<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/NCT03809481</url>
  </required_header>
  <id_info>
    <org_study_id>ERGCR-18-ORGHIT-001</org_study_id>
    <nct_id>NCT03809481</nct_id>
  </id_info>
  <brief_title>Open-Label, Randomised, Active Controlled, Multi-Centre Phase 3 Study Safety and Efficacy of Danaparoid vs Argatroban</brief_title>
  <acronym>HITSOVA</acronym>
  <official_title>Open-Label, Randomised, Active Controlled, Multi-Centre Ph 3 Study to Evaluate the Safety and Efficacy of Danaparoid vs Argatroban in Acute HIT</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Aspen Global Incorporated</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Aspen Global Incorporated</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      An Open-Label, Randomised, Active Controlled, Multi-Centre Phase 3 Study to Evaluate the&#xD;
      Safety and Efficacy of Danaparoid vs Argatroban in Treatment of Subjects with Acute HIT&#xD;
      (HITSOVA study)&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Objectives:&#xD;
&#xD;
      Primary:&#xD;
&#xD;
      To show that for the treatment of subjects with acute heparin-induced thrombocytopenia (HIT)&#xD;
      danaparoid use is not inferior to argatroban in terms of efficacy. The primary efficacy&#xD;
      endpoint (composite endpoint) is defined as treatment response at Day 44.&#xD;
&#xD;
      A subject will be considered a treatment responder, if none of the following events occur by&#xD;
      Day 44:&#xD;
&#xD;
        -  New or extended venous and/or arterial thrombosis, including gangrene/skin necrosis&#xD;
           Note: 'thrombosis' denotes venous and/or arterial here and throughout the protocol&#xD;
&#xD;
        -  All-cause mortality&#xD;
&#xD;
        -  Unplanned amputation, including ischemic gut resection&#xD;
&#xD;
      Secondary/Exploratory:&#xD;
&#xD;
      To collect additional efficacy data&#xD;
&#xD;
        -  Percentage of subjects with increase in platelet count to values ≥ 100,000/ μL at day 14&#xD;
&#xD;
        -  Deaths due to TE or bleeding up until Day 44&#xD;
&#xD;
        -  Incidence of fatal or non-fatal major bleeding up until Day 44&#xD;
&#xD;
      Note: As outlined by the Control of Anticoagulation Subcommittee major bleeding in&#xD;
      non-surgical subjects is defined as:&#xD;
&#xD;
        1. Fatal bleeding, and/or&#xD;
&#xD;
        2. 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, and/or&#xD;
&#xD;
        3. Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/ L) or more, or leading&#xD;
           to transfusion of two or more units of whole blood or red cells&#xD;
&#xD;
             -  New or extended thrombosis, including gangrene/skin necrosis&#xD;
&#xD;
             -  Unplanned amputation, including ischemic gut resection&#xD;
&#xD;
             -  All-cause mortality&#xD;
&#xD;
      Exploratory&#xD;
&#xD;
        -  Time to first event (new/extended thrombosis, all cause mortality, unplanned amputation)&#xD;
&#xD;
        -  Time to reach consistent increase in 3 consecutive alternate day platelet count&#xD;
           measurements during acute treatment&#xD;
&#xD;
        -  Incidence of new or extended TE events, including gangrene/skin necrosis up until Day 14&#xD;
&#xD;
        -  Incidence of all-cause mortality up until Day 14&#xD;
&#xD;
        -  Incidence of unplanned amputation up until Day 14&#xD;
&#xD;
        -  Incidence of fatal or non-fatal major bleeding up until Day 14&#xD;
&#xD;
      To describe the safety of danaparoid in comparison to argatroban&#xD;
&#xD;
        -  All-cause mortality&#xD;
&#xD;
        -  Incidence of fatal and non-fatal major bleeding events (as defined above) during the&#xD;
           acute treatment and then the entire follow-up period (until Day 44)&#xD;
&#xD;
        -  Incidence of serious adverse events (SAEs)&#xD;
&#xD;
        -  Incidence of adverse events (AEs)&#xD;
&#xD;
        -  Changes in vital parameters (heart rate, blood pressure, and respiratory rate) and&#xD;
           12-lead electrocardiogram (ECG)&#xD;
&#xD;
        -  Incidence of positive pre-danaparoid cross reactivity in the Heparin-induced Platelet&#xD;
           Activation (HIPA) assay (Greinacher. 1991)&#xD;
&#xD;
        -  Safety laboratory parameters&#xD;
&#xD;
      Design:&#xD;
&#xD;
      This is a Phase 3, open-label, randomized, active-controlled, multi-center study to evaluate&#xD;
      the safety and efficacy of danaparoid versus argatroban in treatment of subjects with&#xD;
      acuteHIT.&#xD;
&#xD;
      Subjects who develop a reduction in platelet count (PC) greater than or equal to 30% compared&#xD;
      with the higher of their pre-heparin treatment count or their highest platelet count after&#xD;
      the start of heparin either&#xD;
&#xD;
        1. Between Days 4 and 14 of the start of heparin treatment with or without thrombosis or&#xD;
&#xD;
        2. At Day 1 of heparin treatment and recent heparin exposure (within the last 30 days with&#xD;
           or without thrombosis) and who have a score on the 4Ts test of &gt;3 will be considered for&#xD;
           study enrollment as a Suspected HIT.&#xD;
&#xD;
      Subjects who have tested negative in available screening tests for HIT within the last 48&#xD;
      hours before enrollment will not be considered for study enrollment, unless new clinical&#xD;
      symptoms occurred.The following will occur for all subjects (regardless of whether they had a&#xD;
      screening HIT test performed in the enrolling hospital or not):&#xD;
&#xD;
        1. All heparin administration must be ceased after strong clinical suspicion of HIT, based&#xD;
           on clinical evaluation of the subject, including the use of heparin-bonded vascular&#xD;
           access catheters and circuits as well as heparin flushes.&#xD;
&#xD;
        2. Subject must be randomized into the study and treated with the study drug or transferred&#xD;
           to alternative non-heparin anticoagulant in situations where study drug cannot be&#xD;
           started within 2 hours after stop of heparin.&#xD;
&#xD;
        3. A blood sample may be taken at the same time for HIT testing according to local&#xD;
           practice.&#xD;
&#xD;
        4. The investigator will assess the subject for eligibility for the HITSOVA study by&#xD;
           clinical criteria (4T score &gt;3) and inclusion and exclusion criteria.&#xD;
&#xD;
        5. If eligible, written informed consent will be obtained from the subject or a legal&#xD;
           guardian and the subject will be randomized to receive study drug. .&#xD;
&#xD;
        6. A new blood sample for HIPA/ PF4/heparin IgG ELISA and anti-danaparoid antibodies and&#xD;
           cross reactivity has to be obtained to allow consistent blood sample labelling and&#xD;
           documentation before start of study drug, regardless whether another blood sample for&#xD;
           HIT testing according to local practice had been obtained at the time of suspicion of&#xD;
           HIT&#xD;
&#xD;
      Note, although use of non-heparin treatment for suspected HIT is allowed before enrollment of&#xD;
      the subject into the HITSOVA study, the study drug should be started as soon as possible, but&#xD;
      no later than 48 hours. In such situation, all time points specified in this protocol, will&#xD;
      be calculated from the time of first dose of study drug.&#xD;
&#xD;
      HIT diagnosis will be confirmed serologically by the HIPA assay and a specific PF4/heparin&#xD;
      IgG ELISA test for the HIT IgG by the nominated central laboratory based in Greifswald,&#xD;
      Germany Subjects with a positive HIPA assay and a positive HIT IgG antigen test with optical&#xD;
      density (OD) &gt; 0.5 will be classified as confirmed HIT, and treatment with randomized study&#xD;
      drug will continue.Subjects with negative HIPA assay and a positive HIT IgG antigen test with&#xD;
      an optical density (OD) &gt;0.5 and subjects with a positive HIPA assay but a negative HIT IgG&#xD;
      antigen test OD ≤0.5 will be classified as suspected HIT and treatment with randomized study&#xD;
      drug will continue. These subjects will later be adjudicated retrospectively by the&#xD;
      Adjudication Committee (AdjC) and then grouped into highly likely HIT or non-HIT.&#xD;
&#xD;
      All other subjects will be considered as non-HIT and the subjects will be removed from the&#xD;
      protocol, study drug will be discontinued, and further procedures and treatment will be given&#xD;
      at the discretion of the Investigator according to local standard practice. These subjects&#xD;
      will be followed to Day 44 after their first dose of study drug for assessment of safety.&#xD;
&#xD;
      During the treatment period if it becomes necessary for an operation, invasive vascular&#xD;
      procedure or acute kidney injury requiring the use of an extracorporeal circulation machine&#xD;
      develops, then specific dosing instructions are available.&#xD;
&#xD;
      If the acute kidney injury does not recover during the treatment period and the use of an&#xD;
      extracorporeal circulation machine is required longer, then the subject will not be eligible&#xD;
      to be included in the per protocol set (PPS), but will still be eligible to be included in&#xD;
      the full analysis set (FAS).&#xD;
&#xD;
      Study Population:&#xD;
&#xD;
      All subjects who develop a reduction in platelet count (PC) ≥ 30% compared to the higher of&#xD;
      their pre-heparin treatment count or their highest platelet count after the start of heparin&#xD;
      at either&#xD;
&#xD;
      a) between Days 4 and 14 of the start of heparin treatment with or without thrombosis or b)&#xD;
      at Day 1 of heparin treatment (and recent heparin exposure within the last 30 days) with or&#xD;
      without thrombosis and who have a score on the 4Ts test of &gt;3 and who are later suspected HIT&#xD;
      by the HIPA assay or HIT IgG..&#xD;
&#xD;
      Clinical signs of HIT are&#xD;
&#xD;
        -  New thrombosis, on either side (arterial or venous) of the circulation&#xD;
&#xD;
        -  Acute systemic reaction when heparin infusion was given:&#xD;
&#xD;
             -  Fever&#xD;
&#xD;
             -  Chills&#xD;
&#xD;
             -  High blood pressure&#xD;
&#xD;
             -  Tachycardia&#xD;
&#xD;
             -  Shortness of breath&#xD;
&#xD;
             -  Chest pain&#xD;
&#xD;
        -  Transient global amnesia&#xD;
&#xD;
        -  White clot syndrome&#xD;
&#xD;
        -  Skin necrosis&#xD;
&#xD;
        -  Occlusion of an extracorporeal circuit&#xD;
&#xD;
      Pediatric subjects will not be included in every country in this study. The countries that&#xD;
      allow inclusion of pediatric patients are France, USA,and Italy.&#xD;
&#xD;
      It is anticipated that some subjects will be dosed with alternative non-heparin&#xD;
      anti-coagulants prior to completing enrollment steps for this study. These subjects can be&#xD;
      enrolled in the study as long as the exposure to those treatments is less than 48 hours.&#xD;
&#xD;
      Baseline/screening (Day 0) and enrollment into the study (Day1) can occur on the same day. In&#xD;
      this case the assesments for Day 0 and Day 1, should only be performed once.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Prolonged delay as a result of impact of Covid19 pandemic&#xD;
  </why_stopped>
  <start_date type="Actual">May 16, 2019</start_date>
  <completion_date type="Actual">June 10, 2022</completion_date>
  <primary_completion_date type="Actual">June 10, 2022</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, randomized, active-controlled</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Composite Efficacy Response</measure>
    <time_frame>Day 44</time_frame>
    <description>Efficacy will be assessed by the number of subjects with suspected HIT who respond to treatment. A responder is defined as a subject who has not experienced any of the following from Day 1 to Day 44:&#xD;
New or extended venous and/or arterial thrombosis, including gangrene/skin necrosis&#xD;
All-cause mortality&#xD;
Unplanned amputation, including ischemic gut resection&#xD;
Efficacy endpoints as defined above will be assessed by clinical exam with special attention to assessments for thromboses, gangrene, and skin necrosis. Clinically suspected thrombosis will be confirmed/ruled out by objective measures, e.g. compression ultrasound.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Consistent increases in platelet count</measure>
    <time_frame>Days 14</time_frame>
    <description>Percentage of subjects with increase in platelet count to values ≥ 100,000/ μL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Death due to TE or bleeding</measure>
    <time_frame>Day 44</time_frame>
    <description>Death due to TE or bleeding</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Major Bleeding</measure>
    <time_frame>Day 44</time_frame>
    <description>Incidence of fatal or non-fatal major bleeding</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>New or extended thrombosis</measure>
    <time_frame>Day 44</time_frame>
    <description>New of extended thrombosis, including gangrene/skin necrosis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Unplanned amputation</measure>
    <time_frame>Day 44</time_frame>
    <description>Unplanned amputation, including ischemic gut resection</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All-cause mortality</measure>
    <time_frame>Day 44</time_frame>
    <description>All-cause mortality</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">7</enrollment>
  <condition>Heparin-induced Thrombocytopenia</condition>
  <arm_group>
    <arm_group_label>Danaparoid Sodium</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will receive danaparoid via IV infusion for at least 7 days then transition to a VKA. IV loading bolus injection of 2250 U, followed by 400 U/h for 4 hours, then 300 U/h for 4 hours, then a maintenance infusion of 150-200 U/h.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Argatroban</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Subjects will receive argatroban 2 microgram/kg/min as a continuous infusion, titrated to an aPTT that is 1.5 to 3.0 x initial baseline value, but not exceeding 100 seconds.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Danaparoid Sodium</intervention_name>
    <description>inhibits thrombin generation by indirect anti-Xa inhibition and direct inhibition of factor IX activation</description>
    <arm_group_label>Danaparoid Sodium</arm_group_label>
    <other_name>Orgaran</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Argatroban</intervention_name>
    <description>Synthetic direct thrombin inhibitor</description>
    <arm_group_label>Argatroban</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        At the time of enrollment subjects are eligible to be included in the study only if all of&#xD;
        the following criteria apply:&#xD;
&#xD;
          1. Signed written informed consent by the subject who is able to assess the nature,&#xD;
             significance and scope of the clinical trial. If the subject is in emergency situation&#xD;
             and temporarily incapable of consent, the consent of a legal representative or&#xD;
             authorized representative will be waived if permitted under applicable local&#xD;
             regulations/ethics committee recommendations. Consent must be obtained for further&#xD;
             participation in the clinical trial as soon as this is possible and reasonable for the&#xD;
             subject to do so to confirm understanding/willingness to participate in the clinical&#xD;
             study and ability to comply with study procedures and the study visit schedule.&#xD;
&#xD;
          2. Males or females aged ≥2 weeks&#xD;
&#xD;
          3. Subjects with suspected HIT by 4Ts of &gt;3 and with reduction of platelet count of ≥ 30%&#xD;
             at either:&#xD;
&#xD;
               1. Between Day 4 and 14 of the start of heparin exposure or&#xD;
&#xD;
               2. At Day 1 of heparin exposure with pre-treatment with heparin within the last 30&#xD;
                  days, with or without thrombosis.&#xD;
&#xD;
          4. Have adequate renal function: estimated glomerular filtration rate (eeGFR) ≥ 15&#xD;
             mL/min/1.73 m²&#xD;
&#xD;
          5. Male participants:&#xD;
&#xD;
             A male participant must agree to use contraception during the treatment period and for&#xD;
             at least 5 days after the last dose of study intervention and refrain from donating&#xD;
             sperm during this period.&#xD;
&#xD;
          6. Female participants: female participant is eligible to participate if 1 of the&#xD;
             following conditions applies:&#xD;
&#xD;
        Not a woman of childbearing potential or A woman of childbearing potential who agrees to&#xD;
        follow the contraceptive guidance during the treatment period and during the entire VKA use&#xD;
        and for one month after cessation of its use. Subjects should continue with adequate&#xD;
        contraception after the study end if they continue with VKA use. (Subjects taking oral&#xD;
        contraceptives or hormone replacement therapy must have a stable dose and regimen for ≥ 3&#xD;
        months prior to entry into the study.)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        At the time of enrollmentsubjects are excluded from the study if any of the following&#xD;
        criteria apply:&#xD;
&#xD;
          1. Premature infants (corrected age &lt;37 weeks gestational age)&#xD;
&#xD;
          2. Subjects undergoing Extracorporeal Membrane Oxygenation (ECMO) treatment&#xD;
&#xD;
          3. Fibrinolytic therapy &lt;24 hours before enrollment&#xD;
&#xD;
          4. Lumbar puncture or spinal/epidural catheter placement within the past 48 hours&#xD;
&#xD;
          5. Severe hepatic impairment (Child-Pugh Class C) Note: in patients with&#xD;
             suspected/confirmed severe liver disease, Child-Pugh C stage of liver disease must be&#xD;
             excluded before start of treatment. For calculating Child-Pugh score, laboratory&#xD;
             parameters in the patient file on INR, prothrombin time, serum albumin and total&#xD;
             bilirubin taken can be taken, if they have been obtained within the last 48 hours&#xD;
             before randomization. In all other patients these parameters have to be measured&#xD;
             before start of treatment to identify potential exclusion criteria.&#xD;
&#xD;
          6. Active bleeding&#xD;
&#xD;
          7. Subjects with the following conditions to be excluded if alternative antithrombotic&#xD;
             treatments are available:&#xD;
&#xD;
             (i) Severe hemorrhagic diathesis, (ii) Traumatic damage to the central nervous system&#xD;
             (iii) Brain, spinal or ophthalmologic surgery (iv) Active stomach/duodenal ulcers or&#xD;
             active peptic ulcer unless this ulcer is the cause of the surgical procedure&#xD;
&#xD;
          8. An unexplained activated partial thromboplastin time (aPTT) &gt; 2 x the normal range&#xD;
&#xD;
          9. A hemorrhagic cerebrovascular accident within the previous 3 months&#xD;
&#xD;
         10. Severe, uncontrolled hypertension defined as blood pressure &gt;180/110 mmHg&#xD;
&#xD;
         11. Diabetic retinopathy&#xD;
&#xD;
         12. Acute bacterial endocarditis&#xD;
&#xD;
         13. Expectation of a long-term (&gt; 3 weeks) hemodialysis requirement before the end of the&#xD;
             acute treatment&#xD;
&#xD;
         14. Hypersensitivity to the active substances or to any of the excipients&#xD;
&#xD;
         15. Hypersensitivity to sulphite&#xD;
&#xD;
         16. Any investigational drug(s) use within 4 weeks preceding screening or anticipated use&#xD;
             during the course of the study&#xD;
&#xD;
         17. Pregnant or breastfeeding woman&#xD;
&#xD;
         18. Use of intra-aortic balloon pump, or ventricular assist device&#xD;
&#xD;
         19. Use of any non-heparin anticoagulant treatment for suspected HIT for more than 48&#xD;
             hours before enrollment.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>2 Weeks</minimum_age>
    <maximum_age>100 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Shands University of Florida</name>
      <address>
        <city>Gainesville</city>
        <state>Florida</state>
        <zip>32068</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Minnesota Medical Center</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55455</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Duke University Medical Center</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Ohio State University Wexner Medical Center</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The University of Texas MD Anderson Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77004</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Center of the Republic of Srpska, Medical Intesnive Care Unit</name>
      <address>
        <city>Banja Luka</city>
        <state>Republika Srpska</state>
        <zip>78000</zip>
        <country>Bosnia and Herzegovina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Clinical Centre of the Republic of Srpska, Clinic for cardiology</name>
      <address>
        <city>Banja Luka</city>
        <country>Bosnia and Herzegovina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Clinical Centre of the Republic of Srpska, Lung Clinic</name>
      <address>
        <city>Banja Luka</city>
        <country>Bosnia and Herzegovina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Center University of Sarajevo, Clinic for Heart, Blood Vessels and Rheumatic Diseases</name>
      <address>
        <city>Sarajevo</city>
        <zip>71000</zip>
        <country>Bosnia and Herzegovina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Center University of Sarajevo, Clinic for Lung Diseases</name>
      <address>
        <city>Sarajevo</city>
        <zip>78000</zip>
        <country>Bosnia and Herzegovina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Jewish General Hospital</name>
      <address>
        <city>Montréal</city>
        <zip>H3T 1E2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>DIJON University Hospital</name>
      <address>
        <city>Dijon</city>
        <state>Burgundy</state>
        <zip>2100</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU St Etienne; Avenue Albert Raimond</name>
      <address>
        <city>Saint-Priest-en-Jarez</city>
        <state>Rhone- Alpes</state>
        <zip>42270</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier Universitaire Amiens Picardie</name>
      <address>
        <city>Amiens</city>
        <state>Somme</state>
        <zip>80054</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vivantes Klinikum im Friedrichhain Hämophiliezentrum, Gerinnungssprechstunde Landsberger Allee 49</name>
      <address>
        <city>Berlin</city>
        <state>Berlin-Brandenburg</state>
        <zip>10249</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Gießen und Marburg GmbH, Klinik für Herz-, Kinderherz- und Gefäßchirurgie Standort Gießen</name>
      <address>
        <city>Giesen</city>
        <state>Lower Saxony</state>
        <zip>35392</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitatstklinikum Halle (Saale), Medizinische Klinik III</name>
      <address>
        <city>Halle (Saale)</city>
        <state>Saxony-Anhalt</state>
        <zip>06120</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Städtisches Klinkum Dresden</name>
      <address>
        <city>Dresden</city>
        <state>Saxony</state>
        <zip>1067</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Greifswald Dpt. of Hematology</name>
      <address>
        <city>Greifswald</city>
        <zip>17489</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Zentrum für Klinische Transfusionsmedizin</name>
      <address>
        <city>Tübingen</city>
        <zip>72076</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedaliero Universitaria S.Orsola-Malpighi - UO Angiologia e Malattie della Coagulazione</name>
      <address>
        <city>Bologna</city>
        <state>Emilia-Romagna</state>
        <zip>40138</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AOU Careggi, SOD Malattie Aterotrombotiche</name>
      <address>
        <city>Firenze</city>
        <state>Florence</state>
        <zip>50134</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>ASST Papa Giovanni XIII, Servizio di Immunoematologia e Medicina Trasfusionale</name>
      <address>
        <city>Bergamo</city>
        <state>Lombardy</state>
        <zip>24127</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Instituto Scientifico San Raffaele- Servizio Coagulazione e Centro Trombosi</name>
      <address>
        <city>Milano</city>
        <zip>20132</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centrum Medyczne HCP Sp. z o.o. Szpital im. Św. Jana Pawła II</name>
      <address>
        <city>Poznań</city>
        <zip>61485</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Wojewódzki Szpital Zespolony im. L. Rydygiera</name>
      <address>
        <city>Toruń</city>
        <zip>87100</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>First City Hospital N.A. E.E. Volosevich</name>
      <address>
        <city>Arkhangelsk</city>
        <zip>163001</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Moscow City Hospital 67</name>
      <address>
        <city>Moscow</city>
        <zip>123423</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oncology Center</name>
      <address>
        <city>Omsk</city>
        <zip>644013</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Regional Hospital after N.N Burdenko</name>
      <address>
        <city>Penza</city>
        <zip>440026</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Hospital № 122 N. A. L.G. Sokolov</name>
      <address>
        <city>Saint Petersburg</city>
        <zip>194291</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Institute for Pulmonary Disease of Vojvodina, Pulmonary thromboembolism department</name>
      <address>
        <city>Novi Sad</city>
        <state>Sremska Kamenica</state>
        <zip>21204</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Centre of Serbia, Clinic for Emergency Internal Medicine</name>
      <address>
        <city>Belgrade</city>
        <zip>11000</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical centre of Serbia, Clinic for Pulmonology</name>
      <address>
        <city>Belgrade</city>
        <zip>11000</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Instiute of Cardiovascular Diseases &quot;Dedinje&quot;</name>
      <address>
        <city>Belgrade</city>
        <zip>11040</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Bosnia and Herzegovina</country>
    <country>Canada</country>
    <country>France</country>
    <country>Germany</country>
    <country>Italy</country>
    <country>Poland</country>
    <country>Russian Federation</country>
    <country>Serbia</country>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Croatia</country>
    <country>Czechia</country>
    <country>Hungary</country>
  </removed_countries>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>January 17, 2019</study_first_submitted>
  <study_first_submitted_qc>January 17, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 18, 2019</study_first_posted>
  <last_update_submitted>December 6, 2022</last_update_submitted>
  <last_update_submitted_qc>December 6, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 8, 2022</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>Thrombocytopenia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Danaparoid</mesh_term>
    <mesh_term>Argatroban</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03809481
org study id: ERGCR-18-ORGHIT-001
nct id: NCT03809481
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
An Open-Label, Randomised, Active Controlled, Multi-Centre Phase 3 Study to Evaluate the
      Safety and Efficacy of Danaparoid vs Argatroban in Treatment of Subjects with Acute HIT
      (HITSOVA study)
Objectives:

      Primary:

      To show that for the treatment of subjects with acute heparin-induced thrombocytopenia (HIT)
      danaparoid use is not inferior to argatroban in terms of efficacy. The primary efficacy
      endpoint (composite endpoint) is defined as treatment response at Day 44.

      A subject will be considered a treatment responder, if none of the following events occur by
      Day 44:

        -  New or extended venous and/or arterial thrombosis, including gangrene/skin necrosis
           Note: 'thrombosis' denotes venous and/or arterial here and throughout the protocol

        -  All-cause mortality

        -  Unplanned amputation, including ischemic gut resection

      Secondary/Exploratory:

      To collect additional efficacy data

        -  Percentage of subjects with increase in platelet count to values ≥ 100,000/ μL at day 14

        -  Deaths due to TE or bleeding up until Day 44

        -  Incidence of fatal or non-fatal major bleeding up until Day 44

      Note: As outlined by the Control of Anticoagulation Subcommittee major bleeding in
      non-surgical subjects is defined as:

        1. Fatal bleeding, and/or

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

        3. Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/ L) or more, or leading
           to transfusion of two or more units of whole blood or red cells

             -  New or extended thrombosis, including gangrene/skin necrosis

             -  Unplanned amputation, including ischemic gut resection

             -  All-cause mortality

      Exploratory

        -  Time to first event (new/extended thrombosis, all cause mortality, unplanned amputation)

        -  Time to reach consistent increase in 3 consecutive alternate day platelet count
           measurements during acute treatment

        -  Incidence of new or extended TE events, including gangrene/skin necrosis up until Day 14

        -  Incidence of all-cause mortality up until Day 14

        -  Incidence of unplanned amputation up until Day 14

        -  Incidence of fatal or non-fatal major bleeding up until Day 14

      To describe the safety of danaparoid in comparison to argatroban

        -  All-cause mortality

        -  Incidence of fatal and non-fatal major bleeding events (as defined above) during the
           acute treatment and then the entire follow-up period (until Day 44)

        -  Incidence of serious adverse events (SAEs)

        -  Incidence of adverse events (AEs)

        -  Changes in vital parameters (heart rate, blood pressure, and respiratory rate) and
           12-lead electrocardiogram (ECG)

        -  Incidence of positive pre-danaparoid cross reactivity in the Heparin-induced Platelet
           Activation (HIPA) assay (Greinacher. 1991)

        -  Safety laboratory parameters

      Design:

      This is a Phase 3, open-label, randomized, active-controlled, multi-center study to evaluate
      the safety and efficacy of danaparoid versus argatroban in treatment of subjects with
      acuteHIT.

      Subjects who develop a reduction in platelet count (PC) greater than or equal to 30% compared
      with the higher of their pre-heparin treatment count or their highest platelet count after
      the start of heparin either

        1. Between Days 4 and 14 of the start of heparin treatment with or without thrombosis or

        2. At Day 1 of heparin treatment and recent heparin exposure (within the last 30 days with
           or without thrombosis) and who have a score on the 4Ts test of >3 will be considered for
           study enrollment as a Suspected HIT.

      Subjects who have tested negative in available screening tests for HIT within the last 48
      hours before enrollment will not be considered for study enrollment, unless new clinical
      symptoms occurred.The following will occur for all subjects (regardless of whether they had a
      screening HIT test performed in the enrolling hospital or not):

        1. All heparin administration must be ceased after strong clinical suspicion of HIT, based
           on clinical evaluation of the subject, including the use of heparin-bonded vascular
           access catheters and circuits as well as heparin flushes.

        2. Subject must be randomized into the study and treated with the study drug or transferred
           to alternative non-heparin anticoagulant in situations where study drug cannot be
           started within 2 hours after stop of heparin.

        3. A blood sample may be taken at the same time for HIT testing according to local
           practice.

        4. The investigator will assess the subject for eligibility for the HITSOVA study by
           clinical criteria (4T score >3) and inclusion and exclusion criteria.

        5. If eligible, written informed consent will be obtained from the subject or a legal
           guardian and the subject will be randomized to receive study drug. .

        6. A new blood sample for HIPA/ PF4/heparin IgG ELISA and anti-danaparoid antibodies and
           cross reactivity has to be obtained to allow consistent blood sample labelling and
           documentation before start of study drug, regardless whether another blood sample for
           HIT testing according to local practice had been obtained at the time of suspicion of
           HIT

      Note, although use of non-heparin treatment for suspected HIT is allowed before enrollment of
      the subject into the HITSOVA study, the study drug should be started as soon as possible, but
      no later than 48 hours. In such situation, all time points specified in this protocol, will
      be calculated from the time of first dose of study drug.

      HIT diagnosis will be confirmed serologically by the HIPA assay and a specific PF4/heparin
      IgG ELISA test for the HIT IgG by the nominated central laboratory based in Greifswald,
      Germany Subjects with a positive HIPA assay and a positive HIT IgG antigen test with optical
      density (OD) > 0.5 will be classified as confirmed HIT, and treatment with randomized study
      drug will continue.Subjects with negative HIPA assay and a positive HIT IgG antigen test with
      an optical density (OD) >0.5 and subjects with a positive HIPA assay but a negative HIT IgG
      antigen test OD ≤0.5 will be classified as suspected HIT and treatment with randomized study
      drug will continue. These subjects will later be adjudicated retrospectively by the
      Adjudication Committee (AdjC) and then grouped into highly likely HIT or non-HIT.

      All other subjects will be considered as non-HIT and the subjects will be removed from the
      protocol, study drug will be discontinued, and further procedures and treatment will be given
      at the discretion of the Investigator according to local standard practice. These subjects
      will be followed to Day 44 after their first dose of study drug for assessment of safety.

      During the treatment period if it becomes necessary for an operation, invasive vascular
      procedure or acute kidney injury requiring the use of an extracorporeal circulation machine
      develops, then specific dosing instructions are available.

      If the acute kidney injury does not recover during the treatment period and the use of an
      extracorporeal circulation machine is required longer, then the subject will not be eligible
      to be included in the per protocol set (PPS), but will still be eligible to be included in
      the full analysis set (FAS).

      Study Population:

      All subjects who develop a reduction in platelet count (PC) ≥ 30% compared to the higher of
      their pre-heparin treatment count or their highest platelet count after the start of heparin
      at either

      a) between Days 4 and 14 of the start of heparin treatment with or without thrombosis or b)
      at Day 1 of heparin treatment (and recent heparin exposure within the last 30 days) with or
      without thrombosis and who have a score on the 4Ts test of >3 and who are later suspected HIT
      by the HIPA assay or HIT IgG..

      Clinical signs of HIT are

        -  New thrombosis, on either side (arterial or venous) of the circulation

        -  Acute systemic reaction when heparin infusion was given:

             -  Fever

             -  Chills

             -  High blood pressure

             -  Tachycardia

             -  Shortness of breath

             -  Chest pain

        -  Transient global amnesia

        -  White clot syndrome

        -  Skin necrosis

        -  Occlusion of an extracorporeal circuit

      Pediatric subjects will not be included in every country in this study. The countries that
      allow inclusion of pediatric patients are France, USA,and Italy.

      It is anticipated that some subjects will be dosed with alternative non-heparin
      anti-coagulants prior to completing enrollment steps for this study. These subjects can be
      enrolled in the study as long as the exposure to those treatments is less than 48 hours.

      Baseline/screening (Day 0) and enrollment into the study (Day1) can occur on the same day. In
      this case the assesments for Day 0 and Day 1, should only be performed once.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Open-label, randomized, active-controlled
primary purpose: Treatment
masking: Single (Outcomes Assessor)
measure: Composite Efficacy Response
time frame: Day 44
description: Efficacy will be assessed by the number of subjects with suspected HIT who respond to treatment. A responder is defined as a subject who has not experienced any of the following from Day 1 to Day 44:
New or extended venous and/or arterial thrombosis, including gangrene/skin necrosis
All-cause mortality
Unplanned amputation, including ischemic gut resection
Efficacy endpoints as defined above will be assessed by clinical exam with special attention to assessments for thromboses, gangrene, and skin necrosis. Clinically suspected thrombosis will be confirmed/ruled out by objective measures, e.g. compression ultrasound.
measure: Consistent increases in platelet count
time frame: Days 14
description: Percentage of subjects with increase in platelet count to values ≥ 100,000/ μL
measure: Death due to TE or bleeding
time frame: Day 44
description: Death due to TE or bleeding
measure: Major Bleeding
time frame: Day 44
description: Incidence of fatal or non-fatal major bleeding
measure: New or extended thrombosis
time frame: Day 44
description: New of extended thrombosis, including gangrene/skin necrosis
measure: Unplanned amputation
time frame: Day 44
description: Unplanned amputation, including ischemic gut resection
measure: All-cause mortality
time frame: Day 44
description: All-cause mortality
arm group label: Danaparoid Sodium
arm group type: Experimental
description: Subjects will receive danaparoid via IV infusion for at least 7 days then transition to a VKA. IV loading bolus injection of 2250 U, followed by 400 U/h for 4 hours, then 300 U/h for 4 hours, then a maintenance infusion of 150-200 U/h.
arm group label: Argatroban
arm group type: Active Comparator
description: Subjects will receive argatroban 2 microgram/kg/min as a continuous infusion, titrated to an aPTT that is 1.5 to 3.0 x initial baseline value, but not exceeding 100 seconds.
intervention type: Drug
intervention name: Danaparoid Sodium
description: inhibits thrombin generation by indirect anti-Xa inhibition and direct inhibition of factor IX activation
arm group label: Danaparoid Sodium
other name: Orgaran
intervention type: Drug
intervention name: Argatroban
description: Synthetic direct thrombin inhibitor
arm group label: Argatroban
criteria: 
gender: All
minimum age: 2 Weeks
maximum age: 100 Years
healthy volunteers: No
facility: 
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country: Bosnia and Herzegovina
country: Canada
country: France
country: Germany
country: Italy
country: Poland
country: Russian Federation
country: Serbia
country: United States
country: Croatia
country: Czechia
country: Hungary
responsible party type: Sponsor
mesh term: Thrombocytopenia
mesh term: Danaparoid
mesh term: Argatroban
sharing ipd: No