Efficacy and Safety of Ramelteon Sublingual in Adult Patients With Acute Depressive Episodes Associated With Bipolar I Disorder

Ramelteon sublingual formulation is being developed by Takeda Pharmaceutical Company Limited
for maintenance therapy of Bipolar I disorder.

Participants will be seen twice during the first week of treatment, weekly during the first
2 weeks of treatment and then every 2 weeks up to the end of the 8-week treatment period.
Participants who complete the 8-week treatment period will have a follow-up visit
approximately seven days after the last visit. A safety follow-up phone call will be made 30
days after completion of the 8-week treatment period.

After careful consideration and in consultation with the Data Monitoring Committee, Takeda
has made a decision to terminate this study. This is a business decision. There were no
safety or efficacy 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 is a man or woman aged between 18 and 75 years, inclusive.

4. The participant suffers from Bipolar I Disorder, Most Recent Episode Depressed as the
primary diagnosis according to DSM-IV-TR criteria (classification code 296.5x) and
confirmed by the Structured Clinical Interview for DSM Disorders (SCID).

5. The reported duration of the current Major Depressive Episode (MDE) is at least four
weeks and less than 12 months.

6. The participant has a YMRS score of ≤10 both at the Screening and Baseline visits.

7. The participant has a MADRS total score ≥24 at the Screening and Baseline Visits.

8. The participant has a CGI-S score of ≥4 at the Screening and Baseline Visits.

9. HAM-A score is ≤21 at Screening and Baseline visits.

10. The participant has a lithium and/or valproate levels within therapeutic range (0.6 -
1.2 mEq/L for lithium or 50-125 mcg/ml for valproate) at screening. If the patient
does not have a lithium and/or valproate level within therapeutic range at screening,
they must have a lithium and/or valproate levels within the therapeutic range between
Day - 15 to Day -30 of screening.

11. A female participant of childbearing potential who is sexually active and 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.

12. 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.

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 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 (e.g., spouse, parent, child, sibling) or may consent under duress.

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

- Any current psychiatric disorder other than Bipolar I Disorder, Most Recent
Episode Depressed as defined in the DSM-IV-TR, as assessed by the SCID.

- Current or history of: schizophrenia, unipolar depression with psychotic
features, bipolar depression with psychotic features, any other psychotic
disorder (with the exception of psychosis associated with a manic episode),
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 or dependence
(excluding nicotine or caffeine) as defined in the DSM-IV-TR that has not been
in full and sustained remission for at least one year from the day of screening.
(Participant must also have negative urine drug screen prior to Baseline).

- Presence or history of a clinically significant neurological disorder (including
epilepsy).

- 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 current depressive symptoms of the participant are considered by the investigator
to have been resistant to 2 adequate treatment trials with any of the mood
stabilizers (specifically started to treat the current depressive episode) and/or
antidepressant medications of at least 6 weeks duration each.

7. The participant is on any other psychotropic medications except for lithium (serum
levels 0.8 to mEq/L) or valproate (serum levels 50 to 125 mcg/ml) at the Screening
visit.

8. The participant is on lithium and/or valproate for less than 30 days prior to
screening.

9. If the participant is on antidepressant medications and/or antipsychotic medications
(used as a mood stabilizer) and the patient is considered appropriate by the PI,
these medications must be washed out for at least 2 weeks prior to the Screening
visit.

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

11. The participant has started receiving formal cognitive or behavioral therapy,
systematic psychotherapy within 30 days prior to screening or plans to initiate such
therapy during the study.

12. 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.

13. The participant has taken or is anticipated that the participant will take at least 1
of the disallowed concomitant medications.

14. 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 as determined by Investigator.

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

16. 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.

17. 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.

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

19. 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. If TSH is outside the normal range, a free T4 will be obtained.

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

21. The participant has an abnormal electrocardiogram (ECG) as determined by the central
reader and confirmed as clinically significant by the investigator.

22. 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.

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