<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/NCT04427098</url>
  </required_header>
  <id_info>
    <org_study_id>2020-001308-40</org_study_id>
    <nct_id>NCT04427098</nct_id>
  </id_info>
  <brief_title>Enoxaparin in COVID-19 Moderate to Severe Hospitalized Patients</brief_title>
  <acronym>INHIXACOV19</acronym>
  <official_title>Intermediate Dose Enoxaparin in Hospitalized Patients With Moderate-severe COVID19: A Pilot Phase II Single-arm Study, INHIXACOVID19</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>IRCCS Azienda Ospedaliero-Universitaria di Bologna</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>IRCCS Azienda Ospedaliero-Universitaria di Bologna</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      General objective of the study To assess the efficacy and safety of enoxaparin in&#xD;
      hospitalized patients with moderate to severe COVID-19 (Coronavirus Disease 2019) infection.&#xD;
&#xD;
      Study Design&#xD;
&#xD;
      The study consists of two parts:&#xD;
&#xD;
        -  a phase II single-arm interventional prospective study including all patients treated&#xD;
           with the study drug;&#xD;
&#xD;
        -  an observational prospective cohort study including all patients screened for receiving&#xD;
           the study drug but not included in the phase II study.&#xD;
&#xD;
      Patients will be enrolled from &quot;date of study approval&quot; for 1 month. Each patient will be&#xD;
      followed-up for a minimum of 90 days after COVID19 diagnosis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      General objective of the study To assess the efficacy and safety of enoxaparin in&#xD;
      hospitalized patients with moderate to severe COVID-19 infection.&#xD;
&#xD;
      Specific objectives Primary Endpoints To investigate the efficacy of enoxaparin in improving&#xD;
      the clinical outcome of hospitalized patients with moderate to severe COVID-19.&#xD;
&#xD;
        -  All-cause in-hospital, 30-day and 90-day mortality rates.&#xD;
&#xD;
        -  Evolution of the clinical severity during treatment.&#xD;
&#xD;
        -  ICU admission and length of ICU stay.&#xD;
&#xD;
        -  Length of hospital stay.&#xD;
&#xD;
      Secondary Endpoints To analyse the safety of enoxaparin in hospitalized patients with with&#xD;
      moderate to severe COVID-19.&#xD;
&#xD;
        -  Rate of adverse events (AEs) during treatment, at the end of treatment (EOT) and at 30&#xD;
           days after EOT.&#xD;
&#xD;
        -  Severity of AEs classified according to common terminology criteria for adverse events&#xD;
           (CTCAE). The worst degree ever suffered will be considered.&#xD;
&#xD;
      To describe the rates and the types of thromboembolic events among hospitalized patients with&#xD;
      confirmed diagnosis of COVID-19.&#xD;
&#xD;
        -  Occurrence of thromboembolic event at 90 days after COVID-19 diagnosis.&#xD;
&#xD;
        -  Description of the type, distribution and severity of thromboembolic events.&#xD;
&#xD;
      Study Design Overall Design&#xD;
&#xD;
      The study consists of two parts:&#xD;
&#xD;
        -  a phase II single-arm interventional prospective study including all patients treated&#xD;
           with the study drug;&#xD;
&#xD;
        -  an observational prospective cohort study including all patients screened for receiving&#xD;
           the study drug but not included in the phase II study.&#xD;
&#xD;
      Patients will be enrolled from &quot;date of study approval&quot; for 1 month. Each patient will be&#xD;
      followed-up for a minimum of 90 days after COVID19 diagnosis.&#xD;
&#xD;
      End of Study Definition A participant is considered to have completed the study if he/she has&#xD;
      completed the last scheduled procedure shown in the Schedule of assessments. The end of the&#xD;
      study is defined as the date of the last scheduled procedure shown in the Schedule of&#xD;
      assessments for the last participant in the trial.&#xD;
&#xD;
      Study Population&#xD;
&#xD;
      Definitions&#xD;
&#xD;
      Clinical severity of COVID-19 will be assessed at the diagnosis of COVID19, during the&#xD;
      treatment with the study drug, and at the end of treatment according to the following&#xD;
      criteria (1):&#xD;
&#xD;
        -  Mild patients: only show mild symptoms without radiographic features&#xD;
&#xD;
        -  Moderate patients: have fever, respiratory symptoms, and radiographic signs of pneumonia&#xD;
&#xD;
        -  Severe patients: have fever, respiratory symptoms, and radiographic signs of pneumonia&#xD;
           plus at least one of three criteria: (1) RR (respiratory rate) &gt;30 times/min, (2) oxygen&#xD;
           saturation &lt;93% on ambient air, (3) PaO2/FiO2 (Oxigen partial pressure/inspired oxygen&#xD;
           fraction ) &lt;300 mmHg.&#xD;
&#xD;
        -  Critical patients: meet one of three criteria: (1) respiratory failure needing invasive&#xD;
           ventilation, (2) septic shock, (3) multiple organ failure.&#xD;
&#xD;
      Major bleeding will be defined according to the ISTH (International Society of Thrombosis and&#xD;
      Haemostasis) criteria as one of the following:&#xD;
&#xD;
        -  Fatal bleeding&#xD;
&#xD;
        -  Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal,&#xD;
           intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with&#xD;
           compartment syndrome&#xD;
&#xD;
        -  Bleeding causing a fall in haemoglobin level of 2 g/dL or more, or leading to&#xD;
           transfusion of two or more units of whole blood or red cells (11).&#xD;
&#xD;
      Treatments Administration and monitoring of study drug&#xD;
&#xD;
      All patients screened for being included in the study will receive standard&#xD;
      thrombo-prophylaxis with LMWH (low molecular weight heparin) (e.g. enoxaparin 40 mg/die).&#xD;
      Patients included in the observational cohort will continue on standard thrombo-prophylaxis,&#xD;
      while patients included in the interventional study will receive subcutaneous enoxaparin in a&#xD;
      single daily dose of:&#xD;
&#xD;
        -  60 mg once daily in case of body weight of 45 to 60 kg&#xD;
&#xD;
        -  80 mg per day in case of weight from 61 to 100 kg or&#xD;
&#xD;
        -  100 mg once daily in case of bodyweight &gt;100 kg Enoxaparin will be started on the first&#xD;
           day of COVID19 diagnosis and continued for 14 days, after determination of baseline PT&#xD;
           (prothrombin time), aPTT (activated partial thromboplastin time), complete blood cell&#xD;
           count and creatinine levels.&#xD;
&#xD;
      After reaching the steady state (usually after the third dose), heparin levels will be&#xD;
      measured with the determination of anti-Xa activity on a blood sample obtained at 4 hours&#xD;
      after the morning injection. LMWH dose may be then increased or reduced on the basis of&#xD;
      target anti-Xa activity (0.4-0.6 antiFXa (Anti Factor X activated) UI/ml (International&#xD;
      Unit/ml) for intermediate doses). The determination of anti-Xa activity will be repeated on&#xD;
      the fifth or sixth day to monitor any drug accumulation.&#xD;
&#xD;
      Complete blood cell count will be obtained every second day to monitor for heparin induced&#xD;
      thrombocytopenia.&#xD;
&#xD;
      Single low dose antiplatelet agents will be allowed. In all patients, RT-PCR (reverse&#xD;
      transcription-polymerase chain reaction) nasopharyngeal swabs will be performed every 7 days&#xD;
      to assess virus clearance and blood samples will be collected at baseline and on day 7 and&#xD;
      will be retrospectively analysed to measure viral load.&#xD;
&#xD;
      Follow up procedures Patients will be followed-up to 90 days after study drug initiation.&#xD;
      Follow-up information will be collected via telephone calls, patient medical records and/or&#xD;
      clinical visits according to clinical evolution.&#xD;
&#xD;
      This is a pilot study and an initial sample of 100 patients for the phase II single-arm&#xD;
      interventional trial is established. Even if currently precise data are not available, it can&#xD;
      be assumed that the composite endpoint is around 30% in patient treated with the standard&#xD;
      thromboprophylaxis dose of enoxaparin. To verify the hypothesis that the experimental&#xD;
      treatment may produce a halving of this endpoint (from 30% to 15%), 300 patients (200 for the&#xD;
      observational cohort and 100 for the phase II cohort; ratio 2:1) are needed with a 80% power&#xD;
      and a 0,05 bilateral alpha error. As stated above a first safety analysis after enrolling the&#xD;
      first 50 patients in the interventional study arm is planned and it will be done by an&#xD;
      independent committee. According to safety and efficacy data obtained, using as control the&#xD;
      observational cohort, a large study with a more robust design is planned.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">May 22, 2020</start_date>
  <completion_date type="Anticipated">October 30, 2020</completion_date>
  <primary_completion_date type="Anticipated">October 30, 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>The study consists of two parts:&#xD;
a phase II single-arm interventional prospective study including all patients treated with the study drug;&#xD;
an observational prospective cohort study including all patients screened for receiving the study drug but not included in the phase II study.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>To investigate the efficacy of enoxaparin in improving the clinical outcome of hospitalized patients with moderate-severe COVID-19.</measure>
    <time_frame>30 days and 90 days from the first LMWH subcutaneous injection</time_frame>
    <description>Rates of hospitalized patients dead for all-cause within 30 days and 90 days from the first LMWH subcutaneous injection</description>
  </primary_outcome>
  <primary_outcome>
    <measure>To investigate the efficacy of enoxaparin in improving the clinical outcome of hospitalized patients with moderate-severe COVID-19.</measure>
    <time_frame>This evaluation will be performed at 30 days and 90 days from the first LMWH subcutaneous injection</time_frame>
    <description>Based on the four levels scale of severity of symptoms. Any change from one level to another will be detected for all the enrolled patients, in order to evalutate the clinical efficacy of enoxaparin on the outcome of COVID 19.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>To investigate the efficacy of enoxaparin in improving the clinical outcome of hospitalized patients with moderate-severe COVID-19.</measure>
    <time_frame>This evaluation will be performed at 14 days (the last day of treatment adminstration), at 30 days and 90 days from the first LMWH subcutaneous injection</time_frame>
    <description>Evolution of the clinical severity during treatment, based on the number and rate of patients admitted to ICU and the length of their ICU stay</description>
  </primary_outcome>
  <primary_outcome>
    <measure>To investigate the efficacy of enoxaparin in improving the clinical outcome of hospitalized patients with moderate-severe COVID-19.</measure>
    <time_frame>This evaluation will be performed at 90 days from admission</time_frame>
    <description>Difference between groups in number of days of hospitalization from admission to discharge</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>To analyse the safety of enoxaparin in hospitalized patients with moderatesevere COVID-19.</measure>
    <time_frame>45 days</time_frame>
    <description>Rate of adverse events (AEs) during treatment, at the end of treatment (EOT) and at 30 days after EOT.&#xD;
• Severity of AEs classified according to common terminology criteria for adverse events (CTCAE). The worst degree ever suffered will be considered.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To describe the rates and the types of thromboembolic events among hospitalized patients with confirmed diagnosis of COVID-19.</measure>
    <time_frame>90 days</time_frame>
    <description>Occurrence of thromboembolic event at 90 days after COVID-19 diagnosis. Description of the type, distribution and severity of thromboembolic events.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">300</enrollment>
  <condition>COVID-19</condition>
  <arm_group>
    <arm_group_label>a phase II single-arm interventional prospective study</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients included in the interventional study will receive subcutaneous enoxaparin in a single daily dose of:&#xD;
60 mg once daily in case of body weight of 45 to 60 kg&#xD;
80 mg per day in case of weight from 61 to 100 kg or&#xD;
100 mg once daily in case of bodyweight &gt;100 kg&#xD;
Enoxaparin will be started on the first day of COVID19 diagnosis and continued for 14 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>observational cohort study</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients included in the observational cohort will will receive standard thrombo-prophylaxis with subcutaneous enoxaparin 40 mg/die</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Enoxaparin 40 Mg/0.4 mL Injectable Solution</intervention_name>
    <description>Subcutaneous enoxaparin 40 mg once daily for 14 days.</description>
    <arm_group_label>a phase II single-arm interventional prospective study</arm_group_label>
    <other_name>INHIXA 4,000 UI (40 mg) / 0.4 ml</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Enoxaparin</intervention_name>
    <description>Subcutaneous enoxaparin for 14 days: 60 mg once daily in case of body weight of 45 to 60 kg; 80 mg once daily in case of weight from 61 to 100 kg; 100 mg once daily in case of bodyweight &gt;100 kg</description>
    <arm_group_label>observational cohort study</arm_group_label>
    <other_name>INHIXA 6,000 UI (60 mg) / 0.6 ml</other_name>
    <other_name>INHIXA 8,000 UI (80 mg) / 0.8 ml</other_name>
    <other_name>INHIXA 10,000 UI (100 mg)/ 1 ml</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  For both interventional study and observational cohort, hospitalized patients are&#xD;
             eligible to be included if the following criteria apply:&#xD;
&#xD;
        Inclusion criteria:&#xD;
&#xD;
          -  Age &gt;=18 y&#xD;
&#xD;
          -  Microbiologically confirmed COVID-19 infection&#xD;
&#xD;
          -  Patients with moderate to severe disease according to study definitions (see below)&#xD;
&#xD;
          -  Informed consent to participate and to use data for interventional study, only to use&#xD;
             data for observational cohort&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Participants are excluded from the interventional study if any of the following&#xD;
             criteria apply:&#xD;
&#xD;
               -  Thrombocytopenia (platelet count &lt; 50.000 mm3)&#xD;
&#xD;
               -  Coagulopathy: INR (International normalized ratio) &gt;1.5, aPTT ratio &gt;1.4&#xD;
&#xD;
               -  Impaired renal function (clearance to creatinine less than 15 ml/min)&#xD;
&#xD;
               -  Known hypersensitivity to heparin&#xD;
&#xD;
               -  History of heparin induced thrombocytopenia&#xD;
&#xD;
               -  Presence of an active bleeding or a pathology susceptible of bleeding in presence&#xD;
                  of anticoagulation (e.g. recent haemorrhagic stroke, peptic ulcer, malignant&#xD;
                  tumors at hig risk of haemorrhages, recent neurosurgery or ophthalmic surgery,&#xD;
                  vascular aneurysms, arteriovenous malformations)&#xD;
&#xD;
               -  Body weight &lt;45 or &gt; 150 kg&#xD;
&#xD;
               -  Concomitant anticoagulant treatment for other indications ( eg atrial&#xD;
                  fibrillation, venous thromboembolism , prosthetic heart valves).&#xD;
&#xD;
               -  Dual antiplatelet therapy&#xD;
&#xD;
               -  Pregnant or breast-feeding women&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Pierluigi Viale, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Infectious Diseases Unit, Dep. Med. and Surg. Science University of Bologna</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Andrea Romagnoli, MD</last_name>
    <phone>0039 050 0984040</phone>
    <email>aromagnoli@ricerchenuove.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Stefano Triscornia, BS</last_name>
    <phone>0039 050 0984040</phone>
    <email>striscornia@ricerchenuove.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Policlinico S. Orsola Malpighi Dipartimento Malattie Infettive</name>
      <address>
        <city>Bologna</city>
        <state>Emilia Romagna</state>
        <zip>40138</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Pierluigi Viale, MD</last_name>
      <phone>00390516363353</phone>
      <email>pierluigi.viale@unibo.it</email>
    </contact>
    <contact_backup>
      <last_name>Maddalena Giannella, MD</last_name>
      <phone>00390516363353</phone>
      <email>maddalena.giannella@unibo.it</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedaliero-Universitaria di Parma Anestesia e Rianimazione Dipartimento di Medicina e Chirurgia</name>
      <address>
        <city>Parma</city>
        <state>Emilia Romagna</state>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Elena Giovanna Bignami, MD</last_name>
      <phone>0039 3388326680</phone>
      <email>elenagiovanna.bignami@unipr.it</email>
    </contact>
    <contact_backup>
      <last_name>Marco Baciarello, MD</last_name>
      <phone>0039 3280387722</phone>
      <email>marco.baciarello@unipr.it</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>I.R.C.C.S. &quot;Casa Sollievo della Sofferenza&quot;, San Giovanni Rotondo (FG) UOVD Emostasi e trombosi- Poliambulatorio Giovanni Paolo II Viale Padre Pio n.7 San Giovanni Rotondo (FG)</name>
      <address>
        <city>San Giovanni Rotondo</city>
        <state>Foggia</state>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Elvira Grandone, MD</last_name>
      <phone>0039 0882416286</phone>
      <email>elvira.grandone@operapadrepio.it</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Fondazione Poliambulanza Chirurgia Vascolare</name>
      <address>
        <city>Brescia</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Raffaello Bellosta, MD</last_name>
      <phone>00390303518255</phone>
      <email>raffaello.bellosta@poliambulanza.it</email>
    </contact>
    <contact_backup>
      <last_name>Renzo Rossini, MD</last_name>
      <phone>0039Tel 0303515795</phone>
      <email>renzo.rossini@poliambulanza.it</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Piazzale Spedali Civili, 1, 25123 Brescia BS Medicina Interna UniBS 2° Medicina ASST Spedali Civili</name>
      <address>
        <city>Brescia</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Massimo Salvetti, MD</last_name>
      <phone>00390303995251</phone>
      <email>massimo.salvetti@unibs.it</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedaliero-Universitaria &quot;Policlinico - V. Emanuele&quot;, Catania Anestesia e Rianimazione UO Malattie Infettive</name>
      <address>
        <city>Catania</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Arturo Montineri, MD</last_name>
      <phone>00390954794191</phone>
      <email>a.montineri@libero.it</email>
    </contact>
    <contact_backup>
      <last_name>Marco Mangiafico, MD</last_name>
      <email>marcomangiafico@hotmail.it</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>ASST Cremona Unità Operativa di Chirurgia Vascolare Dipartimento di Medicina di Laboratorio e di Radiologia- Centro Emostasi e Trombosi</name>
      <address>
        <city>Cremona</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Sophie Testa, MD</last_name>
      <phone>0039 0372405111</phone>
      <email>s.testa@asst-cremona.it</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Ospedale Morgagni Pierantoni U.O.C. Malattie Infettive</name>
      <address>
        <city>Forlì</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Francesco Cristini, MD</last_name>
      <phone>0039 3936022615</phone>
      <email>francesco.cristini@auslromagna.it</email>
    </contact>
    <contact_backup>
      <last_name>Aria Patacca, MD</last_name>
      <phone>0039 3280623035</phone>
      <email>aria.patacca@auslromagna.it</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Ospedale Carlo Poma di Mantova MALATTIE INFETTIVE Padiglione 37 Str. Lago Paiolo, 10, 46100 Mantova</name>
      <address>
        <city>Mantova</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Salvatore Casari</last_name>
      <phone>0039 0376201539</phone>
      <email>salvatore.casari@asst-mantova.it</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>AZIENDA OSPEDALIERA Regionale S CARLO POTENZA Struttura Complessa Interaziendale &quot;Malattie Infettive&quot;</name>
      <address>
        <city>Matera</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Giulio De Stefano, MD</last_name>
      <phone>0039 0835253344</phone>
      <email>giulio.destefano@ospedalesancarlo.it</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Ospedale San Raffaele Unità Funzionale dell'Unità Operativa di Malattie Infettive Osp. San Raffaele</name>
      <address>
        <city>Milano</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Antonella Castagna, MD</last_name>
      <phone>0039 02 2643 5392</phone>
      <email>castagna.antonella@hsr.it</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Ospedale Amedeo di Savoia Torino Università di Torino Malattie Infettive</name>
      <address>
        <city>Torino</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Giovanni Di Perri, MD</last_name>
      <phone>0039 0114393979</phone>
      <email>giovanni.diperri@unito.it</email>
    </contact>
    <contact_backup>
      <last_name>Stefano Bonorq, MD</last_name>
      <phone>0039 349193281</phone>
      <email>stefano.bonora@unito.it</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedaliera Universitaria Integrata Verona UOC Malattie Infettive e Tropicali</name>
      <address>
        <city>Verona</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Evelina Tacconelli, MD</last_name>
      <phone>00390458128284</phone>
      <email>evelina.tacconelli@univr.it</email>
    </contact>
    <contact_backup>
      <last_name>Fulvia Mazzaferri, MD</last_name>
      <phone>0039 3387310642</phone>
      <email>fulvia.mazzaferri@aovr-veneto.it</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>May 29, 2020</study_first_submitted>
  <study_first_submitted_qc>June 10, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 11, 2020</study_first_posted>
  <last_update_submitted>June 15, 2020</last_update_submitted>
  <last_update_submitted_qc>June 15, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 17, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>IRCCS Azienda Ospedaliero-Universitaria di Bologna</investigator_affiliation>
    <investigator_full_name>Pierluigi Viale</investigator_full_name>
    <investigator_title>Professor of Infectious Diseases</investigator_title>
  </responsible_party>
  <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>
    <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>April 2, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/98/NCT04427098/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04427098
org study id: 2020-001308-40
nct id: NCT04427098
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
General objective of the study To assess the efficacy and safety of enoxaparin in
      hospitalized patients with moderate to severe COVID-19 (Coronavirus Disease 2019) infection.

      Study Design

      The study consists of two parts:

        -  a phase II single-arm interventional prospective study including all patients treated
           with the study drug;

        -  an observational prospective cohort study including all patients screened for receiving
           the study drug but not included in the phase II study.

      Patients will be enrolled from "date of study approval" for 1 month. Each patient will be
      followed-up for a minimum of 90 days after COVID19 diagnosis.
General objective of the study To assess the efficacy and safety of enoxaparin in
      hospitalized patients with moderate to severe COVID-19 infection.

      Specific objectives Primary Endpoints To investigate the efficacy of enoxaparin in improving
      the clinical outcome of hospitalized patients with moderate to severe COVID-19.

        -  All-cause in-hospital, 30-day and 90-day mortality rates.

        -  Evolution of the clinical severity during treatment.

        -  ICU admission and length of ICU stay.

        -  Length of hospital stay.

      Secondary Endpoints To analyse the safety of enoxaparin in hospitalized patients with with
      moderate to severe COVID-19.

        -  Rate of adverse events (AEs) during treatment, at the end of treatment (EOT) and at 30
           days after EOT.

        -  Severity of AEs classified according to common terminology criteria for adverse events
           (CTCAE). The worst degree ever suffered will be considered.

      To describe the rates and the types of thromboembolic events among hospitalized patients with
      confirmed diagnosis of COVID-19.

        -  Occurrence of thromboembolic event at 90 days after COVID-19 diagnosis.

        -  Description of the type, distribution and severity of thromboembolic events.

      Study Design Overall Design

      The study consists of two parts:

        -  a phase II single-arm interventional prospective study including all patients treated
           with the study drug;

        -  an observational prospective cohort study including all patients screened for receiving
           the study drug but not included in the phase II study.

      Patients will be enrolled from "date of study approval" for 1 month. Each patient will be
      followed-up for a minimum of 90 days after COVID19 diagnosis.

      End of Study Definition A participant is considered to have completed the study if he/she has
      completed the last scheduled procedure shown in the Schedule of assessments. The end of the
      study is defined as the date of the last scheduled procedure shown in the Schedule of
      assessments for the last participant in the trial.

      Study Population

      Definitions

      Clinical severity of COVID-19 will be assessed at the diagnosis of COVID19, during the
      treatment with the study drug, and at the end of treatment according to the following
      criteria (1):

        -  Mild patients: only show mild symptoms without radiographic features

        -  Moderate patients: have fever, respiratory symptoms, and radiographic signs of pneumonia

        -  Severe patients: have fever, respiratory symptoms, and radiographic signs of pneumonia
           plus at least one of three criteria: (1) RR (respiratory rate) >30 times/min, (2) oxygen
           saturation <93% on ambient air, (3) PaO2/FiO2 (Oxigen partial pressure/inspired oxygen
           fraction ) <300 mmHg.

        -  Critical patients: meet one of three criteria: (1) respiratory failure needing invasive
           ventilation, (2) septic shock, (3) multiple organ failure.

      Major bleeding will be defined according to the ISTH (International Society of Thrombosis and
      Haemostasis) criteria as one of the following:

        -  Fatal bleeding

        -  Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal,
           intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with
           compartment syndrome

        -  Bleeding causing a fall in haemoglobin level of 2 g/dL or more, or leading to
           transfusion of two or more units of whole blood or red cells (11).

      Treatments Administration and monitoring of study drug

      All patients screened for being included in the study will receive standard
      thrombo-prophylaxis with LMWH (low molecular weight heparin) (e.g. enoxaparin 40 mg/die).
      Patients included in the observational cohort will continue on standard thrombo-prophylaxis,
      while patients included in the interventional study will receive subcutaneous enoxaparin in a
      single daily dose of:

        -  60 mg once daily in case of body weight of 45 to 60 kg

        -  80 mg per day in case of weight from 61 to 100 kg or

        -  100 mg once daily in case of bodyweight >100 kg Enoxaparin will be started on the first
           day of COVID19 diagnosis and continued for 14 days, after determination of baseline PT
           (prothrombin time), aPTT (activated partial thromboplastin time), complete blood cell
           count and creatinine levels.

      After reaching the steady state (usually after the third dose), heparin levels will be
      measured with the determination of anti-Xa activity on a blood sample obtained at 4 hours
      after the morning injection. LMWH dose may be then increased or reduced on the basis of
      target anti-Xa activity (0.4-0.6 antiFXa (Anti Factor X activated) UI/ml (International
      Unit/ml) for intermediate doses). The determination of anti-Xa activity will be repeated on
      the fifth or sixth day to monitor any drug accumulation.

      Complete blood cell count will be obtained every second day to monitor for heparin induced
      thrombocytopenia.

      Single low dose antiplatelet agents will be allowed. In all patients, RT-PCR (reverse
      transcription-polymerase chain reaction) nasopharyngeal swabs will be performed every 7 days
      to assess virus clearance and blood samples will be collected at baseline and on day 7 and
      will be retrospectively analysed to measure viral load.

      Follow up procedures Patients will be followed-up to 90 days after study drug initiation.
      Follow-up information will be collected via telephone calls, patient medical records and/or
      clinical visits according to clinical evolution.

      This is a pilot study and an initial sample of 100 patients for the phase II single-arm
      interventional trial is established. Even if currently precise data are not available, it can
      be assumed that the composite endpoint is around 30% in patient treated with the standard
      thromboprophylaxis dose of enoxaparin. To verify the hypothesis that the experimental
      treatment may produce a halving of this endpoint (from 30% to 15%), 300 patients (200 for the
      observational cohort and 100 for the phase II cohort; ratio 2:1) are needed with a 80% power
      and a 0,05 bilateral alpha error. As stated above a first safety analysis after enrolling the
      first 50 patients in the interventional study arm is planned and it will be done by an
      independent committee. According to safety and efficacy data obtained, using as control the
      observational cohort, a large study with a more robust design is planned.
allocation: Non-Randomized
intervention model: Parallel Assignment
intervention model description: The study consists of two parts:
a phase II single-arm interventional prospective study including all patients treated with the study drug;
an observational prospective cohort study including all patients screened for receiving the study drug but not included in the phase II study.
primary purpose: Treatment
masking: None (Open Label)
measure: To investigate the efficacy of enoxaparin in improving the clinical outcome of hospitalized patients with moderate-severe COVID-19.
time frame: 30 days and 90 days from the first LMWH subcutaneous injection
description: Rates of hospitalized patients dead for all-cause within 30 days and 90 days from the first LMWH subcutaneous injection
measure: To investigate the efficacy of enoxaparin in improving the clinical outcome of hospitalized patients with moderate-severe COVID-19.
time frame: This evaluation will be performed at 30 days and 90 days from the first LMWH subcutaneous injection
description: Based on the four levels scale of severity of symptoms. Any change from one level to another will be detected for all the enrolled patients, in order to evalutate the clinical efficacy of enoxaparin on the outcome of COVID 19.
measure: To investigate the efficacy of enoxaparin in improving the clinical outcome of hospitalized patients with moderate-severe COVID-19.
time frame: This evaluation will be performed at 14 days (the last day of treatment adminstration), at 30 days and 90 days from the first LMWH subcutaneous injection
description: Evolution of the clinical severity during treatment, based on the number and rate of patients admitted to ICU and the length of their ICU stay
measure: To investigate the efficacy of enoxaparin in improving the clinical outcome of hospitalized patients with moderate-severe COVID-19.
time frame: This evaluation will be performed at 90 days from admission
description: Difference between groups in number of days of hospitalization from admission to discharge
measure: To analyse the safety of enoxaparin in hospitalized patients with moderatesevere COVID-19.
time frame: 45 days
description: Rate of adverse events (AEs) during treatment, at the end of treatment (EOT) and at 30 days after EOT.
• Severity of AEs classified according to common terminology criteria for adverse events (CTCAE). The worst degree ever suffered will be considered.
measure: To describe the rates and the types of thromboembolic events among hospitalized patients with confirmed diagnosis of COVID-19.
time frame: 90 days
description: Occurrence of thromboembolic event at 90 days after COVID-19 diagnosis. Description of the type, distribution and severity of thromboembolic events.
arm group label: a phase II single-arm interventional prospective study
arm group type: Active Comparator
description: Patients included in the interventional study will receive subcutaneous enoxaparin in a single daily dose of:
60 mg once daily in case of body weight of 45 to 60 kg
80 mg per day in case of weight from 61 to 100 kg or
100 mg once daily in case of bodyweight >100 kg
Enoxaparin will be started on the first day of COVID19 diagnosis and continued for 14 days.
arm group label: observational cohort study
arm group type: Experimental
description: Patients included in the observational cohort will will receive standard thrombo-prophylaxis with subcutaneous enoxaparin 40 mg/die
intervention type: Drug
intervention name: Enoxaparin 40 Mg/0.4 mL Injectable Solution
description: Subcutaneous enoxaparin 40 mg once daily for 14 days.
arm group label: a phase II single-arm interventional prospective study
other name: INHIXA 4,000 UI (40 mg) / 0.4 ml
intervention type: Drug
intervention name: Enoxaparin
description: Subcutaneous enoxaparin for 14 days: 60 mg once daily in case of body weight of 45 to 60 kg; 80 mg once daily in case of weight from 61 to 100 kg; 100 mg once daily in case of bodyweight >100 kg
arm group label: observational cohort study
other name: INHIXA 6,000 UI (60 mg) / 0.6 ml
other name: INHIXA 8,000 UI (80 mg) / 0.8 ml
other name: INHIXA 10,000 UI (100 mg)/ 1 ml
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: Pierluigi Viale, MD
role: Principal Investigator
affiliation: Infectious Diseases Unit, Dep. Med. and Surg. Science University of Bologna
last name: Andrea Romagnoli, MD
phone: 0039 050 0984040
email: aromagnoli@ricerchenuove.com
last name: Stefano Triscornia, BS
phone: 0039 050 0984040
email: striscornia@ricerchenuove.com
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Not yet recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
contact backup: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
contact backup: 
country: Italy
responsible party type: Principal Investigator
investigator affiliation: IRCCS Azienda Ospedaliero-Universitaria di Bologna
investigator full name: Pierluigi Viale
investigator title: Professor of Infectious Diseases
mesh term: COVID-19
mesh term: Enoxaparin
mesh term: Enoxaparin sodium
sharing ipd: No
provided document: 