<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/NCT02222714</url>
  </required_header>
  <id_info>
    <org_study_id>ZZ-3K3A-201 (NN104)</org_study_id>
    <secondary_id>1U01NS088312-01</secondary_id>
    <secondary_id>U01NS077352</secondary_id>
    <secondary_id>U01NS077179-01</secondary_id>
    <nct_id>NCT02222714</nct_id>
  </id_info>
  <brief_title>Safety Evaluation of 3K3A-APC in Ischemic Stroke</brief_title>
  <acronym>RHAPSODY</acronym>
  <official_title>A Multi-center, Phase 2 Study Using a Continual Reassessment Method to Determine the Safety and Tolerability of 3K3A-APC in Combination With tPA, Mechanical Thrombectomy or Both in Moderate to Severe Acute Ischemic Stroke</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>ZZ Biotech, LLC</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute of Neurological Disorders and Stroke (NINDS)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>Cedars-Sinai Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Massachusetts General Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Iowa</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>ZZ Biotech, LLC</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>
      The purpose of this study was to evaluate the safety, pharmacokinetics (PK) and preliminary&#xD;
      efficacy of multiple ascending intravenous doses of 3K3A-APC, a Recombinant Variant of Human&#xD;
      activated protein C (APC), in in the treatment of acute ischemic stroke following treatment&#xD;
      with recombinant tissue plasminogen activator (tPA), mechanical thrombectomy or both.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This was a multicenter, prospective, randomized, controlled, double-blinded Phase 2 study&#xD;
      intended to evaluate the safety, PK and preliminary efficacy of 3K3A-APC following treatment&#xD;
      with tPA, mechanical thrombectomy or both in subjects with moderate to severe acute ischemic&#xD;
      stroke.&#xD;
&#xD;
      Approximately 115 subjects were to be randomized, which included the planned 88 subjects in&#xD;
      groups of 4 subjects to either 3K3A-APC or placebo (in a 3:1 ratio) and the additional&#xD;
      placebo subjects who were enrolled during safety review pauses. This study used a modified&#xD;
      version of the continual reassessment method (CRM) in order to establish a maximum tolerated&#xD;
      dose (MTD).&#xD;
&#xD;
      Eligible subjects received 3K3A-APC or placebo every 12 hours for up to 5 doses&#xD;
      (approximately 3 days), or until discharge from the hospital, whichever occurred first.&#xD;
      Subjects were monitored for safety evaluations through Day 7 (or discharge, if earlier) and&#xD;
      were expected to be seen on Day 7, 14, 30, and 90 for safety and outcome evaluations.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2014</start_date>
  <completion_date type="Actual">June 29, 2017</completion_date>
  <primary_completion_date type="Actual">April 18, 2017</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>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol</measure>
    <time_frame>48-hours following last dose</time_frame>
    <description>Specific AEs in the study were defined in the protocol to be dose-limiting toxicity events. Any given patient was adjudicated in a binary way to either have had a DLT or not to have had a DLT.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With a Presence of Measurable Bleeds in the Brain (Hemorrhage and Microbleeds) as Determined by 1.5T MRI</measure>
    <time_frame>Day 30</time_frame>
    <description>MRI examination to include-at minimum-T1 and T2 weighted images, as well as diffusion weighted imaging (DWI) and susceptibility weighted imaging (SWI) sequences. Post-tPA microbleeds-defined as hypointensities less than 5mm in diameter seen on SWI-will be counted as tPA-related only if found within the ischemic territory. All other areas of hypointensity on SWI larger than 5mm diameter will be counted as tPA-related regardless of the territory in which they are found. All treated subjects (regardless of dose) will be compared to all placebo subjects using a Pearson chi-square test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PK of 3K3A-APC by Compartmental Analysis (Clearance)</measure>
    <time_frame>Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI</time_frame>
    <description>Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PK of 3K3A-APC by Compartmental Analysis (Volume of Distribution)</measure>
    <time_frame>Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI</time_frame>
    <description>Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PK of 3K3A-APC by Compartmental Analysis (Cmax)</measure>
    <time_frame>Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI</time_frame>
    <description>Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PK of 3K3A-APC by Compartmental Analysis (AUC[0-inf])</measure>
    <time_frame>Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI</time_frame>
    <description>Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PK of 3K3A-APC by Compartmental Analysis (λz)</measure>
    <time_frame>Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI</time_frame>
    <description>Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PK of 3K3A-APC by Compartmental Analysis (Half-life)</measure>
    <time_frame>Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI</time_frame>
    <description>Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.</description>
  </secondary_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Actual">110</enrollment>
  <condition>Ischemic Stroke</condition>
  <arm_group>
    <arm_group_label>120 µg/kg of 3K3A-APC</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>3K3A-APC, q12h for up to 5 doses</description>
  </arm_group>
  <arm_group>
    <arm_group_label>240 µg/kg of 3K3A-APC</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>3K3A-APC, q12h for up to 5 doses</description>
  </arm_group>
  <arm_group>
    <arm_group_label>360 µg/kg of 3K3A-APC</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>3K3A-APC, q12h for up to 5 doses</description>
  </arm_group>
  <arm_group>
    <arm_group_label>540 µg/kg of 3K3A-APC</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>3K3A-APC, q12h for up to 5 doses</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Matching placebo, q12h for up to 5 doses</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>3K3A-APC</intervention_name>
    <description>3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
    <arm_group_label>120 µg/kg of 3K3A-APC</arm_group_label>
    <arm_group_label>240 µg/kg of 3K3A-APC</arm_group_label>
    <arm_group_label>360 µg/kg of 3K3A-APC</arm_group_label>
    <arm_group_label>540 µg/kg of 3K3A-APC</arm_group_label>
    <other_name>3K3A-Activated Protein C</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Matching placebo, 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Matching Placebo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Acute ischemic stroke&#xD;
&#xD;
          -  Able to receive IV tPA, mechanical thrombectomy or both&#xD;
&#xD;
          -  National Institutes of Health Stroke Scale (NIHSS) score of ≥ 5&#xD;
&#xD;
          -  Signed informed consent&#xD;
&#xD;
          -  Mechanical thrombectomy subjects only: onset time to arterial puncture time &lt; 6 hours&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of stroke or penetrating head injury within 90 days prior to enrollment&#xD;
&#xD;
          -  History of previous or current diagnosis of intracranial hemorrhage that represents a&#xD;
             potential for re-hemorrhage if subjected to thrombolytic therapy or mechanical&#xD;
             thrombectomy&#xD;
&#xD;
          -  Moyamoya disease, cerebral arterio-venous malformation (AVM), known unsecured aneurysm&#xD;
             requiring intervention during the acute study period&#xD;
&#xD;
          -  Presence of other neurological or non-neurological co-morbidities that may lead,&#xD;
             independently of the current stroke, to further deterioration in the subject's&#xD;
             neurological status during the trial period&#xD;
&#xD;
          -  Presence of premorbid neurological deficits and functional limitations assessed by a&#xD;
             retrospective Modified Rankin Scale (mRS) score of ≥ 2&#xD;
&#xD;
          -  Mechanical thrombectomy subjects only: baseline non-contrast CT scan revealing a large&#xD;
             core occlusion as defined by local protocol&#xD;
&#xD;
          -  Prolonged prothrombin time (PT) or activated partial thromboplastin time (aPTT)&#xD;
&#xD;
          -  Severe hypertension or hypotension&#xD;
&#xD;
          -  Glomerular filtration rate (GFR) &lt;35 mL/min&#xD;
&#xD;
          -  Blood glucose concentration &lt; 50 mg/dL&#xD;
&#xD;
          -  Prior exposure to any exogenous form of APC&#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>Patrick D. Lyden, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Cedars-Sinai Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Stroke Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90048</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stroke Center</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stroke Center</name>
      <address>
        <city>Kansas City</city>
        <state>Kansas</state>
        <zip>66160</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stroke Center</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stroke Center</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stroke Center</name>
      <address>
        <city>Buffalo</city>
        <state>New York</state>
        <zip>14209</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stroke Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stroke Center</name>
      <address>
        <city>Rochester</city>
        <state>New York</state>
        <zip>14642</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stroke Center</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45208</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stroke Center</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stroke Center</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stroke Center</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stroke Center</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75390</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stroke Center</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84132</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stroke Center</name>
      <address>
        <city>Charlottesville</city>
        <state>Virginia</state>
        <zip>22904</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Lyden P, Levy H, Weymer S, Pryor K, Kramer W, Griffin JH, Davis TP, Zlokovic B. Phase 1 safety, tolerability and pharmacokinetics of 3K3A-APC in healthy adult volunteers. Curr Pharm Des. 2013;19(42):7479-85. doi: 10.2174/1381612819666131230131454.</citation>
    <PMID>24372304</PMID>
  </reference>
  <verification_date>October 2018</verification_date>
  <study_first_submitted>August 18, 2014</study_first_submitted>
  <study_first_submitted_qc>August 19, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 21, 2014</study_first_posted>
  <results_first_submitted>July 27, 2018</results_first_submitted>
  <results_first_submitted_qc>October 10, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">November 8, 2018</results_first_posted>
  <last_update_submitted>October 10, 2018</last_update_submitted>
  <last_update_submitted_qc>October 10, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">November 8, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>ischemic stroke</keyword>
  <keyword>stroke</keyword>
  <keyword>APC</keyword>
  <keyword>3K3A</keyword>
  <keyword>3K3A-APC</keyword>
  <keyword>activated protein C</keyword>
  <keyword>RHAPSODY</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Stroke</mesh_term>
    <mesh_term>Ischemic Stroke</mesh_term>
    <mesh_term>Cerebral Infarction</mesh_term>
    <mesh_term>Ischemia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Protein C</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>December 7, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/14/NCT02222714/SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>October 7, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/14/NCT02222714/Prot_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>120 µg/kg of 3K3A-APC</title>
          <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
        </group>
        <group group_id="P2">
          <title>240 µg/kg of 3K3A-APC</title>
          <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
        </group>
        <group group_id="P3">
          <title>360 µg/kg of 3K3A-APC</title>
          <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
        </group>
        <group group_id="P4">
          <title>540 µg/kg of 3K3A-APC</title>
          <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
        </group>
        <group group_id="P5">
          <title>Placebo</title>
          <description>Matching placebo, q12h for up to 5 doses&#xD;
Placebo: Matching placebo, 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="15"/>
                <participants group_id="P2" count="24"/>
                <participants group_id="P3" count="12"/>
                <participants group_id="P4" count="15"/>
                <participants group_id="P5" count="44"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="15"/>
                <participants group_id="P2" count="22"/>
                <participants group_id="P3" count="8"/>
                <participants group_id="P4" count="11"/>
                <participants group_id="P5" count="37"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="4"/>
                <participants group_id="P4" count="4"/>
                <participants group_id="P5" count="7"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="3"/>
                <participants group_id="P4" count="4"/>
                <participants group_id="P5" count="6"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>120 µg/kg of 3K3A-APC</title>
          <description>3K3A-APC, q12h for up to 5 doses 3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
        </group>
        <group group_id="B2">
          <title>240 µg/kg of 3K3A-APC</title>
          <description>3K3A-APC, q12h for up to 5 doses 3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
        </group>
        <group group_id="B3">
          <title>360 µg/kg of 3K3A-APC</title>
          <description>3K3A-APC, q12h for up to 5 doses 3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
        </group>
        <group group_id="B4">
          <title>540 µg/kg of 3K3A-APC</title>
          <description>3K3A-APC, q12h for up to 5 doses 3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
        </group>
        <group group_id="B5">
          <title>Placebo</title>
          <description>Matching placebo, q12h for up to 5 doses Placebo: Matching placebo, 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
        </group>
        <group group_id="B6">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="15"/>
            <count group_id="B2" value="24"/>
            <count group_id="B3" value="12"/>
            <count group_id="B4" value="15"/>
            <count group_id="B5" value="44"/>
            <count group_id="B6" value="110"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="63.3" lower_limit="28" upper_limit="84"/>
                    <measurement group_id="B2" value="61.4" lower_limit="33" upper_limit="88"/>
                    <measurement group_id="B3" value="65.3" lower_limit="43" upper_limit="89"/>
                    <measurement group_id="B4" value="66.2" lower_limit="42" upper_limit="89"/>
                    <measurement group_id="B5" value="63.8" lower_limit="44" upper_limit="83"/>
                    <measurement group_id="B6" value="63.7" lower_limit="28" upper_limit="89"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="8"/>
                    <measurement group_id="B5" value="20"/>
                    <measurement group_id="B6" value="57"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="7"/>
                    <measurement group_id="B5" value="24"/>
                    <measurement group_id="B6" value="53"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="7"/>
                    <measurement group_id="B6" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="22"/>
                    <measurement group_id="B3" value="12"/>
                    <measurement group_id="B4" value="13"/>
                    <measurement group_id="B5" value="36"/>
                    <measurement group_id="B6" value="94"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="1"/>
                    <measurement group_id="B6" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>History of Hypertension</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="21"/>
                    <measurement group_id="B3" value="9"/>
                    <measurement group_id="B4" value="11"/>
                    <measurement group_id="B5" value="33"/>
                    <measurement group_id="B6" value="85"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>History of Diabetes</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="4"/>
                    <measurement group_id="B5" value="18"/>
                    <measurement group_id="B6" value="36"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol</title>
        <description>Specific AEs in the study were defined in the protocol to be dose-limiting toxicity events. Any given patient was adjudicated in a binary way to either have had a DLT or not to have had a DLT.</description>
        <time_frame>48-hours following last dose</time_frame>
        <population>Evaluable participants</population>
        <group_list>
          <group group_id="O1">
            <title>120 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
          <group group_id="O2">
            <title>240 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
          <group group_id="O3">
            <title>360 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
          <group group_id="O4">
            <title>540 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
          <group group_id="O5">
            <title>Placebo</title>
            <description>Matching placebo, q12h for up to 5 doses&#xD;
Placebo: Matching placebo, 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol</title>
          <description>Specific AEs in the study were defined in the protocol to be dose-limiting toxicity events. Any given patient was adjudicated in a binary way to either have had a DLT or not to have had a DLT.</description>
          <population>Evaluable participants</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="15"/>
                <count group_id="O2" value="24"/>
                <count group_id="O3" value="12"/>
                <count group_id="O4" value="15"/>
                <count group_id="O5" value="44"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>1-hour post dose aPTT out of range</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>SICH associated with neuroworsening</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ALT/AST, TBL, ALP, AT values out of range</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Serious bleeding</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Abnormal lab value related to study treatment</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Any other AE leading to cessation of dosing</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Total</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="2"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With a Presence of Measurable Bleeds in the Brain (Hemorrhage and Microbleeds) as Determined by 1.5T MRI</title>
        <description>MRI examination to include-at minimum-T1 and T2 weighted images, as well as diffusion weighted imaging (DWI) and susceptibility weighted imaging (SWI) sequences. Post-tPA microbleeds-defined as hypointensities less than 5mm in diameter seen on SWI-will be counted as tPA-related only if found within the ischemic territory. All other areas of hypointensity on SWI larger than 5mm diameter will be counted as tPA-related regardless of the territory in which they are found. All treated subjects (regardless of dose) will be compared to all placebo subjects using a Pearson chi-square test.</description>
        <time_frame>Day 30</time_frame>
        <population>Subjects with a Day 30 scan collected.</population>
        <group_list>
          <group group_id="O1">
            <title>3K3A-APC Total</title>
            <description>All 3K3A-APC treated groups combined</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo group</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With a Presence of Measurable Bleeds in the Brain (Hemorrhage and Microbleeds) as Determined by 1.5T MRI</title>
          <description>MRI examination to include-at minimum-T1 and T2 weighted images, as well as diffusion weighted imaging (DWI) and susceptibility weighted imaging (SWI) sequences. Post-tPA microbleeds-defined as hypointensities less than 5mm in diameter seen on SWI-will be counted as tPA-related only if found within the ischemic territory. All other areas of hypointensity on SWI larger than 5mm diameter will be counted as tPA-related regardless of the territory in which they are found. All treated subjects (regardless of dose) will be compared to all placebo subjects using a Pearson chi-square test.</description>
          <population>Subjects with a Day 30 scan collected.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="43"/>
                <count group_id="O2" value="37"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Hemorrhage (&gt;0.06mL)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="24"/>
                    <measurement group_id="O2" value="25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Microbleed (&gt;0)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7"/>
                    <measurement group_id="O2" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>PK of 3K3A-APC by Compartmental Analysis (Clearance)</title>
        <description>Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.</description>
        <time_frame>Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI</time_frame>
        <population>The PK population included all subjects who had sufficient data for PK analysis, and who had not been excluded from analysis for protocol deviations that could impact the calculation or interpretation of the PK parameters.</population>
        <group_list>
          <group group_id="O1">
            <title>120 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
          <group group_id="O2">
            <title>240 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
          <group group_id="O3">
            <title>360 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
          <group group_id="O4">
            <title>540 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
        </group_list>
        <measure>
          <title>PK of 3K3A-APC by Compartmental Analysis (Clearance)</title>
          <description>Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.</description>
          <population>The PK population included all subjects who had sufficient data for PK analysis, and who had not been excluded from analysis for protocol deviations that could impact the calculation or interpretation of the PK parameters.</population>
          <units>mL/hr</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="5"/>
                <count group_id="O4" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20994" spread="57.1"/>
                    <measurement group_id="O2" value="17814" spread="16.7"/>
                    <measurement group_id="O3" value="18504" spread="49.9"/>
                    <measurement group_id="O4" value="24403" spread="70.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>PK of 3K3A-APC by Compartmental Analysis (Volume of Distribution)</title>
        <description>Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.</description>
        <time_frame>Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI</time_frame>
        <population>The PK population included all subjects who had sufficient data for PK analysis, and who had not been excluded from analysis for protocol deviations that could impact the calculation or interpretation of the PK parameters.</population>
        <group_list>
          <group group_id="O1">
            <title>120 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
          <group group_id="O2">
            <title>240 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
          <group group_id="O3">
            <title>360 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
          <group group_id="O4">
            <title>540 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
        </group_list>
        <measure>
          <title>PK of 3K3A-APC by Compartmental Analysis (Volume of Distribution)</title>
          <description>Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.</description>
          <population>The PK population included all subjects who had sufficient data for PK analysis, and who had not been excluded from analysis for protocol deviations that could impact the calculation or interpretation of the PK parameters.</population>
          <units>mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="5"/>
                <count group_id="O4" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8242" spread="46.9"/>
                    <measurement group_id="O2" value="6051" spread="25.6"/>
                    <measurement group_id="O3" value="7164" spread="79.0"/>
                    <measurement group_id="O4" value="11437" spread="125"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>PK of 3K3A-APC by Compartmental Analysis (Cmax)</title>
        <description>Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.</description>
        <time_frame>Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI</time_frame>
        <population>The PK population included all subjects who had sufficient data for PK analysis, and who had not been excluded from analysis for protocol deviations that could impact the calculation or interpretation of the PK parameters.</population>
        <group_list>
          <group group_id="O1">
            <title>120 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
          <group group_id="O2">
            <title>240 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
          <group group_id="O3">
            <title>360 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
          <group group_id="O4">
            <title>540 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
        </group_list>
        <measure>
          <title>PK of 3K3A-APC by Compartmental Analysis (Cmax)</title>
          <description>Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.</description>
          <population>The PK population included all subjects who had sufficient data for PK analysis, and who had not been excluded from analysis for protocol deviations that could impact the calculation or interpretation of the PK parameters.</population>
          <units>ng/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="5"/>
                <count group_id="O4" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.957" spread="59.1"/>
                    <measurement group_id="O2" value="2.37" spread="11.0"/>
                    <measurement group_id="O3" value="2.80" spread="77.6"/>
                    <measurement group_id="O4" value="3.32" spread="138"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>PK of 3K3A-APC by Compartmental Analysis (AUC[0-inf])</title>
        <description>Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.</description>
        <time_frame>Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI</time_frame>
        <population>The PK population included all subjects who had sufficient data for PK analysis, and who had not been excluded from analysis for protocol deviations that could impact the calculation or interpretation of the PK parameters.</population>
        <group_list>
          <group group_id="O1">
            <title>120 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
          <group group_id="O2">
            <title>240 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
          <group group_id="O3">
            <title>360 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
          <group group_id="O4">
            <title>540 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
        </group_list>
        <measure>
          <title>PK of 3K3A-APC by Compartmental Analysis (AUC[0-inf])</title>
          <description>Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.</description>
          <population>The PK population included all subjects who had sufficient data for PK analysis, and who had not been excluded from analysis for protocol deviations that could impact the calculation or interpretation of the PK parameters.</population>
          <units>hr▪ng/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="5"/>
                <count group_id="O4" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.513" spread="64.7"/>
                    <measurement group_id="O2" value="1.16" spread="6.79"/>
                    <measurement group_id="O3" value="1.49" spread="56.1"/>
                    <measurement group_id="O4" value="2.06" spread="92.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>PK of 3K3A-APC by Compartmental Analysis (λz)</title>
        <description>Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.</description>
        <time_frame>Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI</time_frame>
        <population>The PK population included all subjects who had sufficient data for PK analysis, and who had not been excluded from analysis for protocol deviations that could impact the calculation or interpretation of the PK parameters.</population>
        <group_list>
          <group group_id="O1">
            <title>120 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
          <group group_id="O2">
            <title>240 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
          <group group_id="O3">
            <title>360 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
          <group group_id="O4">
            <title>540 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
        </group_list>
        <measure>
          <title>PK of 3K3A-APC by Compartmental Analysis (λz)</title>
          <description>Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.</description>
          <population>The PK population included all subjects who had sufficient data for PK analysis, and who had not been excluded from analysis for protocol deviations that could impact the calculation or interpretation of the PK parameters.</population>
          <units>1/hr</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="5"/>
                <count group_id="O4" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.55" spread="13.4"/>
                    <measurement group_id="O2" value="2.94" spread="10.5"/>
                    <measurement group_id="O3" value="2.58" spread="34.9"/>
                    <measurement group_id="O4" value="2.13" spread="45.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>PK of 3K3A-APC by Compartmental Analysis (Half-life)</title>
        <description>Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.</description>
        <time_frame>Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI</time_frame>
        <population>The PK population included all subjects who had sufficient data for PK analysis, and who had not been excluded from analysis for protocol deviations that could impact the calculation or interpretation of the PK parameters.</population>
        <group_list>
          <group group_id="O1">
            <title>120 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
          <group group_id="O2">
            <title>240 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
          <group group_id="O3">
            <title>360 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
          <group group_id="O4">
            <title>540 µg/kg of 3K3A-APC</title>
            <description>3K3A-APC, q12h for up to 5 doses&#xD;
3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
          </group>
        </group_list>
        <measure>
          <title>PK of 3K3A-APC by Compartmental Analysis (Half-life)</title>
          <description>Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.</description>
          <population>The PK population included all subjects who had sufficient data for PK analysis, and who had not been excluded from analysis for protocol deviations that could impact the calculation or interpretation of the PK parameters.</population>
          <units>hr</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="5"/>
                <count group_id="O4" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.272" spread="13.4"/>
                    <measurement group_id="O2" value="0.235" spread="10.5"/>
                    <measurement group_id="O3" value="0.268" spread="34.9"/>
                    <measurement group_id="O4" value="0.325" spread="45.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>AEs were collected through Study Day 7 and were followed until resolution or a new baseline was established, up to Study Day 90. SAEs were collected through Study Day 30, and were followed until resolution (or resolution with sequelae), up to Study Day 90.</time_frame>
      <desc>Standard definitions of adverse events and serious adverse events were used.</desc>
      <group_list>
        <group group_id="E1">
          <title>120 µg/kg of 3K3A-APC</title>
          <description>3K3A-APC, q12h for up to 5 doses 3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
        </group>
        <group group_id="E2">
          <title>240 µg/kg of 3K3A-APC</title>
          <description>3K3A-APC, q12h for up to 5 doses 3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
        </group>
        <group group_id="E3">
          <title>360 µg/kg of 3K3A-APC</title>
          <description>3K3A-APC, q12h for up to 5 doses 3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
        </group>
        <group group_id="E4">
          <title>540 µg/kg of 3K3A-APC</title>
          <description>3K3A-APC, q12h for up to 5 doses 3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
        </group>
        <group group_id="E5">
          <title>3K3A-APC Total</title>
          <description>All 3K3A-APC treated groups combined</description>
        </group>
        <group group_id="E6">
          <title>Placebo</title>
          <description>Matching placebo, q12h for up to 5 doses Placebo: Matching placebo, 0.9% sodium chloride in water, given as 100 mL IV infusion</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="4" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="9" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="6" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="9" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="30" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="18" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="2" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Leukocytosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="5" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="4" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Bradycardia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Cardiac arrest</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Cardiac failure congestive</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Intracardiac thrombus</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Myocardial infarction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Pericarditis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Duodenal ulcer haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Retroperitoneal haematoma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chest pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Septic shock</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Staphylococcal infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Urosepsis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood fibrinogen decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="3" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Blood glucose increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Blood potassium decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Blood sodium increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Ejection fraction decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Hepatic enzyme increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Troponin increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Brain oedema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="4" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="5" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="3" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Carotid artery stenosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Cerebral haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="3" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="2" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Cerebrovascular accident</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="5" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="3" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Convulsion</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="2" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Haemorrhage intracranial</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Agitation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Acute respiratory failure</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Bronchospasm</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Pneumonia aspiration</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="2" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Pneumothorax</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Pulmonary embolism</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Pulmonary oedema</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Respiratory distress</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Respiratory failure</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="2" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Aneurysm repair</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Deep vein thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="3" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="18" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="8" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="9" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="45" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="36" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="13" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="6" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Leukocytosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="6" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="6" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Bradycardia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="5" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="6" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="4" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="4" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="4" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="10" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="8" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Contusion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="3" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="3" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Activated partial thromboplastin time prolonged</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="4" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="2" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Blood calcium decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="5" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Blood fibrinogen decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="3" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="4" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="3" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="3" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Prothrombin time prolonged</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="5" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="6" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Haemorrhage intracranial</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="4" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="14" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="16" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="3" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="12" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="10" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Haematuria</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="3" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="4" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E5" subjects_affected="3" subjects_at_risk="66"/>
                <counts group_id="E6" subjects_affected="3" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>The study was designed and powered for evaluating DLTs and identifying a maximum tolerated dose, not for efficacy endpoints.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Patrick Lyden, MD, FAAN, FAHA</name_or_title>
      <organization>Cedars-Sinai Medical Center</organization>
      <phone>(310) 423-5166</phone>
      <email>Patrick.Lyden@cshs.org</email>
    </point_of_contact>
  </clinical_results>
</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/NCT02222714
org study id: ZZ-3K3A-201 (NN104)
secondary id: 1U01NS088312-01
secondary id: U01NS077352
secondary id: U01NS077179-01
nct id: NCT02222714
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The purpose of this study was to evaluate the safety, pharmacokinetics (PK) and preliminary
      efficacy of multiple ascending intravenous doses of 3K3A-APC, a Recombinant Variant of Human
      activated protein C (APC), in in the treatment of acute ischemic stroke following treatment
      with recombinant tissue plasminogen activator (tPA), mechanical thrombectomy or both.
This was a multicenter, prospective, randomized, controlled, double-blinded Phase 2 study
      intended to evaluate the safety, PK and preliminary efficacy of 3K3A-APC following treatment
      with tPA, mechanical thrombectomy or both in subjects with moderate to severe acute ischemic
      stroke.

      Approximately 115 subjects were to be randomized, which included the planned 88 subjects in
      groups of 4 subjects to either 3K3A-APC or placebo (in a 3:1 ratio) and the additional
      placebo subjects who were enrolled during safety review pauses. This study used a modified
      version of the continual reassessment method (CRM) in order to establish a maximum tolerated
      dose (MTD).

      Eligible subjects received 3K3A-APC or placebo every 12 hours for up to 5 doses
      (approximately 3 days), or until discharge from the hospital, whichever occurred first.
      Subjects were monitored for safety evaluations through Day 7 (or discharge, if earlier) and
      were expected to be seen on Day 7, 14, 30, and 90 for safety and outcome evaluations.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol
time frame: 48-hours following last dose
description: Specific AEs in the study were defined in the protocol to be dose-limiting toxicity events. Any given patient was adjudicated in a binary way to either have had a DLT or not to have had a DLT.
measure: Number of Participants With a Presence of Measurable Bleeds in the Brain (Hemorrhage and Microbleeds) as Determined by 1.5T MRI
time frame: Day 30
description: MRI examination to include-at minimum-T1 and T2 weighted images, as well as diffusion weighted imaging (DWI) and susceptibility weighted imaging (SWI) sequences. Post-tPA microbleeds-defined as hypointensities less than 5mm in diameter seen on SWI-will be counted as tPA-related only if found within the ischemic territory. All other areas of hypointensity on SWI larger than 5mm diameter will be counted as tPA-related regardless of the territory in which they are found. All treated subjects (regardless of dose) will be compared to all placebo subjects using a Pearson chi-square test.
measure: PK of 3K3A-APC by Compartmental Analysis (Clearance)
time frame: Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI
description: Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.
measure: PK of 3K3A-APC by Compartmental Analysis (Volume of Distribution)
time frame: Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI
description: Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.
measure: PK of 3K3A-APC by Compartmental Analysis (Cmax)
time frame: Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI
description: Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.
measure: PK of 3K3A-APC by Compartmental Analysis (AUC[0-inf])
time frame: Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI
description: Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.
measure: PK of 3K3A-APC by Compartmental Analysis (λz)
time frame: Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI
description: Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.
measure: PK of 3K3A-APC by Compartmental Analysis (Half-life)
time frame: Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI
description: Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.
arm group label: 120 µg/kg of 3K3A-APC
arm group type: Active Comparator
description: 3K3A-APC, q12h for up to 5 doses
arm group label: 240 µg/kg of 3K3A-APC
arm group type: Active Comparator
description: 3K3A-APC, q12h for up to 5 doses
arm group label: 360 µg/kg of 3K3A-APC
arm group type: Active Comparator
description: 3K3A-APC, q12h for up to 5 doses
arm group label: 540 µg/kg of 3K3A-APC
arm group type: Active Comparator
description: 3K3A-APC, q12h for up to 5 doses
arm group label: Placebo
arm group type: Placebo Comparator
description: Matching placebo, q12h for up to 5 doses
intervention type: Biological
intervention name: 3K3A-APC
description: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion
arm group label: 120 µg/kg of 3K3A-APC
arm group label: 240 µg/kg of 3K3A-APC
arm group label: 360 µg/kg of 3K3A-APC
arm group label: 540 µg/kg of 3K3A-APC
other name: 3K3A-Activated Protein C
intervention type: Drug
intervention name: Placebo
description: Matching placebo, 0.9% sodium chloride in water, given as 100 mL IV infusion
arm group label: Placebo
other name: Matching Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: Patrick D. Lyden, MD
role: Principal Investigator
affiliation: Cedars-Sinai Medical Center
facility: 
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country: United States
citation: Lyden P, Levy H, Weymer S, Pryor K, Kramer W, Griffin JH, Davis TP, Zlokovic B. Phase 1 safety, tolerability and pharmacokinetics of 3K3A-APC in healthy adult volunteers. Curr Pharm Des. 2013;19(42):7479-85. doi: 10.2174/1381612819666131230131454.
PMID: 24372304
responsible party type: Sponsor
mesh term: Stroke
mesh term: Ischemic Stroke
mesh term: Cerebral Infarction
mesh term: Ischemia
mesh term: Protein C
sharing ipd: Undecided
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: The study was designed and powered for evaluating DLTs and identifying a maximum tolerated dose, not for efficacy endpoints.
point of contact: 