose after loading dose of 60 mg)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>film-coated tablets of placebo (10 mg daily dose after loading dose of 60 mg)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prasugrel Hydrochloride 10 MG Oral Tablet</intervention_name>
    <description>administration of prasugrel daily for 15 days</description>
    <arm_group_label>prasugrel hydrochloride</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>administration of placebo daily for 15 days</description>
    <arm_group_label>placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Covid-19 pneumonia&#xD;
&#xD;
          -  Age over 18 years&#xD;
&#xD;
          -  Willingness to express consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Active neoplasia or in maintenance therapy&#xD;
&#xD;
          -  Pregnancy and breastfeeding&#xD;
&#xD;
          -  Any absolute contraindication to the use of antiplatelet drugs&#xD;
&#xD;
          -  Pathological bleeding in progress.&#xD;
&#xD;
          -  Recent major bleeding at any location&#xD;
&#xD;
          -  Need to use therapeutic doses of oral anticoagulants or heparins&#xD;
&#xD;
          -  Need to use antiplatelet in combination for clinical indication&#xD;
&#xD;
          -  Hypersensitivity to the active substance prasugrel or any of the excipients&#xD;
&#xD;
          -  Clinical history of stroke or transient ischemic attack (TIA).&#xD;
&#xD;
          -  Severe liver failure (Child-Pugh class C).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Pietro Minuz, Professor</last_name>
    <phone>045-8124414</phone>
    <phone_ext>+39</phone_ext>
    <email>pietro.minuz@univr.it</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Marco Cattaneo, Professor</last_name>
    <phone>02-50323095</phone>
    <phone_ext>+39</phone_ext>
    <email>marco.cattaneo@unimi.it</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Azienda Ospedaliera Universitaria Integrata Verona</name>
      <address>
        <city>Verona</city>
        <zip>37126</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
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  <reference>
    <citation>Ancrenaz V, Deglon J, Samer C, Staub C, Dayer P, Daali Y, Desmeules J. Pharmacokinetic interaction between prasugrel and ritonavir in healthy volunteers. Basic Clin Pharmacol Toxicol. 2013 Feb;112(2):132-7. doi: 10.1111/j.1742-7843.2012.00932.x. Epub 2012 Oct 5.</citation>
    <PMID>22900583</PMID>
  </reference>
  <reference>
    <citation>Bikdeli B, Madhavan MV, Jimenez D, Chuich T, Dreyfus I, Driggin E, Nigoghossian C, Ageno W, Madjid M, Guo Y, Tang LV, Hu Y, Giri J, Cushman M, Quere I, Dimakakos EP, Gibson CM, Lippi G, Favaloro EJ, Fareed J, Caprini JA, Tafur AJ, Burton JR, Francese DP, Wang EY, Falanga A, McLintock C, Hunt BJ, Spyropoulos AC, Barnes GD, Eikelboom JW, Weinberg I, Schulman S, Carrier M, Piazza G, Beckman JA, Steg PG, Stone GW, Rosenkranz S, Goldhaber SZ, Parikh SA, Monreal M, Krumholz HM, Konstantinides SV, Weitz JI, Lip GYH; Global COVID-19 Thrombosis Collaborative Group, Endorsed by the ISTH, NATF, ESVM, and the IUA, Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020 Jun 16;75(23):2950-2973. doi: 10.1016/j.jacc.2020.04.031. Epub 2020 Apr 17.</citation>
    <PMID>32311448</PMID>
  </reference>
  <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>Yin S, Huang M, Li D, Tang N. Difference of coagulation features between severe pneumonia induced by SARS-CoV2 and non-SARS-CoV2. J Thromb Thrombolysis. 2021 May;51(4):1107-1110. doi: 10.1007/s11239-020-02105-8.</citation>
    <PMID>32246317</PMID>
  </reference>
  <reference>
    <citation>Minuz P, Mansueto G, Mazzaferri F, Fava C, Dalbeni A, Ambrosetti MC, Sibani M, Tacconelli E. High rate of pulmonary thromboembolism in patients with SARS-CoV-2 pneumonia. Clin Microbiol Infect. 2020 Nov;26(11):1572-1573. doi: 10.1016/j.cmi.2020.06.011. Epub 2020 Jun 18. No abstract available.</citation>
    <PMID>32565320</PMID>
  </reference>
  <reference>
    <citation>Cattaneo M, Bertinato EM, Birocchi S, Brizio C, Malavolta D, Manzoni M, Muscarella G, Orlandi M. Pulmonary Embolism or Pulmonary Thrombosis in COVID-19? Is the Recommendation to Use High-Dose Heparin for Thromboprophylaxis Justified? Thromb Haemost. 2020 Aug;120(8):1230-1232. doi: 10.1055/s-0040-1712097. Epub 2020 Apr 29. No abstract available.</citation>
    <PMID>32349132</PMID>
  </reference>
  <reference>
    <citation>Sjalander A, Jansson JH, Bergqvist D, Eriksson H, Carlberg B, Svensson P. Efficacy and safety of anticoagulant prophylaxis to prevent venous thromboembolism in acutely ill medical inpatients: a meta-analysis. J Intern Med. 2008 Jan;263(1):52-60. doi: 10.1111/j.1365-2796.2007.01878.x.</citation>
    <PMID>18088252</PMID>
  </reference>
  <verification_date>May 2020</verification_date>
  <study_first_submitted>June 4, 2020</study_first_submitted>
  <study_first_submitted_qc>June 23, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 24, 2020</study_first_posted>
  <last_update_submitted>June 24, 2020</last_update_submitted>
  <last_update_submitted_qc>June 24, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 26, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
    <mesh_term>Pneumonia</mesh_term>
    <mesh_term>Thrombosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prasugrel Hydrochloride</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04445623
org study id: MGI-COVID-19-prasugrel
nct id: NCT04445623
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Inflammatory diseases favour the onset of venous thromboembolic events in hospitalized
      patients. Thromboprophylaxis with a fixed dose of heparin/low molecular weight heparin (LMWH)
      is recommended if concomitant inflammatory disease. In severe acute respiratory syndrome
      coronavirus 2 (SARS-CoV2) pneumonia an inflammation-dependent thrombotic process occurs and
      platelet activation may promote thrombosis and amplify inflammation, as indicated by previous
      experimental evidence , and the similarities with atherothrombosis and thrombotic
      microangiopathies. Antiplatelet agents represent the cornerstone in the prevention and
      treatment of atherosclerotic arterial thromboembolism, with limited efficacy in the context
      of venous thromboembolism. The use of purinergic receptor P2Y12 inhibitors in pneumococcal
      pneumonia may improve inflammation and respiratory function in humans. There are no validated
      protocols for thrombosis prevention in Covid-19. There is scientific rationale to consider a
      P2Y12 inhibitor for the prevention of thrombosis in the pulmonary circulation and attenuation
      of inflammation. This is supported by numerous demonstrations of the anti-inflammatory
      activity of P2Y12 inhibitors and the evidence of improvement in respiratory function both in
      human and experimental pathology. Prasugrel could be considered as an ideal candidate drug
      for Covid-19 patients because of higher efficacy and limited Interactions with drugs used in
      the treatment of Sars-CoV2. The hypothesis underlying the present study project is that in
      Covid-19 platelet activation occurs through an inflammation-dependent mechanism and that
      early antithrombotic prophylaxis in non-critical patients could reduce the incidence of
      pulmonary thrombosis and respiratory and multi-organ failure improving clinical outcome in
      patients with SARS-CoV2 pneumonia. The prevention of thrombogenic platelet activity with a
      P2Y12 inhibitor could be superior to fixed dose enoxaparin alone. The proposed treatment is
      feasible in all coronavirus disease 2019 (COVID-19) patients, regardless of the treatment
      regimen (antivirals, anti-inflammatory drugs, antibiotics), except for specific
      contraindications.
Severe respiratory failure and multi-organ damage in coronavirus disease 2019 (COVID-19)
      patients have not a unitary pathophysiological interpretation. There is evidence of an
      association between the clinical entity of the disease and its severity with the plasma
      levels of D-dimer and inflammatory indexes. On the basis of retrospective investigations
      there is accumulating evidence of alterations in the haemostatic parameters that with
      increased D-dimer values, increased coagulation time and platelets may be predictors of worse
      prognosis. A systematic survey conducted in the coronavirus disease 2019 (COVID-19) Centre of
      the AOUI Verona, as part of the Database and Study on the role of platelets in the clinical
      manifestations of COVID-19 (Ethics Committee CESC Verona and Rovigo approved) revealed by
      means of computerized tomography (CT) angiograph in patients with a persistent respiratory
      deficit and very high D-dimer values mainly multiple, bilateral vascular occlusions involving
      the segmental and subsegmental branches of the pulmonary arteries. This finding is suggestive
      of a frequent and clinically relevant thrombotic process in a appreciable number
      (approximately 20%) of patients with COVID-19 pneumonia hospitalized in medical wards. It is
      a well-established clinical notion that acute and chronic inflammatory diseases may favour
      the onset of venous thromboembolic events in hospitalized patients. Thromboprophylaxis with a
      fixed dose of heparin/low molecular weight heparin (LMWH) is recommended for medical patient
      with concomitant neoplasia or inflammatory disease. It is conceivable that under conditions,
      such as SARS-CoV2 pneumonia, an inflammation-dependent thrombotic process takes place and
      that platelet activation may play a pathogenic role both in the thrombotic process and in the
      amplification of the inflammatory process. In fact, there is experimental evidence that
      platelet activation in inflammation would lead to accelerated coagulation and a thrombotic
      vascular occlusion, with similarities to what is widely documented in atherothrombosis and
      thrombotic microangiopathies. The administration of antiplatelet drugs represents the
      cornerstone for the prevention and treatment of arterial thromboembolism in atherosclerotic
      disease and has also shown some limited efficacy also in the context of venous and arterial
      thromboembolism associated with atrial fibrillation. Preliminary observations indicate that
      the use of purinergic receptor P2Y12 inhibitors during pneumococcal pneumonia may improve the
      inflammatory process and respiratory function in humans. There are currently no validated
      protocols for thrombosis prevention in the field of pulmonary viral diseases, in particular
      COVID-19. There is adequate scientific rationale to consider the use of a P2Y12 inhibitor
      antiplatelet drug for the prevention of thrombosis in the pulmonary circulation and the
      attenuation of pulmonary inflammation. The use of a P2Y12 inhibitor is motivated by numerous
      experimental demonstrations of the anti-inflammatory activity of P2Y12 inhibitors and by the
      evidence of improvement of respiratory function parameters both in humans and experimental
      models. Prasugrel could be considered as an ideal candidate drug for administration in
      Covid-19 patients because of its higher efficacy in acute coronary syndrome compared to
      clopidogrel. Interactions of prasugrel with drugs used for the treatment of SARS-CoV2 are
      limited. The hypothesis underlying the present study project is that in Covid-19 platelet
      activation occurs via an inflammation-dependent mechanism and that early antithrombotic
      prophylaxis in non-critical patients, like those admitted to medical wards, could reduce the
      incidence of pulmonary thrombosis as well as respiratory and multi-organ failure,
      contributing to improve clinical outcome of the patients with pneumonia caused by SARS-CoV2
      viruses. The anticoagulant activity exerted by a fixed dose of enoxaparin (4000U/day),
      recommended in patients with the clinical features described, according to a note of the
      "Italian Medicines Agency" (AIFA), together with the prevention of thrombogenic activity of
      platelets by means of a P2Y12 inhibitor could prevent aggravation of COVID-19 patients to a
      greater extent than enoxaparin alone given at the same dose. Early initiation of treatment
      should mitigate the presentation of pneumonia. The proposed treatment is feasible in all
      COVID-19 patients, regardless of the treatment regimen used for their condition (antivirals,
      anti-inflammatory drugs, antibiotics), except for specific contraindications to the use of
      prasugrel, or placebo if patients are treated with antiplatelet drugs.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Experimental phase 3 drug trial, randomized 1:1, double-blind, multicentre in patients treated with prasugrel vs placebo.
primary purpose: Treatment
masking: Double (Participant, Care Provider)
masking description: use of placebo tablets of the same shape, colour of the investigational drug. Identical time and route of administration.
measure: P/F ratio at day 7
time frame: day 7
description: PaO2/FiO2 ratio (arterial oxygen tension divided by the fraction of inspired oxygen) detected after 7 days of treatment
measure: Daily P/F ratio
time frame: 15 days
description: PaO2/FiO2 ratio (arterial oxygen tension divided by the fraction of inspired oxygen) detected daily for 15 days
measure: Daily need for oxygen supply
time frame: 15 days
description: daily need for oxygen supply for 15 days
measure: Need for ICU
time frame: day 15 and day 30
description: Number of patients requiring transfer to the intensive care unit (ICU) by treatment arm
measure: Death
time frame: 15 day and day 30
description: death by day 15 and day 30 by treatment arm
measure: MOF
time frame: day 15 and day 30
description: Multi-organ failure (MOF) by day 15 and day 30 assessed using sequential organ failure assessment score (SOFA) score (Units 0-4 better outcome, over 30 worse outcome) by treatment arm
measure: Discharge
time frame: day 15 and day 30
description: Number of patients discharged after improvement by day 15 and day 30 by treatment arm
measure: Clinical progression of the disease SOFA score
time frame: day 15 and day 30
description: Clinical progression of the disease evaluated by SOFA score (Units 0-6 better outcome, 15-24 worse outcome) by day 15 and day 30
measure: Clinical progression of the disease APACHE II
time frame: day 15 and day 30
description: Clinical progression of the disease evaluated by Acute Physiology And Chronic Health Evaluation (APACHE II) score (Units 1-5 better outcome, over 30 worse outcome) by day 15 and day 30
measure: Venous thrombosis/ pulmonary embolism/thrombosis
time frame: day 15 and day 30
description: Number of patients with venous thrombosis/ pulmonary embolism/thrombosis by day 15 and day 30
measure: Need for CT imaging
time frame: day 15
description: Number of patients requiring computerized tomography (CT) imaging due to worsening of respiratory function by treatment arm
measure: Daily Temperature
time frame: 15 days
description: Body temperature measured twice daily for 15 days, C°
measure: Daily blood pressure
time frame: 15 days
description: Blood pressure measured twice daily for 15 days, mmHg
measure: Daily total blood count Hemoglobin
time frame: 15 days
description: Total blood count measured in venous blood for 15 days, Hemoglobin, g/L (cell/mcL
measure: Daily total blood count Red Blood Cells
time frame: 15 days
description: Total blood count measured in venous blood for 15 days, Red Blood cells (cell/mcL)
measure: Daily total blood count Leukocytes
time frame: 15 days
description: Total blood count measured in venous blood for 15 days, Leukocytes (cell/mcL)
measure: Daily total blood count Platelets
time frame: 15 days
description: Total blood count measured in venous blood for 15 days, platelets (cell/mcL)
measure: Daily indices of organ damage Liver
time frame: 15 days
description: ALT U/L in venous blood
measure: Indices of inflammation C-reactive protein
time frame: day 1, 2, 7, 15
description: C-reactive protein microg/L in venous blood
measure: Indices of haemostasis PT
time frame: day 1, 2, 7,15
description: PT ratio in venous blood by treatment arm
measure: Daily progression at imaging (chest-X-ray)
time frame: 15 days
description: progression of lung infiltrates as detected by chest-X-ray by treatment arm
measure: Major bleeding
time frame: day 1, 2, 7, 15, 30
description: Major and/or clinically relevant bleeding according to International Society of Thrombosis and Haemostasis (ISTH) bleeding scale (Unit 0 better outcome, 4 worse outcome, 11 items) during treatment.
measure: Total bleeding
time frame: day 1, 2, 7, 15, 30
description: Total bleeding according to International Society of Thrombosis and Haemostasis (ISTH bleeding) scale (Unit 0 better outcome, 4 worse outcome, 11 items) during treatment.
measure: Unexpected clinical or laboratory findings
time frame: day 1, 2, 7, 15
description: Number of unexpected changes in clinical or laboratory findings not included in the predefined list of outcomes during treatment. .
measure: Indices of inflammation D-dimer
time frame: day 1, 2, 7, 15
description: D-dimer microg/L in venous blood
measure: Indices of inflammation Fibrinogen
time frame: day 1, 2, 7, 15
description: Fibrinogen g/L in venous blood
measure: Indices of inflammation IL-6
time frame: day 1, 2, 7, 15
description: Interleukin (IL)-6 pg/mL in venous blood by treatment arm
measure: Indices of inflammation IL-1
time frame: day 1, 2, 7, 15
description: Interleukin (IL)-1 pg/mL in venous blood by treatment arm
measure: Daily indices of organ damage kidney
time frame: 15 days
description: serum creatinine micromol/L by treatment arm
measure: Daily indices of organ damage heart
time frame: 15 days
description: troponin t ng/L by treatment arm
measure: Haemostasis aPTT
time frame: day 1, 2, 7,15
description: aPTT ratio by treatment arm
measure: Haemostasis VASP PRI
time frame: day 1, 2, 7,15
description: Vasodilator stimulated phosphoprotein (VASP) phosphorylation (PRI) % by treatment arm
measure: Haemostasis platelet-leukocytes aggregates
time frame: day 1, 2, 7,15
description: Platelet-leukocytes aggregates % in peripheral by treatment arm
arm group label: prasugrel hydrochloride
arm group type: Active Comparator
description: film-coated tablets of prasugrel hydrochloride (10 mg daily dose after loading dose of 60 mg)
arm group label: placebo
arm group type: Placebo Comparator
description: film-coated tablets of placebo (10 mg daily dose after loading dose of 60 mg)
intervention type: Drug
intervention name: Prasugrel Hydrochloride 10 MG Oral Tablet
description: administration of prasugrel daily for 15 days
arm group label: prasugrel hydrochloride
intervention type: Drug
intervention name: Placebo
description: administration of placebo daily for 15 days
arm group label: placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 99 Years
healthy volunteers: No
last name: Pietro Minuz, Professor
phone: 045-8124414
phone ext: +39
email: pietro.minuz@univr.it
last name: Marco Cattaneo, Professor
phone: 02-50323095
phone ext: +39
email: marco.cattaneo@unimi.it
facility: 
country: Italy
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PMID: 30477976
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PMID: 28886622
citation: Becattini C, Agnelli G, Schenone A, Eichinger S, Bucherini E, Silingardi M, Bianchi M, Moia M, Ageno W, Vandelli MR, Grandone E, Prandoni P; WARFASA Investigators. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012 May 24;366(21):1959-67. doi: 10.1056/NEJMoa1114238. Erratum In: N Engl J Med. 2012 Oct 18;367(16):1573.
PMID: 22621626
citation: Simes J, Becattini C, Agnelli G, Eikelboom JW, Kirby AC, Mister R, Prandoni P, Brighton TA; INSPIRE Study Investigators (International Collaboration of Aspirin Trials for Recurrent Venous Thromboembolism). Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE collaboration. Circulation. 2014 Sep 23;130(13):1062-71. doi: 10.1161/CIRCULATIONAHA.114.008828. Epub 2014 Aug 25.
PMID: 25156992
citation: Sexton TR, Zhang G, Macaulay TE, Callahan LA, Charnigo R, Vsevolozhskaya OA, Li Z, Smyth S. Ticagrelor Reduces Thromboinflammatory Markers in Patients With Pneumonia. JACC Basic Transl Sci. 2018 Aug 28;3(4):435-449. doi: 10.1016/j.jacbts.2018.05.005. eCollection 2018 Aug.
PMID: 30175268
citation: Rudolph TK, Fuchs A, Klinke A, Schlichting A, Friedrichs K, Hellmich M, Mollenhauer M, Schwedhelm E, Baldus S, Rudolph V. Prasugrel as opposed to clopidogrel improves endothelial nitric oxide bioavailability and reduces platelet-leukocyte interaction in patients with unstable angina pectoris: A randomized controlled trial. Int J Cardiol. 2017 Dec 1;248:7-13. doi: 10.1016/j.ijcard.2017.06.099. Epub 2017 Jul 1.
PMID: 28709700
citation: Johnston LR, La Flamme AC, Larsen PD, Harding SA. Prasugrel inhibits platelet-enhanced pro-inflammatory CD4+ T cell responses in humans. Atherosclerosis. 2015 Mar;239(1):283-6. doi: 10.1016/j.atherosclerosis.2015.01.006. Epub 2015 Jan 14.
PMID: 25635327
citation: Totani L, Dell'Elba G, Martelli N, Di Santo A, Piccoli A, Amore C, Evangelista V. Prasugrel inhibits platelet-leukocyte interaction and reduces inflammatory markers in a model of endotoxic shock in the mouse. Thromb Haemost. 2012 Jun;107(6):1130-40. doi: 10.1160/TH11-12-0867. Epub 2012 Mar 22.
PMID: 22436970
citation: Ancrenaz V, Deglon J, Samer C, Staub C, Dayer P, Daali Y, Desmeules J. Pharmacokinetic interaction between prasugrel and ritonavir in healthy volunteers. Basic Clin Pharmacol Toxicol. 2013 Feb;112(2):132-7. doi: 10.1111/j.1742-7843.2012.00932.x. Epub 2012 Oct 5.
PMID: 22900583
citation: Bikdeli B, Madhavan MV, Jimenez D, Chuich T, Dreyfus I, Driggin E, Nigoghossian C, Ageno W, Madjid M, Guo Y, Tang LV, Hu Y, Giri J, Cushman M, Quere I, Dimakakos EP, Gibson CM, Lippi G, Favaloro EJ, Fareed J, Caprini JA, Tafur AJ, Burton JR, Francese DP, Wang EY, Falanga A, McLintock C, Hunt BJ, Spyropoulos AC, Barnes GD, Eikelboom JW, Weinberg I, Schulman S, Carrier M, Piazza G, Beckman JA, Steg PG, Stone GW, Rosenkranz S, Goldhaber SZ, Parikh SA, Monreal M, Krumholz HM, Konstantinides SV, Weitz JI, Lip GYH; Global COVID-19 Thrombosis Collaborative Group, Endorsed by the ISTH, NATF, ESVM, and the IUA, Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020 Jun 16;75(23):2950-2973. doi: 10.1016/j.jacc.2020.04.031. Epub 2020 Apr 17.
PMID: 32311448
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: Yin S, Huang M, Li D, Tang N. Difference of coagulation features between severe pneumonia induced by SARS-CoV2 and non-SARS-CoV2. J Thromb Thrombolysis. 2021 May;51(4):1107-1110. doi: 10.1007/s11239-020-02105-8.
PMID: 32246317
citation: Minuz P, Mansueto G, Mazzaferri F, Fava C, Dalbeni A, Ambrosetti MC, Sibani M, Tacconelli E. High rate of pulmonary thromboembolism in patients with SARS-CoV-2 pneumonia. Clin Microbiol Infect. 2020 Nov;26(11):1572-1573. doi: 10.1016/j.cmi.2020.06.011. Epub 2020 Jun 18. No abstract available.
PMID: 32565320
citation: Cattaneo M, Bertinato EM, Birocchi S, Brizio C, Malavolta D, Manzoni M, Muscarella G, Orlandi M. Pulmonary Embolism or Pulmonary Thrombosis in COVID-19? Is the Recommendation to Use High-Dose Heparin for Thromboprophylaxis Justified? Thromb Haemost. 2020 Aug;120(8):1230-1232. doi: 10.1055/s-0040-1712097. Epub 2020 Apr 29. No abstract available.
PMID: 32349132
citation: Sjalander A, Jansson JH, Bergqvist D, Eriksson H, Carlberg B, Svensson P. Efficacy and safety of anticoagulant prophylaxis to prevent venous thromboembolism in acutely ill medical inpatients: a meta-analysis. J Intern Med. 2008 Jan;263(1):52-60. doi: 10.1111/j.1365-2796.2007.01878.x.
PMID: 18088252
responsible party type: Sponsor
mesh term: COVID-19
mesh term: Pneumonia
mesh term: Thrombosis
mesh term: Prasugrel Hydrochloride