Efficacy and Safety of Ramelteon Sublingual as Adjunctive Therapy for 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.

After careful consideration and in consultation with the Data Monitoring Committee, Takeda
has made the decision to terminate this study. This was a business decision. There were no
safety concerns.

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 PI for at least 8 weeks
prior to baseline from their most recent mood episode.

8. The participant has a MADRS total score ≤12 at the Screening and Baseline visits.

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

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