Trial Outcomes & Findings for Efficacy and Safety of Ramelteon Sublingual in Adult Patients With Acute Depressive Episodes Associated With Bipolar I Disorder (NCT NCT01467700)

Last Updated: 2016-05-16

Results Overview

The change between MADRS score at week 6 relative to Baseline. MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (i.e., apparent sadness, reported sadness, inner tension, etc.) rated on a 7-point Likert scale from 0 (normal) to 6 (most abnormal) with a total score range from 0 to 60. Higher scores indicate greater severity of symptoms. A negative change from Baseline indicates improvement. A mixed measures repeated measures (MMRM) model was used for analysis with baseline\*week, pooled center, week, treatment, baseline, and week\*treatment as factors in the analysis.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

490 participants

Primary outcome timeframe

Baseline and Week 6

Results posted on

2016-05-16

Participant Flow

Participants took part in the study at 98 investigative sites in Argentina, Chile, Colombia, Mexico and the United States 12 December 2011 (first participant signed the informed consent form) to 10 March 2015.

Participants with a diagnosis of acute depressive episode were enrolled equally in 1 of 4 treatment groups, once a day placebo, ramelteon \[TAK-375 SL (sublingual)\] 0.1 mg, 0.4 mg or 0.8 mg.

Participant milestones

Participant milestones
Measure	Placebo Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 8 weeks.	Ramelteon SL 0.1 mg Ramelteon SL 0.1 mg, tablets, SL, once daily (QD), every night at bedtime for up to 8 weeks.	Ramelteon SL 0.4 mg Ramelteon SL 0.4 mg, tablets, SL, once daily, every night at bedtime for up to 8 weeks.	Ramelteon SL 0.8 mg Ramelteon SL 0.8 mg tablets, SL, once daily, every night at bedtime for up to 8 weeks.
Overall Study STARTED	115	128	124	123
Overall Study Safety Set - Received Treatment	115	127	124	123
Overall Study COMPLETED	86	100	97	96
Overall Study NOT COMPLETED	29	28	27	27

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 8 weeks.	Ramelteon SL 0.1 mg Ramelteon SL 0.1 mg, tablets, SL, once daily (QD), every night at bedtime for up to 8 weeks.	Ramelteon SL 0.4 mg Ramelteon SL 0.4 mg, tablets, SL, once daily, every night at bedtime for up to 8 weeks.	Ramelteon SL 0.8 mg Ramelteon SL 0.8 mg tablets, SL, once daily, every night at bedtime for up to 8 weeks.
Overall Study Pretreatment Event or Adverse Event	6	4	2	3
Overall Study Major Protocol Deviation	3	3	2	3
Overall Study Lost to Follow-up	6	5	2	3
Overall Study Voluntary Withdrawal	5	7	6	2
Overall Study Study Termination	6	5	10	7
Overall Study Pregnancy	0	1	1	0
Overall Study Lack of Efficacy	2	0	2	1
Overall Study Reason not Specified	1	3	2	8

Baseline Characteristics

Efficacy and Safety of Ramelteon Sublingual in Adult Patients With Acute Depressive Episodes Associated With Bipolar I Disorder

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=115 Participants Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 8 weeks.	Ramelteon SL 0.1 mg n=128 Participants Ramelteon SL 0.1 mg, tablets, SL, once daily (QD), every night at bedtime for up to 8 weeks.	Ramelteon SL 0.4 mg n=124 Participants Ramelteon SL 0.4 mg, tablets, SL, once daily, every night at bedtime for up to 8 weeks.	Ramelteon SL 0.8 mg n=123 Participants Ramelteon SL 0.8 mg tablets, SL, once daily, every night at bedtime for up to 8 weeks.	Total n=490 Participants Total of all reporting groups
Age, Continuous	44.95 years STANDARD_DEVIATION 10.867 • n=5 Participants	43.01 years STANDARD_DEVIATION 11.998 • n=7 Participants	42.96 years STANDARD_DEVIATION 13.211 • n=5 Participants	43.97 years STANDARD_DEVIATION 10.243 • n=4 Participants	43.69 years STANDARD_DEVIATION 11.646 • n=21 Participants
Age, Customized <=50 Years	85 participants n=5 Participants	92 participants n=7 Participants	88 participants n=5 Participants	97 participants n=4 Participants	362 participants n=21 Participants
Age, Customized >50 Years	30 participants n=5 Participants	36 participants n=7 Participants	36 participants n=5 Participants	26 participants n=4 Participants	128 participants n=21 Participants
Age, Customized <=65 years	111 participants n=5 Participants	126 participants n=7 Participants	119 participants n=5 Participants	121 participants n=4 Participants	477 participants n=21 Participants
Age, Customized >65 Years	4 participants n=5 Participants	2 participants n=7 Participants	5 participants n=5 Participants	2 participants n=4 Participants	13 participants n=21 Participants
Sex: Female, Male Female	74 Participants n=5 Participants	71 Participants n=7 Participants	78 Participants n=5 Participants	69 Participants n=4 Participants	292 Participants n=21 Participants
Sex: Female, Male Male	41 Participants n=5 Participants	57 Participants n=7 Participants	46 Participants n=5 Participants	54 Participants n=4 Participants	198 Participants n=21 Participants
Race/Ethnicity, Customized Hispanic or Latino	36 participants n=5 Participants	38 participants n=7 Participants	35 participants n=5 Participants	37 participants n=4 Participants	146 participants n=21 Participants
Race/Ethnicity, Customized Non-Hispanic and Non-Latino	79 participants n=5 Participants	90 participants n=7 Participants	89 participants n=5 Participants	86 participants n=4 Participants	344 participants n=21 Participants
Race/Ethnicity, Customized White	76 participants n=5 Participants	81 participants n=7 Participants	85 participants n=5 Participants	79 participants n=4 Participants	321 participants n=21 Participants
Race/Ethnicity, Customized Black	29 participants n=5 Participants	42 participants n=7 Participants	32 participants n=5 Participants	38 participants n=4 Participants	141 participants n=21 Participants
Race/Ethnicity, Customized Asian	3 participants n=5 Participants	0 participants n=7 Participants	2 participants n=5 Participants	0 participants n=4 Participants	5 participants n=21 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	5 participants n=5 Participants	3 participants n=7 Participants	0 participants n=5 Participants	4 participants n=4 Participants	12 participants n=21 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	1 participants n=4 Participants	3 participants n=21 Participants
Race/Ethnicity, Customized Multiple	1 participants n=5 Participants	2 participants n=7 Participants	4 participants n=5 Participants	1 participants n=4 Participants	8 participants n=21 Participants
Region of Enrollment United States	85 participants n=5 Participants	97 participants n=7 Participants	95 participants n=5 Participants	94 participants n=4 Participants	371 participants n=21 Participants
Region of Enrollment Argentina	12 participants n=5 Participants	11 participants n=7 Participants	11 participants n=5 Participants	11 participants n=4 Participants	45 participants n=21 Participants
Region of Enrollment Chile	5 participants n=5 Participants	5 participants n=7 Participants	6 participants n=5 Participants	3 participants n=4 Participants	19 participants n=21 Participants
Region of Enrollment Colombia	3 participants n=5 Participants	3 participants n=7 Participants	1 participants n=5 Participants	3 participants n=4 Participants	10 participants n=21 Participants
Region of Enrollment Mexico	10 participants n=5 Participants	12 participants n=7 Participants	11 participants n=5 Participants	12 participants n=4 Participants	45 participants n=21 Participants
Height	166.93 cm STANDARD_DEVIATION 10.345 • n=5 Participants	169.00 cm STANDARD_DEVIATION 9.937 • n=7 Participants	167.22 cm STANDARD_DEVIATION 9.677 • n=5 Participants	168.15 cm STANDARD_DEVIATION 10.590 • n=4 Participants	167.85 cm STANDARD_DEVIATION 10.139 • n=21 Participants
Weight	85.44 kg STANDARD_DEVIATION 20.034 • n=5 Participants	87.58 kg STANDARD_DEVIATION 21.555 • n=7 Participants	85.09 kg STANDARD_DEVIATION 20.873 • n=5 Participants	86.69 kg STANDARD_DEVIATION 21.535 • n=4 Participants	86.22 kg STANDARD_DEVIATION 20.989 • n=21 Participants
Body Mass Index (BMI)	30.62 kg/m^2 STANDARD_DEVIATION 6.778 • n=5 Participants	30.63 kg/m^2 STANDARD_DEVIATION 7.254 • n=7 Participants	30.37 kg/m^2 STANDARD_DEVIATION 6.808 • n=5 Participants	30.61 kg/m^2 STANDARD_DEVIATION 6.825 • n=4 Participants	30.56 kg/m^2 STANDARD_DEVIATION 6.904 • n=21 Participants
Smoking Classification Participant Has Never Smoked	47 participants n=5 Participants	55 participants n=7 Participants	49 participants n=5 Participants	45 participants n=4 Participants	196 participants n=21 Participants
Smoking Classification Participant is a Current Smoker	50 participants n=5 Participants	58 participants n=7 Participants	58 participants n=5 Participants	58 participants n=4 Participants	224 participants n=21 Participants
Smoking Classification Participant is an Ex-smoker	18 participants n=5 Participants	15 participants n=7 Participants	17 participants n=5 Participants	20 participants n=4 Participants	70 participants n=21 Participants
Participant Drinking Status Has Never Drunk	52 participants n=5 Participants	41 participants n=7 Participants	45 participants n=5 Participants	49 participants n=4 Participants	187 participants n=21 Participants
Participant Drinking Status Ex-Drinker	25 participants n=5 Participants	36 participants n=7 Participants	28 participants n=5 Participants	37 participants n=4 Participants	126 participants n=21 Participants
Participant Drinking Status Current Drinker	22 participants n=5 Participants	34 participants n=7 Participants	33 participants n=5 Participants	25 participants n=4 Participants	114 participants n=21 Participants
Participant Drinking Status Missing	16 participants n=5 Participants	17 participants n=7 Participants	18 participants n=5 Participants	12 participants n=4 Participants	63 participants n=21 Participants
If Drinker, Amount Consumed < 4 drinks per day	22 participants n=5 Participants	34 participants n=7 Participants	33 participants n=5 Participants	25 participants n=4 Participants	114 participants n=21 Participants
If Drinker, Amount Consumed >= 4 drinks per day	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	0 participants n=4 Participants	0 participants n=21 Participants
Does Participant Consume Caffeine? Yes	77 participants n=5 Participants	84 participants n=7 Participants	83 participants n=5 Participants	81 participants n=4 Participants	325 participants n=21 Participants
Does Participant Consume Caffeine? No	22 participants n=5 Participants	27 participants n=7 Participants	23 participants n=5 Participants	30 participants n=4 Participants	102 participants n=21 Participants
Does Participant Consume Caffeine? Missing	16 participants n=5 Participants	17 participants n=7 Participants	18 participants n=5 Participants	12 participants n=4 Participants	63 participants n=21 Participants

PRIMARY outcome

Timeframe: Baseline and Week 6

Population: Participants from full analysis set (FAS), all randomized participants who, received at least 1 dose of study drug, and had at least 1 valid post-baseline value for assessment of primary efficacy, with data available for analyses.

Outcome measures

Outcome measures
Measure	Placebo n=93 Participants Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 8 weeks.	Ramelteon SL 0.1 mg n=109 Participants Ramelteon SL 0.1 mg, tablets, SL, once daily (QD), every night at bedtime for up to 8 weeks.	Ramelteon SL 0.4 mg n=101 Participants Ramelteon SL 0.4 mg, tablets, SL, once daily, every night at bedtime for up to 8 weeks,	Ramelteon SL 0.8 mg n=103 Participants Ramelteon SL 0.8 mg tablets, SL, once daily, every night at bedtime for up to 8 weeks.
Change From Baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score at Week 6	-14.5 score on a scale Standard Error 0.94	-14.4 score on a scale Standard Error 0.89	-11.8 score on a scale Standard Error 0.91	-14.8 score on a scale Standard Error 0.91

SECONDARY outcome

Timeframe: Baseline and Week 6

Population: Participants from FAS, all randomized participants who, received at least 1 dose of study drug, and had at least 1 valid post-baseline value for assessment of primary efficacy, with data available for analyses.

Q-LES-Q -SF is a self-administered, 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 two 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 total possible score, with higher scores indicating better health status. A positive change from Baseline indicates improvement. A MMRM model was used for analysis with baseline\*week, pooled center, week, treatment, baseline, and week\*treatment as factors in the analysis.

Outcome measures

Outcome measures
Measure	Placebo n=82 Participants Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 8 weeks.	Ramelteon SL 0.1 mg n=95 Participants Ramelteon SL 0.1 mg, tablets, SL, once daily (QD), every night at bedtime for up to 8 weeks.	Ramelteon SL 0.4 mg n=85 Participants Ramelteon SL 0.4 mg, tablets, SL, once daily, every night at bedtime for up to 8 weeks,	Ramelteon SL 0.8 mg n=93 Participants Ramelteon SL 0.8 mg tablets, SL, once daily, every night at bedtime for up to 8 weeks.
Change From Baseline in Quality of Life, Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF) Short Form Total Score at Week 6	8.4 percent of maximum score on a scale Standard Error 1.67	13.1 percent of maximum score on a scale Standard Error 1.56	9.2 percent of maximum score on a scale Standard Error 1.61	14.8 percent of maximum score on a scale Standard Error 1.57

SECONDARY outcome

Timeframe: Baseline and Week 6

MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (i.e., apparent sadness, reported sadness, inner tension, etc.) rated on a 7-point Likert scale from 0 (normal) to 6 (most abnormal) with a total score range from 0 to 60. Higher scores indicate greater severity of symptoms.

Outcome measures

Outcome measures
Measure	Placebo n=93 Participants Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 8 weeks.	Ramelteon SL 0.1 mg n=109 Participants Ramelteon SL 0.1 mg, tablets, SL, once daily (QD), every night at bedtime for up to 8 weeks.	Ramelteon SL 0.4 mg n=101 Participants Ramelteon SL 0.4 mg, tablets, SL, once daily, every night at bedtime for up to 8 weeks,	Ramelteon SL 0.8 mg n=103 Participants Ramelteon SL 0.8 mg tablets, SL, once daily, every night at bedtime for up to 8 weeks.
Percentage of Participants With MADRS Response at Week 6, With Response Defined as a ≥ 50% Decrease in the MADRS Total Score From Baseline	45.2 percentage of participants	50.5 percentage of participants	47.5 percentage of participants	52.4 percentage of participants

SECONDARY outcome

Timeframe: Baseline and Week 6

The YMRS total score at week 6 relative to baseline. YMRS is a four item scale to assess manic symptoms, rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe), with 7 items rated on a scale from 0 (symptom not present) to 4 (symptom extremely severe) 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. Higher scores indicate greater severity of symptoms. A negative change from Baseline indicates improvement. A MMRM model was used for analyses with baseline\*week, pooled center, week, treatment, baseline, and week\*treatment as factors in the analysis.

Outcome measures

Outcome measures
Measure	Placebo n=93 Participants Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 8 weeks.	Ramelteon SL 0.1 mg n=109 Participants Ramelteon SL 0.1 mg, tablets, SL, once daily (QD), every night at bedtime for up to 8 weeks.	Ramelteon SL 0.4 mg n=101 Participants Ramelteon SL 0.4 mg, tablets, SL, once daily, every night at bedtime for up to 8 weeks,	Ramelteon SL 0.8 mg n=103 Participants Ramelteon SL 0.8 mg tablets, SL, once daily, every night at bedtime for up to 8 weeks.
Change From Baseline in Young Mania Rating Scale (YMRS) Total Score at Week 6	-0.9 score on a scale Standard Error 0.35	-0.8 score on a scale Standard Error 0.33	-0.7 score on a scale Standard Error 0.34	-0.4 score on a scale Standard Error 0.34

SECONDARY outcome

Timeframe: 6 Weeks

The CGI-I assesses the clinician's impression of the participant's state of mental illness improvement and consists of one 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 seven-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). Higher scores indicate greater severity of illness. A MMRM model was used for analysis with baseline\*week, pooled center, week, treatment, baseline, and week\*treatment as factors in the analysis.

Outcome measures

Outcome measures
Measure	Placebo n=93 Participants Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 8 weeks.	Ramelteon SL 0.1 mg n=109 Participants Ramelteon SL 0.1 mg, tablets, SL, once daily (QD), every night at bedtime for up to 8 weeks.	Ramelteon SL 0.4 mg n=101 Participants Ramelteon SL 0.4 mg, tablets, SL, once daily, every night at bedtime for up to 8 weeks,	Ramelteon SL 0.8 mg n=102 Participants Ramelteon SL 0.8 mg tablets, SL, once daily, every night at bedtime for up to 8 weeks.
Clinical Global Impression Scale-Improvement (CGI-I) Score at Week 6	2.6 score on a scale Standard Error 0.10	2.6 score on a scale Standard Error 0.10	2.8 score on a scale Standard Error 0.10	2.6 score on a scale Standard Error 0.10

SECONDARY outcome

Timeframe: Baseline and Week 6

The CGI-S at week 6 relative to Baseline. The CGI-S assesses the clinician's impression of the participant's current state of mental illness and consists of one 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 seven-point scale (1=normal, not ill at all; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill). Higher scores indicate greater severity of illness. A MMRM model was used for analysis with baseline\*week, pooled center, week, treatment, baseline, and week\*treatment as factors in the analysis.

Outcome measures

Outcome measures
Measure	Placebo n=93 Participants Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 8 weeks.	Ramelteon SL 0.1 mg n=109 Participants Ramelteon SL 0.1 mg, tablets, SL, once daily (QD), every night at bedtime for up to 8 weeks.	Ramelteon SL 0.4 mg n=101 Participants Ramelteon SL 0.4 mg, tablets, SL, once daily, every night at bedtime for up to 8 weeks,	Ramelteon SL 0.8 mg n=103 Participants Ramelteon SL 0.8 mg tablets, SL, once daily, every night at bedtime for up to 8 weeks.
Change From Baseline in Clinical Global Impression Scale-Severity (CGI-S) at Week 6	-1.3 score on a scale Standard Error 0.11	-1.3 score on a scale Standard Error 0.10	-1.1 score on a scale Standard Error 0.10	-1.3 score on a scale Standard Error 0.10

SECONDARY outcome

Timeframe: Week 6

Outcome measures

Outcome measures
Measure	Placebo n=93 Participants Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 8 weeks.	Ramelteon SL 0.1 mg n=109 Participants Ramelteon SL 0.1 mg, tablets, SL, once daily (QD), every night at bedtime for up to 8 weeks.	Ramelteon SL 0.4 mg n=101 Participants Ramelteon SL 0.4 mg, tablets, SL, once daily, every night at bedtime for up to 8 weeks,	Ramelteon SL 0.8 mg n=103 Participants Ramelteon SL 0.8 mg tablets, SL, once daily, every night at bedtime for up to 8 weeks.
Percentage of Participants With MADRS Remission at Week 6, With Remission Defined as a MADRS Total Score ≤10	30.1 percentage of participants	36.7 percentage of participants	31.7 percentage of participants	35.9 percentage of participants

SECONDARY outcome

Timeframe: Baseline and Week 6

The 16 item QIDS-SR16 version is designed to assess the severity of depressive symptoms. The QIDS-SR16 assesses all the criterion symptom domains designated by the American Psychiatry Association Diagnostic and Statistical Manual of Mental Disorders - 4th edition, DSM-IV, to diagnose a major depressive episode. QIDS-SR16 assessment has been used to screen for depression and also to measure symptom severity. This scale is also used to distinguish response from remission, as well as to quantify between group treatments effects in open label and randomized controlled trials. The patient is 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. Higher scores indicate greater severity of impairment. A negative change from Baseline indicates improvement. A MMRM model was used for analysis with baseline\*week, pooled center, week, treatment, baseline, and week\*treatment as factors in the analysis.

Outcome measures

Outcome measures
Measure	Placebo n=66 Participants Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 8 weeks.	Ramelteon SL 0.1 mg n=82 Participants Ramelteon SL 0.1 mg, tablets, SL, once daily (QD), every night at bedtime for up to 8 weeks.	Ramelteon SL 0.4 mg n=78 Participants Ramelteon SL 0.4 mg, tablets, SL, once daily, every night at bedtime for up to 8 weeks,	Ramelteon SL 0.8 mg n=78 Participants Ramelteon SL 0.8 mg tablets, SL, once daily, every night at bedtime for up to 8 weeks.
Change From Baseline in the Quick Inventory of Depressive Symptomatology - Self-Rated16 (QIDS-SR16) Total Score at Week 6	-6.1 score on a scale Standard Error 0.59	-6.2 score on a scale Standard Error 0.54	-4.3 score on a scale Standard Error 0.54	-6.2 score on a scale Standard Error 0.55

SECONDARY outcome

Timeframe: Baseline and Week 6

The SDS comprises patient-rated items designed to measure the extent to which the subject's life is impaired by panic, anxiety, phobic, or depressive symptoms. The participant rates the extent to which his or her (1) work, (2) social life or leisure activities, and (3) home life or family responsibilities, are impaired by his or her symptoms on 10-point visual analogue scales from 0 (not at all) to 10 (extremely) with a total score range from 0 to 30. Higher scores indicate greater severity of impairment. There are verbal descriptors for the points on the scales as well as numerical scores that provide more precise levels of the verbal descriptors. In addition, the SDS addresses the number of days lost and the number of days under-productive due to the symptoms. A negative change from Baseline indicates improvement. A MMRM model was used for analysis with baseline\*week, pooled center, week, treatment, baseline, and week\*treatment as factors in the analysis.

Outcome measures

Outcome measures
Measure	Placebo n=92 Participants Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 8 weeks.	Ramelteon SL 0.1 mg n=109 Participants Ramelteon SL 0.1 mg, tablets, SL, once daily (QD), every night at bedtime for up to 8 weeks.	Ramelteon SL 0.4 mg n=100 Participants Ramelteon SL 0.4 mg, tablets, SL, once daily, every night at bedtime for up to 8 weeks,	Ramelteon SL 0.8 mg n=102 Participants Ramelteon SL 0.8 mg tablets, SL, once daily, every night at bedtime for up to 8 weeks.
Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 6	-5.1 score on a scale Standard Error 0.71	-6.8 score on a scale Standard Error 0.66	-4.1 score on a scale Standard Error 0.67	-5.7 score on a scale Standard Error 0.68

Adverse Events

Placebo

Serious events: 4 serious events

Other events: 10 other events

Deaths: 0 deaths

Ramelteon SL 0.1 mg

Serious events: 5 serious events

Other events: 17 other events

Deaths: 0 deaths

Ramelteon SL 0.4 mg

Serious events: 3 serious events

Other events: 19 other events

Deaths: 0 deaths

Ramelteon SL 0.8 mg

Serious events: 1 serious events

Other events: 19 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=115 participants at risk Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 8 weeks.	Ramelteon SL 0.1 mg n=127 participants at risk Ramelteon SL 0.1 mg, tablets, SL, once daily (QD), every night at bedtime for up to 8 weeks.	Ramelteon SL 0.4 mg n=124 participants at risk Ramelteon SL 0.4 mg, tablets, SL, once daily, every night at bedtime for up to 8 weeks.	Ramelteon SL 0.8 mg n=123 participants at risk Ramelteon SL 0.8 mg tablets, SL, once daily, every night at bedtime for up to 8 weeks.
Injury, poisoning and procedural complications Toxicity to various agents	0.87% 1/115 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	0.00% 0/127 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	0.00% 0/124 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	0.00% 0/123 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.
Pregnancy, puerperium and perinatal conditions Abortion spontaneous	0.00% 0/115 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	0.79% 1/127 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	0.00% 0/124 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	0.00% 0/123 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.
Psychiatric disorders Suicidal ideation	2.6% 3/115 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	3.1% 4/127 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	0.00% 0/124 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	0.81% 1/123 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.
Psychiatric disorders Bipolar I disorder	0.00% 0/115 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	0.00% 0/127 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	1.6% 2/124 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	0.00% 0/123 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.
Psychiatric disorders Depression	0.00% 0/115 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	0.00% 0/127 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	0.81% 1/124 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	0.00% 0/123 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.
Psychiatric disorders Depressive symptom	0.87% 1/115 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	0.00% 0/127 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	0.00% 0/124 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	0.00% 0/123 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.
Psychiatric disorders Mania	0.87% 1/115 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	0.00% 0/127 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	0.00% 0/124 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	0.00% 0/123 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.
Respiratory, thoracic and mediastinal disorders Asthma	0.00% 0/115 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	0.00% 0/127 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	0.81% 1/124 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	0.00% 0/123 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.

Other adverse events

Other adverse events
Measure	Placebo n=115 participants at risk Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 8 weeks.	Ramelteon SL 0.1 mg n=127 participants at risk Ramelteon SL 0.1 mg, tablets, SL, once daily (QD), every night at bedtime for up to 8 weeks.	Ramelteon SL 0.4 mg n=124 participants at risk Ramelteon SL 0.4 mg, tablets, SL, once daily, every night at bedtime for up to 8 weeks.	Ramelteon SL 0.8 mg n=123 participants at risk Ramelteon SL 0.8 mg tablets, SL, once daily, every night at bedtime for up to 8 weeks.
Gastrointestinal disorders Dry mouth	0.87% 1/115 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	1.6% 2/127 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	6.5% 8/124 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	4.1% 5/123 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.
Infections and infestations Nasopharyngitis	1.7% 2/115 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	5.5% 7/127 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	1.6% 2/124 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	4.9% 6/123 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.
Nervous system disorders Headache	7.0% 8/115 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	2.4% 3/127 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	4.8% 6/124 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	4.9% 6/123 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.
Nervous system disorders Somnolence	0.00% 0/115 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	5.5% 7/127 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	4.0% 5/124 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.	4.1% 5/123 • Approximately 30 days after the last dose of study drug (up to 12 Weeks) 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.

Additional Information

Medical Director, Clinical Science

Takeda

Phone: +1-877-825-3327

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER