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

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.