<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/NCT03240133</url>
  </required_header>
  <id_info>
    <org_study_id>BCX7353-202</org_study_id>
    <nct_id>NCT03240133</nct_id>
  </id_info>
  <brief_title>Study of BCX7353 as a Treatment for Attacks of Hereditary Angioedema</brief_title>
  <official_title>A Randomized, Double-blind, Placebo-controlled, Dose-ranging, Study to Evaluate the Efficacy, Safety and Tolerability of Single Doses of BCX7353 as an Acute Attack Treatment in Subjects With Hereditary Angioedema</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>BioCryst Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>BioCryst Pharmaceuticals</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This 3-part study will evaluate the efficacy and safety of an oral kallikrein inhibitor,&#xD;
      BCX7353, in the treatment angioedema attacks in subjects with Type I or II hereditary&#xD;
      angioedema (HAE). In each study part, subjects will treat 3 attacks with BCX7353 (2 attacks)&#xD;
      or placebo (1 attack), in a randomly allocated order. In Part 1, the dose of 750mg will be&#xD;
      assessed relative to placebo in up to 36 patients. If this is shown to be effective, then a&#xD;
      further 12 patients will be enrolled at a 500mg dose (Part 1), followed by a further 12 (if&#xD;
      efficacy still shown) at a dose of 250mg (Part 3) to determine the minimum effective dose of&#xD;
      BCX7353 compared to placebo for treating HAE attacks. Efficacy will be determined by subject&#xD;
      diary entries completed at pre-defined times post-dose.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 31, 2017</start_date>
  <completion_date type="Actual">January 29, 2019</completion_date>
  <primary_completion_date type="Actual">January 29, 2019</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>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Proportion of Subjects With Improved or Stable Composite Visual Analog Scale (VAS) Score</measure>
    <time_frame>Mean composite VAS for HAE attack symptoms severity prior to IMP treatment and 4 hours post-dose</time_frame>
    <description>Subjects completed a 3-component VAS on a 100 mm scale for severity of abdominal pain, skin pain and skin swelling associated with the HAE attack, where zero indicated no pain or swelling and 100 mm indicated worst possible pain or swelling. Subjects completed the VAS immediately prior to study drug administration, then at 1, 2, 3, 4, approximately 8 &amp; at 24 hours post-dose. The primary endpoint was the proportion of subject attacks with an improved or stable 3-symptom composite VAS score at 4 hours post dose. The 3-symptom composite was calculated as the average of the VAS scores for abdominal pain, skin pain, and skin swelling. A subject was considered improved or stable if the change from baseline (CFB; time of drug administration) in VAS was ≤ 0.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percentage of Attacks Treated With Standard of Care Acute Attack Medication (SOC-Rx) Through 24 Hours</measure>
    <time_frame>24 hours</time_frame>
    <description>The proportion of attacks for which subjects took SOC-Rx in the 24 hours following treatment with study drug. HAE Rescue Medications included C1-INH (Berinert, Cinryze, Ruconest) and Firazyr/Icatibant.</description>
  </primary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">58</enrollment>
  <condition>Hereditary Angioedema (HAE)</condition>
  <arm_group>
    <arm_group_label>Part1: BCX7353 750 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 2: BCX7353 500 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 3: BCX7353 250 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Parts 1, 2 and 3: placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>BCX7353</intervention_name>
    <description>oral liquid formulation</description>
    <arm_group_label>Part 2: BCX7353 500 mg</arm_group_label>
    <arm_group_label>Part 3: BCX7353 250 mg</arm_group_label>
    <arm_group_label>Part1: BCX7353 750 mg</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>oral liquid formulation to match BCX7353</description>
    <arm_group_label>Parts 1, 2 and 3: placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Able to provide written, informed consent.&#xD;
&#xD;
          2. A clinical diagnosis of hereditary angioedema Type 1 or Type 2 as documented at any&#xD;
             time in the medical records or at the screening visit.&#xD;
&#xD;
          3. Access to and ability to use standard of care acute attack treatment for attacks of&#xD;
             HAE.&#xD;
&#xD;
          4. Sexually active women of child-bearing potential and sexually active men must utilize&#xD;
             effective contraception.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Women who are pregnant or breast-feeding.&#xD;
&#xD;
          2. Any clinical condition or medical history that would interfere with the subject's&#xD;
             safety or ability to participate in the study.&#xD;
&#xD;
          3. Use of C1INH, androgens or tranexamic acid for prophylaxis of HAE attacks.&#xD;
&#xD;
          4. History of or current alcohol or drug abuse.&#xD;
&#xD;
          5. Infection with hepatitis B, hepatitis C or HIV.&#xD;
&#xD;
          6. Participation in any other investigational drug study currently or within the last 30&#xD;
             days.&#xD;
&#xD;
          7. Positive drugs of abuse screen (unless as used as medical treatment, e.g., with a&#xD;
             prescription).&#xD;
&#xD;
          8. An immediate family relationship to either Sponsor employees, the Investigator or&#xD;
             employees of the study site.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Hilary Longhurst, MBBS, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Barts &amp; The London NHS Trust</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Study Center</name>
      <address>
        <city>Graz</city>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Study Center</name>
      <address>
        <city>Odense</city>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Study Center</name>
      <address>
        <city>Grenoble</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Study Center</name>
      <address>
        <city>Lille</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Study Center</name>
      <address>
        <city>Berlin</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Study Center</name>
      <address>
        <city>Frankfurt</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Study Center</name>
      <address>
        <city>Budapest</city>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Study Center</name>
      <address>
        <city>Ashkelon</city>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Study Center</name>
      <address>
        <city>Tel Aviv</city>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Study Center</name>
      <address>
        <city>Tel HaShomer</city>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Study Center</name>
      <address>
        <city>Milano</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Study center</name>
      <address>
        <city>Padova</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Study Center</name>
      <address>
        <city>Salerno</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Study Center</name>
      <address>
        <city>Skopje</city>
        <country>North Macedonia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Study Center</name>
      <address>
        <city>Kraków</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Study Center</name>
      <address>
        <city>Târgu-Mureş</city>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Study Center</name>
      <address>
        <city>Zürich</city>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Study Center</name>
      <address>
        <city>Birmingham</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Study Center</name>
      <address>
        <city>Bristol</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Study Center</name>
      <address>
        <city>Cambridge</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Study Center</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Study Center</name>
      <address>
        <city>Manchester</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Study Center</name>
      <address>
        <city>Plymouth</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Study Center</name>
      <address>
        <city>Southampton</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Austria</country>
    <country>Denmark</country>
    <country>France</country>
    <country>Germany</country>
    <country>Hungary</country>
    <country>Israel</country>
    <country>Italy</country>
    <country>North Macedonia</country>
    <country>Poland</country>
    <country>Romania</country>
    <country>Switzerland</country>
    <country>United Kingdom</country>
  </location_countries>
  <removed_countries>
    <country>Macedonia, The Former Yugoslav Republic of</country>
  </removed_countries>
  <verification_date>March 2021</verification_date>
  <study_first_submitted>August 2, 2017</study_first_submitted>
  <study_first_submitted_qc>August 3, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 4, 2017</study_first_posted>
  <results_first_submitted>November 17, 2020</results_first_submitted>
  <results_first_submitted_qc>March 8, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">April 1, 2021</results_first_posted>
  <last_update_submitted>March 8, 2021</last_update_submitted>
  <last_update_submitted_qc>March 8, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 1, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>HAE</keyword>
  <keyword>hereditary angioedema</keyword>
  <keyword>kallikrein inhibitor</keyword>
  <keyword>plasma kallikrein</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Angioedema</mesh_term>
    <mesh_term>Angioedemas, Hereditary</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Berotralstat</mesh_term>
  </intervention_browse>
  <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>January 29, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/33/NCT03240133/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>March 16, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/33/NCT03240133/Prot_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>HAE subjects attended a Screening Visit up to 35 days before the baseline visit, for assessment of eligibility to participate in the study.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Part 1: Berotralstat (750 mg) &amp; Placebo Treated HAE Attacks</title>
          <description>Each subject treated 3 HAE attacks, 1 with placebo and 2 with 750 mg berotralstat. Placebo vs berotralstat treatment of an HAE attack was assigned by randomization.</description>
        </group>
        <group group_id="P2">
          <title>Part 2: Berotralstat (500 mg) &amp; Placebo Treated HAE Attacks</title>
          <description>Each subject treated 3 HAE attacks, 1 with placebo and 2 with 500 mg berotralstat. Placebo vs berotralstat treatment of an HAE attack was assigned by randomization.</description>
        </group>
        <group group_id="P3">
          <title>Part 3: Berotralstat (250 mg) &amp; Placebo Treated HAE Attacks</title>
          <description>Each subject treated 3 HAE attacks, 1 with placebo and 2 with 250 mg berotralstat. Placebo vs berotralstat treatment of an HAE attack was assigned by randomization.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="33"/>
                <participants group_id="P2" count="14"/>
                <participants group_id="P3" count="11"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Completed Period 1</title>
              <participants_list>
                <participants group_id="P1" count="33"/>
                <participants group_id="P2" count="14"/>
                <participants group_id="P3" count="11"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Completed Period 2</title>
              <participants_list>
                <participants group_id="P1" count="32"/>
                <participants group_id="P2" count="11"/>
                <participants group_id="P3" count="11"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Completed Period 3</title>
              <participants_list>
                <participants group_id="P1" count="30"/>
                <participants group_id="P2" count="11"/>
                <participants group_id="P3" count="11"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="30"/>
                <participants group_id="P2" count="11"/>
                <participants group_id="P3" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Rash</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>sponsor closure/completion of Part 1 of the study</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Intercurrent illness.</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Sponsor/competent authority/IRB/IEC discontinuation</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Part 1: Berotralstat (750 mg) &amp; Placebo Treated HAE Attacks</title>
          <description>Each subject treated 3 HAE attacks, 1 with placebo and 2 with 750 mg berotralstat. Placebo vs berotralstat treatment of an HAE attack was assigned by randomization.</description>
        </group>
        <group group_id="B2">
          <title>Part 2: Berotralstat (500 mg) &amp; Placebo Treated HAE Attacks</title>
          <description>Each subject treated 3 HAE attacks, 1 with placebo and 2 with 500 mg berotralstat. Placebo vs berotralstat treatment of an HAE attack was assigned by randomization.</description>
        </group>
        <group group_id="B3">
          <title>Part 3: Berotralstat (250 mg) &amp; Placebo Treated HAE Attacks</title>
          <description>Each subject treated 3 HAE attacks, 1 with placebo and 2 with 250 mg berotralstat. Placebo vs berotralstat treatment of an HAE attack was assigned by randomization.</description>
        </group>
        <group group_id="B4">
          <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="33"/>
            <count group_id="B2" value="14"/>
            <count group_id="B3" value="11"/>
            <count group_id="B4" value="58"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="32"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="11"/>
                    <measurement group_id="B4" value="57"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="43.7" spread="12.5"/>
                    <measurement group_id="B2" value="42.1" spread="10.5"/>
                    <measurement group_id="B3" value="34.9" spread="10.9"/>
                    <measurement group_id="B4" value="41.6" spread="12.0"/>
                  </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="17"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="7"/>
                    <measurement group_id="B4" value="35"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="16"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="33"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="11"/>
                    <measurement group_id="B4" value="58"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Austria</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Romania</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hungary</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Denmark</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>North Macedonia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Poland</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Italy</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>United Kingdom</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Israel</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>France</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Switzerland</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Germany</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Adjusted qualifying HAE attack rate</title>
          <units>HAE attacks/month</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3.08" spread="1.40"/>
                    <measurement group_id="B2" value="3.03" spread="1.23"/>
                    <measurement group_id="B3" value="3.23" spread="1.82"/>
                    <measurement group_id="B4" value="3.09" spread="1.42"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Proportion of Subjects With Improved or Stable Composite Visual Analog Scale (VAS) Score</title>
        <description>Subjects completed a 3-component VAS on a 100 mm scale for severity of abdominal pain, skin pain and skin swelling associated with the HAE attack, where zero indicated no pain or swelling and 100 mm indicated worst possible pain or swelling. Subjects completed the VAS immediately prior to study drug administration, then at 1, 2, 3, 4, approximately 8 &amp; at 24 hours post-dose. The primary endpoint was the proportion of subject attacks with an improved or stable 3-symptom composite VAS score at 4 hours post dose. The 3-symptom composite was calculated as the average of the VAS scores for abdominal pain, skin pain, and skin swelling. A subject was considered improved or stable if the change from baseline (CFB; time of drug administration) in VAS was ≤ 0.</description>
        <time_frame>Mean composite VAS for HAE attack symptoms severity prior to IMP treatment and 4 hours post-dose</time_frame>
        <population>The number of participants analyzed in each analysis set corresponds to number of HAE attacks treated with placebo or berotralstat.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1: Berotralstat 750 mg - Predose</title>
            <description>HAE attack prior to dosing with 750mg berotralstat</description>
          </group>
          <group group_id="O2">
            <title>Part 1: Placebo - Pre-dose</title>
            <description>HAE attack prior to dosing with placebo</description>
          </group>
          <group group_id="O3">
            <title>Part 1: Berotralstat 750 mg - 4hr Post-dose</title>
            <description>HAE attack 4 hr post dosing with 750mg berotralstat</description>
          </group>
          <group group_id="O4">
            <title>Part 1: Placebo - 4hr Post-dose</title>
            <description>HAE attack 4 hr post dosing with placebo</description>
          </group>
          <group group_id="O5">
            <title>Part 2: Berotralstat 500 mg - Predose</title>
            <description>HAE attack prior to dosing with 500mg berotralstat</description>
          </group>
          <group group_id="O6">
            <title>Part 2: Placebo - Pre-dose</title>
            <description>HAE attack prior to dosing with placebo</description>
          </group>
          <group group_id="O7">
            <title>Part 2: Berotralstat 500 mg - 4hr Post-dose</title>
            <description>HAE attack 4 hr post dosing with 50mg berotralstat</description>
          </group>
          <group group_id="O8">
            <title>Part 2: Placebo - 4hr Post-dose</title>
            <description>HAE attack 4 hr post dosing with placebo</description>
          </group>
          <group group_id="O9">
            <title>Part 3: Berotralstat 250 mg - Predose</title>
            <description>HAE attack prior to dosing with 250mg berotralstat</description>
          </group>
          <group group_id="O10">
            <title>Part 3: Placebo - Pre-dose</title>
            <description>HAE attack prior to dosing with placebo</description>
          </group>
          <group group_id="O11">
            <title>Part 3: Berotralstat 250 mg - 4hr Post-dose</title>
            <description>HAE attack 4 hr post dosing with 250mg berotralstat</description>
          </group>
          <group group_id="O12">
            <title>Part 3: Placebo - 4hr Post-dose</title>
            <description>HAE attack 4 hr post dosing with placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Proportion of Subjects With Improved or Stable Composite Visual Analog Scale (VAS) Score</title>
          <description>Subjects completed a 3-component VAS on a 100 mm scale for severity of abdominal pain, skin pain and skin swelling associated with the HAE attack, where zero indicated no pain or swelling and 100 mm indicated worst possible pain or swelling. Subjects completed the VAS immediately prior to study drug administration, then at 1, 2, 3, 4, approximately 8 &amp; at 24 hours post-dose. The primary endpoint was the proportion of subject attacks with an improved or stable 3-symptom composite VAS score at 4 hours post dose. The 3-symptom composite was calculated as the average of the VAS scores for abdominal pain, skin pain, and skin swelling. A subject was considered improved or stable if the change from baseline (CFB; time of drug administration) in VAS was ≤ 0.</description>
          <population>The number of participants analyzed in each analysis set corresponds to number of HAE attacks treated with placebo or berotralstat.</population>
          <units>VAS score - millimeters</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <units_analyzed>HAE Attacks</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="33"/>
                <count group_id="O2" value="28"/>
                <count group_id="O3" value="33"/>
                <count group_id="O4" value="28"/>
                <count group_id="O5" value="14"/>
                <count group_id="O6" value="9"/>
                <count group_id="O7" value="14"/>
                <count group_id="O8" value="9"/>
                <count group_id="O9" value="11"/>
                <count group_id="O10" value="11"/>
                <count group_id="O11" value="11"/>
                <count group_id="O12" value="11"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>HAE Attacks</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="59"/>
                <count group_id="O2" value="28"/>
                <count group_id="O3" value="59"/>
                <count group_id="O4" value="28"/>
                <count group_id="O5" value="24"/>
                <count group_id="O6" value="9"/>
                <count group_id="O7" value="24"/>
                <count group_id="O8" value="9"/>
                <count group_id="O9" value="21"/>
                <count group_id="O10" value="11"/>
                <count group_id="O11" value="21"/>
                <count group_id="O12" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13.96" spread="9.84"/>
                    <measurement group_id="O2" value="15.04" spread="11.90"/>
                    <measurement group_id="O3" value="10.54" spread="11.39"/>
                    <measurement group_id="O4" value="18.42" spread="14.19"/>
                    <measurement group_id="O5" value="17.69" spread="15.25"/>
                    <measurement group_id="O6" value="13.48" spread="16.11"/>
                    <measurement group_id="O7" value="11.31" spread="15.75"/>
                    <measurement group_id="O8" value="9.26" spread="11.53"/>
                    <measurement group_id="O9" value="14.57" spread="11.78"/>
                    <measurement group_id="O10" value="11.33" spread="10.17"/>
                    <measurement group_id="O11" value="10.92" spread="10.31"/>
                    <measurement group_id="O12" value="9.21" spread="9.67"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Change in HAE attack symptoms from pre-dose to 4 hours post-dose was assessed following treatment with either 750mg berotralstat or placebo.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>Comparisons were performed separately at each time point using a mixed effect linear model including treatment, period and sequence as fixed effects, subject within sequence as a random effect, and predose 3-symptom composite VAS score as a covariate.</non_inferiority_desc>
            <p_value>0.0024</p_value>
            <method>Mixed effect linear model</method>
            <param_type>Difference in Least Square Means</param_type>
            <param_value>-6.98</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-11.37</ci_lower_limit>
            <ci_upper_limit>-2.6</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O5</group_id>
              <group_id>O6</group_id>
              <group_id>O7</group_id>
              <group_id>O8</group_id>
            </group_id_list>
            <groups_desc>Change in HAE attack symptoms from pre-dose to 4 hours post-dose was assessed following treatment with either 500mg berotralstat or placebo.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>Comparisons were performed separately at each time point using a mixed effect linear model including treatment, period and sequence as fixed effects, subject within sequence as a random effect, and predose 3-symptom composite VAS score as a covariate.</non_inferiority_desc>
            <p_value>0.6424</p_value>
            <method>Mixed effect linear model</method>
            <param_type>Difference in Least Square Means</param_type>
            <param_value>-2.1</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-11.49</ci_lower_limit>
            <ci_upper_limit>7.29</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O9</group_id>
              <group_id>O10</group_id>
              <group_id>O11</group_id>
              <group_id>O12</group_id>
            </group_id_list>
            <groups_desc>Change in HAE attack symptoms from pre-dose to 4 hours post-dose was assessed following treatment with either 250mg berotralstat or placebo.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>Comparisons were performed separately at each time point using a mixed effect linear model including treatment, period and sequence as fixed effects, subject within sequence as a random effect, and predose 3-symptom composite VAS score as a covariate.</non_inferiority_desc>
            <p_value>0.8283</p_value>
            <method>Mixed effect linear model</method>
            <param_type>Difference in Least Square Means</param_type>
            <param_value>0.57</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-4.9</ci_lower_limit>
            <ci_upper_limit>6.03</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Percentage of Attacks Treated With Standard of Care Acute Attack Medication (SOC-Rx) Through 24 Hours</title>
        <description>The proportion of attacks for which subjects took SOC-Rx in the 24 hours following treatment with study drug. HAE Rescue Medications included C1-INH (Berinert, Cinryze, Ruconest) and Firazyr/Icatibant.</description>
        <time_frame>24 hours</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Part 1: Berotralstat 750 mg</title>
            <description>HAE attack treated with 750mg berotralstat</description>
          </group>
          <group group_id="O2">
            <title>Part 1: Placebo</title>
            <description>HAE attack treated with placebo</description>
          </group>
          <group group_id="O3">
            <title>Part 2: Berotralstat 500 mg</title>
            <description>HAE attack treated with 500mg berotralstat</description>
          </group>
          <group group_id="O4">
            <title>Part 2: Placebo</title>
            <description>HAE attack treated with placebo</description>
          </group>
          <group group_id="O5">
            <title>Part 3: Berotralstat 250 mg</title>
            <description>HAE attack treated with 250mg berotralstat</description>
          </group>
          <group group_id="O6">
            <title>Part 3: Placebo</title>
            <description>HAE attack treated with placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Attacks Treated With Standard of Care Acute Attack Medication (SOC-Rx) Through 24 Hours</title>
          <description>The proportion of attacks for which subjects took SOC-Rx in the 24 hours following treatment with study drug. HAE Rescue Medications included C1-INH (Berinert, Cinryze, Ruconest) and Firazyr/Icatibant.</description>
          <units>Percentage attacks treated with SOC-Rx</units>
          <param>Number</param>
          <units_analyzed>HAE Attacks</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="33"/>
                <count group_id="O2" value="28"/>
                <count group_id="O3" value="14"/>
                <count group_id="O4" value="9"/>
                <count group_id="O5" value="11"/>
                <count group_id="O6" value="11"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>HAE Attacks</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="59"/>
                <count group_id="O2" value="28"/>
                <count group_id="O3" value="24"/>
                <count group_id="O4" value="9"/>
                <count group_id="O5" value="21"/>
                <count group_id="O6" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="29.7"/>
                    <measurement group_id="O2" value="61.3"/>
                    <measurement group_id="O3" value="32.0"/>
                    <measurement group_id="O4" value="45.5"/>
                    <measurement group_id="O5" value="38.1"/>
                    <measurement group_id="O6" value="45.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Analyses were performed using a generalized logistic model including treatment, period and sequence as fixed effects, and subject within sequence as a random effect. The odds of a berotralstat 750 mg-treated-attack requiring SOC-Rx was 0.196 that of a placebo attack.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0029</p_value>
            <method>logistic mixed effect model</method>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>0.196</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.069</ci_lower_limit>
            <ci_upper_limit>0.559</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Analyses were performed using a generalized logistic model including treatment, period and sequence as fixed effects, and subject within sequence as a random effect. The odds of a berotralstat 500 mg-treated-attack requiring SOC-Rx was 0.472 that of a placebo attack.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.4048</p_value>
            <method>logistic mixed effect model</method>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>0.472</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.074</ci_lower_limit>
            <ci_upper_limit>2.988</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O5</group_id>
              <group_id>O6</group_id>
            </group_id_list>
            <groups_desc>Analyses were performed using a generalized logistic model including treatment, period and sequence as fixed effects, and subject within sequence as a random effect. The odds of a berotralstat 250 mg-treated-attack requiring SOC-Rx was 0.587 that of a placebo attack.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.5984</p_value>
            <method>logistic mixed effect model</method>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>0.587</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.073</ci_lower_limit>
            <ci_upper_limit>4.733</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days.</time_frame>
      <desc>AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.</desc>
      <group_list>
        <group group_id="E1">
          <title>Part1: Berotralstat 750 mg</title>
          <description>Berotralstat : oral liquid formulation</description>
        </group>
        <group group_id="E2">
          <title>Part 2: Berotralstat 500 mg</title>
          <description>Berotralstat: oral liquid formulation</description>
        </group>
        <group group_id="E3">
          <title>Part 3: Berotralstat 250 mg</title>
          <description>Berotralstat: oral liquid formulation</description>
        </group>
        <group group_id="E4">
          <title>Parts 1, 2 and 3: Placebo</title>
          <description>Placebo: oral liquid formulation to match Berotralstat</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (19.0)</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="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="53"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="53"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>kidney contusion</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="53"/>
              </event>
              <event>
                <sub_title>Ankle fracture</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="53"/>
              </event>
              <event>
                <sub_title>Ligament sprain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="53"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>2</frequency_threshold>
        <default_vocab>MedDRA (19.0)</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="12" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="14"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="17" subjects_at_risk="53"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal discomfort</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="53"/>
              </event>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="53"/>
              </event>
              <event>
                <sub_title>Faeces discoloured</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="53"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="14"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="53"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="33"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="14"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="53"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="14"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="53"/>
              </event>
              <event>
                <sub_title>Epigastric discomfort</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="53"/>
              </event>
              <event>
                <sub_title>Gastrooesophageal reflux disease</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="53"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="53"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="53"/>
              </event>
              <event>
                <sub_title>Vessel puncture site reaction</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="53"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="53"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Cholelithiasis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="53"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="53"/>
              </event>
              <event>
                <sub_title>Rhinitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="53"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="53"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="53"/>
              </event>
              <event>
                <sub_title>Contusion</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="53"/>
              </event>
              <event>
                <sub_title>Infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="53"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="53"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Arthropod bite</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="53"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="53"/>
              </event>
              <event>
                <sub_title>Limb injury</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="53"/>
              </event>
              <event>
                <sub_title>Muscle contusion</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="53"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood creatine phosphokinase increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="53"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Dysplastic naevus</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="53"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="53"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="53"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="53"/>
              </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>In this interim clinical study report (CSR), the VAS change from pre-dose at 4 hours and the proportion of attacks requiring SOC-Rx through the 24 hour post dose were discussed. Assessment of other efficacy endpoints were to be discussed in a final CSR, but this is no longer planned due to a decision to not proceed further with trials of acute treatment of HAE attacks with berotralstat.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Study Director</name_or_title>
      <organization>BioCryst Pharmaceuticals Inc</organization>
      <phone>+1 919-859-1302</phone>
      <email>clinicaltrials@biocryst.com</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/NCT03240133
org study id: BCX7353-202
nct id: NCT03240133
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This 3-part study will evaluate the efficacy and safety of an oral kallikrein inhibitor,
      BCX7353, in the treatment angioedema attacks in subjects with Type I or II hereditary
      angioedema (HAE). In each study part, subjects will treat 3 attacks with BCX7353 (2 attacks)
      or placebo (1 attack), in a randomly allocated order. In Part 1, the dose of 750mg will be
      assessed relative to placebo in up to 36 patients. If this is shown to be effective, then a
      further 12 patients will be enrolled at a 500mg dose (Part 1), followed by a further 12 (if
      efficacy still shown) at a dose of 250mg (Part 3) to determine the minimum effective dose of
      BCX7353 compared to placebo for treating HAE attacks. Efficacy will be determined by subject
      diary entries completed at pre-defined times post-dose.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Proportion of Subjects With Improved or Stable Composite Visual Analog Scale (VAS) Score
time frame: Mean composite VAS for HAE attack symptoms severity prior to IMP treatment and 4 hours post-dose
description: Subjects completed a 3-component VAS on a 100 mm scale for severity of abdominal pain, skin pain and skin swelling associated with the HAE attack, where zero indicated no pain or swelling and 100 mm indicated worst possible pain or swelling. Subjects completed the VAS immediately prior to study drug administration, then at 1, 2, 3, 4, approximately 8 & at 24 hours post-dose. The primary endpoint was the proportion of subject attacks with an improved or stable 3-symptom composite VAS score at 4 hours post dose. The 3-symptom composite was calculated as the average of the VAS scores for abdominal pain, skin pain, and skin swelling. A subject was considered improved or stable if the change from baseline (CFB; time of drug administration) in VAS was ≤ 0.
measure: Percentage of Attacks Treated With Standard of Care Acute Attack Medication (SOC-Rx) Through 24 Hours
time frame: 24 hours
description: The proportion of attacks for which subjects took SOC-Rx in the 24 hours following treatment with study drug. HAE Rescue Medications included C1-INH (Berinert, Cinryze, Ruconest) and Firazyr/Icatibant.
arm group label: Part1: BCX7353 750 mg
arm group type: Experimental
arm group label: Part 2: BCX7353 500 mg
arm group type: Experimental
arm group label: Part 3: BCX7353 250 mg
arm group type: Experimental
arm group label: Parts 1, 2 and 3: placebo
arm group type: Placebo Comparator
intervention type: Drug
intervention name: BCX7353
description: oral liquid formulation
arm group label: Part 2: BCX7353 500 mg
arm group label: Part 3: BCX7353 250 mg
arm group label: Part1: BCX7353 750 mg
intervention type: Drug
intervention name: Placebo
description: oral liquid formulation to match BCX7353
arm group label: Parts 1, 2 and 3: placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Hilary Longhurst, MBBS, PhD
role: Principal Investigator
affiliation: Barts & The London NHS Trust
facility: 
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country: Austria
country: Denmark
country: France
country: Germany
country: Hungary
country: Israel
country: Italy
country: North Macedonia
country: Poland
country: Romania
country: Switzerland
country: United Kingdom
country: Macedonia, The Former Yugoslav Republic of
responsible party type: Sponsor
mesh term: Angioedema
mesh term: Angioedemas, Hereditary
mesh term: Berotralstat
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: In this interim clinical study report (CSR), the VAS change from pre-dose at 4 hours and the proportion of attacks requiring SOC-Rx through the 24 hour post dose were discussed. Assessment of other efficacy endpoints were to be discussed in a final CSR, but this is no longer planned due to a decision to not proceed further with trials of acute treatment of HAE attacks with berotralstat.
point of contact: 