Business Decision; No Safety Concerns.

The purpose of this study is to determine the efficacy and safety of ramelteon, once nightly before bedtime (QHS), sublingual (SL), in the maintenance treatment of Bipolar I Disorder in adult patients.

TAK-375SL (ramelteon sublingual formulation) is being developed by Takeda Pharmaceutical Company Limited as an adjunctive treatment in the maintenance therapy of bipolar I disorder.

Participants will be seen twice a month for the first two months and then once every month up to the end of the 9-month treatment period. Participants who complete the 9-month treatment period will have a follow-up visit approximately seven days after the last visit. A safety followup phone call will be made 30 days after completion of the 9-month treatment period.

Based on the recommendation of the Independent Data Monitoring Committee which determined that the study data had met pre-determined criteria for futility, Takeda has made a decision to terminate the study. No safety concerns were identified by the Independent Data Monitoring Committee

Inclusion Criteria:

1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.
3. The participant suffers from bipolar I disorder, according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria and is confirmed by the Structured Clinical Interview for DSM Disorders (SCID).
4. The participant is a man or woman aged between 18 and 75 years, inclusive.
5. The participant has an identified caregiver or person responsible (e.g. family member, spouse, case worker or nurse at a residential living (facility) that is considered reliable by the investigator.
6. The most recent mood episode (depression, mania, mixed episode) is within the past 9 months from screening.
7. The participant has been in remission in the opinion of the principal investigator (PI) for at least 8 weeks prior to baseline from their most recent mood episode.
8. The participant has a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≤12 at the Screening and Baseline visits.
9. The participant has a Young Mania Rating Scale (YMRS) score of ≤10 both at the Screening and Baseline visits.
10. The participant has a Clinical Global Impression Scale - Severity (CGI-S) score of ≤2 at the Screening and Baseline visits.
11. Hamilton Rating Scale for Anxiety (HAM-A) score is ≤21 at Screening and Baseline visits.
12. The participant's medications for bipolar I disorder are stable i.e., no dose adjustment has been made for at least 8 weeks prior to the randomization
13. A male participant who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception from signing of informed consent through the duration of the study and for 30 days after the last dose.
14. A female participant of childbearing potential who is sexually active with a non sterilized male partner agrees to use routinely adequate contraception from signing of informed consent throughout the duration of the study and for 30 days after the last dose.

Exclusion Criteria:

1. The participant has received any investigational compound <30 days before Screening or 5 half-lives prior to Screening.

2. The participant has ever received ramelteon in a previous clinical study or has ever used ramelteon.

3. The participant is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.

4. The participant has one or more of the following:

   • Any current psychiatric disorder which is the primary focus of treatment other than bipolar I disorder as defined in the DSM-IV-TR, as assessed by the SCID.
   • Current or history of: schizophrenia or any other psychotic disorder, including major depression with psychotic features, bipolar depression with psychotic features (with the exception of psychosis associated with a manic or mixed episode), obsessive-compulsive disorder (OCD), mental retardation, organic mental disorders, or mental disorders due to a general medical condition as defined in the DSM-IV-TR.
   • Current diagnosis or history of alcohol or other substance abuse (excluding nicotine or caffeine) as defined in the DSM-IV-TR that has not been in full and sustained remission for at three months from the day of screening (Participant must also have negative urine drug screen at Screening and Baseline; only exception is for benzodiazepines and opiates provided the participant has a valid prescription).
   • Current diagnosis or history of alcohol or other substance dependence (excluding nicotine or caffeine) as defined in the DSM-IV-TR that has not been in full and sustained remission for at six months from the day of screening.(Participant must also have negative urine drug screen at Screening and Baseline; only exception is for benzodiazepines and opiates provided the participant has a valid prescription).
   • Presence or history of a clinically significant neurological disorder (including epilepsy) as determined by the investigator.
   • Neurodegenerative disorder (Alzheimer disease, Parkinson disease, multiple sclerosis, Huntington disease, etc).
   • Any Axis II disorder that might compromise the study.
   • History of Rapid Cycling bipolar disorder: Patients who have more than 8 episodes of mood disorder per year.

5. The participant experienced the first episode of mood disorder after the age of 65 years.

6. The participant is on any other medications other than antidepressants (except fluvoxamine), mood stabilizers (lithium, valproate, lamotrigine), or atypical antipsychotics (risperidone, lithium and/or valproate, the levels should be in the specified range: lithium (serum levels up to 1.2 mEq/L); valproate (serum levels up to 125 mcg/ml) at screening.

7. The participant has received electroconvulsive therapy, vagal nerve stimulation, or repetitive transcranial magnetic stimulation within 6 months prior to Screening.

8. The participant has started receiving formal cognitive or behavioral therapy, systematic psychotherapy within 30 days from screening or plans to initiate such therapy during the study (supportive therapy, marital therapy and bereavement counseling are allowed).

9. The participant has a significant risk of suicide according to the investigator's clinical judgment or has a score ≥5 on item 10 (suicidal thoughts) of the MADRS or has made a suicide attempt in the previous 6 months.

10. The participant is required to take excluded medications or it is anticipated that the participant will require treatment with at least 1 of the disallowed concomitant medications during the study.

11. The participant has a clinically significant unstable illness, for example hepatic impairment or renal insufficiency, or a cardiovascular, pulmonary, gastrointestinal, endocrine, neurological, rheumatologic, immunologic, hematological, infectious, dermatological disorder or metabolic disturbance.

12. The participant has a history or current diagnosis of Fibromyalgia, Chronic Fatigue Syndrome, Chronic Pain Syndrome and Sleep apnea.

13. The participant has a previous history of cancer that had been in remission for less than 5 years prior to the first dose of study medication. This criterion does not include those participants with basal cell or stage I squamous cell carcinoma of the skin.

14. The participant has 1 or more laboratory value outside the normal range, based on the blood or urine samples taken at the Screening Visit, that are considered by the investigator to be clinically significant; or the participant has any of the following values at the Screening Visit:

    • A serum creatinine value >1.5 times the upper limits of normal (xULN).
    • A serum total bilirubin value >1.5 xULN.
    • A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value >2 xULN.

15. The participant has glycosylated hemoglobin (HbA1C) ≥7% at screening and no prior diagnosis of diabetes and/or treatment for diabetes. NOTE: Participants with known diabetes are not excluded.

16. The participant has a thyroid stimulating hormone (TSH) value outside the normal range at the Screening Visit that is deemed clinically significant by the investigator. NOTE: T4 will be checked if TSH is out of range. If T4 is abnormal the participant will be excluded.

17. The participant has clinically significant abnormal vital signs as determined by the investigator.

18. The participant has an abnormal electrocardiogram as determined by the central reader and confirmed as clinically significant by the investigator.

19. The participant has a disease or takes medication that, in the opinion of the investigator, could interfere with the assessments of safety, tolerability, or efficacy.

20. The participant has a positive urine drug screen. NOTE: Positive urine drug screens for benzodiazepines and opiates for which the participant has a valid prescription will be allowed.

21. The participant has a disease or takes medication that, in the opinion of the investigator, could interfere with the assessments of safety, tolerability, or efficacy.

22. The participant has a positive urine drug screen. NOTE: Positive urine drug screens for benzodiazepines and opiates for which the participant has a valid prescription will be allowed.

23. The participant, in the opinion of the investigator, is unlikely to comply with the clinical study protocol or is unsuitable for any reason.