<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/NCT01727726</url>
  </required_header>
  <id_info>
    <org_study_id>331-12-282</org_study_id>
    <nct_id>NCT01727726</nct_id>
  </id_info>
  <brief_title>A Study of Flexible-dose Brexpiprazole as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder, the Delphinus Trial</brief_title>
  <official_title>A Phase 3, Multicenter, Randomized, Double-blind, Placebo and Active Comparator Controlled Trial of Flexible-dose Brexpiprazole (OPC-34712) as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder, the Delphinus Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Otsuka Pharmaceutical Development &amp; Commercialization, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Otsuka Pharmaceutical Development &amp; Commercialization, Inc.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      To compare the efficacy of brexpiprazole (flexible dose) with placebo as adjunctive therapy&#xD;
      to an assigned open label antidepressant therapy (ADT) in the proposed subject population&#xD;
      with MDD.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a trial designed to assess the safety and efficacy of brexpiprazole (flexible dose)&#xD;
      as adjunctive therapy to an assigned known anti-depressant in depressed subjects. The trial&#xD;
      consists of a continuous 18-week double-blind treatment period with a 30-day follow-up.&#xD;
      Subjects who complete all trial visits through the Week 18 visit may be offered entry into an&#xD;
      optional open-label rollover trial.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>December 2012</start_date>
  <completion_date type="Actual">November 10, 2016</completion_date>
  <primary_completion_date type="Actual">October 17, 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>Montgomery Asberg Depression Rating Scale (MADRS)</measure>
    <time_frame>Randomization Visit (week 8 or week 10) to End of Double-Blind Treatment (week 14 or week 16).</time_frame>
    <description>To determine the efficacy of brexpiprazole (flexible dose) with placebo as adjunctive therapy by assessment of MADRS total score. The MADRS depression rating scale was used to assess the subject's level of depression by utilizing the structured interview guide for the MADRS (SIGMA). The MADRS consisted of 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts and suicidal thoughts), each rated 0 to 6. The overall score ranged from 0 (symptoms absent) to 60 (severe depression). Lower score indicated decreased severity of depression.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Sheehan Disability Scale (SDS)</measure>
    <time_frame>Randomization Visit (week 8 or week 10) to End of Double-Blind Treatment (week 14 or week 16).</time_frame>
    <description>To evaluate mean change in SDS score from randomization (End of Phase A) to end of Phase B. The Sheehan Disability Scale is a measurement of functional disability and impairment due to psychiatric symptoms. The SDS is a visual analogue scale that uses spatio-visual, numeric, and verbal descriptive anchors simultaneously to assess disability across the three domains ( work/social life/family life/home responsibilities). The number most representative of how much each area was disrupted by symptoms is marked along the line from 0 = not at all, to 10 = extremely. Scores of 5 and above are associated with significant functional impairment. Additionally, SDS included 2 questions related to productivity losses due to the psychiatric symptoms and impairment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From End of Phase A in MADRS Total Score for Trial Week 2 and Week 4.</measure>
    <time_frame>Change from baseline to week 2 and week 4 in Phase B (week 10/12 and week 12/14)</time_frame>
    <description>Change from end of Phase A in MADRS Total Score. The MADRS was used to assess the subject's level of depression by utilizing the structured interview guide for the MADRS (SIGMA). The MADRS depression rating scale was used to assess the subject's level of depression by utilizing the structured interview guide for the MADRS (SIGMA). The MADRS consisted of 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts and suicidal thoughts), each rated 0 to 6. The overall score ranged from 0 (symptoms absent) to 60 (severe depression). Lower score indicated decreased severity of depression.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Global Impression Score</measure>
    <time_frame>From randomization to Phase B week 6 (14/16 weeks after randomization).</time_frame>
    <description>Mean change from end of Phase A in Clinical Global Impression - Severity of Illness scale (CGI-S) score and Improvement scale (CGI-I) during double-blind randomized Phase B treatment. CGI-S score assessed how mentally ill the patient was at that time. CGI-S score is calculated from 0 to 7 (0 indicates not assessed 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and7 indicated among the most extremely ill patient). CGI-I score is compared to his/her condition at baseline, how much has the patient changed. CGI-I score is calculated from 0 to 7 (0 indicates not assessed and 7 indicates very much worse).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MADRS Response at Week 6</measure>
    <time_frame>Phase B week 6 (14/16 weeks after randomization).</time_frame>
    <description>MADRS Response Rate, where response was defined as 50% reduction in MADRS Total Score, during double-blind randomized Phase B treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With MADRS</measure>
    <time_frame>Phase B week 6 (14/16 weeks after randomization).</time_frame>
    <description>MADRS Remission Rate, where remission was defined as MADRS Total Score ≤ 10 and 50% reduction in MADRS Total Score, for every trial week visit during double-blind randomized Phase B treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CGI-I Response Rate</measure>
    <time_frame>Phase B week 6 (14/16 weeks after randomization).</time_frame>
    <description>CGI-I Response rate, where response was defined as a CGI-I score of 1 or 2 (very much improved or much improved), during double-blind randomized Phase B treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Adverse Events</measure>
    <time_frame>From screening (Day -28 to Day-1) upto post treatment follow-up.</time_frame>
    <description>To evaluate the safety and tolerability of brexpiprazole (flexible dose) as adjunctive therapy to ADT in the proposed subject population with MDD as AE variables.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sheehan Disability Scale (SDS) Individual Item Scores.</measure>
    <time_frame>Randomization Visit (week 8 or week 10) to End of Double-Blind Treatment (week 14 or week 16).</time_frame>
    <description>To evaluate mean change in SDS score from randomization (End of Phase A) to end of Phase B. The Sheehan Disability Scale (a self rated questionnaire) was used for measurement of functional disability and impairment due to psychiatric symptoms. The SDS is a visual analogue scale that uses spatio-visual, numeric, and verbal descriptive anchors simultaneously to assess disability across the three domains (work/school work, social life/leisure activities and family life/home responsibilities). All domains were rated on a score scale ranged from 0 (no impairment) to 10 (most severe). Score of 5 and above indicated significant functional impairment. A total score was addition of the 3 individual scores and the total score ranged from 0 (no impairment) to 30 (most severe).</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">2182</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>Placebo + ADT</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Matching Placebo and assigned ADT</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Brexpiprazole + ADT</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Brexpiprazole, flexible dose and assigned ADT</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Seroquel XR + ADT</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Seroquel XR, flexible dose and assigned ADT</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Brexpiprazole</intervention_name>
    <description>tablet/capsule</description>
    <arm_group_label>Brexpiprazole + ADT</arm_group_label>
    <other_name>OPC-34712</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Seroquel XR</intervention_name>
    <description>tablet/capsule</description>
    <arm_group_label>Seroquel XR + ADT</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>tablet/capsule</description>
    <arm_group_label>Placebo + ADT</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male and female outpatients 18 to 65 years of age, inclusive, at the time of informed&#xD;
             consent.&#xD;
&#xD;
          -  Subjects with both a diagnosis of MDD, and in a current major depressive episode, as&#xD;
             defined by DSM-IV-TR criteria&#xD;
&#xD;
          -  Subjects willing to discontinue all prohibited psychotropic medications to meet&#xD;
             protocol-required washouts prior to and during the trial period.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Females who are breast-feeding and/or who have a positive pregnancy test result during&#xD;
             screening prior to receiving trial medication&#xD;
&#xD;
          -  Subject has a current Axis I (DSM-IV-TR) diagnosis of: dementia, Schizophrenia,&#xD;
             Bipolar, Eating disorder , Obsessive-compulsive disorder, Panic disorder,&#xD;
             Posttraumatic stress disorder&#xD;
&#xD;
          -  Subjects experiencing hallucinations, delusions or any psychotic symptomatology in the&#xD;
             current major depressive episode.&#xD;
&#xD;
          -  Subjects who have met DSM-IV-TR criteria for substance abuse or dependence within the&#xD;
             past 180 days&#xD;
&#xD;
          -  Subjects currently treated with insulin for diabetes.&#xD;
&#xD;
          -  Subjects with uncontrolled hypertension&#xD;
&#xD;
          -  Subjects with known ischemic heart disease or history of myocardial infarction,&#xD;
             congestive heart failure, angioplasty, stenting, or coronary artery bypass Surgery&#xD;
&#xD;
          -  Subjects with a positive drug screen for cocaine, marijuana, or other illicit drugs&#xD;
&#xD;
          -  Inability to swallow tablets or tolerate oral medication&#xD;
&#xD;
          -  Abnormal laboratory test results, vital signs and ECG results&#xD;
&#xD;
          -  Subjects who previously participated in any prior brexpiprazole clinical trial.&#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>Mary Hobart</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>Phoenix</city>
        <state>Arizona</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Little Rock</city>
        <state>Arkansas</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Bellflower</city>
        <state>California</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>Costa Mesa</city>
        <state>California</state>
        <zip>92626</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Glendale</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Irvine</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Redlands</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>San Diego</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Upland</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Gainesville</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Jacksonville Beach</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Jacksonville</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Leesburg</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Melbourne</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33015</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33145</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Oakland Park</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Orange City</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>Decatur</city>
        <state>Georgia</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Lake Charles</city>
        <state>Louisiana</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>Belmont</city>
        <state>Massachusetts</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Roslindale</city>
        <state>Massachusetts</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Watertown</city>
        <state>Massachusetts</state>
        <zip>02472</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Creve Coeur</city>
        <state>Missouri</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Lebanon</city>
        <state>New Hampshire</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10003</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10168</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Dayton</city>
        <state>Ohio</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Edmond</city>
        <state>Oklahoma</state>
        <zip>73013</zip>
        <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>Dallas</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>Herndon</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>Bellevue</city>
        <state>Washington</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Kirkland</city>
        <state>Washington</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>Brown Deer</city>
        <state>Wisconsin</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Penticton</city>
        <state>British Columbia</state>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Dijon</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Douai</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Elancourt</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Jarnac</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Montepellier</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Orvault</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Achim</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Mittweida</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Stralsund</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Wuerzburg</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Belchatow</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Bydgoszcz</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Gdynia</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Kielce</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Lublin</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Tuszyn</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Wroclaw</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Arkhangelsk</city>
        <zip>163530</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Moscow</city>
        <zip>107076</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Moscow</city>
        <zip>127083</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Saint-Petersburg</city>
        <zip>190020</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Saint-Petersburg</city>
        <zip>191040</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Saint-Petersburg</city>
        <zip>192019</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Saint-Petersburg</city>
        <zip>199034</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Smolensk</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Tonnelniy</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Belgrade</city>
        <zip>11000</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Belgrade</city>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Kragujevac</city>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Nis</city>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Novi Knezevac</city>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
    <country>France</country>
    <country>Germany</country>
    <country>Poland</country>
    <country>Russian Federation</country>
    <country>Serbia</country>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2018</verification_date>
  <study_first_submitted>October 31, 2012</study_first_submitted>
  <study_first_submitted_qc>November 12, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 16, 2012</study_first_posted>
  <results_first_submitted>January 3, 2018</results_first_submitted>
  <results_first_submitted_qc>May 10, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">June 8, 2018</results_first_posted>
  <last_update_submitted>May 10, 2018</last_update_submitted>
  <last_update_submitted_qc>May 10, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">June 8, 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>
  <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>Quetiapine Fumarate</mesh_term>
    <mesh_term>Brexpiprazole</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Trial was conducted at 75 trial sites in 7 countries (United States, Russia, Poland, France, Serbia,Germany &amp; Canada). Phase A non-responders entered Phase B (503 subjects randomized in 2:2:1 (197+100+206) ratio - brexpiprazole/Seroquel extended release tablets/placebo +ADT).</recruitment_details>
      <pre_assignment_details>Screening period ranged from a minimum of 7 days to a maximum of 28 days and began when informed consent was signed. The purpose of the screening period was to assess eligibility criteria at 1 or more visits (as necessary to complete screening assessments) and to washout (minimum of 24 hours) prohibited concomitant pharmacotherapy, if applicable.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Brexpiprazole + ADT</title>
          <description>Brexpiprazole, flexible dose and assigned ADT&#xD;
Brexpiprazole: tablet/capsule at 1 mg, 2 mg, 3 mg.</description>
        </group>
        <group group_id="P2">
          <title>Seroquel XR + ADT</title>
          <description>Seroquel XR, flexible dose and assigned ADT&#xD;
Seroquel XR: tablet/capsule at 50 mg, 150 mg, 300 mg.</description>
        </group>
        <group group_id="P3">
          <title>Placebo + ADT</title>
          <description>Matching Placebo and assigned ADT&#xD;
Placebo: tablet/capsule</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="197"/>
                <participants group_id="P2" count="100"/>
                <participants group_id="P3" count="206"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="171"/>
                <participants group_id="P2" count="86"/>
                <participants group_id="P3" count="186"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="26"/>
                <participants group_id="P2" count="14"/>
                <participants group_id="P3" count="20"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Randomized sample comprised all subjects who were randomized in Phase B. Subjects were considered randomized when they were assigned a treatment number by IVRS at the end of Phase A. A subject receiving IMP outside of the IVRS was not considered randomized, but safety was reported.</population>
      <group_list>
        <group group_id="B1">
          <title>Brexpiprazole + ADT</title>
          <description>Brexpiprazole, flexible dose and assigned ADT&#xD;
Brexpiprazole: tablet/capsule</description>
        </group>
        <group group_id="B2">
          <title>Seroquel XR + ADT</title>
          <description>Seroquel XR, flexible dose and assigned ADT&#xD;
Seroquel XR: tablet/capsule</description>
        </group>
        <group group_id="B3">
          <title>Placebo + ADT</title>
          <description>Matching Placebo and assigned ADT&#xD;
Placebo: tablet/capsule</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="197"/>
            <count group_id="B2" value="100"/>
            <count group_id="B3" value="206"/>
            <count group_id="B4" value="503"/>
          </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="197"/>
                    <measurement group_id="B2" value="100"/>
                    <measurement group_id="B3" value="206"/>
                    <measurement group_id="B4" value="503"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 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_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="43.6" spread="11.5"/>
                    <measurement group_id="B2" value="44.6" spread="11.6"/>
                    <measurement group_id="B3" value="41.8" spread="11.7"/>
                    <measurement group_id="B4" value="43" spread="11.7"/>
                  </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="128"/>
                    <measurement group_id="B2" value="66"/>
                    <measurement group_id="B3" value="149"/>
                    <measurement group_id="B4" value="343"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="69"/>
                    <measurement group_id="B2" value="34"/>
                    <measurement group_id="B3" value="57"/>
                    <measurement group_id="B4" value="160"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Montgomery Asberg Depression Rating Scale (MADRS)</title>
        <description>To determine the efficacy of brexpiprazole (flexible dose) with placebo as adjunctive therapy by assessment of MADRS total score. The MADRS depression rating scale was used to assess the subject's level of depression by utilizing the structured interview guide for the MADRS (SIGMA). The MADRS consisted of 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts and suicidal thoughts), each rated 0 to 6. The overall score ranged from 0 (symptoms absent) to 60 (severe depression). Lower score indicated decreased severity of depression.</description>
        <time_frame>Randomization Visit (week 8 or week 10) to End of Double-Blind Treatment (week 14 or week 16).</time_frame>
        <population>All subjects in the Safety Sample who have an end of Phase A (ie, Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.</population>
        <group_list>
          <group group_id="O1">
            <title>Brexpiprazole + ADT</title>
            <description>Brexpiprazole, flexible dose and assigned ADT&#xD;
Brexpiprazole: tablet/capsule</description>
          </group>
          <group group_id="O2">
            <title>Seroquel XR + ADT</title>
            <description>Seroquel XR, flexible dose and assigned ADT&#xD;
Seroquel XR: tablet/capsule</description>
          </group>
          <group group_id="O3">
            <title>Placebo + ADT</title>
            <description>Matching Placebo and assigned ADT&#xD;
Placebo: tablet/capsule</description>
          </group>
        </group_list>
        <measure>
          <title>Montgomery Asberg Depression Rating Scale (MADRS)</title>
          <description>To determine the efficacy of brexpiprazole (flexible dose) with placebo as adjunctive therapy by assessment of MADRS total score. The MADRS depression rating scale was used to assess the subject's level of depression by utilizing the structured interview guide for the MADRS (SIGMA). The MADRS consisted of 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts and suicidal thoughts), each rated 0 to 6. The overall score ranged from 0 (symptoms absent) to 60 (severe depression). Lower score indicated decreased severity of depression.</description>
          <population>All subjects in the Safety Sample who have an end of Phase A (ie, Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in 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="99"/>
                <count group_id="O3" value="205"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-6.04" spread="0.43"/>
                    <measurement group_id="O2" value="-4.86" spread="0.57"/>
                    <measurement group_id="O3" value="-4.57" spread="0.41"/>
                  </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>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0078</p_value>
            <method>Cochran-Mantel-Haenszel</method>
            <method_desc>Mixed-model repeated measures (MMRM)</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-1.48</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-2.56</ci_lower_limit>
            <ci_upper_limit>-0.39</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.6642</p_value>
            <method>Cochran-Mantel-Haenszel</method>
            <method_desc>Mixed-model repeated measures (MMRM)</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-0.30</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-1.63</ci_lower_limit>
            <ci_upper_limit>1.04</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Sheehan Disability Scale (SDS)</title>
        <description>To evaluate mean change in SDS score from randomization (End of Phase A) to end of Phase B. The Sheehan Disability Scale is a measurement of functional disability and impairment due to psychiatric symptoms. The SDS is a visual analogue scale that uses spatio-visual, numeric, and verbal descriptive anchors simultaneously to assess disability across the three domains ( work/social life/family life/home responsibilities). The number most representative of how much each area was disrupted by symptoms is marked along the line from 0 = not at all, to 10 = extremely. Scores of 5 and above are associated with significant functional impairment. Additionally, SDS included 2 questions related to productivity losses due to the psychiatric symptoms and impairment.</description>
        <time_frame>Randomization Visit (week 8 or week 10) to End of Double-Blind Treatment (week 14 or week 16).</time_frame>
        <population>All subjects in the Safety Sample who have an end of Phase A (ie, Week 8 or 10) value and at least one post-randomization efficacy evaluation for SDS Score in Phase B.</population>
        <group_list>
          <group group_id="O1">
            <title>Brexpiprazole + ADT</title>
            <description>Brexpiprazole, flexible dose and assigned ADT&#xD;
Brexpiprazole: tablet/capsule</description>
          </group>
          <group group_id="O2">
            <title>Seroquel XR + ADT</title>
            <description>Seroquel XR, flexible dose and assigned ADT&#xD;
Seroquel XR: tablet/capsule</description>
          </group>
          <group group_id="O3">
            <title>Placebo + ADT</title>
            <description>Matching Placebo and assigned ADT&#xD;
Placebo: tablet/capsule</description>
          </group>
        </group_list>
        <measure>
          <title>Sheehan Disability Scale (SDS)</title>
          <description>To evaluate mean change in SDS score from randomization (End of Phase A) to end of Phase B. The Sheehan Disability Scale is a measurement of functional disability and impairment due to psychiatric symptoms. The SDS is a visual analogue scale that uses spatio-visual, numeric, and verbal descriptive anchors simultaneously to assess disability across the three domains ( work/social life/family life/home responsibilities). The number most representative of how much each area was disrupted by symptoms is marked along the line from 0 = not at all, to 10 = extremely. Scores of 5 and above are associated with significant functional impairment. Additionally, SDS included 2 questions related to productivity losses due to the psychiatric symptoms and impairment.</description>
          <population>All subjects in the Safety Sample who have an end of Phase A (ie, Week 8 or 10) value and at least one post-randomization efficacy evaluation for SDS Score in 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="99"/>
                <count group_id="O3" value="205"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.97" spread="0.12"/>
                    <measurement group_id="O2" value="-0.32" spread="0.16"/>
                    <measurement group_id="O3" value="-0.74" spread="0.11"/>
                  </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>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.1334</p_value>
            <method>MMRM</method>
            <method_desc>Mixed-model repeated measures (MMRM)</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-0.23</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.52</ci_lower_limit>
            <ci_upper_limit>0.07</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0237</p_value>
            <method>MMRM</method>
            <method_desc>Mixed-model repeated measures (MMRM)</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>0.42</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.06</ci_lower_limit>
            <ci_upper_limit>0.78</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From End of Phase A in MADRS Total Score for Trial Week 2 and Week 4.</title>
        <description>Change from end of Phase A in MADRS Total Score. The MADRS was used to assess the subject's level of depression by utilizing the structured interview guide for the MADRS (SIGMA). The MADRS depression rating scale was used to assess the subject's level of depression by utilizing the structured interview guide for the MADRS (SIGMA). The MADRS consisted of 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts and suicidal thoughts), each rated 0 to 6. The overall score ranged from 0 (symptoms absent) to 60 (severe depression). Lower score indicated decreased severity of depression.</description>
        <time_frame>Change from baseline to week 2 and week 4 in Phase B (week 10/12 and week 12/14)</time_frame>
        <population>All subjects in the Safety Sample who have an end of Phase A (ie, Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.</population>
        <group_list>
          <group group_id="O1">
            <title>Brexpiprazole + ADT</title>
            <description>Brexpiprazole, flexible dose and assigned ADT&#xD;
Brexpiprazole: tablet/capsule</description>
          </group>
          <group group_id="O2">
            <title>Seroquel XR + ADT</title>
            <description>Seroquel XR, flexible dose and assigned ADT&#xD;
Seroquel XR: tablet/capsule</description>
          </group>
          <group group_id="O3">
            <title>Placebo + ADT</title>
            <description>Matching Placebo and assigned ADT&#xD;
Placebo: tablet/capsule</description>
          </group>
        </group_list>
        <measure>
          <title>Change From End of Phase A in MADRS Total Score for Trial Week 2 and Week 4.</title>
          <description>Change from end of Phase A in MADRS Total Score. The MADRS was used to assess the subject's level of depression by utilizing the structured interview guide for the MADRS (SIGMA). The MADRS depression rating scale was used to assess the subject's level of depression by utilizing the structured interview guide for the MADRS (SIGMA). The MADRS consisted of 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts and suicidal thoughts), each rated 0 to 6. The overall score ranged from 0 (symptoms absent) to 60 (severe depression). Lower score indicated decreased severity of depression.</description>
          <population>All subjects in the Safety Sample who have an end of Phase A (ie, Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in 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="99"/>
                <count group_id="O3" value="205"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Phase B Week 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="188"/>
                    <count group_id="O2" value="99"/>
                    <count group_id="O3" value="203"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-2.57" spread="0.32"/>
                    <measurement group_id="O2" value="-2.26" spread="0.41"/>
                    <measurement group_id="O3" value="-1.04" spread="0.31"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Phase B Week 4</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="178"/>
                    <count group_id="O2" value="94"/>
                    <count group_id="O3" value="192"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-4.39" spread="0.39"/>
                    <measurement group_id="O2" value="-3.30" spread="0.51"/>
                    <measurement group_id="O3" value="-3.22" spread="0.37"/>
                  </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>Phase B week 2</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0001</p_value>
            <method>MMRM</method>
            <method_desc>Mixed-model repeated measures (MMRM)</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-1.53</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-2.29</ci_lower_limit>
            <ci_upper_limit>-0.76</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Phase B Week 2</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0103</p_value>
            <method>MMRM</method>
            <method_desc>Mixed-model repeated measures (MMRM)</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-1.22</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-2.15</ci_lower_limit>
            <ci_upper_limit>-0.29</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Phase B week 4</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0185</p_value>
            <method>MMRM</method>
            <method_desc>Mixed-model repeated measures (MMRM)</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-1.17</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-2.15</ci_lower_limit>
            <ci_upper_limit>-0.20</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Phase B Week 4</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.8949</p_value>
            <method>MMRM</method>
            <method_desc>Mixed-model repeated measures (MMRM)</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-0.08</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-1.27</ci_lower_limit>
            <ci_upper_limit>1.11</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Clinical Global Impression Score</title>
        <description>Mean change from end of Phase A in Clinical Global Impression - Severity of Illness scale (CGI-S) score and Improvement scale (CGI-I) during double-blind randomized Phase B treatment. CGI-S score assessed how mentally ill the patient was at that time. CGI-S score is calculated from 0 to 7 (0 indicates not assessed 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and7 indicated among the most extremely ill patient). CGI-I score is compared to his/her condition at baseline, how much has the patient changed. CGI-I score is calculated from 0 to 7 (0 indicates not assessed and 7 indicates very much worse).</description>
        <time_frame>From randomization to Phase B week 6 (14/16 weeks after randomization).</time_frame>
        <population>All subjects in the Safety Sample who have an end of Phase A (ie, Week 8 or 10) value and at least one post-randomization efficacy evaluation for CGI-S score and CGI-I score in Phase B.</population>
        <group_list>
          <group group_id="O1">
            <title>Brexpiprazole + ADT</title>
            <description>Brexpiprazole, flexible dose and assigned ADT&#xD;
Brexpiprazole: tablet/capsule</description>
          </group>
          <group group_id="O2">
            <title>Seroquel XR + ADT</title>
            <description>Seroquel XR, flexible dose and assigned ADT&#xD;
Seroquel XR: tablet/capsule</description>
          </group>
          <group group_id="O3">
            <title>Placebo + ADT</title>
            <description>Matching Placebo and assigned ADT&#xD;
Placebo: tablet/capsule</description>
          </group>
        </group_list>
        <measure>
          <title>Clinical Global Impression Score</title>
          <description>Mean change from end of Phase A in Clinical Global Impression - Severity of Illness scale (CGI-S) score and Improvement scale (CGI-I) during double-blind randomized Phase B treatment. CGI-S score assessed how mentally ill the patient was at that time. CGI-S score is calculated from 0 to 7 (0 indicates not assessed 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and7 indicated among the most extremely ill patient). CGI-I score is compared to his/her condition at baseline, how much has the patient changed. CGI-I score is calculated from 0 to 7 (0 indicates not assessed and 7 indicates very much worse).</description>
          <population>All subjects in the Safety Sample who have an end of Phase A (ie, Week 8 or 10) value and at least one post-randomization efficacy evaluation for CGI-S score and CGI-I score in Phase B.</population>
          <units>Mean score</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="191"/>
                <count group_id="O2" value="99"/>
                <count group_id="O3" value="205"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>CGI-Severity of Illness Scale</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.98" spread="0.56"/>
                    <measurement group_id="O2" value="4.07" spread="0.58"/>
                    <measurement group_id="O3" value="4.02" spread="0.58"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CGI-Improvement Scale Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.55" spread="0.84"/>
                    <measurement group_id="O2" value="2.71" spread="0.87"/>
                    <measurement group_id="O3" value="2.74" spread="0.83"/>
                  </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>CGI-Severity of Illness Scale Score</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0350</p_value>
            <method>Cochran-Mantel-Haenszel</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-0.15</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.29</ci_lower_limit>
            <ci_upper_limit>-0.01</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>CGI-Severity of Illness Scale Score</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.5601</p_value>
            <method>Cochran-Mantel-Haenszel</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-0.05</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.22</ci_lower_limit>
            <ci_upper_limit>0.12</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>CGI-Improvement Scale Score</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0146</p_value>
            <method>Cochran-Mantel-Haenszel</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-0.19</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.35</ci_lower_limit>
            <ci_upper_limit>-0.04</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>CGI-Improvement Scale Score</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.7127</p_value>
            <method>Cochran-Mantel-Haenszel</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-0.04</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.23</ci_lower_limit>
            <ci_upper_limit>0.15</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>MADRS Response at Week 6</title>
        <description>MADRS Response Rate, where response was defined as 50% reduction in MADRS Total Score, during double-blind randomized Phase B treatment.</description>
        <time_frame>Phase B week 6 (14/16 weeks after randomization).</time_frame>
        <population>All subjects in the Safety Sample who have an end of Phase A (ie, Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.</population>
        <group_list>
          <group group_id="O1">
            <title>Brexpiprazole + ADT</title>
            <description>Brexpiprazole, flexible dose and assigned ADT&#xD;
Brexpiprazole: tablet/capsule</description>
          </group>
          <group group_id="O2">
            <title>Seroquel XR + ADT</title>
            <description>Seroquel XR, flexible dose and assigned ADT&#xD;
Seroquel XR: tablet/capsule</description>
          </group>
          <group group_id="O3">
            <title>Placebo + ADT</title>
            <description>Matching Placebo and assigned ADT&#xD;
Placebo: tablet/capsule</description>
          </group>
        </group_list>
        <measure>
          <title>MADRS Response at Week 6</title>
          <description>MADRS Response Rate, where response was defined as 50% reduction in MADRS Total Score, during double-blind randomized Phase B treatment.</description>
          <population>All subjects in the Safety Sample who have an end of Phase A (ie, Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="191"/>
                <count group_id="O2" value="99"/>
                <count group_id="O3" value="205"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20"/>
                    <measurement group_id="O2" value="8"/>
                    <measurement group_id="O3" value="14"/>
                  </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>Phase B Week 6</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.2242</p_value>
            <method>Cochran-Mantel-Haenszel</method>
            <param_type>Ratio of response rate</param_type>
            <param_value>1.49</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.78</ci_lower_limit>
            <ci_upper_limit>2.84</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Phase B Week 6</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.5998</p_value>
            <method>Cochran-Mantel-Haenszel</method>
            <param_type>Ratio of Response Rate</param_type>
            <param_value>1.26</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.53</ci_lower_limit>
            <ci_upper_limit>2.98</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With MADRS</title>
        <description>MADRS Remission Rate, where remission was defined as MADRS Total Score ≤ 10 and 50% reduction in MADRS Total Score, for every trial week visit during double-blind randomized Phase B treatment.</description>
        <time_frame>Phase B week 6 (14/16 weeks after randomization).</time_frame>
        <population>Number of subjects in the Safety Sample who had an end of Phase A (ie, Week 8 or 10) value and at least one post randomization efficacy evaluation for MADRS Total Score in Phase B.</population>
        <group_list>
          <group group_id="O1">
            <title>Brexpiprazole + ADT</title>
            <description>Brexpiprazole, flexible dose and assigned ADT&#xD;
Brexpiprazole: tablet/capsule</description>
          </group>
          <group group_id="O2">
            <title>Seroquel XR + ADT</title>
            <description>Seroquel XR, flexible dose and assigned ADT&#xD;
Seroquel XR: tablet/capsule</description>
          </group>
          <group group_id="O3">
            <title>Placebo + ADT</title>
            <description>Matching Placebo and assigned ADT&#xD;
Placebo: tablet/capsule</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With MADRS</title>
          <description>MADRS Remission Rate, where remission was defined as MADRS Total Score ≤ 10 and 50% reduction in MADRS Total Score, for every trial week visit during double-blind randomized Phase B treatment.</description>
          <population>Number of subjects in the Safety Sample who had an end of Phase A (ie, Week 8 or 10) value and at least one post randomization efficacy evaluation for MADRS Total Score in Phase B.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="191"/>
                <count group_id="O2" value="99"/>
                <count group_id="O3" value="205"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13"/>
                    <measurement group_id="O2" value="2"/>
                    <measurement group_id="O3" value="9"/>
                  </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>Phase B Week 6</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.3321</p_value>
            <method>Cochran-Mantel-Haenszel</method>
            <param_type>Ratio of Response Rate</param_type>
            <param_value>1.52</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>3.49</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Phase B Week 6</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.3917</p_value>
            <method>Cochran-Mantel-Haenszel</method>
            <param_type>Ratio of Response Rate</param_type>
            <param_value>0.51</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.11</ci_lower_limit>
            <ci_upper_limit>2.46</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>CGI-I Response Rate</title>
        <description>CGI-I Response rate, where response was defined as a CGI-I score of 1 or 2 (very much improved or much improved), during double-blind randomized Phase B treatment.</description>
        <time_frame>Phase B week 6 (14/16 weeks after randomization).</time_frame>
        <population>All subjects in the Safety Sample who have an end of Phase A (ie, Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.</population>
        <group_list>
          <group group_id="O1">
            <title>Brexpiprazole + ADT</title>
            <description>Brexpiprazole, flexible dose and assigned ADT&#xD;
Brexpiprazole: tablet/capsule</description>
          </group>
          <group group_id="O2">
            <title>Seroquel XR + ADT</title>
            <description>Seroquel XR, flexible dose and assigned ADT&#xD;
Seroquel XR: tablet/capsule</description>
          </group>
          <group group_id="O3">
            <title>Placebo + ADT</title>
            <description>Matching Placebo and assigned ADT&#xD;
Placebo: tablet/capsule</description>
          </group>
        </group_list>
        <measure>
          <title>CGI-I Response Rate</title>
          <description>CGI-I Response rate, where response was defined as a CGI-I score of 1 or 2 (very much improved or much improved), during double-blind randomized Phase B treatment.</description>
          <population>All subjects in the Safety Sample who have an end of Phase A (ie, Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="191"/>
                <count group_id="O2" value="99"/>
                <count group_id="O3" value="205"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="100"/>
                    <measurement group_id="O2" value="48"/>
                    <measurement group_id="O3" value="79"/>
                  </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>Phase B Week 6</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0032</p_value>
            <method>Cochran-Mantel-Haenszel</method>
            <param_type>Ratio of Response Rate</param_type>
            <param_value>1.35</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.10</ci_lower_limit>
            <ci_upper_limit>1.66</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Phase B Week 6</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0898</p_value>
            <method>Cochran-Mantel-Haenszel</method>
            <param_type>Ratio of Response Rate</param_type>
            <param_value>1.24</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.98</ci_lower_limit>
            <ci_upper_limit>1.59</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Adverse Events</title>
        <description>To evaluate the safety and tolerability of brexpiprazole (flexible dose) as adjunctive therapy to ADT in the proposed subject population with MDD as AE variables.</description>
        <time_frame>From screening (Day -28 to Day-1) upto post treatment follow-up.</time_frame>
        <population>Randomized subjects in Phase B who received at least one dose of double-blind trial medication as indicated on the dosing record.</population>
        <group_list>
          <group group_id="O1">
            <title>Brexpiprazole + ADT</title>
            <description>Brexpiprazole, flexible dose and assigned ADT&#xD;
Brexpiprazole: tablet/capsule</description>
          </group>
          <group group_id="O2">
            <title>Seroquel XR + ADT</title>
            <description>Seroquel XR, flexible dose and assigned ADT&#xD;
Seroquel XR: tablet/capsule</description>
          </group>
          <group group_id="O3">
            <title>Placebo + ADT</title>
            <description>Matching Placebo and assigned ADT&#xD;
Placebo: tablet/capsule</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Adverse Events</title>
          <description>To evaluate the safety and tolerability of brexpiprazole (flexible dose) as adjunctive therapy to ADT in the proposed subject population with MDD as AE variables.</description>
          <population>Randomized subjects in Phase B who received at least one dose of double-blind trial medication as indicated on the dosing record.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="197"/>
                <count group_id="O2" value="100"/>
                <count group_id="O3" value="206"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Death</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Serious TEAE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Discontinuation due to TEAE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="4"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Any TEAE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="100"/>
                    <measurement group_id="O2" value="58"/>
                    <measurement group_id="O3" value="107"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Sheehan Disability Scale (SDS) Individual Item Scores.</title>
        <description>To evaluate mean change in SDS score from randomization (End of Phase A) to end of Phase B. The Sheehan Disability Scale (a self rated questionnaire) was used for measurement of functional disability and impairment due to psychiatric symptoms. The SDS is a visual analogue scale that uses spatio-visual, numeric, and verbal descriptive anchors simultaneously to assess disability across the three domains (work/school work, social life/leisure activities and family life/home responsibilities). All domains were rated on a score scale ranged from 0 (no impairment) to 10 (most severe). Score of 5 and above indicated significant functional impairment. A total score was addition of the 3 individual scores and the total score ranged from 0 (no impairment) to 30 (most severe).</description>
        <time_frame>Randomization Visit (week 8 or week 10) to End of Double-Blind Treatment (week 14 or week 16).</time_frame>
        <population>All subjects in the Safety Sample who have an end of Phase A (ie, Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.</population>
        <group_list>
          <group group_id="O1">
            <title>Brexpiprazole + ADT</title>
            <description>Brexpiprazole, flexible dose and assigned ADT&#xD;
Brexpiprazole: tablet/capsule</description>
          </group>
          <group group_id="O2">
            <title>Seroquel XR + ADT</title>
            <description>Seroquel XR, flexible dose and assigned ADT&#xD;
Seroquel XR: tablet/capsule</description>
          </group>
          <group group_id="O3">
            <title>Placebo + ADT</title>
            <description>Matching Placebo and assigned ADT&#xD;
Placebo: tablet/capsule</description>
          </group>
        </group_list>
        <measure>
          <title>Sheehan Disability Scale (SDS) Individual Item Scores.</title>
          <description>To evaluate mean change in SDS score from randomization (End of Phase A) to end of Phase B. The Sheehan Disability Scale (a self rated questionnaire) was used for measurement of functional disability and impairment due to psychiatric symptoms. The SDS is a visual analogue scale that uses spatio-visual, numeric, and verbal descriptive anchors simultaneously to assess disability across the three domains (work/school work, social life/leisure activities and family life/home responsibilities). All domains were rated on a score scale ranged from 0 (no impairment) to 10 (most severe). Score of 5 and above indicated significant functional impairment. A total score was addition of the 3 individual scores and the total score ranged from 0 (no impairment) to 30 (most severe).</description>
          <population>All subjects in the Safety Sample who have an end of Phase A (ie, Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in 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="99"/>
                <count group_id="O3" value="205"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Work/School Score</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="125"/>
                    <count group_id="O2" value="67"/>
                    <count group_id="O3" value="136"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.59" spread="0.16"/>
                    <measurement group_id="O2" value="-0.22" spread="0.21"/>
                    <measurement group_id="O3" value="-0.74" spread="0.16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Social Life Score</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="191"/>
                    <count group_id="O2" value="99"/>
                    <count group_id="O3" value="205"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.03" spread="0.13"/>
                    <measurement group_id="O2" value="-0.26" spread="0.17"/>
                    <measurement group_id="O3" value="-0.70" spread="0.12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Family Life Score</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="191"/>
                    <count group_id="O2" value="99"/>
                    <count group_id="O3" value="205"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.02" spread="0.13"/>
                    <measurement group_id="O2" value="-0.34" spread="0.18"/>
                    <measurement group_id="O3" value="-0.67" spread="0.13"/>
                  </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>Work/School Score</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.4480</p_value>
            <method>MMRM</method>
            <method_desc>Mixed-model repeated measures (MMRM)</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>0.16</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.25</ci_lower_limit>
            <ci_upper_limit>0.56</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Work/School Score</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0380</p_value>
            <method>MMRM</method>
            <method_desc>Mixed-model repeated measures (MMRM)</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>0.52</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.03</ci_lower_limit>
            <ci_upper_limit>1.02</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Social Life Score</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0436</p_value>
            <method>MMRM</method>
            <method_desc>Mixed-model repeated measures (MMRM)</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-0.34</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>-0.01</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Social Life Score</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0350</p_value>
            <method>MMRM</method>
            <method_desc>Mixed-model repeated measures (MMRM)</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>0.43</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.03</ci_lower_limit>
            <ci_upper_limit>0.84</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Family Life Score</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0424</p_value>
            <method>MMRM</method>
            <method_desc>Mixed-model repeated measures (MMRM)</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-0.35</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.69</ci_lower_limit>
            <ci_upper_limit>-0.01</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Family Life Score</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.1230</p_value>
            <method>MMRM</method>
            <method_desc>Mixed-model repeated measures (MMRM)</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>0.33</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.09</ci_lower_limit>
            <ci_upper_limit>0.75</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events were recorded from screening (Day -28 to Day-1) upto post treatment follow-up.</time_frame>
      <desc>All adverse events which started after start of double blind study drug treatment; or if the event was continuous from end of phase A and was worsening, serious, study drug related, or resulted in death, discontinuation, interruption or reduction of study therapy. Subjects in Phase B who received at least one dose of double-blind IMP as indicated on the dosing record. If a subject was dispensed IMP and was lost to follow up, he/she was considered exposed.</desc>
      <group_list>
        <group group_id="E1">
          <title>Brexpiprazole + ADT</title>
          <description>Brexpiprazole, flexible dose and assigned ADT&#xD;
Brexpiprazole: tablet/capsule</description>
        </group>
        <group group_id="E2">
          <title>Seroquel XR + ADT</title>
          <description>Seroquel XR, flexible dose and assigned ADT&#xD;
Seroquel XR: tablet/capsule</description>
        </group>
        <group group_id="E3">
          <title>Placebo + ADT</title>
          <description>Matching Placebo and assigned ADT&#xD;
Placebo: tablet/capsule</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="197"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="206"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="197"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="206"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>malignanat melanoma</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="197"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="206"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>panic attack</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="197"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="206"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>2</frequency_threshold>
        <default_vocab>MedDRA</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="62" subjects_at_risk="197"/>
                <counts group_id="E2" subjects_affected="33" subjects_at_risk="100"/>
                <counts group_id="E3" subjects_affected="39" subjects_at_risk="206"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Asthenia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="197"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="100"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="206"/>
              </event>
              <event>
                <sub_title>fatigue</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="197"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="100"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="206"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="197"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="100"/>
                <counts group_id="E3" subjects_affected="9" subjects_at_risk="206"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Weight Increased</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="197"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="100"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="206"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Increased Appetite</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="197"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="100"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="206"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Akathisia</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="197"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="100"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="206"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="197"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="100"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="206"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="197"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E3" subjects_affected="10" subjects_at_risk="206"/>
              </event>
              <event>
                <sub_title>Somnolence</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="197"/>
                <counts group_id="E2" subjects_affected="18" subjects_at_risk="100"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="206"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="197"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="100"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="206"/>
              </event>
              <event>
                <sub_title>Irritability</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="197"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="206"/>
              </event>
              <event>
                <sub_title>Restlessness</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="197"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="206"/>
              </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 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>Global Clinical Development</name_or_title>
      <organization>Otsuka Pharmaceutical Development &amp; Commercialization, Inc.</organization>
      <email>DT-inquiry@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/NCT01727726
org study id: 331-12-282
nct id: NCT01727726
lead sponsor: 
has dmc: No
To compare the efficacy of brexpiprazole (flexible dose) with placebo as adjunctive therapy
      to an assigned open label antidepressant therapy (ADT) in the proposed subject population
      with MDD.
This is a trial designed to assess the safety and efficacy of brexpiprazole (flexible dose)
      as adjunctive therapy to an assigned known anti-depressant in depressed subjects. The trial
      consists of a continuous 18-week double-blind treatment period with a 30-day follow-up.
      Subjects who complete all trial visits through the Week 18 visit may be offered entry into an
      optional open-label rollover trial.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Montgomery Asberg Depression Rating Scale (MADRS)
time frame: Randomization Visit (week 8 or week 10) to End of Double-Blind Treatment (week 14 or week 16).
description: To determine the efficacy of brexpiprazole (flexible dose) with placebo as adjunctive therapy by assessment of MADRS total score. The MADRS depression rating scale was used to assess the subject's level of depression by utilizing the structured interview guide for the MADRS (SIGMA). The MADRS consisted of 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts and suicidal thoughts), each rated 0 to 6. The overall score ranged from 0 (symptoms absent) to 60 (severe depression). Lower score indicated decreased severity of depression.
measure: Sheehan Disability Scale (SDS)
time frame: Randomization Visit (week 8 or week 10) to End of Double-Blind Treatment (week 14 or week 16).
description: To evaluate mean change in SDS score from randomization (End of Phase A) to end of Phase B. The Sheehan Disability Scale is a measurement of functional disability and impairment due to psychiatric symptoms. The SDS is a visual analogue scale that uses spatio-visual, numeric, and verbal descriptive anchors simultaneously to assess disability across the three domains ( work/social life/family life/home responsibilities). The number most representative of how much each area was disrupted by symptoms is marked along the line from 0 = not at all, to 10 = extremely. Scores of 5 and above are associated with significant functional impairment. Additionally, SDS included 2 questions related to productivity losses due to the psychiatric symptoms and impairment.
measure: Change From End of Phase A in MADRS Total Score for Trial Week 2 and Week 4.
time frame: Change from baseline to week 2 and week 4 in Phase B (week 10/12 and week 12/14)
description: Change from end of Phase A in MADRS Total Score. The MADRS was used to assess the subject's level of depression by utilizing the structured interview guide for the MADRS (SIGMA). The MADRS depression rating scale was used to assess the subject's level of depression by utilizing the structured interview guide for the MADRS (SIGMA). The MADRS consisted of 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts and suicidal thoughts), each rated 0 to 6. The overall score ranged from 0 (symptoms absent) to 60 (severe depression). Lower score indicated decreased severity of depression.
measure: Clinical Global Impression Score
time frame: From randomization to Phase B week 6 (14/16 weeks after randomization).
description: Mean change from end of Phase A in Clinical Global Impression - Severity of Illness scale (CGI-S) score and Improvement scale (CGI-I) during double-blind randomized Phase B treatment. CGI-S score assessed how mentally ill the patient was at that time. CGI-S score is calculated from 0 to 7 (0 indicates not assessed 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and7 indicated among the most extremely ill patient). CGI-I score is compared to his/her condition at baseline, how much has the patient changed. CGI-I score is calculated from 0 to 7 (0 indicates not assessed and 7 indicates very much worse).
measure: MADRS Response at Week 6
time frame: Phase B week 6 (14/16 weeks after randomization).
description: MADRS Response Rate, where response was defined as 50% reduction in MADRS Total Score, during double-blind randomized Phase B treatment.
measure: Number of Participants With MADRS
time frame: Phase B week 6 (14/16 weeks after randomization).
description: MADRS Remission Rate, where remission was defined as MADRS Total Score ≤ 10 and 50% reduction in MADRS Total Score, for every trial week visit during double-blind randomized Phase B treatment.
measure: CGI-I Response Rate
time frame: Phase B week 6 (14/16 weeks after randomization).
description: CGI-I Response rate, where response was defined as a CGI-I score of 1 or 2 (very much improved or much improved), during double-blind randomized Phase B treatment.
measure: Number of Participants With Adverse Events
time frame: From screening (Day -28 to Day-1) upto post treatment follow-up.
description: To evaluate the safety and tolerability of brexpiprazole (flexible dose) as adjunctive therapy to ADT in the proposed subject population with MDD as AE variables.
measure: Sheehan Disability Scale (SDS) Individual Item Scores.
time frame: Randomization Visit (week 8 or week 10) to End of Double-Blind Treatment (week 14 or week 16).
description: To evaluate mean change in SDS score from randomization (End of Phase A) to end of Phase B. The Sheehan Disability Scale (a self rated questionnaire) was used for measurement of functional disability and impairment due to psychiatric symptoms. The SDS is a visual analogue scale that uses spatio-visual, numeric, and verbal descriptive anchors simultaneously to assess disability across the three domains (work/school work, social life/leisure activities and family life/home responsibilities). All domains were rated on a score scale ranged from 0 (no impairment) to 10 (most severe). Score of 5 and above indicated significant functional impairment. A total score was addition of the 3 individual scores and the total score ranged from 0 (no impairment) to 30 (most severe).
arm group label: Placebo + ADT
arm group type: Placebo Comparator
description: Matching Placebo and assigned ADT
arm group label: Brexpiprazole + ADT
arm group type: Experimental
description: Brexpiprazole, flexible dose and assigned ADT
arm group label: Seroquel XR + ADT
arm group type: Active Comparator
description: Seroquel XR, flexible dose and assigned ADT
intervention type: Drug
intervention name: Brexpiprazole
description: tablet/capsule
arm group label: Brexpiprazole + ADT
other name: OPC-34712
intervention type: Drug
intervention name: Seroquel XR
description: tablet/capsule
arm group label: Seroquel XR + ADT
intervention type: Drug
intervention name: Placebo
description: tablet/capsule
arm group label: Placebo + ADT
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Mary Hobart
role: Study Director
affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc.
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country: Canada
country: France
country: Germany
country: Poland
country: Russian Federation
country: Serbia
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: Quetiapine Fumarate
mesh term: Brexpiprazole
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certain agreements: 
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