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

• Sponsor: Takeda (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01677182
• Collaborator: (none)
• Enrollment: 535
• Locations: 104
• Arms: 3
• Duration (Months): 25
• Patients Per Site: 5.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Bipolar Disorder	Drug: Ramelteon; Drug: Placebo	Phase 3

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 535 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Aug 1, 2012
• Actual Primary Completion Date: Aug 1, 2014
• Actual Study Completion Date: Sep 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ramelteon SL (Dose 1) Ramelteon SL tablets, sublingual, once daily, at night time for up to 6 weeks.	Drug: Ramelteon; Ramelteon tablets for sublingual administration; Other Names: TAK-375SL Rozerem
Experimental: Ramelteon (Dose 2) Ramelteon SL tablets, sublingual, once daily, at night time for up to 6 weeks.	Drug: Ramelteon; Ramelteon tablets for sublingual administration; Other Names: TAK-375SL Rozerem
Placebo Comparator: Placebo Ramelteon SL placebo-matching tablets, sublingual, once daily, at night time for up to 6 weeks.	Drug: Placebo; Ramelteon placebo-matching tablets for sublingual administration

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at Week 6 [Baseline and Week 6]

   The MADRS is a clinician rated, validated and widely used scale to measure overall severity of depressive symptoms. It consists of 10-item rated from 0(normal) to 6(most abnormal) with a total score range from 0 to 60. Higher scores indicate greater severity of symptoms.

Secondary Outcome Measures

1. Change From Baseline in Young Mania Rating Scale (YMRS) Total Score at Week 6 [Baseline and Week 6]

   The YMRS is a 11-item scale to assess manic symptoms. Four items are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe), and 7 items are rated on a scale from 0 to 4 with higher scores reflecting greater levels of mania. The YMRS total score is calculated as the sum of the 11 individual item scores and ranges from 0-60.

2. Clinical Global Impression Scale-Improvement (CGI-I) Score [Week 6]

   The CGI-I assesses the clinician's impression of the participant's state of mental illness improvement and consists of 1 question for the investigator: "Compared to his condition at the start of the study, how much has this patient changed?" which is rated on a 7-point scale (1=very much improved; 2=much improved; 3=minimally improved; 4=no change relative to baseline; 5=minimally worse; 6= much worse; 7=very much worse). In all cases, the assessment was independent of whether the rater believed the improvement was drug-related or not.

3. Change From Baseline in Clinical Global Impression Scale-Severity (CGI-S) to Week 6 [Baseline and Week 6]

   The CGI-S assesses the clinician's impression of the participant's current state of mental illness and consists of 1 question for the investigator: "Considering your total clinical experience with this particular population, how mentally ill is the patient at this time?" which is rated on a 7-point scale (1=normal, not ill at all; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill).

4. Change From Baseline in the Quick Inventory of Depressive Symptomatology - Self-Rated16 (QIDS-SR16) Total Score at Week 6 [Baseline and Week 6]

   The 16-item QIDS-SR16 version is a widely used validated scale designed to assess the severity of depressive symptoms. The participant was asked to rate the severity and frequency of specific symptoms present over the last 7 days. The QIDS-SR16 total scores range from 0 to 27, where higher scores indicate higher severity of symptoms.

5. Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 6 [Baseline and Week 6]

   The SDS is a 3-item rating scale to assess functional impairment (panic, anxiety, phobic and depressive symptoms) over 3 inter-related domains (work/school, social life, and family life/home responsibilities) rated on an 11-point scale from 0 (not at all) to 10 (extremely) with a total score range from 0 to 30 where higher scores indicates greater severity of impairment.

6. Change From Baseline in Quality of Life, Enjoyment, and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) Total Score at Week 6 [Baseline and Week 6]

   Q-LES-Q-SF is a self-administered, widely used 16-item questionnaire to assess the degree of enjoyment and satisfaction experienced by participants in various areas of daily functioning, such as social relationships, living/housing, physical health, medication, and global satisfaction. The questionnaire consists of 16 items rated by the participants on a 5-point scale. Of these, 14 items are summed to produce a total quality of life score with a maximum of 70 points. In addition, there are 2 global items that are scored individually. These items rate satisfaction with study medication and overall life satisfaction. The questionnaire is usually scored as a percent of the total possible score, with higher scores indicating better health status.

7. Percentage of Participants With MADRS Response [Week 6]

   MADRS response is defined as greater than or equal to (>=) 50 percent (%) decrease in the MADRS total score from baseline. The MADRS is a clinician rated, validated and widely used scale to measure overall severity of depressive symptoms. It consists of 10-item rated from 0 (normal) to 6 (most abnormal) with a total score range from 0 to 60, where higher scores indicate greater severity of symptoms.

8. Percentage of Participants With MADRS Remission [Week 6]

   MADRS remission is defined as a MADRS total score less than or equal to (<=) 10. The MADRS is a clinician rated, validated and widely used scale to measure overall severity of depressive symptoms. It consists of 10-item rated from 0 (normal) to 6 (most abnormal) with a total score range from 0 to 60, where higher scores indicate greater severity of symptoms.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

5. 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.

6. 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.

7. 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.

8. 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.

9. Presence or history of a clinically significant neurological disorder (including epilepsy).

10. Neurodegenerative disorder (Alzheimer disease, Parkinson disease, multiple sclerosis, Huntington disease, etc).

11. Any Axis II disorder that might compromise the study.

12. 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.

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

14. 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.

15. 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.

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

17. 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.

18. 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.

19. 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).

20. 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.

21. 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.

22. 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.

23. 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:

24. A serum creatinine value >1.5 times the upper limits of normal (xULN).

25. A serum total bilirubin value >1.5 xULN.

26. A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value

2 xULN.

1. 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.

2. 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.

3. 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.

4. 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.

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

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

7. 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.

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States
2		Anaheim	California	United States
3		Glendale	California	United States
4		Imperial	California	United States
5		Los Angeles	California	United States
6		Oakland	California	United States
7		Oceanside	California	United States
8		Pico Rivera	California	United States
9		San Diego	California	United States
10		Stanford	California	United States
11		Hartford	Connecticut	United States
12		Coral Springs	Florida	United States
13		Deerfield Beach	Florida	United States
14		Gainesville	Florida	United States
15		Jacksonville	Florida	United States
16		Maitland	Florida	United States
17		Oakland Park	Florida	United States
18		Orlando	Florida	United States
19		Tampa	Florida	United States
20		West Palm Beach	Florida	United States
21		Chicago	Illinois	United States
22		Joliet	Illinois	United States
23		Naperville	Illinois	United States
24		Oak Brook	Illinois	United States
25		Lafayette	Indiana	United States
26		Boston	Massachusetts	United States
27		Saint Louis	Missouri	United States
28		Bronx	New York	United States
29		Buffalo	New York	United States
30		New York	New York	United States
31		Staten Island	New York	United States
32		Avon Lake	Ohio	United States
33		Cincinnati	Ohio	United States
34		Garfield Heights	Ohio	United States
35		Mason	Ohio	United States
36		Oklahoma City	Oklahoma	United States
37		Memphis	Tennessee	United States
38		San Antonio	Texas	United States
39		Bothell	Washington	United States
40		Spokane	Washington	United States
41		Waukesha	Wisconsin	United States
42		Bourgas		Bulgaria
43		Kazanlak		Bulgaria
44		Lovech		Bulgaria
45		Novi Iskar		Bulgaria
46		Pleven		Bulgaria
47		Plovdiv		Bulgaria
48		Rousse		Bulgaria
49		Sofia		Bulgaria
50		Tzerova Koria		Bulgaria
51		Varna		Bulgaria
52		Brno		Czech Republic
53		Litomerice		Czech Republic
54		Olomouc		Czech Republic
55		Plzen		Czech Republic
56		Praha 10		Czech Republic
57		Praha 2		Czech Republic
58		Praha 6		Czech Republic
59		Praha 8		Czech Republic
60		Praha		Czech Republic
61		Bochum	NRW	Germany
62		Berlin		Germany
63		Westerstede		Germany
64		Bialystok		Poland
65		Choroszcz		Poland
66		Oradea	Bihor	Romania
67		Cluj-Napoca	Cluj	Romania
68		Targoviste	Dambovita	Romania
69		Craiova	Dolj	Romania
70		Arad		Romania
71		Bucuresti		Romania
72		Cluj-Napoca		Romania
73		Craiova		Romania
74		Iasi		Romania
75		Targoviste		Romania
76		Talagi	Arkhangelsk region	Russian Federation
77		Orenburg	Orenburg region	Russian Federation
78		Staritsa settlement	Orenburg region	Russian Federation
79		town. Tonnelniy	Stavropol region	Russian Federation
80		Arkhangelsk		Russian Federation
81		Moscow		Russian Federation
82		Nizhniy Novgorod		Russian Federation
83		Smolensk		Russian Federation
84		St. Petersburg		Russian Federation
85		Stavropol		Russian Federation
86		Kragujevac	Sumadija	Serbia
87		Novi Sad	Vojvodina	Serbia
88		Belgrade		Serbia
89		Kragujevac		Serbia
90		Nis		Serbia
91		Novi Knezevac		Serbia
92		Simferopol	Crimea	Ukraine
93		Oleksandrivka, Kominternivske District	Odesa Region	Ukraine
94		Simferopol	the Autonomous Republic of Crimea	Ukraine
95		Kharkiv		Ukraine
96		Luhansk		Ukraine
97		Odesa		Ukraine
98		Poltava		Ukraine
99		Ternopil		Ukraine
100		Vinnytsia		Ukraine
101		Oxford	Oxfordshire	United Kingdom
102		Birmingham		United Kingdom
103		London		United Kingdom
104		Newcastle upon Tyne		United Kingdom

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director Clinical Science, Takeda Global Research and Development Center, Inc.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Rozerem Package Insert

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT01677182
• Other Study ID Numbers: TAK-375SL_301; 2012-001357-10; U1111-1129-5184; 12/EM/0391
• First Posted: Aug 31, 2012
• Last Update Posted: Mar 16, 2016
• Last Verified: Feb 1, 2016

• Keywords provided by Takeda: Drug therapy
• Additional relevant MeSH terms: Bipolar Disorder

Study Results

Participant Flow

Recruitment Details	Participants took part at 98 sites in Bulgaria, the Czech Republic, Germany, Great Britain, Poland, Romania, Russia, Serbia, Ukraine, and the United States from 29 August 2012 to 03 September 2014.
Pre-assignment Detail	Participants with a historical diagnosis of bipolar 1 disorder were enrolled in 1 of 3 treatment groups as follows: placebo; TAK-375 0.1 milligram (mg); TAK-375 0.4 mg.

Arm/Group Title	Placebo	TAK-375SL 0.1 mg	TAK-375SL 0.4 mg
Arm/Group Description	TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.
Period Title: Overall Study
STARTED	184	169	182
COMPLETED	150	141	143
NOT COMPLETED	34	28	39

Baseline Characteristics

Arm/Group Title	Placebo	TAK-375SL 0.1 mg	TAK-375SL 0.4 mg	Total
Arm/Group Description	TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.	Total of all reporting groups
Overall Participants	184	169	182	535
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.67 (11.332)	45.44 (11.490)	44.87 (11.608)	45.67 (11.480)
Age, Customized (participants) [Number]
Less than or equal to (<=) 50 years	105 57.1%	100 59.2%	107 58.8%	312 58.3%
Greater than (>) 50 years	79 42.9%	69 40.8%	75 41.2%	223 41.7%
Sex: Female, Male (Count of Participants)
Female	119 64.7%	98 58%	108 59.3%	325 60.7%
Male	65 35.3%	71 42%	74 40.7%	210 39.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	12 6.5%	10 5.9%	9 4.9%	31 5.8%
Not Hispanic or Latino	63 34.2%	61 36.1%	63 34.6%	187 35%
Unknown or Not Reported	109 59.2%	98 58%	110 60.4%	317 59.3%
Race/Ethnicity, Customized (participants) [Number]
American Indian or Alaska Native	1 0.5%	1 0.6%	0 0%	2 0.4%
Asian	0 0%	1 0.6%	2 1.1%	3 0.6%
Native Hawaiian or Other Pacific Islander	1 0.5%	1 0.6%	1 0.5%	3 0.6%
Black or African American	11 6%	12 7.1%	12 6.6%	35 6.5%
White	171 92.9%	154 91.1%	166 91.2%	491 91.8%
More than one race	0 0%	0 0%	1 0.5%	1 0.2%
Region of Enrollment (participants) [Number]
Bulgaria	31 16.8%	27 16%	30 16.5%	88 16.4%
Czech Republic	9 4.9%	7 4.1%	8 4.4%	24 4.5%
Germany	3 1.6%	5 3%	3 1.6%	11 2.1%
United Kingdom	1 0.5%	0 0%	0 0%	1 0.2%
Poland	2 1.1%	4 2.4%	4 2.2%	10 1.9%
Romania	8 4.3%	7 4.1%	9 4.9%	24 4.5%
Russian Federation	12 6.5%	9 5.3%	13 7.1%	34 6.4%
Serbia	22 12%	20 11.8%	25 13.7%	67 12.5%
Ukraine	20 10.9%	19 11.2%	18 9.9%	57 10.7%
United States	76 41.3%	71 42%	72 39.6%	219 40.9%
Height (centimeter (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter (cm)]	168.86 (9.227)	170.66 (8.423)	169.80 (8.870)	169.75 (8.871)
Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	80.82 (23.503)	83.21 (18.638)	82.38 (19.202)	82.11 (20.605)
Body Mass Index (BMI) (kilogram per square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per square meter (kg/m^2)]	28.25 (7.583)	28.57 (6.130)	28.52 (6.156)	28.44 (6.663)
Smoking Classification (participants) [Number]
Had Never Smoked	84 45.7%	75 44.4%	79 43.4%	238 44.5%
Current Smoker	75 40.8%	70 41.4%	82 45.1%	227 42.4%
Ex-smoker	25 13.6%	24 14.2%	21 11.5%	70 13.1%
Subject Drinking Status (participants) [Number]
Had Never Drunk	97 52.7%	92 54.4%	109 59.9%	298 55.7%
Ex-Drinker	51 27.7%	41 24.3%	36 19.8%	128 23.9%
Current Drinker	36 19.6%	36 21.3%	37 20.3%	109 20.4%
Amount of Alcohol Consumed if Current Drinker (participants) [Number]
< 4 drinks per day	36 19.6%	36 21.3%	37 20.3%	109 20.4%
>= 4 drinks per day	0 0%	0 0%	0 0%	0 0%
Consumption of Caffeine (participants) [Number]
Consumer	140 76.1%	128 75.7%	144 79.1%	412 77%
Not a consumer	44 23.9%	41 24.3%	38 20.9%	123 23%
Psychiatric History for response to Lithium treatment for Bipolar 1 Disorder (participants) [Number]
Failed to Respond	7 3.8%	7 4.1%	7 3.8%	21 3.9%
Responded	101 54.9%	92 54.4%	100 54.9%	293 54.8%
Not Applicable	69 37.5%	63 37.3%	68 37.4%	200 37.4%
Unknown	7 3.8%	7 4.1%	7 3.8%	21 3.9%
Psychiatric History for response to Valproic Acid Treatment of Bipolar 1 Disorder (participants) [Number]
Failed to Respond	6 3.3%	8 4.7%	9 4.9%	23 4.3%
Responded	133 72.3%	124 73.4%	136 74.7%	393 73.5%
Not Applicable	35 19%	29 17.2%	27 14.8%	91 17%
Unknown	10 5.4%	8 4.7%	10 5.5%	28 5.2%
Female Reproductive Status (participants) [Number]
Postmenopausal	44 23.9%	30 17.8%	34 18.7%	108 20.2%
Surgically Sterile	20 10.9%	14 8.3%	12 6.6%	46 8.6%
Child-Bearing Potential	55 29.9%	54 32%	62 34.1%	171 32%
Not applicable (male participants)	65 35.3%	71 42%	74 40.7%	210 39.3%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at Week 6
Description	The MADRS is a clinician rated, validated and widely used scale to measure overall severity of depressive symptoms. It consists of 10-item rated from 0(normal) to 6(most abnormal) with a total score range from 0 to 60. Higher scores indicate greater severity of symptoms.
Time Frame	Baseline and Week 6

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy.

Arm/Group Title	Placebo	TAK-375SL 0.1 mg	TAK-375SL 0.4 mg
Arm/Group Description	TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.
Measure Participants	179	167	176
Baseline (n= 179, 167, 176)	30.8 (0.28)	30.2 (0.29)	30.4 (0.29)
Change at Week 6 (n= 149, 139, 143)	-14.7 (0.69)	-14.0 (0.71)	-15.1 (0.70)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-375SL 0.1 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.783
	Comments	Mixed Model Repeated Measures (MMRM) model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.
	Method	Mixed Model Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Differences
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 97.5%; -1.4 to 3.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.98
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-375SL 0.4 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.329
	Comments	MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.
	Method	Mixed Model Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 97.5%; -2.6 to 1.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.97
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Young Mania Rating Scale (YMRS) Total Score at Week 6
Description	The YMRS is a 11-item scale to assess manic symptoms. Four items are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe), and 7 items are rated on a scale from 0 to 4 with higher scores reflecting greater levels of mania. The YMRS total score is calculated as the sum of the 11 individual item scores and ranges from 0-60.
Time Frame	Baseline and Week 6

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy.

Arm/Group Title	Placebo	TAK-375SL 0.1 mg	TAK-375SL 0.4 mg
Arm/Group Description	TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.
Measure Participants	179	167	176
Baseline (n= 179, 167, 176)	4.4 (0.16)	4.3 (0.16)	4.4 (0.16)
Change at Week 6 (n= 149, 139, 143)	-1.4 (0.19)	-0.9 (0.20)	-1.5 (0.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-375SL 0.1 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.088
	Comments	MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.
	Method	Mixed Model Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 97.5%; -0.1 to 1.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.27
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-375SL 0.4 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.642
	Comments	MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.
	Method	Mixed Model Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 97.5%; -0.7 to 0.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.27
	Estimation Comments

3. Secondary Outcome

Title	Clinical Global Impression Scale-Improvement (CGI-I) Score
Description	The CGI-I assesses the clinician's impression of the participant's state of mental illness improvement and consists of 1 question for the investigator: "Compared to his condition at the start of the study, how much has this patient changed?" which is rated on a 7-point scale (1=very much improved; 2=much improved; 3=minimally improved; 4=no change relative to baseline; 5=minimally worse; 6= much worse; 7=very much worse). In all cases, the assessment was independent of whether the rater believed the improvement was drug-related or not.
Time Frame	Week 6

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy.

Arm/Group Title	Placebo	TAK-375SL 0.1 mg	TAK-375SL 0.4 mg
Arm/Group Description	TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.
Measure Participants	149	139	143
Least Squares Mean (Standard Error) [units on a scale]	2.5 (0.08)	2.5 (0.09)	2.3 (0.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-375SL 0.1 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.792
	Comments	MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.
	Method	Mixed Model Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 97.5%; -0.2 to 0.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-375SL 0.4 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.171
	Comments	MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.
	Method	Mixed Model Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 97.5%; -0.4 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in Clinical Global Impression Scale-Severity (CGI-S) to Week 6
Description	The CGI-S assesses the clinician's impression of the participant's current state of mental illness and consists of 1 question for the investigator: "Considering your total clinical experience with this particular population, how mentally ill is the patient at this time?" which is rated on a 7-point scale (1=normal, not ill at all; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill).
Time Frame	Baseline and Week 6

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy.

Arm/Group Title	Placebo	TAK-375SL 0.1 mg	TAK-375SL 0.4 mg
Arm/Group Description	TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.
Measure Participants	179	167	176
Baseline (n= 179, 167, 176)	4.5 (0.04)	4.5 (0.04)	4.5 (0.04)
Change at Week 6 (n= 149, 139, 143)	-1.4 (0.08)	-1.3 (0.09)	-1.4 (0.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-375SL 0.1 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.653
	Comments	MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.
	Method	Mixed Model Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 97.5%; -0.2 to 0.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-375SL 0.4 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.673
	Comments	MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.
	Method	Mixed Model Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.0
	Confidence Interval	(2-Sided) 97.5%; -0.3 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in the Quick Inventory of Depressive Symptomatology - Self-Rated16 (QIDS-SR16) Total Score at Week 6
Description	The 16-item QIDS-SR16 version is a widely used validated scale designed to assess the severity of depressive symptoms. The participant was asked to rate the severity and frequency of specific symptoms present over the last 7 days. The QIDS-SR16 total scores range from 0 to 27, where higher scores indicate higher severity of symptoms.
Time Frame	Baseline and Week 6

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy.

Arm/Group Title	Placebo	TAK-375SL 0.1 mg	TAK-375SL 0.4 mg
Arm/Group Description	TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.
Measure Participants	179	167	176
Baseline (n= 178, 167, 176)	14.8 (0.26)	14.5 (0.27)	14.2 (0.26)
Change at Week 6 (n= 148, 139, 143)	-7.2 (0.36)	-6.4 (0.38)	-7.3 (0.37)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-375SL 0.1 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.119
	Comments	MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.
	Method	Mixed Model Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 97.5%; -0.4 to 2.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.51
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-375SL 0.4 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.791
	Comments	MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.
	Method	Mixed Model Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 97.5%; -1.3 to 1.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.51
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 6
Description	The SDS is a 3-item rating scale to assess functional impairment (panic, anxiety, phobic and depressive symptoms) over 3 inter-related domains (work/school, social life, and family life/home responsibilities) rated on an 11-point scale from 0 (not at all) to 10 (extremely) with a total score range from 0 to 30 where higher scores indicates greater severity of impairment.
Time Frame	Baseline and Week 6

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy.

Arm/Group Title	Placebo	TAK-375SL 0.1 mg	TAK-375SL 0.4 mg
Arm/Group Description	TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.
Measure Participants	179	167	176
Baseline (n= 174, 163, 172)	18.1 (0.43)	17.1 (0.44)	15.9 (0.43)
Change at Week 6 (n= 148, 139, 143)	-6.8 (0.51)	-6.2 (0.52)	-6.4 (0.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-375SL 0.1 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.422
	Comments	MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.
	Method	Mixed Model Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.6
	Confidence Interval	(2-Sided) 97.5%; -1.0 to 2.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.70
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-375SL 0.4 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.655
	Comments	MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.
	Method	Mixed Model Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 97.5%; -1.3 to 1.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.70
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in Quality of Life, Enjoyment, and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) Total Score at Week 6
Description	Q-LES-Q-SF is a self-administered, widely used 16-item questionnaire to assess the degree of enjoyment and satisfaction experienced by participants in various areas of daily functioning, such as social relationships, living/housing, physical health, medication, and global satisfaction. The questionnaire consists of 16 items rated by the participants on a 5-point scale. Of these, 14 items are summed to produce a total quality of life score with a maximum of 70 points. In addition, there are 2 global items that are scored individually. These items rate satisfaction with study medication and overall life satisfaction. The questionnaire is usually scored as a percent of the total possible score, with higher scores indicating better health status.
Time Frame	Baseline and Week 6

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy.

Arm/Group Title	Placebo	TAK-375SL 0.1 mg	TAK-375SL 0.4 mg
Arm/Group Description	TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.
Measure Participants	179	167	176
Baseline (n= 174, 163, 172)	38.3 (0.93)	38.8 (0.95)	41.0 (0.93)
Change at Week 6 (n= 148, 139, 143)	15.6 (1.19)	14.7 (1.22)	15.7 (1.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-375SL 0.1 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.696
	Comments	MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.
	Method	Mixed Model Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.8
	Confidence Interval	(2-Sided) 97.5%; -4.5 to 2.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.64
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-375SL 0.4 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.472
	Comments	MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.
	Method	Mixed Model Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 97.5%; -3.6 to 3.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.63
	Estimation Comments

8. Secondary Outcome

Title	Percentage of Participants With MADRS Response
Description	MADRS response is defined as greater than or equal to (>=) 50 percent (%) decrease in the MADRS total score from baseline. The MADRS is a clinician rated, validated and widely used scale to measure overall severity of depressive symptoms. It consists of 10-item rated from 0 (normal) to 6 (most abnormal) with a total score range from 0 to 60, where higher scores indicate greater severity of symptoms.
Time Frame	Week 6

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy. Last observation carried forward (LOCF) method was used to impute missing data.

Arm/Group Title	Placebo	TAK-375SL 0.1 mg	TAK-375SL 0.4 mg
Arm/Group Description	TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.
Measure Participants	179	167	176
Number [percentage of participants]	43.6 23.7%	43.1 25.5%	40.3 22.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-375SL 0.1 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.994
	Comments	Odds ratio, 95% confidence intervals and p-values are analyzed from logistic regression with explanatory variables for treatment and baseline MADRS total score.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.998
	Confidence Interval	(2-Sided) 95%; 0.651 to 1.530
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-375SL 0.4 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.575
	Comments	Odds ratio, 95% confidence intervals and p-values are analyzed from logistic regression with explanatory variables for treatment and baseline MADRS total score.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.886
	Confidence Interval	(2-Sided) 95%; 0.580 to 1.352
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Percentage of Participants With MADRS Remission
Description	MADRS remission is defined as a MADRS total score less than or equal to (<=) 10. The MADRS is a clinician rated, validated and widely used scale to measure overall severity of depressive symptoms. It consists of 10-item rated from 0 (normal) to 6 (most abnormal) with a total score range from 0 to 60, where higher scores indicate greater severity of symptoms.
Time Frame	Week 6

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline value and at least 1 valid post-baseline value for assessment of primary efficacy. LOCF method was used to impute missing data.

Arm/Group Title	Placebo	TAK-375SL 0.1 mg	TAK-375SL 0.4 mg
Arm/Group Description	TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.
Measure Participants	179	167	176
Number [percentage of participants]	26.8 14.6%	26.9 15.9%	24.4 13.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-375SL 0.1 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.927
	Comments	Odds ratio, 95% confidence intervals and p-values are analyzed from logistic regression with explanatory variables for treatment and baseline MADRS total score.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.978
	Confidence Interval	(2-Sided) 95%; 0.606 to 1.577
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-375SL 0.4 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.553
	Comments	Odds ratio, 95% confidence intervals and p-values are analyzed from logistic regression with explanatory variables for treatment and baseline MADRS total score.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.865
	Confidence Interval	(2-Sided) 95%; 0.536 to 1.397
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 30 days for a serious adverse event after the last dose of double-blind study drug.
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Placebo		TAK-375SL 0.1 mg		TAK-375SL 0.4 mg
Arm/Group Description	TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.		TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.		TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.
All Cause Mortality
	Placebo		TAK-375SL 0.1 mg		TAK-375SL 0.4 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		TAK-375SL 0.1 mg		TAK-375SL 0.4 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/184 (0.5%)		0/169 (0%)		5/182 (2.7%)
Infections and infestations
Cellulitis	0/184 (0%)		0/169 (0%)		1/182 (0.5%)
Pyelonephritis	0/184 (0%)		0/169 (0%)		1/182 (0.5%)
Psychiatric disorders
Depression	0/184 (0%)		0/169 (0%)		1/182 (0.5%)
Hypomania	0/184 (0%)		0/169 (0%)		1/182 (0.5%)
Mania	0/184 (0%)		0/169 (0%)		1/182 (0.5%)
Psychiatric symptom	1/184 (0.5%)		0/169 (0%)		0/182 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		TAK-375SL 0.1 mg		TAK-375SL 0.4 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/184 (9.8%)		14/169 (8.3%)		10/182 (5.5%)
Nervous system disorders
Headache	18/184 (9.8%)		14/169 (8.3%)		10/182 (5.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.