<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/NCT03303092</url>
  </required_header>
  <id_info>
    <org_study_id>406-102-00002</org_study_id>
    <secondary_id>JapicCTI-173725</secondary_id>
    <nct_id>NCT03303092</nct_id>
  </id_info>
  <brief_title>Efficacy and Safety of Subcutaneous Administration of TEV-48125 for the Preventive Treatment of Episodic Migraine</brief_title>
  <official_title>A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Trial Evaluating the Efficacy and Safety of Subcutaneous Administration of TEV-48125 for the Preventive Treatment of Episodic Migraine</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Otsuka Pharmaceutical Co., Ltd.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Otsuka Pharmaceutical Co., Ltd.</source>
  <oversight_info>
    <has_dmc>No</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>
      To evaluate the efficacy and safety of subcutaneous (SC) administration of TEV-48125 (monthly&#xD;
      TEV-48125 225 mg and TEV-48125 675 mg once over a period of 3 months) compared with placebo&#xD;
      for preventive treatment in Episodic Migraine patients&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 19, 2017</start_date>
  <completion_date type="Actual">November 22, 2019</completion_date>
  <primary_completion_date type="Actual">November 22, 2019</primary_completion_date>
  <phase>Phase 2/Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Mean Change From Baseline in the Monthly (28 Days) Average Number of Migraine Days During the 12-week Period After the First Dose of Investigational Medicinal Product (IMP)</measure>
    <time_frame>Baseline, 12 weeks</time_frame>
    <description>Headache-related efficacy endpoints were derived from headache variables collected using an eDiary. On each day, the subjects were asked to enter headache data in the electronic headache diary for the previous 24-hour period.&#xD;
Subjects who reported headache on the previous day answered questions about the headache (ie, occurrence of headache, duration of headache, maximum severity of headache, presence/absence of associated symptoms, and use of acute headache medications).&#xD;
Overall headache duration was recorded numerically, in hours, as well as number of hours with headache of at least moderate severity.&#xD;
If headache was reported, then headache severity was subjectively rated by the subject as follows: Mild headache, Moderate headache, Severe headache. Subjects also recorded the presence or absence of photophobia, phonophobia, nausea, or vomiting, and the status of use of any acute headache medications.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Proportion of Subjects Reaching at Least 50% Reduction in the Monthly Average Number of Migraine Days During the 12-week Period After the First Dose of IMP</measure>
    <time_frame>12 weeks</time_frame>
    <description>Headache-related efficacy endpoints were derived from headache variables collected using an eDiary. On each day, the subjects were asked to enter headache data in the electronic headache diary for the previous 24-hour period.&#xD;
Subjects who reported headache on the previous day answered questions about the headache (ie, occurrence of headache, duration of headache, maximum severity of headache, presence/absence of associated symptoms, and use of acute headache medications).&#xD;
Overall headache duration was recorded numerically, in hours, as well as number of hours with headache of at least moderate severity.&#xD;
If headache was reported, then headache severity was subjectively rated by the subject as follows: Mild headache, Moderate headache, Severe headache. Subjects also recorded the presence or absence of photophobia, phonophobia, nausea, or vomiting, and the status of use of any acute headache medications.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Change From Baseline in the Monthly Average Number of Days With Use of Any Acute Headache Medications During the 12-week Period After the First Dose of IMP</measure>
    <time_frame>Baseline, 12 weeks</time_frame>
    <description>Headache-related efficacy endpoints were derived from headache variables collected using an eDiary. On each day, subjects entered headache data in the electronic headache diary for the previous 24-hour period. Subjects who reported headache on the previous day answered questions about the headache (ie, occurrence of headache, duration of headache, maximum severity of headache, presence/absence of associated symptoms, and use of acute headache medications).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Change From Baseline in the Monthly Average Number of Migraine Days During the 12-week Period After the First Dose of IMP in Patients Not Receiving Concomitant Preventive Migraine Medications</measure>
    <time_frame>Baseline, 12 weeks</time_frame>
    <description>Headache-related efficacy endpoints were derived from headache variables collected using an eDiary. On each day, the subjects were asked to enter headache data in the electronic headache diary for the previous 24-hour period.&#xD;
Subjects who reported headache on the previous day answered questions about the headache (ie, occurrence of headache, duration of headache, maximum severity of headache, presence/absence of associated symptoms, and use of acute headache medications).&#xD;
Overall headache duration was recorded numerically, in hours, as well as number of hours with headache of at least moderate severity.&#xD;
If headache was reported, then headache severity was subjectively rated by the subject as follows: Mild headache, Moderate headache, Severe headache. Subjects also recorded the presence or absence of photophobia, phonophobia, nausea, or vomiting, and the status of use of any acute headache medications.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Change From Baseline in Disability Score, as Measured by Migraine Disability Assessment (MIDAS) Questionnaire at 4 Weeks After the Final (Third) Dose of IMP</measure>
    <time_frame>Baseline, 4 weeks</time_frame>
    <description>Using the MIDAS questionnaire, subjects assessed the degree of headache-related disability based on lost days of activity in 3 domains (work, household work, and nonwork) over the last 3 months. The MIDAS questionnaire was a 5-item instrument. The total of the scores of the first 5 questions was used for grading the level of disability, with scores of 0 to 5, 6 to 10, 11 to 20, and ≥ 21 interpreted as disability grades I (little or no disability), II (mild disability), III (moderate disability), and IV (severe disability), respectively.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">357</enrollment>
  <condition>Migraine</condition>
  <arm_group>
    <arm_group_label>TEV-48125 (225/225/225 mg) group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>TEV-48125 will be subcutaneously administered once monthly for 3 months (225/225/225 mg).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>TEV-48125 (675 mg/placebo/placebo) group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>TEV-48125 or placebo will be subcutaneously administered once monthly for 3 months (675 mg/placebo/placebo).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo will be subcutaneously administered once monthly for 3 months (placebo/placebo/placebo).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TEV-48125</intervention_name>
    <description>TEV-48125 will be subcutaneously administered once monthly for 3 months.</description>
    <arm_group_label>TEV-48125 (225/225/225 mg) group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TEV-48125 or placebo</intervention_name>
    <description>TEV-48125 or placebo will be subcutaneously administered once monthly for 3 months.</description>
    <arm_group_label>TEV-48125 (675 mg/placebo/placebo) group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo will be subcutaneously administered once monthly for 3 months.</description>
    <arm_group_label>Placebo group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patient has a history of migraine (according to The International Classification of&#xD;
             Headache Disorders, third edition [beta version] criteria) or clinical judgment&#xD;
             suggests a migraine diagnosis&#xD;
&#xD;
          -  Patient fulfills the criteria for Episodic migraine in baseline information collected&#xD;
             during the 28 day screening period&#xD;
&#xD;
          -  Not using preventive migraine medications for migraine or other medical conditions or&#xD;
             using no more than 1 preventive migraine medication for migraine or other medical&#xD;
             conditions if the dose and regimen have been stable for at least 2 months prior to&#xD;
             giving informed consent.&#xD;
&#xD;
          -  Patient demonstrates compliance with the electronic headache diary during the&#xD;
             screening period by entry of headache data on a minimum of 24 of 28 days and the&#xD;
             entered data is judged appropriate by the investigator.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Patients who have previously failed (lack of efficacy) 2 or more of the clusters of the&#xD;
        medications for treatment of migraine after use for at least 3 months at accepted migraine&#xD;
        therapeutic doses&#xD;
&#xD;
        - Hematological, cardiac, renal, endocrine, pulmonary, gastrointestinal, genitourinary,&#xD;
        neurologic, hepatic, or ocular disease considered clinically significant in the judgment of&#xD;
        the investigator&#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>Takehisa Matsumaru</last_name>
    <role>Study Director</role>
    <affiliation>Otsuka Pharmaceutical Co., Ltd.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Saitama Medical University Hospital</name>
      <address>
        <city>Iruma</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Japan</country>
  </location_countries>
  <verification_date>July 2021</verification_date>
  <study_first_submitted>October 2, 2017</study_first_submitted>
  <study_first_submitted_qc>October 2, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 5, 2017</study_first_posted>
  <results_first_submitted>June 16, 2021</results_first_submitted>
  <results_first_submitted_qc>June 16, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">July 8, 2021</results_first_posted>
  <last_update_submitted>July 7, 2021</last_update_submitted>
  <last_update_submitted_qc>July 7, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">July 29, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Migraine Disorders</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Antibodies, Monoclonal</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <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>July 8, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/92/NCT03303092/Prot_000.pdf</document_url>
    </provided_document>
    <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 12, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/92/NCT03303092/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>TEV-48125 (225/225/225 mg) Group</title>
          <description>TEV-48125 will be subcutaneously administered once monthly for 3 months (225/225/225 mg).</description>
        </group>
        <group group_id="P2">
          <title>TEV-48125 (675 mg/Placebo/Placebo) Group</title>
          <description>TEV-48125 or placebo will be subcutaneously administered once monthly for 3 months (675 mg/placebo/placebo).</description>
        </group>
        <group group_id="P3">
          <title>Placebo Group</title>
          <description>Placebo will be subcutaneously administered once monthly for 3 months (placebo/placebo/placebo).</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="121"/>
                <participants group_id="P2" count="119"/>
                <participants group_id="P3" count="117"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="118"/>
                <participants group_id="P2" count="113"/>
                <participants group_id="P3" count="112"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="6"/>
                <participants group_id="P3" count="5"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="5"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>TEV-48125 (225/225/225 mg) Group</title>
          <description>TEV-48125 will be subcutaneously administered once monthly for 3 months (225/225/225 mg).</description>
        </group>
        <group group_id="B2">
          <title>TEV-48125 (675 mg/Placebo/Placebo) Group</title>
          <description>TEV-48125 or placebo will be subcutaneously administered once monthly for 3 months (675 mg/placebo/placebo).</description>
        </group>
        <group group_id="B3">
          <title>Placebo Group</title>
          <description>Placebo will be subcutaneously administered once monthly for 3 months (placebo/placebo/placebo).</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="121"/>
            <count group_id="B2" value="119"/>
            <count group_id="B3" value="117"/>
            <count group_id="B4" value="357"/>
          </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="120"/>
                    <measurement group_id="B2" value="116"/>
                    <measurement group_id="B3" value="112"/>
                    <measurement group_id="B4" value="348"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="5"/>
                    <measurement group_id="B4" value="9"/>
                  </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="44.4" spread="9.5"/>
                    <measurement group_id="B2" value="41.9" spread="10.1"/>
                    <measurement group_id="B3" value="44.2" spread="10.7"/>
                    <measurement group_id="B4" value="43.5" spread="10.1"/>
                  </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="101"/>
                    <measurement group_id="B2" value="101"/>
                    <measurement group_id="B3" value="100"/>
                    <measurement group_id="B4" value="302"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="18"/>
                    <measurement group_id="B3" value="17"/>
                    <measurement group_id="B4" value="55"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Asian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="121"/>
                    <measurement group_id="B2" value="119"/>
                    <measurement group_id="B3" value="117"/>
                    <measurement group_id="B4" value="357"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Japan</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="102"/>
                    <measurement group_id="B2" value="101"/>
                    <measurement group_id="B3" value="98"/>
                    <measurement group_id="B4" value="301"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>South Korea</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="19"/>
                    <measurement group_id="B2" value="18"/>
                    <measurement group_id="B3" value="19"/>
                    <measurement group_id="B4" value="56"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Mean Change From Baseline in the Monthly (28 Days) Average Number of Migraine Days During the 12-week Period After the First Dose of Investigational Medicinal Product (IMP)</title>
        <description>Headache-related efficacy endpoints were derived from headache variables collected using an eDiary. On each day, the subjects were asked to enter headache data in the electronic headache diary for the previous 24-hour period.&#xD;
Subjects who reported headache on the previous day answered questions about the headache (ie, occurrence of headache, duration of headache, maximum severity of headache, presence/absence of associated symptoms, and use of acute headache medications).&#xD;
Overall headache duration was recorded numerically, in hours, as well as number of hours with headache of at least moderate severity.&#xD;
If headache was reported, then headache severity was subjectively rated by the subject as follows: Mild headache, Moderate headache, Severe headache. Subjects also recorded the presence or absence of photophobia, phonophobia, nausea, or vomiting, and the status of use of any acute headache medications.</description>
        <time_frame>Baseline, 12 weeks</time_frame>
        <population>Full Analysis set (FAS): Subjects who received the IMP at least once and had baseline and Week 12 data on monthly average number of migraine days.</population>
        <group_list>
          <group group_id="O1">
            <title>TEV-48125 (225/225/225 mg) Group</title>
            <description>TEV-48125 will be subcutaneously administered once monthly for 3 months (225/225/225 mg).</description>
          </group>
          <group group_id="O2">
            <title>TEV-48125 (675 mg/Placebo/Placebo) Group</title>
            <description>TEV-48125 or placebo will be subcutaneously administered once monthly for 3 months (675 mg/placebo/placebo).</description>
          </group>
          <group group_id="O3">
            <title>Placebo Group</title>
            <description>Placebo will be subcutaneously administered once monthly for 3 months (placebo/placebo/placebo).</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Change From Baseline in the Monthly (28 Days) Average Number of Migraine Days During the 12-week Period After the First Dose of Investigational Medicinal Product (IMP)</title>
          <description>Headache-related efficacy endpoints were derived from headache variables collected using an eDiary. On each day, the subjects were asked to enter headache data in the electronic headache diary for the previous 24-hour period.&#xD;
Subjects who reported headache on the previous day answered questions about the headache (ie, occurrence of headache, duration of headache, maximum severity of headache, presence/absence of associated symptoms, and use of acute headache medications).&#xD;
Overall headache duration was recorded numerically, in hours, as well as number of hours with headache of at least moderate severity.&#xD;
If headache was reported, then headache severity was subjectively rated by the subject as follows: Mild headache, Moderate headache, Severe headache. Subjects also recorded the presence or absence of photophobia, phonophobia, nausea, or vomiting, and the status of use of any acute headache medications.</description>
          <population>Full Analysis set (FAS): Subjects who received the IMP at least once and had baseline and Week 12 data on monthly average number of migraine days.</population>
          <units>days/month</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="121"/>
                <count group_id="O2" value="117"/>
                <count group_id="O3" value="116"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-4.00" spread="0.37"/>
                    <measurement group_id="O2" value="-4.02" spread="0.38"/>
                    <measurement group_id="O3" value="-1.02" spread="0.38"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Proportion of Subjects Reaching at Least 50% Reduction in the Monthly Average Number of Migraine Days During the 12-week Period After the First Dose of IMP</title>
        <description>Headache-related efficacy endpoints were derived from headache variables collected using an eDiary. On each day, the subjects were asked to enter headache data in the electronic headache diary for the previous 24-hour period.&#xD;
Subjects who reported headache on the previous day answered questions about the headache (ie, occurrence of headache, duration of headache, maximum severity of headache, presence/absence of associated symptoms, and use of acute headache medications).&#xD;
Overall headache duration was recorded numerically, in hours, as well as number of hours with headache of at least moderate severity.&#xD;
If headache was reported, then headache severity was subjectively rated by the subject as follows: Mild headache, Moderate headache, Severe headache. Subjects also recorded the presence or absence of photophobia, phonophobia, nausea, or vomiting, and the status of use of any acute headache medications.</description>
        <time_frame>12 weeks</time_frame>
        <population>Full Analysis set (FAS): Subjects who received the IMP at least once and had baseline and Week 12 data on monthly average number of migraine days. &quot;Overall Number of Participants Analyzed&quot; = the number of subjects meeting responder criteria.</population>
        <group_list>
          <group group_id="O1">
            <title>TEV-48125 (225/225/225 mg) Group</title>
            <description>TEV-48125 will be subcutaneously administered once monthly for 3 months (225/225/225 mg).</description>
          </group>
          <group group_id="O2">
            <title>TEV-48125 (675 mg/Placebo/Placebo) Group</title>
            <description>TEV-48125 or placebo will be subcutaneously administered once monthly for 3 months (675 mg/placebo/placebo).</description>
          </group>
          <group group_id="O3">
            <title>Placebo Group</title>
            <description>Placebo will be subcutaneously administered once monthly for 3 months (placebo/placebo/placebo).</description>
          </group>
        </group_list>
        <measure>
          <title>Proportion of Subjects Reaching at Least 50% Reduction in the Monthly Average Number of Migraine Days During the 12-week Period After the First Dose of IMP</title>
          <description>Headache-related efficacy endpoints were derived from headache variables collected using an eDiary. On each day, the subjects were asked to enter headache data in the electronic headache diary for the previous 24-hour period.&#xD;
Subjects who reported headache on the previous day answered questions about the headache (ie, occurrence of headache, duration of headache, maximum severity of headache, presence/absence of associated symptoms, and use of acute headache medications).&#xD;
Overall headache duration was recorded numerically, in hours, as well as number of hours with headache of at least moderate severity.&#xD;
If headache was reported, then headache severity was subjectively rated by the subject as follows: Mild headache, Moderate headache, Severe headache. Subjects also recorded the presence or absence of photophobia, phonophobia, nausea, or vomiting, and the status of use of any acute headache medications.</description>
          <population>Full Analysis set (FAS): Subjects who received the IMP at least once and had baseline and Week 12 data on monthly average number of migraine days. &quot;Overall Number of Participants Analyzed&quot; = the number of subjects meeting responder criteria.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="50"/>
                <count group_id="O2" value="53"/>
                <count group_id="O3" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="41.3"/>
                    <measurement group_id="O2" value="45.3"/>
                    <measurement group_id="O3" value="11.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Change From Baseline in the Monthly Average Number of Days With Use of Any Acute Headache Medications During the 12-week Period After the First Dose of IMP</title>
        <description>Headache-related efficacy endpoints were derived from headache variables collected using an eDiary. On each day, subjects entered headache data in the electronic headache diary for the previous 24-hour period. Subjects who reported headache on the previous day answered questions about the headache (ie, occurrence of headache, duration of headache, maximum severity of headache, presence/absence of associated symptoms, and use of acute headache medications).</description>
        <time_frame>Baseline, 12 weeks</time_frame>
        <population>Full Analysis set (FAS): Subjects who received the IMP at least once and had baseline and Week 12 data on monthly average number of migraine days. &quot;Overall Number of Participants Analyzed&quot; = the number of subjects with both baseline and assessment at each visit.</population>
        <group_list>
          <group group_id="O1">
            <title>TEV-48125 (225/225/225 mg) Group</title>
            <description>TEV-48125 will be subcutaneously administered once monthly for 3 months (225/225/225 mg).</description>
          </group>
          <group group_id="O2">
            <title>TEV-48125 (675 mg/Placebo/Placebo) Group</title>
            <description>TEV-48125 or placebo will be subcutaneously administered once monthly for 3 months (675 mg/placebo/placebo).</description>
          </group>
          <group group_id="O3">
            <title>Placebo Group</title>
            <description>Placebo will be subcutaneously administered once monthly for 3 months (placebo/placebo/placebo).</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Change From Baseline in the Monthly Average Number of Days With Use of Any Acute Headache Medications During the 12-week Period After the First Dose of IMP</title>
          <description>Headache-related efficacy endpoints were derived from headache variables collected using an eDiary. On each day, subjects entered headache data in the electronic headache diary for the previous 24-hour period. Subjects who reported headache on the previous day answered questions about the headache (ie, occurrence of headache, duration of headache, maximum severity of headache, presence/absence of associated symptoms, and use of acute headache medications).</description>
          <population>Full Analysis set (FAS): Subjects who received the IMP at least once and had baseline and Week 12 data on monthly average number of migraine days. &quot;Overall Number of Participants Analyzed&quot; = the number of subjects with both baseline and assessment at each visit.</population>
          <units>days/month</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="121"/>
                <count group_id="O2" value="117"/>
                <count group_id="O3" value="116"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-3.30" spread="0.34"/>
                    <measurement group_id="O2" value="-3.29" spread="0.36"/>
                    <measurement group_id="O3" value="-0.46" spread="0.35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Change From Baseline in the Monthly Average Number of Migraine Days During the 12-week Period After the First Dose of IMP in Patients Not Receiving Concomitant Preventive Migraine Medications</title>
        <description>Headache-related efficacy endpoints were derived from headache variables collected using an eDiary. On each day, the subjects were asked to enter headache data in the electronic headache diary for the previous 24-hour period.&#xD;
Subjects who reported headache on the previous day answered questions about the headache (ie, occurrence of headache, duration of headache, maximum severity of headache, presence/absence of associated symptoms, and use of acute headache medications).&#xD;
Overall headache duration was recorded numerically, in hours, as well as number of hours with headache of at least moderate severity.&#xD;
If headache was reported, then headache severity was subjectively rated by the subject as follows: Mild headache, Moderate headache, Severe headache. Subjects also recorded the presence or absence of photophobia, phonophobia, nausea, or vomiting, and the status of use of any acute headache medications.</description>
        <time_frame>Baseline, 12 weeks</time_frame>
        <population>Full Analysis set (FAS): Subjects who received the IMP at least once and had baseline and Week 12 data on monthly average number of migraine days. &quot;Overall Number of Participants Analyzed&quot; = the number of subjects with both baseline and assessment at each visit.</population>
        <group_list>
          <group group_id="O1">
            <title>TEV-48125 (225/225/225 mg) Group</title>
            <description>TEV-48125 will be subcutaneously administered once monthly for 3 months (225/225/225 mg).</description>
          </group>
          <group group_id="O2">
            <title>TEV-48125 (675 mg/Placebo/Placebo) Group</title>
            <description>TEV-48125 or placebo will be subcutaneously administered once monthly for 3 months (675 mg/placebo/placebo).</description>
          </group>
          <group group_id="O3">
            <title>Placebo Group</title>
            <description>Placebo will be subcutaneously administered once monthly for 3 months (placebo/placebo/placebo).</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Change From Baseline in the Monthly Average Number of Migraine Days During the 12-week Period After the First Dose of IMP in Patients Not Receiving Concomitant Preventive Migraine Medications</title>
          <description>Headache-related efficacy endpoints were derived from headache variables collected using an eDiary. On each day, the subjects were asked to enter headache data in the electronic headache diary for the previous 24-hour period.&#xD;
Subjects who reported headache on the previous day answered questions about the headache (ie, occurrence of headache, duration of headache, maximum severity of headache, presence/absence of associated symptoms, and use of acute headache medications).&#xD;
Overall headache duration was recorded numerically, in hours, as well as number of hours with headache of at least moderate severity.&#xD;
If headache was reported, then headache severity was subjectively rated by the subject as follows: Mild headache, Moderate headache, Severe headache. Subjects also recorded the presence or absence of photophobia, phonophobia, nausea, or vomiting, and the status of use of any acute headache medications.</description>
          <population>Full Analysis set (FAS): Subjects who received the IMP at least once and had baseline and Week 12 data on monthly average number of migraine days. &quot;Overall Number of Participants Analyzed&quot; = the number of subjects with both baseline and assessment at each visit.</population>
          <units>days/month</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="97"/>
                <count group_id="O2" value="94"/>
                <count group_id="O3" value="94"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-4.42" spread="0.36"/>
                    <measurement group_id="O2" value="-4.21" spread="0.37"/>
                    <measurement group_id="O3" value="-1.40" spread="0.37"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Change From Baseline in Disability Score, as Measured by Migraine Disability Assessment (MIDAS) Questionnaire at 4 Weeks After the Final (Third) Dose of IMP</title>
        <description>Using the MIDAS questionnaire, subjects assessed the degree of headache-related disability based on lost days of activity in 3 domains (work, household work, and nonwork) over the last 3 months. The MIDAS questionnaire was a 5-item instrument. The total of the scores of the first 5 questions was used for grading the level of disability, with scores of 0 to 5, 6 to 10, 11 to 20, and ≥ 21 interpreted as disability grades I (little or no disability), II (mild disability), III (moderate disability), and IV (severe disability), respectively.</description>
        <time_frame>Baseline, 4 weeks</time_frame>
        <population>Full Analysis set (FAS): Subjects who received the IMP at least once and had baseline and Week 12 data on monthly average number of migraine days. &quot;Overall Number of Participants Analyzed&quot; = the number of subjects with both baseline and assessment at each visit.</population>
        <group_list>
          <group group_id="O1">
            <title>TEV-48125 (225/225/225 mg) Group</title>
            <description>TEV-48125 will be subcutaneously administered once monthly for 3 months (225/225/225 mg).</description>
          </group>
          <group group_id="O2">
            <title>TEV-48125 (675 mg/Placebo/Placebo) Group</title>
            <description>TEV-48125 or placebo will be subcutaneously administered once monthly for 3 months (675 mg/placebo/placebo).</description>
          </group>
          <group group_id="O3">
            <title>Placebo Group</title>
            <description>Placebo will be subcutaneously administered once monthly for 3 months (placebo/placebo/placebo).</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Change From Baseline in Disability Score, as Measured by Migraine Disability Assessment (MIDAS) Questionnaire at 4 Weeks After the Final (Third) Dose of IMP</title>
          <description>Using the MIDAS questionnaire, subjects assessed the degree of headache-related disability based on lost days of activity in 3 domains (work, household work, and nonwork) over the last 3 months. The MIDAS questionnaire was a 5-item instrument. The total of the scores of the first 5 questions was used for grading the level of disability, with scores of 0 to 5, 6 to 10, 11 to 20, and ≥ 21 interpreted as disability grades I (little or no disability), II (mild disability), III (moderate disability), and IV (severe disability), respectively.</description>
          <population>Full Analysis set (FAS): Subjects who received the IMP at least once and had baseline and Week 12 data on monthly average number of migraine days. &quot;Overall Number of Participants Analyzed&quot; = the number of subjects with both baseline and assessment at each visit.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="118"/>
                <count group_id="O2" value="112"/>
                <count group_id="O3" value="112"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-12.64" spread="1.42"/>
                    <measurement group_id="O2" value="-12.55" spread="1.49"/>
                    <measurement group_id="O3" value="-7.41" spread="1.46"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Double-blind treatment period (12 weeks)</time_frame>
      <desc>Safety set (SS):Subjects who received the IMP at least once.</desc>
      <group_list>
        <group group_id="E1">
          <title>TEV-48125 (225/225/225 mg) Group</title>
          <description>TEV-48125 will be subcutaneously administered once monthly for 3 months (225/225/225 mg).</description>
        </group>
        <group group_id="E2">
          <title>TEV-48125 (675 mg/Placebo/Placebo) Group</title>
          <description>TEV-48125 or placebo will be subcutaneously administered once monthly for 3 months (675 mg/placebo/placebo).</description>
        </group>
        <group group_id="E3">
          <title>Placebo Group</title>
          <description>Placebo will be subcutaneously administered once monthly for 3 months (placebo/placebo/placebo).</description>
        </group>
      </group_list>
      <serious_events>
        <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="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>MedDRA Ver. 22.0</default_vocab>
        <default_assessment>Non-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="69" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="74" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="77" subjects_at_risk="117"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Eosinophilia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Lymphadenitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Purpura non-thrombocytopenic</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Vertigo positional</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Sudden hearing loss</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Chalazion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Dry eye</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Eye pruritus</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Glaucoma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Keratitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Dental caries</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Gastritis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Gastrooesophageal reflux disease</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Stomatitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Toothache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Abdominal discomfort</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Gastrointestinal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Injection site erythema</sub_title>
                <counts group_id="E1" subjects_affected="19" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="14" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="15" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Injection site induration</sub_title>
                <counts group_id="E1" subjects_affected="18" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="14" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="12" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Injection site pain</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="16" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Injection site pruritus</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Injection site swelling</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Injection site rash</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Injection site dermatitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Injection site haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Injection site macule</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Chest discomfort</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Chest pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Feeling abnormal</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Feeling cold</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Injection site bruising</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Injection site eczema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Injection site haematoma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Injection site urticaria</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Injection site warmth</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Hepatic function abnormal</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Seasonal allergy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="15" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="16" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Bacterial vulvovaginitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Helicobacter infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Pharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Streptococcal infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Anal abscess</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Cystitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Gastroenteritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Herpes simplex</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Hordeolum</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Otitis externa</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Periodontitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Tonsillitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Muscle strain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Contusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Joint dislocation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Thermal burn</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Ligament sprain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Rib fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Skin abrasion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Blood creatine phosphokinase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Blood urine present</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Glucose urine present</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Blood glucose decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Blood pressure increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Gamma-glutamyltransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Occult blood positive</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Urine leukocyte esterase positive</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Weight decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="117"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperlipidaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Hypoglycaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Joint swelling</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Temporomandibular joint syndrome</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Intervertebral disc protrusion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Musculoskeletal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Osteoarthritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Synovial cyst</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Uterine leiomyoma</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Hyperaesthesia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Sciatica</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Vascular headache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Hypoaesthesia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Migraine</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Radial nerve palsy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Somnolence</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Panic disorder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Stress</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Calculus urinary</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Pollakiuria</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Pelvic pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Cervical polyp</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Dysmenorrhoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Menstruation irregular</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Rhinitis allergic</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Hyperventilation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract inflammation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Eczema</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Urticaria</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Haemorrhage subcutaneous</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Tumour excision</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="121"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="117"/>
              </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>
    <point_of_contact>
      <name_or_title>Director of Clinical Trials</name_or_title>
      <organization>Otsuka Pharmaceutical Co., LTD.</organization>
      <phone>+81-3-6361-7366</phone>
      <email>CL_OPCJ_RDA_Team@otsuka.jp</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/NCT03303092
org study id: 406-102-00002
secondary id: JapicCTI-173725
nct id: NCT03303092
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
To evaluate the efficacy and safety of subcutaneous (SC) administration of TEV-48125 (monthly
      TEV-48125 225 mg and TEV-48125 675 mg once over a period of 3 months) compared with placebo
      for preventive treatment in Episodic Migraine patients
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Mean Change From Baseline in the Monthly (28 Days) Average Number of Migraine Days During the 12-week Period After the First Dose of Investigational Medicinal Product (IMP)
time frame: Baseline, 12 weeks
description: Headache-related efficacy endpoints were derived from headache variables collected using an eDiary. On each day, the subjects were asked to enter headache data in the electronic headache diary for the previous 24-hour period.
Subjects who reported headache on the previous day answered questions about the headache (ie, occurrence of headache, duration of headache, maximum severity of headache, presence/absence of associated symptoms, and use of acute headache medications).
Overall headache duration was recorded numerically, in hours, as well as number of hours with headache of at least moderate severity.
If headache was reported, then headache severity was subjectively rated by the subject as follows: Mild headache, Moderate headache, Severe headache. Subjects also recorded the presence or absence of photophobia, phonophobia, nausea, or vomiting, and the status of use of any acute headache medications.
measure: Proportion of Subjects Reaching at Least 50% Reduction in the Monthly Average Number of Migraine Days During the 12-week Period After the First Dose of IMP
time frame: 12 weeks
description: Headache-related efficacy endpoints were derived from headache variables collected using an eDiary. On each day, the subjects were asked to enter headache data in the electronic headache diary for the previous 24-hour period.
Subjects who reported headache on the previous day answered questions about the headache (ie, occurrence of headache, duration of headache, maximum severity of headache, presence/absence of associated symptoms, and use of acute headache medications).
Overall headache duration was recorded numerically, in hours, as well as number of hours with headache of at least moderate severity.
If headache was reported, then headache severity was subjectively rated by the subject as follows: Mild headache, Moderate headache, Severe headache. Subjects also recorded the presence or absence of photophobia, phonophobia, nausea, or vomiting, and the status of use of any acute headache medications.
measure: Mean Change From Baseline in the Monthly Average Number of Days With Use of Any Acute Headache Medications During the 12-week Period After the First Dose of IMP
time frame: Baseline, 12 weeks
description: Headache-related efficacy endpoints were derived from headache variables collected using an eDiary. On each day, subjects entered headache data in the electronic headache diary for the previous 24-hour period. Subjects who reported headache on the previous day answered questions about the headache (ie, occurrence of headache, duration of headache, maximum severity of headache, presence/absence of associated symptoms, and use of acute headache medications).
measure: Mean Change From Baseline in the Monthly Average Number of Migraine Days During the 12-week Period After the First Dose of IMP in Patients Not Receiving Concomitant Preventive Migraine Medications
time frame: Baseline, 12 weeks
description: Headache-related efficacy endpoints were derived from headache variables collected using an eDiary. On each day, the subjects were asked to enter headache data in the electronic headache diary for the previous 24-hour period.
Subjects who reported headache on the previous day answered questions about the headache (ie, occurrence of headache, duration of headache, maximum severity of headache, presence/absence of associated symptoms, and use of acute headache medications).
Overall headache duration was recorded numerically, in hours, as well as number of hours with headache of at least moderate severity.
If headache was reported, then headache severity was subjectively rated by the subject as follows: Mild headache, Moderate headache, Severe headache. Subjects also recorded the presence or absence of photophobia, phonophobia, nausea, or vomiting, and the status of use of any acute headache medications.
measure: Mean Change From Baseline in Disability Score, as Measured by Migraine Disability Assessment (MIDAS) Questionnaire at 4 Weeks After the Final (Third) Dose of IMP
time frame: Baseline, 4 weeks
description: Using the MIDAS questionnaire, subjects assessed the degree of headache-related disability based on lost days of activity in 3 domains (work, household work, and nonwork) over the last 3 months. The MIDAS questionnaire was a 5-item instrument. The total of the scores of the first 5 questions was used for grading the level of disability, with scores of 0 to 5, 6 to 10, 11 to 20, and ≥ 21 interpreted as disability grades I (little or no disability), II (mild disability), III (moderate disability), and IV (severe disability), respectively.
arm group label: TEV-48125 (225/225/225 mg) group
arm group type: Experimental
description: TEV-48125 will be subcutaneously administered once monthly for 3 months (225/225/225 mg).
arm group label: TEV-48125 (675 mg/placebo/placebo) group
arm group type: Experimental
description: TEV-48125 or placebo will be subcutaneously administered once monthly for 3 months (675 mg/placebo/placebo).
arm group label: Placebo group
arm group type: Placebo Comparator
description: Placebo will be subcutaneously administered once monthly for 3 months (placebo/placebo/placebo).
intervention type: Drug
intervention name: TEV-48125
description: TEV-48125 will be subcutaneously administered once monthly for 3 months.
arm group label: TEV-48125 (225/225/225 mg) group
intervention type: Drug
intervention name: TEV-48125 or placebo
description: TEV-48125 or placebo will be subcutaneously administered once monthly for 3 months.
arm group label: TEV-48125 (675 mg/placebo/placebo) group
intervention type: Drug
intervention name: Placebo
description: Placebo will be subcutaneously administered once monthly for 3 months.
arm group label: Placebo group
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Takehisa Matsumaru
role: Study Director
affiliation: Otsuka Pharmaceutical Co., Ltd.
facility: 
country: Japan
responsible party type: Sponsor
mesh term: Migraine Disorders
mesh term: Antibodies, Monoclonal
sharing ipd: Undecided
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 