Overview

A Safety and Efficacy Study of Ramelteon Tablets for Sublingual Administration (TAK-375SL) in the Maintenance Treatment of Bipolar 1 Disorder

Status:
Withdrawn
Trial end date:
2015-11-01
Target enrollment:
0
Participant gender:
All
Summary
To evaluate the efficacy and safety of once a day ramelteon tablets for sublingual administration (TAK-375SL) in the maintenance treatment of bipolar 1 disorder.
Phase:
Phase 3
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
Takeda
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 a 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, 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 subject is a man or woman aged between 18 and 75 years, inclusive.

5. The subject has an identified caregiver or person responsible (eg. 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, hypomania) is between
8 weeks and 9 months prior to screening.

7. The subject has been stable in the opinion of the PI for at least 8 weeks prior to
baseline from their most recent mood episode.

8. The subject has a MADRS total score ≤12 at the Screening and Baseline visits.

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

10. The subject has a CGI-S score of ≤2 at the Screening and Baseline visits.

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

12. The subject's medications for bipolar 1 disorder are stable ie, no change in
psychotropic medications and no dose adjustment of psychotropic medications for
bipolar 1 disorder has been made for at least 8 weeks prior to the randomization.

13. A male subject who is nonsterilized and sexually active with a 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.

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.

Exclusion Criteria:

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

2. The subject has ever received TAK-375 or TAK-375 SL 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 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 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 as defined in the DSM-IV-TR, as assessed by the SCID.

2. Current or history of: schizophrenia or any other psychotic disorder, including
schizoaffective disorder, major depression with psychotic features, bipolar
depression with psychotic features (with the exception of psychosis associated
with a manic or mixed episode), OCD, mental retardation, organic mental
disorders, 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; only
exception is for benzodiazepines and opiates 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; only
exception is for benzodiazepines and opiates provided the subject has a valid
prescription).

5. Presence or history of a clinically significant neurological disorder (including
epilepsy) as determined by the investigator.

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: Subjects 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 subject is on any other medications other than antidepressants (except
fluvoxamine), mood stabilizers (lithium, valproate, lamotrigine), or atypical
antipsychotics (risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole,) for
bipolar 1 disorder. If the subject is on 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. If the subject is on any other psychotropic
medications, at the investigators discretion, withdrawal of these medications is
allowed two weeks prior to the baseline visit.

7. The subject is on no medications or taking only antidepressant medications (or taking
only other medications not commonly used as standard treatment for bipolar I disorder,
such as benzodiazepines).

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 from screening or plans to initiate such therapy during
the study (supportive therapy, marital therapy and bereavement counseling are
allowed).

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 is required to take excluded medications or it is anticipated that the
subject will require treatment with at least 1 of the disallowed concomitant
medications during the study.

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.

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 glycosylated hemoglobin (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 T4 will be checked if TSH is out of range. If free T4 is abnormal the subject
will be excluded.

18. Positive for Hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV)
antibodies, or 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 electrocardiogram (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 has a positive urine drug screen. NOTE: Positive urine drug screens for
benzodiazepines and opiates for which the subject has a valid prescription will be
allowed.

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