<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/NCT02196506</url>
  </required_header>
  <id_info>
    <org_study_id>331-13-214</org_study_id>
    <nct_id>NCT02196506</nct_id>
  </id_info>
  <brief_title>Study of the Safety and Efficacy of Fixed-dose Brexpiprazole (OPC-34712) as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder With and Without Anxious Distress</brief_title>
  <official_title>A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial of the Safety and Efficacy of Fixed-dose Brexpiprazole (OPC-34712) as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder With and Without Anxious Distress</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Otsuka Pharmaceutical Development &amp; Commercialization, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>H. Lundbeck A/S</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Otsuka Pharmaceutical Development &amp; Commercialization, Inc.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to assess the tolerability, safety, and efficacy of&#xD;
      brexpiprazole (2.0 mg/day) as adjunctive therapy in adult subjects with a diagnosis of MDD&#xD;
      with and without anxious distress&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The introduction of atypical antipsychotics has created a renewed interest in adjunctive&#xD;
      therapy for MDD, particularly for treatment-resistant MDD. Several atypical antipsychotics&#xD;
      have been shown to enhance the response to ADT. This is a phase 3, multicenter, randomized,&#xD;
      double-blind, placebo-controlled, fixed-dose trial designed to assess the safety and efficacy&#xD;
      of brexpiprazole (2.0 mg/day) as adjunctive therapy to an assigned open-label ADT in&#xD;
      depressed subjects with and without anxious distress.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>July 2014</start_date>
  <completion_date type="Actual">May 2016</completion_date>
  <primary_completion_date type="Actual">April 2016</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in the Montgomery-Asberg Depression</measure>
    <time_frame>From baseline (end of Phase A [Week 8]) to week 14</time_frame>
    <description>To assess the change in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score from Baseline (End of Phase A [Week 8]) to Week 14. The MADRS was utilized as the primary efficacy assessment of the participant's level of depression and was administered utilizing the Structured Interview Guide for the MADRS (SIGMA). The MADRS consisted of 10 items each with 7 defined grades of severity. The rater decided whether the rating lied on predefined scale steps (0, 2, 4, 6) or between them (1, 3, 5). The 10 items were apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score was 60; 0, no symptom; 60, severely affected.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in the Sheehan Disability Scale (SDS) From Baseline to End of Treatment</measure>
    <time_frame>From baseline (end of Phase A [Week 8]) to week 14</time_frame>
    <description>To assess the change in the Sheehan Disability Scale (SDS) Score (the mean of 3 individual item scores) from Baseline (End of Phase A [Week 8]) to Week 14 (End of Phase B). SDS was a 3-item clinician-rated questionnaire used to evaluate impairments in the domains of work, social life, and family life/home responsibility. Each item was scored using a scale of 0 to 10 (a higher score indicates symptoms have disrupted work, social life, and family life/home responsibility extremely). The maximum total score was 30; 0 = not at all, to 30 = extremely.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From End of Phase A to End of Phase B in MADRS Total Score for the Subpopulation With &lt;25% Improvement From Baseline of Phase A to End of Phase A in MADRS Total Score</measure>
    <time_frame>From baseline (end of Phase A [Week 8]) to week 14</time_frame>
    <description>To assess the change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in MADRS Total Score for the subpopulation with &lt; 25% improvement from baseline of Phase A (Week 0) to end of Phase A (Week 8) in MADRS Total Score. The MADRS was utilized as the primary efficacy assessment of the participant's level of depression and was administered utilizing the Structured Interview Guide for the MADRS (SIGMA). The MADRS consisted of 10 items each with 7 defined grades of severity. The 10 items were apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score was 60; 0, no symptom; 60, severely affected.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From End of Phase A to End of Phase B in MADRS Total Score for the Subpopulations With Anxious Distress as Specified in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V).</measure>
    <time_frame>From baseline (end of Phase A [Week 8]) to week 14</time_frame>
    <description>To assess the change from end of Phase A (Week 8) to end of Phase B (Week 14) in MADRS Total Score for the subpopulations with anxious distress as specified in DSM-V. The MADRS was utilized as the primary efficacy assessment of the participant's level of depression and was administered utilizing the Structured Interview Guide for the MADRS (SIGMA). The MADRS consisted of 10 items each with 7 defined grades of severity. The 10 items were apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score was 60; 0, no symptom; 60, severely affected.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">837</enrollment>
  <condition>Depressive Disorder</condition>
  <condition>Depression</condition>
  <condition>Depressive Disorder, Major</condition>
  <condition>Mood Disorders</condition>
  <condition>Mental Disorders</condition>
  <arm_group>
    <arm_group_label>Brexpiprazole + ADT</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Brexpiprazole + ADT</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo + ADT</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo + ADT</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo + ADT</intervention_name>
    <description>Placebo + ADT Placebo + FDA Approved Antidepressant (ADT)</description>
    <arm_group_label>Placebo + ADT</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Brexpiprazole +ADT</intervention_name>
    <description>Brexpiprazole + ADT Tablet, Oral, 2mg brexpiprazole and FDA Approved Antidepressant (ADT)</description>
    <arm_group_label>Brexpiprazole + ADT</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male and Female subjects between 18-65 years of age, with diagnosis of major&#xD;
             depressive disorder with or without anxious distress&#xD;
&#xD;
          -  Current depressive episode must be at least 8 weeks in duration&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subjects with a history of Neuroleptic Malignant Syndrome or Serotonin Syndrome&#xD;
&#xD;
          -  Subjects who report an inadequate response to more than 3 antidepressant treatments in&#xD;
             the current episode&#xD;
&#xD;
          -  Subjects with a current Axis I diagnosis of: Delirium, dementia, amnestic or other&#xD;
             cognitive disorder, Schizophrenia, schizoaffective disorder, or other psychotic&#xD;
             disorder, Bipolar I or II disorder&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Claudette Brewer</last_name>
    <role>Study Director</role>
    <affiliation>Otsuka Pharmaceutical Development &amp; Commercialization, Inc.</affiliation>
  </overall_official>
  <location>
    <facility>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Beverly Hills</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Denver</city>
        <state>Colorado</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Hialeah</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Orlando</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Alpharetta</city>
        <state>Georgia</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Smyrna</city>
        <state>Georgia</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Rochester Hills</city>
        <state>Michigan</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Cherry Hill</city>
        <state>New Jersey</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Jamaica</city>
        <state>New York</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>New York</city>
        <state>New York</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Staten Island</city>
        <state>New York</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Raleigh</city>
        <state>North Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Edmond</city>
        <state>Oklahoma</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Salem</city>
        <state>Oregon</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Lincoln</city>
        <state>Rhode Island</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Columbia</city>
        <state>South Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Memphis</city>
        <state>Tennessee</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Wichita Falls</city>
        <state>Texas</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Murray</city>
        <state>Utah</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Woodstock</city>
        <state>Vermont</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Charlottesville</city>
        <state>Virginia</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Richmond</city>
        <state>Virginia</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Spokane</city>
        <state>Washington</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Achim</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Berlin</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Dusseldorf</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Frankfurt</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Freiburg</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Oranienburg</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Stralsund</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Wurzburg</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Budapest</city>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Gyor</city>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Gdansk</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Lubin</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Sosnowiec</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Warszawa</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Bratislava</city>
        <country>Slovakia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Kosice-Barca</city>
        <country>Slovakia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Liptovsky Mikulas</city>
        <country>Slovakia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
    <country>Hungary</country>
    <country>Poland</country>
    <country>Slovakia</country>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2018</verification_date>
  <study_first_submitted>July 18, 2014</study_first_submitted>
  <study_first_submitted_qc>July 18, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 22, 2014</study_first_posted>
  <results_first_submitted>May 25, 2017</results_first_submitted>
  <results_first_submitted_qc>August 17, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">August 21, 2018</results_first_posted>
  <last_update_submitted>August 17, 2018</last_update_submitted>
  <last_update_submitted_qc>August 17, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">August 21, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>OPC-34712</keyword>
  <keyword>brexpiprazole</keyword>
  <keyword>Major Depressive Disorder</keyword>
  <keyword>Adjunctive Treatment</keyword>
  <keyword>Anxious Distress</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Depression</mesh_term>
    <mesh_term>Depressive Disorder</mesh_term>
    <mesh_term>Depressive Disorder, Major</mesh_term>
    <mesh_term>Mental Disorders</mesh_term>
    <mesh_term>Mood Disorders</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brexpiprazole</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>This trial was conducted in 837 participants at 51 trial sites in the following 5 countries:Germany,Hungary,Poland,Slovakia,andUnited States (US).A total of 1144 participants with major depressive disorder were screened for the trial, 837 enrolled into Phase A,394 were randomized into Phase B and 322 continued treatment with placebo+ADT in Phase A+</recruitment_details>
      <pre_assignment_details>Trial consisted of a screening phase and 3 phases. In phase A (8-week single-blind prospective treatment phase) and in phase A+ (Single-blind phase A Responder), there was single treatment group. In phase B (6-week double-blind randomization phase), there were 2 treatment groups. All Outcome Measures were assessed in phase B.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Phase A: All ADT (Antidepressant Therapy)</title>
          <description>Participants meeting entrance criteria who were experiencing a major depressive episode with a HAM-D17 Total Score of greater than or equal 18 at baseline were enrolled into an 8-week Single-blind Prospective Treatment Phase (Phase A). All participants received single-blind placebo plus an investigator determined, open-label, ADT. Once assigned to an ADT by the investigator, participants remained on the same ADT for the duration of the trial. At the Week 8 visit, the IWRS (Interactive web response system) determined based on scores entered by the investigator, whether a participant was a &quot;Phase A Responder&quot; or a &quot;Phase A Inadequate Responder.&quot;</description>
        </group>
        <group group_id="P2">
          <title>Phase B: Brexpiprazole + ADT</title>
          <description>Participants received brexpiprazole 2 mg and ADT orally once daily for 6 weeks.</description>
        </group>
        <group group_id="P3">
          <title>Phase B: Placebo + ADT</title>
          <description>Participants received matching placebo and ADT orally once daily for 6 weeks.</description>
        </group>
        <group group_id="P4">
          <title>Phase A +: ALL ADT</title>
          <description>Phase A+ included participants who met criteria for a response at the end of the prospective treatment phase (Week 8 visit of Phase A) and participants who were not suitable for randomization in Phase B per the judgment of the investigator or medical monitor. Treatment response in Phase A was determined at the Week 8 visit based on improvement or lack of improvement of the participant's depressive symptoms, which was confirmed by clinical criteria that prospectively defined response. Participant response was determined from clinical data that were entered into the IWRS at each visit. Participants in Phase A+ received single-blind placebo+ADT for an additional 6 weeks, for a total of 14 weeks, and attended visits at Weeks 11 and 14.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Phase A</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="837"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="716"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="121"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Participant Met Withdrawal Criteria</title>
              <participants_list>
                <participants group_id="P1" count="34"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="34"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="22"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Protocol deviation</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Participant withdrawn by investigator</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Phase B</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="192"/>
                <participants group_id="P3" count="202"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="177"/>
                <participants group_id="P3" count="196"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="15"/>
                <participants group_id="P3" count="6"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Participant Met Withdrawal Criteria</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lack of Efficacy</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="2"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Participant</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="8"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Phase A+</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="322"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="308"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="14"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Participant Met Withdrawal Criteria</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Participant</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="5"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="6"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Participant withdrawn by investigator</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Baseline measures are based on the participants from the Double-blind Randomization Phase</population>
      <group_list>
        <group group_id="B1">
          <title>Brexpiprazole + ADT</title>
          <description>Phase B: Brexpiprazole +Antidepressant therapy (ADT):&#xD;
Participants received brexpiprazole 2mg and ADT orally once daily for 6 weeks.</description>
        </group>
        <group group_id="B2">
          <title>Placebo + ADT</title>
          <description>Phase B: Placebo + Antidepressant therapy (ADT):&#xD;
Participants received matching placebo and ADT orally once daily for 6 weeks</description>
        </group>
        <group group_id="B3">
          <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="192"/>
            <count group_id="B2" value="202"/>
            <count group_id="B3" value="394"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="43.0" spread="12.7"/>
                    <measurement group_id="B2" value="42.7" spread="12.5"/>
                    <measurement group_id="B3" value="42.9" spread="12.6"/>
                  </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="147"/>
                    <measurement group_id="B2" value="144"/>
                    <measurement group_id="B3" value="291"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="45"/>
                    <measurement group_id="B2" value="58"/>
                    <measurement group_id="B3" value="103"/>
                  </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>Hispanic or Latino</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Not Hispanic or Latino</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="181"/>
                    <measurement group_id="B2" value="192"/>
                    <measurement group_id="B3" value="373"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Unknown</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Hungary</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="16"/>
                    <measurement group_id="B2" value="16"/>
                    <measurement group_id="B3" value="32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="100"/>
                    <measurement group_id="B2" value="106"/>
                    <measurement group_id="B3" value="206"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Poland</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="26"/>
                    <measurement group_id="B2" value="26"/>
                    <measurement group_id="B3" value="52"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Slovakia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="23"/>
                    <measurement group_id="B2" value="25"/>
                    <measurement group_id="B3" value="48"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Germany</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="27"/>
                    <measurement group_id="B2" value="29"/>
                    <measurement group_id="B3" value="56"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in the Montgomery-Asberg Depression</title>
        <description>To assess the change in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score from Baseline (End of Phase A [Week 8]) to Week 14. The MADRS was utilized as the primary efficacy assessment of the participant's level of depression and was administered utilizing the Structured Interview Guide for the MADRS (SIGMA). The MADRS consisted of 10 items each with 7 defined grades of severity. The rater decided whether the rating lied on predefined scale steps (0, 2, 4, 6) or between them (1, 3, 5). The 10 items were apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score was 60; 0, no symptom; 60, severely affected.</description>
        <time_frame>From baseline (end of Phase A [Week 8]) to week 14</time_frame>
        <population>The primary analysis was performed on Efficacy Sample which included all randomized participants who took at least one dose of trial medication in Phase B and who have both an end of Phase A (Week 8) and at least one post-randomization MADRS Total Score during Phase B.</population>
        <group_list>
          <group group_id="O1">
            <title>Brexpiprazole + ADT</title>
            <description>Phase B: Brexpiprazole +Antidepressant therapy (ADT):&#xD;
Participants received brexpiprazole 2mg and ADT orally once daily for 6 weeks.</description>
          </group>
          <group group_id="O2">
            <title>Placebo + ADT</title>
            <description>Phase B: Placebo + Antidepressant therapy (ADT):&#xD;
Participants received matching placebo and ADT orally once daily for 6 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Change in the Montgomery-Asberg Depression</title>
          <description>To assess the change in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score from Baseline (End of Phase A [Week 8]) to Week 14. The MADRS was utilized as the primary efficacy assessment of the participant's level of depression and was administered utilizing the Structured Interview Guide for the MADRS (SIGMA). The MADRS consisted of 10 items each with 7 defined grades of severity. The rater decided whether the rating lied on predefined scale steps (0, 2, 4, 6) or between them (1, 3, 5). The 10 items were apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score was 60; 0, no symptom; 60, severely affected.</description>
          <population>The primary analysis was performed on Efficacy Sample which included all randomized participants who took at least one dose of trial medication in Phase B and who have both an end of Phase A (Week 8) and at least one post-randomization MADRS Total Score during Phase B.</population>
          <units>Units on a scale</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="191"/>
                <count group_id="O2" value="202"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-10.4" spread="0.63"/>
                    <measurement group_id="O2" value="-8.07" spread="0.61"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Statistical Analysis at Week 14</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0074</p_value>
            <method>Mixed Models Analysis</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-2.30</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-3.97</ci_lower_limit>
            <ci_upper_limit>-0.62</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in the Sheehan Disability Scale (SDS) From Baseline to End of Treatment</title>
        <description>To assess the change in the Sheehan Disability Scale (SDS) Score (the mean of 3 individual item scores) from Baseline (End of Phase A [Week 8]) to Week 14 (End of Phase B). SDS was a 3-item clinician-rated questionnaire used to evaluate impairments in the domains of work, social life, and family life/home responsibility. Each item was scored using a scale of 0 to 10 (a higher score indicates symptoms have disrupted work, social life, and family life/home responsibility extremely). The maximum total score was 30; 0 = not at all, to 30 = extremely.</description>
        <time_frame>From baseline (end of Phase A [Week 8]) to week 14</time_frame>
        <population>The primary analysis was performed on Efficacy Sample which included all randomized participants who took at least one dose of trial medication in Phase B and who have both an end of Phase A (Week 8) and at least one post-randomization MADRS Total Score during Phase B.</population>
        <group_list>
          <group group_id="O1">
            <title>Brexpiprazole + ADT</title>
            <description>Phase B: Brexpiprazole +Antidepressant therapy (ADT):&#xD;
Participants received brexpiprazole 2mg and ADT orally once daily for 6 weeks.</description>
          </group>
          <group group_id="O2">
            <title>Placebo + ADT</title>
            <description>Phase B: Placebo + Antidepressant therapy (ADT):&#xD;
Participants received matching placebo and ADT orally once daily for 6 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Change in the Sheehan Disability Scale (SDS) From Baseline to End of Treatment</title>
          <description>To assess the change in the Sheehan Disability Scale (SDS) Score (the mean of 3 individual item scores) from Baseline (End of Phase A [Week 8]) to Week 14 (End of Phase B). SDS was a 3-item clinician-rated questionnaire used to evaluate impairments in the domains of work, social life, and family life/home responsibility. Each item was scored using a scale of 0 to 10 (a higher score indicates symptoms have disrupted work, social life, and family life/home responsibility extremely). The maximum total score was 30; 0 = not at all, to 30 = extremely.</description>
          <population>The primary analysis was performed on Efficacy Sample which included all randomized participants who took at least one dose of trial medication in Phase B and who have both an end of Phase A (Week 8) and at least one post-randomization MADRS Total Score during Phase B.</population>
          <units>Units on a scale</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="187"/>
                <count group_id="O2" value="200"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.63" spread="0.18"/>
                    <measurement group_id="O2" value="-1.41" spread="0.17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Statistical Analysis at Week 14</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.3331</p_value>
            <method>Mixed Models Analysis</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-0.22</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.66</ci_lower_limit>
            <ci_upper_limit>0.23</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From End of Phase A to End of Phase B in MADRS Total Score for the Subpopulation With &lt;25% Improvement From Baseline of Phase A to End of Phase A in MADRS Total Score</title>
        <description>To assess the change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in MADRS Total Score for the subpopulation with &lt; 25% improvement from baseline of Phase A (Week 0) to end of Phase A (Week 8) in MADRS Total Score. The MADRS was utilized as the primary efficacy assessment of the participant's level of depression and was administered utilizing the Structured Interview Guide for the MADRS (SIGMA). The MADRS consisted of 10 items each with 7 defined grades of severity. The 10 items were apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score was 60; 0, no symptom; 60, severely affected.</description>
        <time_frame>From baseline (end of Phase A [Week 8]) to week 14</time_frame>
        <population>Subpopulation of &lt;25% Improvement Sample: Comprised of all participants in the Efficacy Sample who had &lt;25% improvement at the end of Phase A in MADRS Total Score.</population>
        <group_list>
          <group group_id="O1">
            <title>Brexpiprazole + ADT</title>
            <description>Phase B: Brexpiprazole +Antidepressant therapy (ADT):&#xD;
Participants received brexpiprazole 2mg and ADT orally once daily for 6 weeks.</description>
          </group>
          <group group_id="O2">
            <title>Placebo + ADT</title>
            <description>Phase B: Placebo + Antidepressant therapy (ADT):&#xD;
Participants received matching placebo and ADT orally once daily for 6 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Change From End of Phase A to End of Phase B in MADRS Total Score for the Subpopulation With &lt;25% Improvement From Baseline of Phase A to End of Phase A in MADRS Total Score</title>
          <description>To assess the change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in MADRS Total Score for the subpopulation with &lt; 25% improvement from baseline of Phase A (Week 0) to end of Phase A (Week 8) in MADRS Total Score. The MADRS was utilized as the primary efficacy assessment of the participant's level of depression and was administered utilizing the Structured Interview Guide for the MADRS (SIGMA). The MADRS consisted of 10 items each with 7 defined grades of severity. The 10 items were apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score was 60; 0, no symptom; 60, severely affected.</description>
          <population>Subpopulation of &lt;25% Improvement Sample: Comprised of all participants in the Efficacy Sample who had &lt;25% improvement at the end of Phase A in MADRS Total Score.</population>
          <units>Units on a scale</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="161"/>
                <count group_id="O2" value="158"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-11.1" spread="0.71"/>
                    <measurement group_id="O2" value="-8.87" spread="0.71"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Statistical Analysis at Week 14</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0263</p_value>
            <method>Mixed Models Analysis</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-2.25</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-4.23</ci_lower_limit>
            <ci_upper_limit>-0.27</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From End of Phase A to End of Phase B in MADRS Total Score for the Subpopulations With Anxious Distress as Specified in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V).</title>
        <description>To assess the change from end of Phase A (Week 8) to end of Phase B (Week 14) in MADRS Total Score for the subpopulations with anxious distress as specified in DSM-V. The MADRS was utilized as the primary efficacy assessment of the participant's level of depression and was administered utilizing the Structured Interview Guide for the MADRS (SIGMA). The MADRS consisted of 10 items each with 7 defined grades of severity. The 10 items were apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score was 60; 0, no symptom; 60, severely affected.</description>
        <time_frame>From baseline (end of Phase A [Week 8]) to week 14</time_frame>
        <population>Subpopulation of Anxious Distress Sample: Comprised of all participants in the Efficacy Sample who had anxious distress as specified in DSM-V.</population>
        <group_list>
          <group group_id="O1">
            <title>Brexpiprazole + ADT</title>
            <description>Phase B: Brexpiprazole +Antidepressant therapy (ADT):&#xD;
Participants received brexpiprazole 2mg and ADT orally once daily for 6 weeks.</description>
          </group>
          <group group_id="O2">
            <title>Placebo + ADT</title>
            <description>Phase B: Placebo + Antidepressant therapy (ADT):&#xD;
Participants received matching placebo and ADT orally once daily for 6 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Change From End of Phase A to End of Phase B in MADRS Total Score for the Subpopulations With Anxious Distress as Specified in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V).</title>
          <description>To assess the change from end of Phase A (Week 8) to end of Phase B (Week 14) in MADRS Total Score for the subpopulations with anxious distress as specified in DSM-V. The MADRS was utilized as the primary efficacy assessment of the participant's level of depression and was administered utilizing the Structured Interview Guide for the MADRS (SIGMA). The MADRS consisted of 10 items each with 7 defined grades of severity. The 10 items were apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score was 60; 0, no symptom; 60, severely affected.</description>
          <population>Subpopulation of Anxious Distress Sample: Comprised of all participants in the Efficacy Sample who had anxious distress as specified in DSM-V.</population>
          <units>Units on a scale</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="124"/>
                <count group_id="O2" value="124"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-11.8" spread="0.81"/>
                    <measurement group_id="O2" value="-8.87" spread="0.81"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Statistical Analysis at Week 14</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0099</p_value>
            <method>Mixed Models Analysis</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-2.98</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-5.24</ci_lower_limit>
            <ci_upper_limit>-0.72</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Participants were assessed for the occurrence of adverse events (AEs) once the participant signed informed consent form through completion of the trial; up to 14-weeks after the participant entered the trial and actively monitored up to 30 (+2) days after their last dose of investigational medicinal product (this could be up to 22 weeks depending on duration of trial participation).</time_frame>
      <desc>Safety sample comprised of randomized participants in Phase B who received at least one dose of double-blind trial medication. No adverse events were assessed or collected from Phase A or A+ participants as those phases are single-blind, non-randomized, monotherapy treatment periods of the study and are outside of the pre-specified definition of the safety sample per the trial design.</desc>
      <group_list>
        <group group_id="E1">
          <title>Brexpiprazole + ADT</title>
          <description>Phase B: Brexpiprazole +Antidepressant therapy (ADT):&#xD;
Participants received brexpiprazole 2mg and ADT orally once daily for 6 weeks.</description>
        </group>
        <group group_id="E2">
          <title>Placebo + ADT</title>
          <description>Phase B: Placebo + Antidepressant therapy (ADT):&#xD;
Participants received matching placebo and ADT orally once daily for 6 weeks</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (19.0)</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="192"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="202"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="192"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="202"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="192"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="202"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (19.0)</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="49" subjects_at_risk="192"/>
                <counts group_id="E2" subjects_affected="35" subjects_at_risk="202"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Upper Respiratory Tract Infection</sub_title>
                <counts group_id="E1" events="11" subjects_affected="10" subjects_at_risk="192"/>
                <counts group_id="E2" events="11" subjects_affected="10" subjects_at_risk="202"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Weight Increased</sub_title>
                <counts group_id="E1" events="10" subjects_affected="10" subjects_at_risk="192"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="202"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Akathisia</sub_title>
                <counts group_id="E1" events="17" subjects_affected="16" subjects_at_risk="192"/>
                <counts group_id="E2" events="12" subjects_affected="10" subjects_at_risk="202"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="7" subjects_affected="7" subjects_at_risk="192"/>
                <counts group_id="E2" events="24" subjects_affected="15" subjects_at_risk="202"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Restlessness</sub_title>
                <counts group_id="E1" events="16" subjects_affected="16" subjects_at_risk="192"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="202"/>
              </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>The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Global Medical Affairs</name_or_title>
      <organization>Otsuka Pharmaceutical Development and Commercialization, Inc.</organization>
      <phone>800 562-3974</phone>
    </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/NCT02196506
org study id: 331-13-214
nct id: NCT02196506
lead sponsor: 
collaborator: 
has dmc: No
The purpose of this study is to assess the tolerability, safety, and efficacy of
      brexpiprazole (2.0 mg/day) as adjunctive therapy in adult subjects with a diagnosis of MDD
      with and without anxious distress
The introduction of atypical antipsychotics has created a renewed interest in adjunctive
      therapy for MDD, particularly for treatment-resistant MDD. Several atypical antipsychotics
      have been shown to enhance the response to ADT. This is a phase 3, multicenter, randomized,
      double-blind, placebo-controlled, fixed-dose trial designed to assess the safety and efficacy
      of brexpiprazole (2.0 mg/day) as adjunctive therapy to an assigned open-label ADT in
      depressed subjects with and without anxious distress.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Change in the Montgomery-Asberg Depression
time frame: From baseline (end of Phase A [Week 8]) to week 14
description: To assess the change in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score from Baseline (End of Phase A [Week 8]) to Week 14. The MADRS was utilized as the primary efficacy assessment of the participant's level of depression and was administered utilizing the Structured Interview Guide for the MADRS (SIGMA). The MADRS consisted of 10 items each with 7 defined grades of severity. The rater decided whether the rating lied on predefined scale steps (0, 2, 4, 6) or between them (1, 3, 5). The 10 items were apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score was 60; 0, no symptom; 60, severely affected.
measure: Change in the Sheehan Disability Scale (SDS) From Baseline to End of Treatment
time frame: From baseline (end of Phase A [Week 8]) to week 14
description: To assess the change in the Sheehan Disability Scale (SDS) Score (the mean of 3 individual item scores) from Baseline (End of Phase A [Week 8]) to Week 14 (End of Phase B). SDS was a 3-item clinician-rated questionnaire used to evaluate impairments in the domains of work, social life, and family life/home responsibility. Each item was scored using a scale of 0 to 10 (a higher score indicates symptoms have disrupted work, social life, and family life/home responsibility extremely). The maximum total score was 30; 0 = not at all, to 30 = extremely.
measure: Change From End of Phase A to End of Phase B in MADRS Total Score for the Subpopulation With <25% Improvement From Baseline of Phase A to End of Phase A in MADRS Total Score
time frame: From baseline (end of Phase A [Week 8]) to week 14
description: To assess the change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in MADRS Total Score for the subpopulation with < 25% improvement from baseline of Phase A (Week 0) to end of Phase A (Week 8) in MADRS Total Score. The MADRS was utilized as the primary efficacy assessment of the participant's level of depression and was administered utilizing the Structured Interview Guide for the MADRS (SIGMA). The MADRS consisted of 10 items each with 7 defined grades of severity. The 10 items were apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score was 60; 0, no symptom; 60, severely affected.
measure: Change From End of Phase A to End of Phase B in MADRS Total Score for the Subpopulations With Anxious Distress as Specified in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V).
time frame: From baseline (end of Phase A [Week 8]) to week 14
description: To assess the change from end of Phase A (Week 8) to end of Phase B (Week 14) in MADRS Total Score for the subpopulations with anxious distress as specified in DSM-V. The MADRS was utilized as the primary efficacy assessment of the participant's level of depression and was administered utilizing the Structured Interview Guide for the MADRS (SIGMA). The MADRS consisted of 10 items each with 7 defined grades of severity. The 10 items were apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score was 60; 0, no symptom; 60, severely affected.
arm group label: Brexpiprazole + ADT
arm group type: Experimental
description: Brexpiprazole + ADT
arm group label: Placebo + ADT
arm group type: Placebo Comparator
description: Placebo + ADT
intervention type: Drug
intervention name: Placebo + ADT
description: Placebo + ADT Placebo + FDA Approved Antidepressant (ADT)
arm group label: Placebo + ADT
intervention type: Drug
intervention name: Brexpiprazole +ADT
description: Brexpiprazole + ADT Tablet, Oral, 2mg brexpiprazole and FDA Approved Antidepressant (ADT)
arm group label: Brexpiprazole + ADT
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Claudette Brewer
role: Study Director
affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc.
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country: Germany
country: Hungary
country: Poland
country: Slovakia
country: United States
responsible party type: Sponsor
mesh term: Depression
mesh term: Depressive Disorder
mesh term: Depressive Disorder, Major
mesh term: Mental Disorders
mesh term: Mood Disorders
mesh term: Brexpiprazole
participant flow: 
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reported events: 
certain agreements: 
point of contact: 