<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/NCT01713361</url>
  </required_header>
  <id_info>
    <org_study_id>ISIS 416858-CS3</org_study_id>
    <nct_id>NCT01713361</nct_id>
  </id_info>
  <brief_title>Active Comparator-Controlled Study to Assess Safety and Efficacy of ISIS-FXIRx in Total Knee Arthroplasty</brief_title>
  <official_title>An Open-label, Randomized, Active Comparator-Controlled, Adaptive Parallel-group Phase 2 Study to Assess the Safety and Efficacy of Multiple Doses of ISIS 416858 Administered Subcutaneously to Patients Undergoing Total Knee Arthroplasty</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Ionis Pharmaceuticals, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Ionis Pharmaceuticals, Inc.</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is:&#xD;
&#xD;
        -  To assess the safety and efficacy profile of ISIS-FXIRx, including incidence of bleeding&#xD;
           and VTE, in patients undergoing total knee arthroplasty.&#xD;
&#xD;
        -  To compare the efficacy and safety profile of ISIS-FXIRx in patients who achieve less&#xD;
           than or equal to 0.2 U/mL FXI activity levels to that of enoxaparin.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>October 2012</start_date>
  <completion_date type="Actual">August 2014</completion_date>
  <primary_completion_date type="Actual">May 2014</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Primary efficacy outcome</measure>
    <time_frame>up to 12 days post-surgery</time_frame>
    <description>Composite of asymptomatic DVT (via bilateral venography), and symptomatic VTE, fatal PE, and unexplained death.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Secondary efficacy outcome</measure>
    <time_frame>1st dose to up to Day 76</time_frame>
    <description>All DVTs and PEs up to 4 weeks after bilateral venography</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">315</enrollment>
  <condition>Venous Thromboembolism</condition>
  <arm_group>
    <arm_group_label>ISIS-FXIRx Dose 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Group B: ISIS-FXIRx Dose #2</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ISIS-FXIRx Dose 3</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Group C: ISIS-FXIRx Dose #3</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Enoxaparin</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Enoxaparin (40mg)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ISIS-FXIRx Dose #2</intervention_name>
    <description>Group B: ISIS-FXIRx dose #2 subcutaneously administered 7 times prior to total knee arthroplasty, and 2 times after surgery.</description>
    <arm_group_label>ISIS-FXIRx Dose 2</arm_group_label>
    <other_name>ISIS-FXIRx</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ISIS-FXIRx Dose #3</intervention_name>
    <description>Group C: ISIS-FXIRx dose #3 subcutaneously administered 7 times prior to total knee arthroplasty, and 2 times after surgery.</description>
    <arm_group_label>ISIS-FXIRx Dose 3</arm_group_label>
    <other_name>ISIS-FXIRx</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Enoxaparin</intervention_name>
    <description>Enoxaparin (40mg) will be administered by subcutaneous injection the evening prior to total knee arthroplasty (optionally), 6 to 8 hours after surgery, followed by daily injections for at least 8 additional days post surgery (a total of at least 9 consecutive days). [Except for Canadian region, in which the subcutaneous injection of enoxaparin the evening prior to total knee arthroplasty is expected, resulting in a total of at least 10 consecutive days of enoxaparin.]</description>
    <arm_group_label>Enoxaparin</arm_group_label>
    <other_name>Lovenox</other_name>
    <other_name>Clexane</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Give written informed consent&#xD;
&#xD;
          -  Females must be non-pregnant and non-lactating, and either surgically sterile or&#xD;
             post-menopausal. Males must be surgically sterile, abstinent, or if engaged in sexual&#xD;
             relations of child-bearing potential, must use contraception&#xD;
&#xD;
          -  Undergoing elective, primary unilateral total knee arthroplasty&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Body weight &lt;50 kg&#xD;
&#xD;
          -  Patients at increased risk of bleeding. History of intracranial or intraocular&#xD;
             bleeding. History of gastrointestinal and/or endoscopically verified ulcer disease&#xD;
             within the past year.&#xD;
&#xD;
          -  History of excessive intra- or direct post operative bleeding or a traumatic spinal or&#xD;
             epidural anesthesia&#xD;
&#xD;
          -  Brain, spinal, or ophthalmologic surgery within the past 3 months&#xD;
&#xD;
          -  History of clinically significant liver disease in the past year&#xD;
&#xD;
          -  Screening laboratory results as follows, or any other clinically significant&#xD;
             abnormalities in screening laboratory values&#xD;
&#xD;
               -  aPTT or PT or INR &gt;ULN&#xD;
&#xD;
               -  Factor IX activity &lt;LLN&#xD;
&#xD;
               -  Factor VIII activity, vWF antigen or Ristocetin cofactor activity &lt;0.5 U/mL&#xD;
&#xD;
               -  FXI activity &lt;0.3 U/mL&#xD;
&#xD;
               -  Urine protein or blood persistently positive by dipstick. In the event of&#xD;
                  positive test results, eligibility may be confirmed with urine microscopy or 24&#xD;
                  hour urine protein measurement as applicable&#xD;
&#xD;
               -  ALT or AST &gt;1.5 x ULN&#xD;
&#xD;
               -  Total bilirubin &gt;ULN&#xD;
&#xD;
               -  Platelet count &lt;150,000 (or history of thrombocytopenia)&#xD;
&#xD;
          -  Hypersensitivity to enoxaparin&#xD;
&#xD;
          -  Anticipated concomitant use of anticoagulants/antiplatelet agents or the NSAID&#xD;
             nimesulide that may affect study outcome or any other drug influencing coagulation&#xD;
             (except low dose aspirin and short acting NSAIDs with a half-life &lt;20 hours) at least&#xD;
             7 days before surgery or during treatment with ISIS Rx.&#xD;
&#xD;
          -  Anticipated use of indwelling intrathecal or epidural catheters&#xD;
&#xD;
          -  Anemia at Screening&#xD;
&#xD;
          -  Have any other conditions which could interfere with the patient participating in or&#xD;
             completing the study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sanjay Bhanot, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>VP, Clinical Development, Isis Pharmaceuticals</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Isis Investigational Site</name>
      <address>
        <city>Plovdiv</city>
        <zip>4002</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Isis Investigational Site</name>
      <address>
        <city>Rousse</city>
        <zip>7002</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Isis Investigational Site</name>
      <address>
        <city>Sofia</city>
        <zip>1527</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Isis Investigational Site</name>
      <address>
        <city>Ajax</city>
        <state>Ontario</state>
        <zip>LIS 2J4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Isis Investigational Site</name>
      <address>
        <city>Oshawa</city>
        <state>Ontario</state>
        <zip>LIG 2B9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Isis Investigational Site</name>
      <address>
        <city>Adazi</city>
        <zip>LV 2164</zip>
        <country>Latvia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Isis Investigational Site</name>
      <address>
        <city>Riga</city>
        <zip>LV 1004</zip>
        <country>Latvia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Isis Investigational Site</name>
      <address>
        <city>Valmiera</city>
        <zip>LV4201</zip>
        <country>Latvia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Isis Investigational Site</name>
      <address>
        <city>Chelyabinsk</city>
        <zip>454026</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Isis Investigational Site</name>
      <address>
        <city>Orenburg</city>
        <zip>460000</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Isis Investigational Site</name>
      <address>
        <city>Saint Petersburg</city>
        <zip>193312</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Isis Investigational Site</name>
      <address>
        <city>Saint Petersburg</city>
        <zip>194291</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Isis Investigational Site</name>
      <address>
        <city>Saint Petersburg</city>
        <zip>194354</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Isis Investigational Site</name>
      <address>
        <city>Samara</city>
        <zip>443095</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Isis Investigational Site</name>
      <address>
        <city>Yaroslavl</city>
        <zip>150047</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Isis Investigational Site</name>
      <address>
        <city>Cherkassy</city>
        <zip>18009</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Isis Investigational Site</name>
      <address>
        <city>Ivano-Frankivsk</city>
        <zip>76000</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Isis Investigational Site</name>
      <address>
        <city>Kharkiv</city>
        <zip>61024</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Isis Investigational Site</name>
      <address>
        <city>Kyiv</city>
        <zip>01107</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Isis Investigational Site</name>
      <address>
        <city>Odessa</city>
        <zip>65025</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Isis Investigational Site</name>
      <address>
        <city>Sevastopol</city>
        <zip>99018</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Bulgaria</country>
    <country>Canada</country>
    <country>Latvia</country>
    <country>Russian Federation</country>
    <country>Ukraine</country>
  </location_countries>
  <verification_date>August 2014</verification_date>
  <study_first_submitted>October 4, 2012</study_first_submitted>
  <study_first_submitted_qc>October 23, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 24, 2012</study_first_posted>
  <last_update_submitted>August 25, 2014</last_update_submitted>
  <last_update_submitted_qc>August 25, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">August 27, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>total knee arthroplasty</keyword>
  <keyword>Prophylaxis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Thromboembolism</mesh_term>
    <mesh_term>Venous Thromboembolism</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Enoxaparin</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/NCT01713361
org study id: ISIS 416858-CS3
nct id: NCT01713361
lead sponsor: 
has dmc: Yes
The purpose of this study is:

        -  To assess the safety and efficacy profile of ISIS-FXIRx, including incidence of bleeding
           and VTE, in patients undergoing total knee arthroplasty.

        -  To compare the efficacy and safety profile of ISIS-FXIRx in patients who achieve less
           than or equal to 0.2 U/mL FXI activity levels to that of enoxaparin.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: Primary efficacy outcome
time frame: up to 12 days post-surgery
description: Composite of asymptomatic DVT (via bilateral venography), and symptomatic VTE, fatal PE, and unexplained death.
measure: Secondary efficacy outcome
time frame: 1st dose to up to Day 76
description: All DVTs and PEs up to 4 weeks after bilateral venography
arm group label: ISIS-FXIRx Dose 2
arm group type: Experimental
description: Group B: ISIS-FXIRx Dose #2
arm group label: ISIS-FXIRx Dose 3
arm group type: Experimental
description: Group C: ISIS-FXIRx Dose #3
arm group label: Enoxaparin
arm group type: Active Comparator
description: Enoxaparin (40mg)
intervention type: Drug
intervention name: ISIS-FXIRx Dose #2
description: Group B: ISIS-FXIRx dose #2 subcutaneously administered 7 times prior to total knee arthroplasty, and 2 times after surgery.
arm group label: ISIS-FXIRx Dose 2
other name: ISIS-FXIRx
intervention type: Drug
intervention name: ISIS-FXIRx Dose #3
description: Group C: ISIS-FXIRx dose #3 subcutaneously administered 7 times prior to total knee arthroplasty, and 2 times after surgery.
arm group label: ISIS-FXIRx Dose 3
other name: ISIS-FXIRx
intervention type: Drug
intervention name: Enoxaparin
description: Enoxaparin (40mg) will be administered by subcutaneous injection the evening prior to total knee arthroplasty (optionally), 6 to 8 hours after surgery, followed by daily injections for at least 8 additional days post surgery (a total of at least 9 consecutive days). [Except for Canadian region, in which the subcutaneous injection of enoxaparin the evening prior to total knee arthroplasty is expected, resulting in a total of at least 10 consecutive days of enoxaparin.]
arm group label: Enoxaparin
other name: Lovenox
other name: Clexane
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Sanjay Bhanot, MD, PhD
role: Study Director
affiliation: VP, Clinical Development, Isis Pharmaceuticals
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country: Bulgaria
country: Canada
country: Latvia
country: Russian Federation
country: Ukraine
responsible party type: Sponsor
mesh term: Thromboembolism
mesh term: Venous Thromboembolism
mesh term: Enoxaparin