<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/NCT01677182</url>
  </required_header>
  <id_info>
    <org_study_id>TAK-375SL_301</org_study_id>
    <secondary_id>2012-001357-10</secondary_id>
    <secondary_id>U1111-1129-5184</secondary_id>
    <secondary_id>12/EM/0391</secondary_id>
    <nct_id>NCT01677182</nct_id>
  </id_info>
  <brief_title>Safety and Efficacy Study of Ramelteon (TAK-375) Tablets for Sublingual Administration (SL) in Adults With Bipolar 1 Disorder</brief_title>
  <official_title>A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Once a Day, TAK-375 (Ramelteon) Tablet for Sublingual Administration (TAK-375SL Tablet) as an Adjunctive Therapy in the Treatment of Acute Depressive Episodes Associated With Bipolar 1 Disorder in Adult Subjects</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Takeda</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Takeda</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      To evaluate the efficacy of ramelteon for treatment of acute depressive episodes associated&#xD;
      with Bipolar 1 Disorder.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The drug being tested in this study is called Ramelteon. Ramelteon is being tested to treat&#xD;
      people who have Bipolar 1 Disorder. This study will look at the symptoms of depression in&#xD;
      people who take Ramelteon as a sub-lingual formulation.&#xD;
&#xD;
      This study plans to enroll a minimum of 276 participants and a maximum of up to approximately&#xD;
      870 participants Participants will be randomly assigned (by chance, like flipping a coin) to&#xD;
      one of the three treatment groups-which will remain undisclosed to the patient and study&#xD;
      doctor during the study (unless there is an urgent medical need):&#xD;
&#xD;
        -  Ramelteon (Dose 1)&#xD;
&#xD;
        -  Ramelteon (Dose 2)&#xD;
&#xD;
        -  Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has&#xD;
           no active ingredient All participants will be asked to take one tablet every night at&#xD;
           bedtime throughout the study.&#xD;
&#xD;
      This study plans to conduct one unblinded interim analysis after the first 276 subjects have&#xD;
      been enrolled and treated for the 6-week double-blind treatment period. Based on the interim&#xD;
      analysis, the study plans to adapt limited aspects of the design including: 1) to make no&#xD;
      changes to the study; 2) to reassess sample size based on the interim analysis results.&#xD;
&#xD;
      This multi-centre trial will be conducted in North America and Europe. The overall time to&#xD;
      participate in this study is up to 14 weeks. Participants will make 8 visits to the clinic,&#xD;
      and will be contacted by telephone 30 days after last dose of study drug for a follow-up&#xD;
      assessment.&#xD;
&#xD;
      An independent Data Monitoring Committee (DMC) recently performed a planned interim analysis&#xD;
      of efficacy and safety data from this study. Upon completion of their review, the DMC advised&#xD;
      that the unblinded interim data met the predefined efficacy criteria for study termination.&#xD;
      No safety concerns were identified.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Business Decision; Terminated due to futility, with no safety concerns (see below)&#xD;
  </why_stopped>
  <start_date>August 2012</start_date>
  <completion_date type="Actual">September 2014</completion_date>
  <primary_completion_date type="Actual">August 2014</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at Week 6</measure>
    <time_frame>Baseline and Week 6</time_frame>
    <description>The MADRS is a clinician rated, validated and widely used scale to measure overall severity of depressive symptoms. It consists of 10-item rated from 0(normal) to 6(most abnormal) with a total score range from 0 to 60. Higher scores indicate greater severity of symptoms.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Young Mania Rating Scale (YMRS) Total Score at Week 6</measure>
    <time_frame>Baseline and Week 6</time_frame>
    <description>The YMRS is a 11-item scale to assess manic symptoms. Four items are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe), and 7 items are rated on a scale from 0 to 4 with higher scores reflecting greater levels of mania. The YMRS total score is calculated as the sum of the 11 individual item scores and ranges from 0-60.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Global Impression Scale-Improvement (CGI-I) Score</measure>
    <time_frame>Week 6</time_frame>
    <description>The CGI-I assesses the clinician's impression of the participant's state of mental illness improvement and consists of 1 question for the investigator: &quot;Compared to his condition at the start of the study, how much has this patient changed?&quot; which is rated on a 7-point scale (1=very much improved; 2=much improved; 3=minimally improved; 4=no change relative to baseline; 5=minimally worse; 6= much worse; 7=very much worse). In all cases, the assessment was independent of whether the rater believed the improvement was drug-related or not.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Clinical Global Impression Scale-Severity (CGI-S) to Week 6</measure>
    <time_frame>Baseline and Week 6</time_frame>
    <description>The CGI-S assesses the clinician's impression of the participant's current state of mental illness and consists of 1 question for the investigator: &quot;Considering your total clinical experience with this particular population, how mentally ill is the patient at this time?&quot; which is rated on a 7-point scale (1=normal, not ill at all; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in the Quick Inventory of Depressive Symptomatology - Self-Rated16 (QIDS-SR16) Total Score at Week 6</measure>
    <time_frame>Baseline and Week 6</time_frame>
    <description>The 16-item QIDS-SR16 version is a widely used validated scale designed to assess the severity of depressive symptoms. The participant was asked to rate the severity and frequency of specific symptoms present over the last 7 days. The QIDS-SR16 total scores range from 0 to 27, where higher scores indicate higher severity of symptoms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 6</measure>
    <time_frame>Baseline and Week 6</time_frame>
    <description>The SDS is a 3-item rating scale to assess functional impairment (panic, anxiety, phobic and depressive symptoms) over 3 inter-related domains (work/school, social life, and family life/home responsibilities) rated on an 11-point scale from 0 (not at all) to 10 (extremely) with a total score range from 0 to 30 where higher scores indicates greater severity of impairment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Quality of Life, Enjoyment, and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) Total Score at Week 6</measure>
    <time_frame>Baseline and Week 6</time_frame>
    <description>Q-LES-Q-SF is a self-administered, widely used 16-item questionnaire to assess the degree of enjoyment and satisfaction experienced by participants in various areas of daily functioning, such as social relationships, living/housing, physical health, medication, and global satisfaction. The questionnaire consists of 16 items rated by the participants on a 5-point scale. Of these, 14 items are summed to produce a total quality of life score with a maximum of 70 points. In addition, there are 2 global items that are scored individually. These items rate satisfaction with study medication and overall life satisfaction. The questionnaire is usually scored as a percent of the total possible score, with higher scores indicating better health status.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants With MADRS Response</measure>
    <time_frame>Week 6</time_frame>
    <description>MADRS response is defined as greater than or equal to (&gt;=) 50 percent (%) decrease in the MADRS total score from baseline. The MADRS is a clinician rated, validated and widely used scale to measure overall severity of depressive symptoms. It consists of 10-item rated from 0 (normal) to 6 (most abnormal) with a total score range from 0 to 60, where higher scores indicate greater severity of symptoms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants With MADRS Remission</measure>
    <time_frame>Week 6</time_frame>
    <description>MADRS remission is defined as a MADRS total score less than or equal to (&lt;=) 10. The MADRS is a clinician rated, validated and widely used scale to measure overall severity of depressive symptoms. It consists of 10-item rated from 0 (normal) to 6 (most abnormal) with a total score range from 0 to 60, where higher scores indicate greater severity of symptoms.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">535</enrollment>
  <condition>Bipolar Disorder</condition>
  <arm_group>
    <arm_group_label>Ramelteon SL (Dose 1)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Ramelteon SL tablets, sublingual, once daily, at night time for up to 6 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Ramelteon (Dose 2)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Ramelteon SL tablets, sublingual, once daily, at night time for up to 6 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Ramelteon SL placebo-matching tablets, sublingual, once daily, at night time for up to 6 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ramelteon</intervention_name>
    <description>Ramelteon tablets for sublingual administration</description>
    <arm_group_label>Ramelteon (Dose 2)</arm_group_label>
    <arm_group_label>Ramelteon SL (Dose 1)</arm_group_label>
    <other_name>TAK-375SL</other_name>
    <other_name>Rozerem</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Ramelteon placebo-matching tablets for sublingual administration</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. In the opinion of the investigator, the subject is capable of understanding and&#xD;
             complying with protocol requirements.&#xD;
&#xD;
          2. The subject or, when applicable, the subject's legally acceptable representative signs&#xD;
             and dates a written, informed consent form and any required privacy authorization&#xD;
             prior to the initiation of any study procedures.&#xD;
&#xD;
          3. The subject suffers from Bipolar 1 Disorder, Most Recent Episode Depressed as the&#xD;
             primary diagnosis according to DSM-IV-TR criteria (classification code 296.5x) and&#xD;
             confirmed by the SCID.&#xD;
&#xD;
          4. The subject is a man or woman aged between 18 and 75 years, inclusive.&#xD;
&#xD;
          5. The reported duration of the current Major Depressive Episode (MDE) is at least four&#xD;
             weeks and less than 6 months.&#xD;
&#xD;
          6. The subject has a YMRS total score of ≤10 both at the Screening and Baseline Visits.&#xD;
&#xD;
          7. The subject has a MADRS total score of ≥24 at the Screening and Baseline Visits.&#xD;
&#xD;
          8. The subject has a CGI-S score of ≥4 at the Screening and Baseline Visits.&#xD;
&#xD;
          9. The subject has HAM- A total score of ≤21 at Screening and Baseline Visits.&#xD;
&#xD;
         10. The subject is on lithium and/or one other mood stabilizer (lamotrigine or valproic&#xD;
             acid) and/or one atypical antipsychotic (risperidone or olanzapine or aripiprazole or&#xD;
             ziprasidone). Patients may be on one, two, or three medications but no more than one&#xD;
             from each group.&#xD;
&#xD;
         11. The subject is on the same dose of the protocol allowed medications (identified in&#xD;
             inclusion # 10) for bipolar 1 disorder for at least two weeks prior to screening (and&#xD;
             at least 6 weeks prior to screening for lamotrigine only). Further dose adjustments&#xD;
             will not be allowed from screening until end of study, except for downward dose&#xD;
             adjustments for adverse events.&#xD;
&#xD;
         12. If the subject is on lithium and/or valproic acid, the trough serum levels must be&#xD;
             less than 1.2 mEq/L for lithium and the trough serum must be less than 125 mcg/ml for&#xD;
             valproic acid. Downward dose adjustment is allowed to lower trough serum levels for&#xD;
             lithium and/or valproic acid below the maximum allowed. This must be confirmed at&#xD;
             least two weeks prior to baseline.&#xD;
&#xD;
         13. The subject screened must have &lt;25% improvement in MADRS total score from screening to&#xD;
             baseline visit with a minimum of two weeks between screening and baseline visits.&#xD;
&#xD;
         14. A female subject of childbearing potential who is sexually active with a nonsterilized&#xD;
             male partner agrees to use routinely adequate contraception from signing of informed&#xD;
             consent throughout the duration of the study and for 30 days after the last dose of&#xD;
             the study drug.&#xD;
&#xD;
         15. A male subject who is nonsterilized and sexually active with female partner of&#xD;
             childbearing potential agrees to use adequate contraception from signing of informed&#xD;
             consent throughout the duration of the study and for 30 days after the last dose of&#xD;
             study drug.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. The subject has received any investigational compound &lt;30 days before Screening or 5&#xD;
             half-lives whichever is longer prior to Screening.&#xD;
&#xD;
          2. The subject has received TAK-375 or TAK-375SL in a previous clinical study or has ever&#xD;
             used ramelteon.&#xD;
&#xD;
          3. The subject is an immediate family member, study site employee, or is in a dependant&#xD;
             relationship with a study site employee who is involved in conduct of this study (eg,&#xD;
             spouse, parent, child, sibling) or may consent under duress.&#xD;
&#xD;
          4. The subject has one or more of the following:&#xD;
&#xD;
               1. Any current psychiatric disorder which is the primary focus of treatment other&#xD;
                  than Bipolar 1 Disorder, Most Recent Episode Depressed as defined in the&#xD;
                  DSM-IV-TR, as assessed by the SCID.&#xD;
&#xD;
               2. Current or history of: schizophrenia, schizoaffective disorder, unipolar&#xD;
                  depression with psychotic features, bipolar depression with psychotic features,&#xD;
                  any other psychotic disorder (with the exception of psychosis associated with a&#xD;
                  manic or mixed episode), mental retardation, organic mental disorders, OCD, or&#xD;
                  mental disorders due to a general medical condition as defined in the DSM-IV-TR.&#xD;
&#xD;
               3. Current diagnosis or history of alcohol or other substance abuse (excluding&#xD;
                  nicotine or caffeine) as defined in the DSM-IV-TR that has not been in full and&#xD;
                  sustained remission for at least three months from the day of screening. (Subject&#xD;
                  must also have negative urine drug screen at Screening and Baseline). Note that a&#xD;
                  positive drug screen for opiates and benzodiazepines is allowed provided the&#xD;
                  subject has a valid prescription.&#xD;
&#xD;
               4. Current diagnosis or history of alcohol or other substance dependence (excluding&#xD;
                  nicotine or caffeine) as defined in the DSM-IV-TR that has not been in full and&#xD;
                  sustained remission for at least three months from the day of screening. (Subject&#xD;
                  must also have negative urine drug screen at screening and Baseline). Note that a&#xD;
                  positive drug screen for opiates and benzodiazepines is allowed provided the&#xD;
                  subject has a valid prescription.&#xD;
&#xD;
               5. Presence or history of a clinically significant neurological disorder (including&#xD;
                  epilepsy).&#xD;
&#xD;
               6. Neurodegenerative disorder (Alzheimer disease, Parkinson disease, multiple&#xD;
                  sclerosis, Huntington disease, etc).&#xD;
&#xD;
               7. Any Axis II disorder that might compromise the study.&#xD;
&#xD;
               8. History of Rapid Cycling Bipolar Disorder: Patients who have more than 8 episodes&#xD;
                  of mood disorder per year. The episodes must meet both the duration and symptom&#xD;
                  criteria for a major depressive, manic, mixed, or hypomanic episode and must be&#xD;
                  demarcated by either a period of full remission or by a switch to an episode of&#xD;
                  the opposite polarity. manic, hypomanic, and mixed episodes are counted as being&#xD;
                  on the same pole. Each mood episode must be confirmed by appropriate patient&#xD;
                  history or formal diagnosis by medical practitioner.&#xD;
&#xD;
          5. The subject experienced the first episode of mood disorder after the age of 55 years.&#xD;
&#xD;
          6. The current depressive symptoms of the subject are considered by the investigator to&#xD;
             have been resistant to 2 adequate treatment trials with any of the mood stabilizers&#xD;
             (specifically started to treat the current depressive episode) and/or medications&#xD;
             approved for acute bipolar depression (e.g. quetiapine, olanzapine + fluoxetine [US&#xD;
             only]) for at least 6 weeks duration each.&#xD;
&#xD;
          7. The subject is on any psychotropic medications other than the protocol allowed&#xD;
             medications for at least 2 weeks prior to the Baseline visit. If a subject is taking&#xD;
             any protocol excluded medications (e.g. antidepressants, typical antipsychotics) or is&#xD;
             taking more than one of the allowed mood stabilizer and/or atypical antipsychotic&#xD;
             medications, and if the patient is considered appropriate by the PI, these medications&#xD;
             must be washed out for at least 2 weeks prior to the Baseline visit.&#xD;
&#xD;
          8. The subject has received electroconvulsive therapy, vagal nerve stimulation, or&#xD;
             repetitive transcranial magnetic stimulation within 6 months prior to Screening.&#xD;
&#xD;
          9. The subject has started receiving formal cognitive or behavioral therapy, systematic&#xD;
             psychotherapy within 30 days prior to screening or plans to initiate such therapy&#xD;
             during the study.&#xD;
&#xD;
         10. The subject has a significant risk of suicide according to the investigator's clinical&#xD;
             judgment or has a score ≥5 on item 10 (suicidal thoughts) of the MADRS or has made a&#xD;
             suicide attempt in the previous 6 months.&#xD;
&#xD;
         11. The subject has taken or is anticipated that the subject will take at least 1 of the&#xD;
             disallowed concomitant medications that is listed in the Excluded Medications and&#xD;
             Treatments (Table 7.a).&#xD;
&#xD;
         12. The subject has a clinically significant unstable illness, for example hepatic&#xD;
             impairment or renal insufficiency, or a cardiovascular, pulmonary, gastrointestinal,&#xD;
             endocrine, neurological, rheumatologic, immunologic, hematological, infectious,&#xD;
             dermatological disorder or metabolic disturbance as determined by Investigator.&#xD;
&#xD;
         13. The subject has a history or current diagnosis of fibromyalgia, chronic fatigue&#xD;
             syndrome, chronic pain syndrome or sleep apnea (central and/or obstructive). If&#xD;
             obstructive sleep apnea is corrected surgically, a polysomnogram showing normal&#xD;
             apnea-hypopnea index is required.&#xD;
&#xD;
         14. The subject has a previous history of cancer that had been in remission for less than&#xD;
             5 years prior to the first dose of study medication. This criterion does not include&#xD;
             those subjects with basal cell or stage I squamous cell carcinoma of the skin.&#xD;
&#xD;
         15. The subject has 1 or more laboratory value outside the normal range, based on the&#xD;
             blood or urine samples taken at the Screening Visit, that are considered by the&#xD;
             investigator to be clinically significant; or the subject has any of the following&#xD;
             values at the Screening Visit:&#xD;
&#xD;
               1. A serum creatinine value &gt;1.5 times the upper limits of normal (xULN).&#xD;
&#xD;
               2. A serum total bilirubin value &gt;1.5 xULN.&#xD;
&#xD;
               3. A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value&#xD;
                  &gt;2 xULN.&#xD;
&#xD;
         16. The subject has HbA1C ≥7% at screening and no prior diagnosis of diabetes and/or&#xD;
             treatment for diabetes. NOTE: Subjects with known diabetes are not excluded.&#xD;
&#xD;
         17. The subject has a thyroid stimulating hormone (TSH) value outside the normal range at&#xD;
             the Screening Visit that is deemed clinically significant by the investigator. NOTE:&#xD;
             Free thyroxine (T4) will be checked if TSH is out of range. If free T4 is abnormal the&#xD;
             subject will be excluded.&#xD;
&#xD;
         18. The subject is positive for hepatitis B surface antigen (HBsAg), antibodies to&#xD;
             hepatitis C virus (HCV), or has a history of human immunodeficiency virus (HIV)&#xD;
             infection.&#xD;
&#xD;
         19. If male, the subject intends to donate sperm during the course of this study or for 12&#xD;
             weeks thereafter. If female, the subject is pregnant or lactating or intending to&#xD;
             become pregnant before, during, or within 30 days after participating in this study;&#xD;
             or intending to donate ova during such time period.&#xD;
&#xD;
         20. The subject has clinically significant abnormal vital signs as determined by the&#xD;
             investigator.&#xD;
&#xD;
         21. The subject has an abnormal ECG as determined by the central reader and confirmed as&#xD;
             clinically significant by the investigator.&#xD;
&#xD;
         22. The subject has a disease or takes medication that, in the opinion of the&#xD;
             investigator, could interfere with the assessments of safety, tolerability, or&#xD;
             efficacy.&#xD;
&#xD;
         23. The subject, in the opinion of the investigator, is unlikely to comply with the&#xD;
             clinical study protocol or is unsuitable for any reason.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Medical Director Clinical Science</last_name>
    <role>Study Director</role>
    <affiliation>Takeda Global Research and Development Center, Inc.</affiliation>
  </overall_official>
  <location>
    <facility>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Anaheim</city>
        <state>California</state>
        <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>Imperial</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Oakland</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Oceanside</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Pico Rivera</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>Stanford</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Hartford</city>
        <state>Connecticut</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Coral Springs</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Deerfield Beach</city>
        <state>Florida</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</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Maitland</city>
        <state>Florida</state>
        <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>Orlando</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>West Palm Beach</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Joliet</city>
        <state>Illinois</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Naperville</city>
        <state>Illinois</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Oak Brook</city>
        <state>Illinois</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Lafayette</city>
        <state>Indiana</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Bronx</city>
        <state>New York</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Buffalo</city>
        <state>New York</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>New York</city>
        <state>New York</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Staten Island</city>
        <state>New York</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Avon Lake</city>
        <state>Ohio</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Garfield Heights</city>
        <state>Ohio</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Mason</city>
        <state>Ohio</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Oklahoma City</city>
        <state>Oklahoma</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Memphis</city>
        <state>Tennessee</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Bothell</city>
        <state>Washington</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Spokane</city>
        <state>Washington</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Waukesha</city>
        <state>Wisconsin</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Bourgas</city>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Kazanlak</city>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Lovech</city>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Novi Iskar</city>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Pleven</city>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Plovdiv</city>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Rousse</city>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Sofia</city>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Tzerova Koria</city>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Varna</city>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Brno</city>
        <country>Czech Republic</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Litomerice</city>
        <country>Czech Republic</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Olomouc</city>
        <country>Czech Republic</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Plzen</city>
        <country>Czech Republic</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Praha 10</city>
        <country>Czech Republic</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Praha 2</city>
        <country>Czech Republic</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Praha 6</city>
        <country>Czech Republic</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Praha 8</city>
        <country>Czech Republic</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Praha</city>
        <country>Czech Republic</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Bochum</city>
        <state>NRW</state>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Berlin</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Westerstede</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Bialystok</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Choroszcz</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Oradea</city>
        <state>Bihor</state>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Cluj-Napoca</city>
        <state>Cluj</state>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Targoviste</city>
        <state>Dambovita</state>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Craiova</city>
        <state>Dolj</state>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Arad</city>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Bucuresti</city>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Cluj-Napoca</city>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Craiova</city>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Iasi</city>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Targoviste</city>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Talagi</city>
        <state>Arkhangelsk region</state>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Orenburg</city>
        <state>Orenburg region</state>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Staritsa settlement</city>
        <state>Orenburg region</state>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>town. Tonnelniy</city>
        <state>Stavropol region</state>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Arkhangelsk</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Moscow</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Nizhniy Novgorod</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Smolensk</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>St. Petersburg</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Stavropol</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Kragujevac</city>
        <state>Sumadija</state>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Novi Sad</city>
        <state>Vojvodina</state>
        <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>
    <facility>
      <address>
        <city>Simferopol</city>
        <state>Crimea</state>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Oleksandrivka, Kominternivske District</city>
        <state>Odesa Region</state>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Simferopol</city>
        <state>the Autonomous Republic of Crimea</state>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Kharkiv</city>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Luhansk</city>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Odesa</city>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Poltava</city>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Ternopil</city>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Vinnytsia</city>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Oxford</city>
        <state>Oxfordshire</state>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Birmingham</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Newcastle upon Tyne</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Bulgaria</country>
    <country>Czech Republic</country>
    <country>Germany</country>
    <country>Poland</country>
    <country>Romania</country>
    <country>Russian Federation</country>
    <country>Serbia</country>
    <country>Ukraine</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2016</verification_date>
  <study_first_submitted>August 29, 2012</study_first_submitted>
  <study_first_submitted_qc>August 29, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 31, 2012</study_first_posted>
  <results_first_submitted>February 16, 2016</results_first_submitted>
  <results_first_submitted_qc>February 16, 2016</results_first_submitted_qc>
  <results_first_posted type="Estimate">March 16, 2016</results_first_posted>
  <last_update_submitted>February 16, 2016</last_update_submitted>
  <last_update_submitted_qc>February 16, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">March 16, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Drug therapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bipolar Disorder</mesh_term>
  </condition_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Participants took part at 98 sites in Bulgaria, the Czech Republic, Germany, Great Britain, Poland, Romania, Russia, Serbia, Ukraine, and the United States from 29 August 2012 to 03 September 2014.</recruitment_details>
      <pre_assignment_details>Participants with a historical diagnosis of bipolar 1 disorder were enrolled in 1 of 3 treatment groups as follows: placebo; TAK-375 0.1 milligram (mg); TAK-375 0.4 mg.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Placebo</title>
          <description>TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.</description>
        </group>
        <group group_id="P2">
          <title>TAK-375SL 0.1 mg</title>
          <description>TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.</description>
        </group>
        <group group_id="P3">
          <title>TAK-375SL 0.4 mg</title>
          <description>TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="184"/>
                <participants group_id="P2" count="169"/>
                <participants group_id="P3" count="182"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="150"/>
                <participants group_id="P2" count="141"/>
                <participants group_id="P3" count="143"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="34"/>
                <participants group_id="P2" count="28"/>
                <participants group_id="P3" count="39"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="8"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="4"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="12"/>
                <participants group_id="P3" count="10"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Study termination</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
                <participants group_id="P2" count="9"/>
                <participants group_id="P3" count="11"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lack of Efficacy</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Other reasons</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="5"/>
                <participants group_id="P3" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Baseline analysis population included all randomized participants.</population>
      <group_list>
        <group group_id="B1">
          <title>Placebo</title>
          <description>TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.</description>
        </group>
        <group group_id="B2">
          <title>TAK-375SL 0.1 mg</title>
          <description>TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.</description>
        </group>
        <group group_id="B3">
          <title>TAK-375SL 0.4 mg</title>
          <description>TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.</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="184"/>
            <count group_id="B2" value="169"/>
            <count group_id="B3" value="182"/>
            <count group_id="B4" value="535"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="46.67" spread="11.332"/>
                    <measurement group_id="B2" value="45.44" spread="11.490"/>
                    <measurement group_id="B3" value="44.87" spread="11.608"/>
                    <measurement group_id="B4" value="45.67" spread="11.480"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age, Customized</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Less than or equal to (&lt;=) 50 years</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="105"/>
                    <measurement group_id="B2" value="100"/>
                    <measurement group_id="B3" value="107"/>
                    <measurement group_id="B4" value="312"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Greater than (&gt;) 50 years</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="79"/>
                    <measurement group_id="B2" value="69"/>
                    <measurement group_id="B3" value="75"/>
                    <measurement group_id="B4" value="223"/>
                  </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="119"/>
                    <measurement group_id="B2" value="98"/>
                    <measurement group_id="B3" value="108"/>
                    <measurement group_id="B4" value="325"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="65"/>
                    <measurement group_id="B2" value="71"/>
                    <measurement group_id="B3" value="74"/>
                    <measurement group_id="B4" value="210"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="9"/>
                    <measurement group_id="B4" value="31"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="63"/>
                    <measurement group_id="B2" value="61"/>
                    <measurement group_id="B3" value="63"/>
                    <measurement group_id="B4" value="187"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="109"/>
                    <measurement group_id="B2" value="98"/>
                    <measurement group_id="B3" value="110"/>
                    <measurement group_id="B4" value="317"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>American Indian or Alaska Native</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Asian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Native Hawaiian or Other Pacific Islander</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Black or African American</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="12"/>
                    <measurement group_id="B4" value="35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>White</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="171"/>
                    <measurement group_id="B2" value="154"/>
                    <measurement group_id="B3" value="166"/>
                    <measurement group_id="B4" value="491"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>More than one race</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Bulgaria</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="31"/>
                    <measurement group_id="B2" value="27"/>
                    <measurement group_id="B3" value="30"/>
                    <measurement group_id="B4" value="88"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Czech Republic</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="8"/>
                    <measurement group_id="B4" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Germany</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>United Kingdom</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Poland</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Romania</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="9"/>
                    <measurement group_id="B4" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Russian Federation</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="13"/>
                    <measurement group_id="B4" value="34"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Serbia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="22"/>
                    <measurement group_id="B2" value="20"/>
                    <measurement group_id="B3" value="25"/>
                    <measurement group_id="B4" value="67"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ukraine</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="19"/>
                    <measurement group_id="B3" value="18"/>
                    <measurement group_id="B4" value="57"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="76"/>
                    <measurement group_id="B2" value="71"/>
                    <measurement group_id="B3" value="72"/>
                    <measurement group_id="B4" value="219"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Height</title>
          <units>centimeter (cm)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="168.86" spread="9.227"/>
                    <measurement group_id="B2" value="170.66" spread="8.423"/>
                    <measurement group_id="B3" value="169.80" spread="8.870"/>
                    <measurement group_id="B4" value="169.75" spread="8.871"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Weight</title>
          <units>kilogram (kg)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="80.82" spread="23.503"/>
                    <measurement group_id="B2" value="83.21" spread="18.638"/>
                    <measurement group_id="B3" value="82.38" spread="19.202"/>
                    <measurement group_id="B4" value="82.11" spread="20.605"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Body Mass Index (BMI)</title>
          <units>kilogram per square meter (kg/m^2)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="28.25" spread="7.583"/>
                    <measurement group_id="B2" value="28.57" spread="6.130"/>
                    <measurement group_id="B3" value="28.52" spread="6.156"/>
                    <measurement group_id="B4" value="28.44" spread="6.663"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Smoking Classification</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Had Never Smoked</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="84"/>
                    <measurement group_id="B2" value="75"/>
                    <measurement group_id="B3" value="79"/>
                    <measurement group_id="B4" value="238"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Current Smoker</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="75"/>
                    <measurement group_id="B2" value="70"/>
                    <measurement group_id="B3" value="82"/>
                    <measurement group_id="B4" value="227"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ex-smoker</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="25"/>
                    <measurement group_id="B2" value="24"/>
                    <measurement group_id="B3" value="21"/>
                    <measurement group_id="B4" value="70"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Subject Drinking Status</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Had Never Drunk</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="97"/>
                    <measurement group_id="B2" value="92"/>
                    <measurement group_id="B3" value="109"/>
                    <measurement group_id="B4" value="298"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ex-Drinker</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="51"/>
                    <measurement group_id="B2" value="41"/>
                    <measurement group_id="B3" value="36"/>
                    <measurement group_id="B4" value="128"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Current Drinker</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="36"/>
                    <measurement group_id="B2" value="36"/>
                    <measurement group_id="B3" value="37"/>
                    <measurement group_id="B4" value="109"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Amount of Alcohol Consumed if Current Drinker</title>
          <description>Participants evaluable for this measure included only those who were current drinkers (36, 36, and 37 for each group, respectively).</description>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>&lt; 4 drinks per day</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="36"/>
                    <measurement group_id="B2" value="36"/>
                    <measurement group_id="B3" value="37"/>
                    <measurement group_id="B4" value="109"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>&gt;= 4 drinks per day</title>
              <category_list>
                <category>
                  <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>Consumption of Caffeine</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Consumer</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="140"/>
                    <measurement group_id="B2" value="128"/>
                    <measurement group_id="B3" value="144"/>
                    <measurement group_id="B4" value="412"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Not a consumer</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="44"/>
                    <measurement group_id="B2" value="41"/>
                    <measurement group_id="B3" value="38"/>
                    <measurement group_id="B4" value="123"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Psychiatric History for response to Lithium treatment for Bipolar 1 Disorder</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Failed to Respond</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="7"/>
                    <measurement group_id="B4" value="21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Responded</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="101"/>
                    <measurement group_id="B2" value="92"/>
                    <measurement group_id="B3" value="100"/>
                    <measurement group_id="B4" value="293"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Not Applicable</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="69"/>
                    <measurement group_id="B2" value="63"/>
                    <measurement group_id="B3" value="68"/>
                    <measurement group_id="B4" value="200"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Unknown</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="7"/>
                    <measurement group_id="B4" value="21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Psychiatric History for response to Valproic Acid Treatment of Bipolar 1 Disorder</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Failed to Respond</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="9"/>
                    <measurement group_id="B4" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Responded</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="133"/>
                    <measurement group_id="B2" value="124"/>
                    <measurement group_id="B3" value="136"/>
                    <measurement group_id="B4" value="393"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Not Applicable</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="35"/>
                    <measurement group_id="B2" value="29"/>
                    <measurement group_id="B3" value="27"/>
                    <measurement group_id="B4" value="91"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Unknown</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="10"/>
                    <measurement group_id="B4" value="28"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Female Reproductive Status</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Postmenopausal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="44"/>
                    <measurement group_id="B2" value="30"/>
                    <measurement group_id="B3" value="34"/>
                    <measurement group_id="B4" value="108"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Surgically Sterile</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="12"/>
                    <measurement group_id="B4" value="46"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Child-Bearing Potential</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="55"/>
                    <measurement group_id="B2" value="54"/>
                    <measurement group_id="B3" value="62"/>
                    <measurement group_id="B4" value="171"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Not applicable (male participants)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="65"/>
                    <measurement group_id="B2" value="71"/>
                    <measurement group_id="B3" value="74"/>
                    <measurement group_id="B4" value="210"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at Week 6</title>
        <description>The MADRS is a clinician rated, validated and widely used scale to measure overall severity of depressive symptoms. It consists of 10-item rated from 0(normal) to 6(most abnormal) with a total score range from 0 to 60. Higher scores indicate greater severity of symptoms.</description>
        <time_frame>Baseline and Week 6</time_frame>
        <population>Full Analysis Set (FAS) included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
          <group group_id="O2">
            <title>TAK-375SL 0.1 mg</title>
            <description>TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
          <group group_id="O3">
            <title>TAK-375SL 0.4 mg</title>
            <description>TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at Week 6</title>
          <description>The MADRS is a clinician rated, validated and widely used scale to measure overall severity of depressive symptoms. It consists of 10-item rated from 0(normal) to 6(most abnormal) with a total score range from 0 to 60. Higher scores indicate greater severity of symptoms.</description>
          <population>Full Analysis Set (FAS) included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy.</population>
          <units>units on 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="179"/>
                <count group_id="O2" value="167"/>
                <count group_id="O3" value="176"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline (n= 179, 167, 176)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="30.8" spread="0.28"/>
                    <measurement group_id="O2" value="30.2" spread="0.29"/>
                    <measurement group_id="O3" value="30.4" spread="0.29"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change at Week 6 (n= 149, 139, 143)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-14.7" spread="0.69"/>
                    <measurement group_id="O2" value="-14.0" spread="0.71"/>
                    <measurement group_id="O3" value="-15.1" spread="0.70"/>
                  </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>Superiority or Other</non_inferiority_type>
            <p_value>0.783</p_value>
            <p_value_desc>Mixed Model Repeated Measures (MMRM) model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.</p_value_desc>
            <method>Mixed Model Repeated Measures</method>
            <param_type>Least Squares Mean Differences</param_type>
            <param_value>0.8</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.98</dispersion_value>
            <ci_percent>97.5</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-1.4</ci_lower_limit>
            <ci_upper_limit>3.0</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.329</p_value>
            <p_value_desc>MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.</p_value_desc>
            <method>Mixed Model Repeated Measures</method>
            <param_type>Least Squares Mean Difference</param_type>
            <param_value>-0.4</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.97</dispersion_value>
            <ci_percent>97.5</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-2.6</ci_lower_limit>
            <ci_upper_limit>1.7</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Young Mania Rating Scale (YMRS) Total Score at Week 6</title>
        <description>The YMRS is a 11-item scale to assess manic symptoms. Four items are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe), and 7 items are rated on a scale from 0 to 4 with higher scores reflecting greater levels of mania. The YMRS total score is calculated as the sum of the 11 individual item scores and ranges from 0-60.</description>
        <time_frame>Baseline and Week 6</time_frame>
        <population>FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
          <group group_id="O2">
            <title>TAK-375SL 0.1 mg</title>
            <description>TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
          <group group_id="O3">
            <title>TAK-375SL 0.4 mg</title>
            <description>TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Young Mania Rating Scale (YMRS) Total Score at Week 6</title>
          <description>The YMRS is a 11-item scale to assess manic symptoms. Four items are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe), and 7 items are rated on a scale from 0 to 4 with higher scores reflecting greater levels of mania. The YMRS total score is calculated as the sum of the 11 individual item scores and ranges from 0-60.</description>
          <population>FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy.</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="179"/>
                <count group_id="O2" value="167"/>
                <count group_id="O3" value="176"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline (n= 179, 167, 176)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.4" spread="0.16"/>
                    <measurement group_id="O2" value="4.3" spread="0.16"/>
                    <measurement group_id="O3" value="4.4" spread="0.16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change at Week 6 (n= 149, 139, 143)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.4" spread="0.19"/>
                    <measurement group_id="O2" value="-0.9" spread="0.20"/>
                    <measurement group_id="O3" value="-1.5" spread="0.20"/>
                  </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>Superiority or Other</non_inferiority_type>
            <p_value>0.088</p_value>
            <p_value_desc>MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.</p_value_desc>
            <method>Mixed Model Repeated Measures</method>
            <param_type>Least Squares Mean Difference</param_type>
            <param_value>0.5</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.27</dispersion_value>
            <ci_percent>97.5</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.1</ci_lower_limit>
            <ci_upper_limit>1.1</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.642</p_value>
            <p_value_desc>MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.</p_value_desc>
            <method>Mixed Model Repeated Measures</method>
            <param_type>Least Squares Mean Difference</param_type>
            <param_value>-0.1</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.27</dispersion_value>
            <ci_percent>97.5</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.7</ci_lower_limit>
            <ci_upper_limit>0.5</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Clinical Global Impression Scale-Improvement (CGI-I) Score</title>
        <description>The CGI-I assesses the clinician's impression of the participant's state of mental illness improvement and consists of 1 question for the investigator: &quot;Compared to his condition at the start of the study, how much has this patient changed?&quot; which is rated on a 7-point scale (1=very much improved; 2=much improved; 3=minimally improved; 4=no change relative to baseline; 5=minimally worse; 6= much worse; 7=very much worse). In all cases, the assessment was independent of whether the rater believed the improvement was drug-related or not.</description>
        <time_frame>Week 6</time_frame>
        <population>FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
          <group group_id="O2">
            <title>TAK-375SL 0.1 mg</title>
            <description>TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
          <group group_id="O3">
            <title>TAK-375SL 0.4 mg</title>
            <description>TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Clinical Global Impression Scale-Improvement (CGI-I) Score</title>
          <description>The CGI-I assesses the clinician's impression of the participant's state of mental illness improvement and consists of 1 question for the investigator: &quot;Compared to his condition at the start of the study, how much has this patient changed?&quot; which is rated on a 7-point scale (1=very much improved; 2=much improved; 3=minimally improved; 4=no change relative to baseline; 5=minimally worse; 6= much worse; 7=very much worse). In all cases, the assessment was independent of whether the rater believed the improvement was drug-related or not.</description>
          <population>FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy.</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="149"/>
                <count group_id="O2" value="139"/>
                <count group_id="O3" value="143"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.5" spread="0.08"/>
                    <measurement group_id="O2" value="2.5" spread="0.09"/>
                    <measurement group_id="O3" value="2.3" spread="0.09"/>
                  </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>Superiority or Other</non_inferiority_type>
            <p_value>0.792</p_value>
            <p_value_desc>MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.</p_value_desc>
            <method>Mixed Model Repeated Measures</method>
            <param_type>Least Squares Mean Difference</param_type>
            <param_value>0.0</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.12</dispersion_value>
            <ci_percent>97.5</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.2</ci_lower_limit>
            <ci_upper_limit>0.3</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.171</p_value>
            <p_value_desc>MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.</p_value_desc>
            <method>Mixed Model Repeated Measures</method>
            <param_type>Least Squares Mean Difference</param_type>
            <param_value>-0.2</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.12</dispersion_value>
            <ci_percent>97.5</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.4</ci_lower_limit>
            <ci_upper_limit>0.1</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Clinical Global Impression Scale-Severity (CGI-S) to Week 6</title>
        <description>The CGI-S assesses the clinician's impression of the participant's current state of mental illness and consists of 1 question for the investigator: &quot;Considering your total clinical experience with this particular population, how mentally ill is the patient at this time?&quot; which is rated on a 7-point scale (1=normal, not ill at all; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill).</description>
        <time_frame>Baseline and Week 6</time_frame>
        <population>FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
          <group group_id="O2">
            <title>TAK-375SL 0.1 mg</title>
            <description>TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
          <group group_id="O3">
            <title>TAK-375SL 0.4 mg</title>
            <description>TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Clinical Global Impression Scale-Severity (CGI-S) to Week 6</title>
          <description>The CGI-S assesses the clinician's impression of the participant's current state of mental illness and consists of 1 question for the investigator: &quot;Considering your total clinical experience with this particular population, how mentally ill is the patient at this time?&quot; which is rated on a 7-point scale (1=normal, not ill at all; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill).</description>
          <population>FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy.</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="179"/>
                <count group_id="O2" value="167"/>
                <count group_id="O3" value="176"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline (n= 179, 167, 176)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.5" spread="0.04"/>
                    <measurement group_id="O2" value="4.5" spread="0.04"/>
                    <measurement group_id="O3" value="4.5" spread="0.04"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change at Week 6 (n= 149, 139, 143)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.4" spread="0.08"/>
                    <measurement group_id="O2" value="-1.3" spread="0.09"/>
                    <measurement group_id="O3" value="-1.4" spread="0.08"/>
                  </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>Superiority or Other</non_inferiority_type>
            <p_value>0.653</p_value>
            <p_value_desc>MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.</p_value_desc>
            <method>Mixed Model Repeated Measures</method>
            <param_type>Least Squares Mean Difference</param_type>
            <param_value>0.1</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.12</dispersion_value>
            <ci_percent>97.5</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.2</ci_lower_limit>
            <ci_upper_limit>0.3</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.673</p_value>
            <p_value_desc>MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.</p_value_desc>
            <method>Mixed Model Repeated Measures</method>
            <param_type>Least Squares Mean Difference</param_type>
            <param_value>-0.0</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.12</dispersion_value>
            <ci_percent>97.5</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.3</ci_lower_limit>
            <ci_upper_limit>0.2</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in the Quick Inventory of Depressive Symptomatology - Self-Rated16 (QIDS-SR16) Total Score at Week 6</title>
        <description>The 16-item QIDS-SR16 version is a widely used validated scale designed to assess the severity of depressive symptoms. The participant was asked to rate the severity and frequency of specific symptoms present over the last 7 days. The QIDS-SR16 total scores range from 0 to 27, where higher scores indicate higher severity of symptoms.</description>
        <time_frame>Baseline and Week 6</time_frame>
        <population>FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
          <group group_id="O2">
            <title>TAK-375SL 0.1 mg</title>
            <description>TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
          <group group_id="O3">
            <title>TAK-375SL 0.4 mg</title>
            <description>TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in the Quick Inventory of Depressive Symptomatology - Self-Rated16 (QIDS-SR16) Total Score at Week 6</title>
          <description>The 16-item QIDS-SR16 version is a widely used validated scale designed to assess the severity of depressive symptoms. The participant was asked to rate the severity and frequency of specific symptoms present over the last 7 days. The QIDS-SR16 total scores range from 0 to 27, where higher scores indicate higher severity of symptoms.</description>
          <population>FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy.</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="179"/>
                <count group_id="O2" value="167"/>
                <count group_id="O3" value="176"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline (n= 178, 167, 176)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14.8" spread="0.26"/>
                    <measurement group_id="O2" value="14.5" spread="0.27"/>
                    <measurement group_id="O3" value="14.2" spread="0.26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change at Week 6 (n= 148, 139, 143)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-7.2" spread="0.36"/>
                    <measurement group_id="O2" value="-6.4" spread="0.38"/>
                    <measurement group_id="O3" value="-7.3" 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>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.119</p_value>
            <p_value_desc>MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.</p_value_desc>
            <method>Mixed Model Repeated Measures</method>
            <param_type>Least Squares Mean Difference</param_type>
            <param_value>0.8</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.51</dispersion_value>
            <ci_percent>97.5</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.4</ci_lower_limit>
            <ci_upper_limit>2.0</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.791</p_value>
            <p_value_desc>MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.</p_value_desc>
            <method>Mixed Model Repeated Measures</method>
            <param_type>Least Squares Mean Difference</param_type>
            <param_value>-0.1</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.51</dispersion_value>
            <ci_percent>97.5</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-1.3</ci_lower_limit>
            <ci_upper_limit>1.0</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 6</title>
        <description>The SDS is a 3-item rating scale to assess functional impairment (panic, anxiety, phobic and depressive symptoms) over 3 inter-related domains (work/school, social life, and family life/home responsibilities) rated on an 11-point scale from 0 (not at all) to 10 (extremely) with a total score range from 0 to 30 where higher scores indicates greater severity of impairment.</description>
        <time_frame>Baseline and Week 6</time_frame>
        <population>FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
          <group group_id="O2">
            <title>TAK-375SL 0.1 mg</title>
            <description>TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
          <group group_id="O3">
            <title>TAK-375SL 0.4 mg</title>
            <description>TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 6</title>
          <description>The SDS is a 3-item rating scale to assess functional impairment (panic, anxiety, phobic and depressive symptoms) over 3 inter-related domains (work/school, social life, and family life/home responsibilities) rated on an 11-point scale from 0 (not at all) to 10 (extremely) with a total score range from 0 to 30 where higher scores indicates greater severity of impairment.</description>
          <population>FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy.</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="179"/>
                <count group_id="O2" value="167"/>
                <count group_id="O3" value="176"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline (n= 174, 163, 172)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="18.1" spread="0.43"/>
                    <measurement group_id="O2" value="17.1" spread="0.44"/>
                    <measurement group_id="O3" value="15.9" spread="0.43"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change at Week 6 (n= 148, 139, 143)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-6.8" spread="0.51"/>
                    <measurement group_id="O2" value="-6.2" spread="0.52"/>
                    <measurement group_id="O3" value="-6.4" spread="0.51"/>
                  </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>Superiority or Other</non_inferiority_type>
            <p_value>0.422</p_value>
            <p_value_desc>MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.</p_value_desc>
            <method>Mixed Model Repeated Measures</method>
            <param_type>Least Squares Mean Difference</param_type>
            <param_value>0.6</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.70</dispersion_value>
            <ci_percent>97.5</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-1.0</ci_lower_limit>
            <ci_upper_limit>2.1</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.655</p_value>
            <p_value_desc>MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.</p_value_desc>
            <method>Mixed Model Repeated Measures</method>
            <param_type>Least Squares Mean Difference</param_type>
            <param_value>0.3</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.70</dispersion_value>
            <ci_percent>97.5</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-1.3</ci_lower_limit>
            <ci_upper_limit>1.9</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Quality of Life, Enjoyment, and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) Total Score at Week 6</title>
        <description>Q-LES-Q-SF is a self-administered, widely used 16-item questionnaire to assess the degree of enjoyment and satisfaction experienced by participants in various areas of daily functioning, such as social relationships, living/housing, physical health, medication, and global satisfaction. The questionnaire consists of 16 items rated by the participants on a 5-point scale. Of these, 14 items are summed to produce a total quality of life score with a maximum of 70 points. In addition, there are 2 global items that are scored individually. These items rate satisfaction with study medication and overall life satisfaction. The questionnaire is usually scored as a percent of the total possible score, with higher scores indicating better health status.</description>
        <time_frame>Baseline and Week 6</time_frame>
        <population>FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
          <group group_id="O2">
            <title>TAK-375SL 0.1 mg</title>
            <description>TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
          <group group_id="O3">
            <title>TAK-375SL 0.4 mg</title>
            <description>TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Quality of Life, Enjoyment, and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) Total Score at Week 6</title>
          <description>Q-LES-Q-SF is a self-administered, widely used 16-item questionnaire to assess the degree of enjoyment and satisfaction experienced by participants in various areas of daily functioning, such as social relationships, living/housing, physical health, medication, and global satisfaction. The questionnaire consists of 16 items rated by the participants on a 5-point scale. Of these, 14 items are summed to produce a total quality of life score with a maximum of 70 points. In addition, there are 2 global items that are scored individually. These items rate satisfaction with study medication and overall life satisfaction. The questionnaire is usually scored as a percent of the total possible score, with higher scores indicating better health status.</description>
          <population>FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy.</population>
          <units>percentage of total possible score</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="179"/>
                <count group_id="O2" value="167"/>
                <count group_id="O3" value="176"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline (n= 174, 163, 172)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="38.3" spread="0.93"/>
                    <measurement group_id="O2" value="38.8" spread="0.95"/>
                    <measurement group_id="O3" value="41.0" spread="0.93"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change at Week 6 (n= 148, 139, 143)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="15.6" spread="1.19"/>
                    <measurement group_id="O2" value="14.7" spread="1.22"/>
                    <measurement group_id="O3" value="15.7" spread="1.21"/>
                  </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>Superiority or Other</non_inferiority_type>
            <p_value>0.696</p_value>
            <p_value_desc>MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.</p_value_desc>
            <method>Mixed Model Repeated Measures</method>
            <param_type>Least Squares Mean Difference</param_type>
            <param_value>-0.8</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>1.64</dispersion_value>
            <ci_percent>97.5</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-4.5</ci_lower_limit>
            <ci_upper_limit>2.8</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.472</p_value>
            <p_value_desc>MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.</p_value_desc>
            <method>Mixed Model Repeated Measures</method>
            <param_type>Least Squares Mean Difference</param_type>
            <param_value>0.1</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>1.63</dispersion_value>
            <ci_percent>97.5</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-3.6</ci_lower_limit>
            <ci_upper_limit>3.8</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants With MADRS Response</title>
        <description>MADRS response is defined as greater than or equal to (&gt;=) 50 percent (%) decrease in the MADRS total score from baseline. The MADRS is a clinician rated, validated and widely used scale to measure overall severity of depressive symptoms. It consists of 10-item rated from 0 (normal) to 6 (most abnormal) with a total score range from 0 to 60, where higher scores indicate greater severity of symptoms.</description>
        <time_frame>Week 6</time_frame>
        <population>FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy. Last observation carried forward (LOCF) method was used to impute missing data.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
          <group group_id="O2">
            <title>TAK-375SL 0.1 mg</title>
            <description>TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
          <group group_id="O3">
            <title>TAK-375SL 0.4 mg</title>
            <description>TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With MADRS Response</title>
          <description>MADRS response is defined as greater than or equal to (&gt;=) 50 percent (%) decrease in the MADRS total score from baseline. The MADRS is a clinician rated, validated and widely used scale to measure overall severity of depressive symptoms. It consists of 10-item rated from 0 (normal) to 6 (most abnormal) with a total score range from 0 to 60, where higher scores indicate greater severity of symptoms.</description>
          <population>FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy. Last observation carried forward (LOCF) method was used to impute missing data.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="179"/>
                <count group_id="O2" value="167"/>
                <count group_id="O3" value="176"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="43.6"/>
                    <measurement group_id="O2" value="43.1"/>
                    <measurement group_id="O3" value="40.3"/>
                  </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>Superiority or Other</non_inferiority_type>
            <p_value>0.994</p_value>
            <p_value_desc>Odds ratio, 95% confidence intervals and p-values are analyzed from logistic regression with explanatory variables for treatment and baseline MADRS total score.</p_value_desc>
            <method>Regression, Logistic</method>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>0.998</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.651</ci_lower_limit>
            <ci_upper_limit>1.530</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.575</p_value>
            <p_value_desc>Odds ratio, 95% confidence intervals and p-values are analyzed from logistic regression with explanatory variables for treatment and baseline MADRS total score.</p_value_desc>
            <method>Regression, Logistic</method>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>0.886</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.580</ci_lower_limit>
            <ci_upper_limit>1.352</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants With MADRS Remission</title>
        <description>MADRS remission is defined as a MADRS total score less than or equal to (&lt;=) 10. The MADRS is a clinician rated, validated and widely used scale to measure overall severity of depressive symptoms. It consists of 10-item rated from 0 (normal) to 6 (most abnormal) with a total score range from 0 to 60, where higher scores indicate greater severity of symptoms.</description>
        <time_frame>Week 6</time_frame>
        <population>FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy. LOCF method was used to impute missing data.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
          <group group_id="O2">
            <title>TAK-375SL 0.1 mg</title>
            <description>TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
          <group group_id="O3">
            <title>TAK-375SL 0.4 mg</title>
            <description>TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With MADRS Remission</title>
          <description>MADRS remission is defined as a MADRS total score less than or equal to (&lt;=) 10. The MADRS is a clinician rated, validated and widely used scale to measure overall severity of depressive symptoms. It consists of 10-item rated from 0 (normal) to 6 (most abnormal) with a total score range from 0 to 60, where higher scores indicate greater severity of symptoms.</description>
          <population>FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy. LOCF method was used to impute missing data.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="179"/>
                <count group_id="O2" value="167"/>
                <count group_id="O3" value="176"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="26.8"/>
                    <measurement group_id="O2" value="26.9"/>
                    <measurement group_id="O3" value="24.4"/>
                  </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>Superiority or Other</non_inferiority_type>
            <p_value>0.927</p_value>
            <p_value_desc>Odds ratio, 95% confidence intervals and p-values are analyzed from logistic regression with explanatory variables for treatment and baseline MADRS total score.</p_value_desc>
            <method>Regression, Logistic</method>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>0.978</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.606</ci_lower_limit>
            <ci_upper_limit>1.577</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.553</p_value>
            <p_value_desc>Odds ratio, 95% confidence intervals and p-values are analyzed from logistic regression with explanatory variables for treatment and baseline MADRS total score.</p_value_desc>
            <method>Regression, Logistic</method>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>0.865</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.536</ci_lower_limit>
            <ci_upper_limit>1.397</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 30 days for a serious adverse event after the last dose of double-blind study drug.</time_frame>
      <desc>At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.</desc>
      <group_list>
        <group group_id="E1">
          <title>Placebo</title>
          <description>TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.</description>
        </group>
        <group group_id="E2">
          <title>TAK-375SL 0.1 mg</title>
          <description>TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.</description>
        </group>
        <group group_id="E3">
          <title>TAK-375SL 0.4 mg</title>
          <description>TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (17.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="184"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="169"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="182"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="184"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="169"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="182"/>
              </event>
              <event>
                <sub_title>Pyelonephritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="184"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="169"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="182"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="184"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="169"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="182"/>
              </event>
              <event>
                <sub_title>Hypomania</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="184"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="169"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="182"/>
              </event>
              <event>
                <sub_title>Mania</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="184"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="169"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="182"/>
              </event>
              <event>
                <sub_title>Psychiatric symptom</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="184"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="169"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="182"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (17.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="18" subjects_at_risk="184"/>
                <counts group_id="E2" subjects_affected="14" subjects_at_risk="169"/>
                <counts group_id="E3" subjects_affected="10" subjects_at_risk="182"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="18" subjects_at_risk="184"/>
                <counts group_id="E2" subjects_affected="14" subjects_at_risk="169"/>
                <counts group_id="E3" subjects_affected="10" subjects_at_risk="182"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Medical Director</name_or_title>
      <organization>Takeda</organization>
      <phone>+1-877-825-3327</phone>
      <email>clinicaltrialregistry@tpna.com</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01677182
org study id: TAK-375SL_301
secondary id: 2012-001357-10
secondary id: U1111-1129-5184
secondary id: 12/EM/0391
nct id: NCT01677182
lead sponsor: 
has dmc: Yes
To evaluate the efficacy of ramelteon for treatment of acute depressive episodes associated
      with Bipolar 1 Disorder.
The drug being tested in this study is called Ramelteon. Ramelteon is being tested to treat
      people who have Bipolar 1 Disorder. This study will look at the symptoms of depression in
      people who take Ramelteon as a sub-lingual formulation.

      This study plans to enroll a minimum of 276 participants and a maximum of up to approximately
      870 participants Participants will be randomly assigned (by chance, like flipping a coin) to
      one of the three treatment groups-which will remain undisclosed to the patient and study
      doctor during the study (unless there is an urgent medical need):

        -  Ramelteon (Dose 1)

        -  Ramelteon (Dose 2)

        -  Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has
           no active ingredient All participants will be asked to take one tablet every night at
           bedtime throughout the study.

      This study plans to conduct one unblinded interim analysis after the first 276 subjects have
      been enrolled and treated for the 6-week double-blind treatment period. Based on the interim
      analysis, the study plans to adapt limited aspects of the design including: 1) to make no
      changes to the study; 2) to reassess sample size based on the interim analysis results.

      This multi-centre trial will be conducted in North America and Europe. The overall time to
      participate in this study is up to 14 weeks. Participants will make 8 visits to the clinic,
      and will be contacted by telephone 30 days after last dose of study drug for a follow-up
      assessment.

      An independent Data Monitoring Committee (DMC) recently performed a planned interim analysis
      of efficacy and safety data from this study. Upon completion of their review, the DMC advised
      that the unblinded interim data met the predefined efficacy criteria for study termination.
      No safety concerns were identified.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at Week 6
time frame: Baseline and Week 6
description: The MADRS is a clinician rated, validated and widely used scale to measure overall severity of depressive symptoms. It consists of 10-item rated from 0(normal) to 6(most abnormal) with a total score range from 0 to 60. Higher scores indicate greater severity of symptoms.
measure: Change From Baseline in Young Mania Rating Scale (YMRS) Total Score at Week 6
time frame: Baseline and Week 6
description: The YMRS is a 11-item scale to assess manic symptoms. Four items are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe), and 7 items are rated on a scale from 0 to 4 with higher scores reflecting greater levels of mania. The YMRS total score is calculated as the sum of the 11 individual item scores and ranges from 0-60.
measure: Clinical Global Impression Scale-Improvement (CGI-I) Score
time frame: Week 6
description: The CGI-I assesses the clinician's impression of the participant's state of mental illness improvement and consists of 1 question for the investigator: "Compared to his condition at the start of the study, how much has this patient changed?" which is rated on a 7-point scale (1=very much improved; 2=much improved; 3=minimally improved; 4=no change relative to baseline; 5=minimally worse; 6= much worse; 7=very much worse). In all cases, the assessment was independent of whether the rater believed the improvement was drug-related or not.
measure: Change From Baseline in Clinical Global Impression Scale-Severity (CGI-S) to Week 6
time frame: Baseline and Week 6
description: The CGI-S assesses the clinician's impression of the participant's current state of mental illness and consists of 1 question for the investigator: "Considering your total clinical experience with this particular population, how mentally ill is the patient at this time?" which is rated on a 7-point scale (1=normal, not ill at all; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill).
measure: Change From Baseline in the Quick Inventory of Depressive Symptomatology - Self-Rated16 (QIDS-SR16) Total Score at Week 6
time frame: Baseline and Week 6
description: The 16-item QIDS-SR16 version is a widely used validated scale designed to assess the severity of depressive symptoms. The participant was asked to rate the severity and frequency of specific symptoms present over the last 7 days. The QIDS-SR16 total scores range from 0 to 27, where higher scores indicate higher severity of symptoms.
measure: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 6
time frame: Baseline and Week 6
description: The SDS is a 3-item rating scale to assess functional impairment (panic, anxiety, phobic and depressive symptoms) over 3 inter-related domains (work/school, social life, and family life/home responsibilities) rated on an 11-point scale from 0 (not at all) to 10 (extremely) with a total score range from 0 to 30 where higher scores indicates greater severity of impairment.
measure: Change From Baseline in Quality of Life, Enjoyment, and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) Total Score at Week 6
time frame: Baseline and Week 6
description: Q-LES-Q-SF is a self-administered, widely used 16-item questionnaire to assess the degree of enjoyment and satisfaction experienced by participants in various areas of daily functioning, such as social relationships, living/housing, physical health, medication, and global satisfaction. The questionnaire consists of 16 items rated by the participants on a 5-point scale. Of these, 14 items are summed to produce a total quality of life score with a maximum of 70 points. In addition, there are 2 global items that are scored individually. These items rate satisfaction with study medication and overall life satisfaction. The questionnaire is usually scored as a percent of the total possible score, with higher scores indicating better health status.
measure: Percentage of Participants With MADRS Response
time frame: Week 6
description: MADRS response is defined as greater than or equal to (>=) 50 percent (%) decrease in the MADRS total score from baseline. The MADRS is a clinician rated, validated and widely used scale to measure overall severity of depressive symptoms. It consists of 10-item rated from 0 (normal) to 6 (most abnormal) with a total score range from 0 to 60, where higher scores indicate greater severity of symptoms.
measure: Percentage of Participants With MADRS Remission
time frame: Week 6
description: MADRS remission is defined as a MADRS total score less than or equal to (<=) 10. The MADRS is a clinician rated, validated and widely used scale to measure overall severity of depressive symptoms. It consists of 10-item rated from 0 (normal) to 6 (most abnormal) with a total score range from 0 to 60, where higher scores indicate greater severity of symptoms.
arm group label: Ramelteon SL (Dose 1)
arm group type: Experimental
description: Ramelteon SL tablets, sublingual, once daily, at night time for up to 6 weeks.
arm group label: Ramelteon (Dose 2)
arm group type: Experimental
description: Ramelteon SL tablets, sublingual, once daily, at night time for up to 6 weeks.
arm group label: Placebo
arm group type: Placebo Comparator
description: Ramelteon SL placebo-matching tablets, sublingual, once daily, at night time for up to 6 weeks.
intervention type: Drug
intervention name: Ramelteon
description: Ramelteon tablets for sublingual administration
arm group label: Ramelteon (Dose 2)
arm group label: Ramelteon SL (Dose 1)
other name: TAK-375SL
other name: Rozerem
intervention type: Drug
intervention name: Placebo
description: Ramelteon placebo-matching tablets for sublingual administration
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Medical Director Clinical Science
role: Study Director
affiliation: Takeda Global Research and Development Center, Inc.
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country: Bulgaria
country: Czech Republic
country: Germany
country: Poland
country: Romania
country: Russian Federation
country: Serbia
country: Ukraine
country: United Kingdom
country: United States
responsible party type: Sponsor
mesh term: Bipolar Disorder
participant flow: 
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outcome list: 
reported events: 
certain agreements: 
point of contact: 