Efficacy and Safety of Ramelteon Sublingual as Adjunctive Therapy for Maintenance Treatment of Bipolar I Disorder
Condition: Bipolar Disorder
MeSH terms: Bipolar Disorder
Intervention: Ramelteon SL; Placebo
Intervention description: Ramelteon sublingual (SL) tablets; Ramelteon sublingual (SL) placebo-matching tablets
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 642.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Drug Therapy

Summary:

      The purpose of this study is to determine the efficacy and safety of ramelteon, once nightly
      before bedtime (QHS), sublingual (SL), in the maintenance treatment of Bipolar I Disorder in
      adult patients.
    

Eligibility criteria:

        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 principal investigator
             (PI) for at least 8 weeks prior to baseline from their most recent mood episode.

          8. The participant has a Montgomery-Åsberg Depression Rating Scale (MADRS) total score
             ≤12 at the Screening and Baseline visits.

          9. The participant has a Young Mania Rating Scale (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 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.

         14. A female participant 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 participant 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 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.

         23. The participant, in the opinion of the investigator, is unlikely to comply with the
             clinical study protocol or is unsuitable for any reason.