Safety and Efficacy Study of Ramelteon (TAK-375) Tablets for Sublingual Administration (SL) in Adults With Bipolar 1 Disorder

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

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.

Inclusion Criteria:

1. In the opinion of the investigator, the subject is capable of understanding and complying with protocol requirements.
2. The subject or, when applicable, the subject'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 subject suffers from Bipolar 1 Disorder, Most Recent Episode Depressed as the primary diagnosis according to DSM-IV-TR criteria (classification code 296.5x) and confirmed by the SCID.
4. The subject is a man or woman aged between 18 and 75 years, inclusive.
5. The reported duration of the current Major Depressive Episode (MDE) is at least four weeks and less than 6 months.
6. The subject has a YMRS total score of ≤10 both at the Screening and Baseline Visits.
7. The subject has a MADRS total score of ≥24 at the Screening and Baseline Visits.
8. The subject has a CGI-S score of ≥4 at the Screening and Baseline Visits.
9. The subject has HAM- A total score of ≤21 at Screening and Baseline Visits.
10. The subject is on lithium and/or one other mood stabilizer (lamotrigine or valproic acid) and/or one atypical antipsychotic (risperidone or olanzapine or aripiprazole or ziprasidone). Patients may be on one, two, or three medications but no more than one from each group.
11. The subject is on the same dose of the protocol allowed medications (identified in inclusion # 10) for bipolar 1 disorder for at least two weeks prior to screening (and at least 6 weeks prior to screening for lamotrigine only). Further dose adjustments will not be allowed from screening until end of study, except for downward dose adjustments for adverse events.
12. If the subject is on lithium and/or valproic acid, the trough serum levels must be less than 1.2 mEq/L for lithium and the trough serum must be less than 125 mcg/ml for valproic acid. Downward dose adjustment is allowed to lower trough serum levels for lithium and/or valproic acid below the maximum allowed. This must be confirmed at least two weeks prior to baseline.
13. The subject screened must have <25% improvement in MADRS total score from screening to baseline visit with a minimum of two weeks between screening and baseline visits.
14. A female subject of childbearing potential who is sexually active with a nonsterilized 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 of the study drug.
15. A male subject who is nonsterilized and sexually active with female partner of childbearing potential agrees to use adequate contraception from signing of informed consent throughout the duration of the study and for 30 days after the last dose of study drug.

Exclusion Criteria:

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

2. The subject has received TAK-375 or TAK-375SL in a previous clinical study or has ever used ramelteon.

3. The subject is an immediate family member, study site employee, or is in a dependant 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 subject has one or more of the following:

   1. Any current psychiatric disorder which is the primary focus of treatment other than Bipolar 1 Disorder, Most Recent Episode Depressed as defined in the DSM-IV-TR, as assessed by the SCID.
   2. Current or history of: schizophrenia, schizoaffective disorder, unipolar depression with psychotic features, bipolar depression with psychotic features, any other psychotic disorder (with the exception of psychosis associated with a manic or mixed episode), mental retardation, organic mental disorders, OCD, or mental disorders due to a general medical condition as defined in the DSM-IV-TR.
   3. 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 least three months from the day of screening. (Subject must also have negative urine drug screen at Screening and Baseline). Note that a positive drug screen for opiates and benzodiazepines is allowed provided the subject has a valid prescription.
   4. 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 least three months from the day of screening. (Subject must also have negative urine drug screen at screening and Baseline). Note that a positive drug screen for opiates and benzodiazepines is allowed provided the subject has a valid prescription.
   5. Presence or history of a clinically significant neurological disorder (including epilepsy).
   6. Neurodegenerative disorder (Alzheimer disease, Parkinson disease, multiple sclerosis, Huntington disease, etc).
   7. Any Axis II disorder that might compromise the study.
   8. History of Rapid Cycling Bipolar Disorder: Patients who have more than 8 episodes of mood disorder per year. The episodes must meet both the duration and symptom criteria for a major depressive, manic, mixed, or hypomanic episode and must be demarcated by either a period of full remission or by a switch to an episode of the opposite polarity. manic, hypomanic, and mixed episodes are counted as being on the same pole. Each mood episode must be confirmed by appropriate patient history or formal diagnosis by medical practitioner.

5. The subject experienced the first episode of mood disorder after the age of 55 years.

6. The current depressive symptoms of the subject 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 medications approved for acute bipolar depression (e.g. quetiapine, olanzapine + fluoxetine [US only]) for at least 6 weeks duration each.

7. The subject is on any psychotropic medications other than the protocol allowed medications for at least 2 weeks prior to the Baseline visit. If a subject is taking any protocol excluded medications (e.g. antidepressants, typical antipsychotics) or is taking more than one of the allowed mood stabilizer and/or atypical antipsychotic medications, and if the patient is considered appropriate by the PI, these medications must be washed out for at least 2 weeks prior to the Baseline visit.

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

9. The subject 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.

10. The subject 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.

11. The subject has taken or is anticipated that the subject will take at least 1 of the disallowed concomitant medications that is listed in the Excluded Medications and Treatments (Table 7.a).

12. The subject 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.

13. The subject has a history or current diagnosis of fibromyalgia, chronic fatigue syndrome, chronic pain syndrome or sleep apnea (central and/or obstructive). If obstructive sleep apnea is corrected surgically, a polysomnogram showing normal apnea-hypopnea index is required.

14. The subject 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 subjects with basal cell or stage I squamous cell carcinoma of the skin.

15. The subject 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 subject has any of the following values at the Screening Visit:

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

16. The subject has HbA1C ≥7% at screening and no prior diagnosis of diabetes and/or treatment for diabetes. NOTE: Subjects with known diabetes are not excluded.

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

18. The subject is positive for hepatitis B surface antigen (HBsAg), antibodies to hepatitis C virus (HCV), or has a history of human immunodeficiency virus (HIV) infection.

19. If male, the subject intends to donate sperm during the course of this study or for 12 weeks thereafter. If female, the subject is pregnant or lactating or intending to become pregnant before, during, or within 30 days after participating in this study; or intending to donate ova during such time period.

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

21. The subject has an abnormal ECG as determined by the central reader and confirmed as clinically significant by the investigator.

22. 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.

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