Safety and Efficacy Study of Ramelteon (TAK-375) Tablets for Sublingual Administration (SL) in Adults With Bipolar 1 Disorder
Condition: Bipolar Disorder
MeSH terms: Bipolar Disorder
Intervention: Ramelteon; Placebo
Intervention description: Ramelteon tablets for sublingual administration; Ramelteon placebo-matching tablets for sublingual administration
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 535.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Drug therapy

Summary:

      To evaluate the efficacy of ramelteon for treatment of acute depressive episodes associated
      with Bipolar 1 Disorder.
    

Eligibility criteria:

        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.