Trial Outcomes & Findings for Safety and Efficacy Study of Ramelteon (TAK-375) Tablets for Sublingual Administration (SL) in Adults With Bipolar 1 Disorder (NCT NCT01677182)

Last Updated: 2016-03-16

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

535 participants

Primary outcome timeframe

Baseline and Week 6

Results posted on

2016-03-16

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	Placebo TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.1 mg TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.4 mg TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.
Overall Study STARTED	184	169	182
Overall Study COMPLETED	150	141	143
Overall Study NOT COMPLETED	34	28	39

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.1 mg TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.4 mg TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.
Overall Study Adverse Event	2	1	8
Overall Study Protocol Violation	5	1	4
Overall Study Lost to Follow-up	4	0	3
Overall Study Withdrawal by Subject	7	12	10
Overall Study Study termination	12	9	11
Overall Study Lack of Efficacy	3	0	1
Overall Study Other reasons	1	5	2

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=184 Participants TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.1 mg n=169 Participants TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.4 mg n=182 Participants TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.	Total n=535 Participants Total of all reporting groups
Age, Continuous	46.67 years STANDARD_DEVIATION 11.332 • n=5 Participants	45.44 years STANDARD_DEVIATION 11.490 • n=7 Participants	44.87 years STANDARD_DEVIATION 11.608 • n=5 Participants	45.67 years STANDARD_DEVIATION 11.480 • n=4 Participants
Age, Customized Less than or equal to (<=) 50 years	105 participants n=5 Participants	100 participants n=7 Participants	107 participants n=5 Participants	312 participants n=4 Participants
Age, Customized Greater than (>) 50 years	79 participants n=5 Participants	69 participants n=7 Participants	75 participants n=5 Participants	223 participants n=4 Participants
Sex: Female, Male Female	119 Participants n=5 Participants	98 Participants n=7 Participants	108 Participants n=5 Participants	325 Participants n=4 Participants
Sex: Female, Male Male	65 Participants n=5 Participants	71 Participants n=7 Participants	74 Participants n=5 Participants	210 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	12 Participants n=5 Participants	10 Participants n=7 Participants	9 Participants n=5 Participants	31 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	63 Participants n=5 Participants	61 Participants n=7 Participants	63 Participants n=5 Participants	187 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	109 Participants n=5 Participants	98 Participants n=7 Participants	110 Participants n=5 Participants	317 Participants n=4 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	1 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	2 participants n=4 Participants
Race/Ethnicity, Customized Asian	0 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants	3 participants n=4 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	1 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants	3 participants n=4 Participants
Race/Ethnicity, Customized Black or African American	11 participants n=5 Participants	12 participants n=7 Participants	12 participants n=5 Participants	35 participants n=4 Participants
Race/Ethnicity, Customized White	171 participants n=5 Participants	154 participants n=7 Participants	166 participants n=5 Participants	491 participants n=4 Participants
Race/Ethnicity, Customized More than one race	0 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	1 participants n=4 Participants
Region of Enrollment Bulgaria	31 participants n=5 Participants	27 participants n=7 Participants	30 participants n=5 Participants	88 participants n=4 Participants
Region of Enrollment Czech Republic	9 participants n=5 Participants	7 participants n=7 Participants	8 participants n=5 Participants	24 participants n=4 Participants
Region of Enrollment Germany	3 participants n=5 Participants	5 participants n=7 Participants	3 participants n=5 Participants	11 participants n=4 Participants
Region of Enrollment United Kingdom	1 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	1 participants n=4 Participants
Region of Enrollment Poland	2 participants n=5 Participants	4 participants n=7 Participants	4 participants n=5 Participants	10 participants n=4 Participants
Region of Enrollment Romania	8 participants n=5 Participants	7 participants n=7 Participants	9 participants n=5 Participants	24 participants n=4 Participants
Region of Enrollment Russian Federation	12 participants n=5 Participants	9 participants n=7 Participants	13 participants n=5 Participants	34 participants n=4 Participants
Region of Enrollment Serbia	22 participants n=5 Participants	20 participants n=7 Participants	25 participants n=5 Participants	67 participants n=4 Participants
Region of Enrollment Ukraine	20 participants n=5 Participants	19 participants n=7 Participants	18 participants n=5 Participants	57 participants n=4 Participants
Region of Enrollment United States	76 participants n=5 Participants	71 participants n=7 Participants	72 participants n=5 Participants	219 participants n=4 Participants
Height	168.86 centimeter (cm) STANDARD_DEVIATION 9.227 • n=5 Participants	170.66 centimeter (cm) STANDARD_DEVIATION 8.423 • n=7 Participants	169.80 centimeter (cm) STANDARD_DEVIATION 8.870 • n=5 Participants	169.75 centimeter (cm) STANDARD_DEVIATION 8.871 • n=4 Participants
Weight	80.82 kilogram (kg) STANDARD_DEVIATION 23.503 • n=5 Participants	83.21 kilogram (kg) STANDARD_DEVIATION 18.638 • n=7 Participants	82.38 kilogram (kg) STANDARD_DEVIATION 19.202 • n=5 Participants	82.11 kilogram (kg) STANDARD_DEVIATION 20.605 • n=4 Participants
Body Mass Index (BMI)	28.25 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 7.583 • n=5 Participants	28.57 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.130 • n=7 Participants	28.52 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.156 • n=5 Participants	28.44 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.663 • n=4 Participants
Smoking Classification Had Never Smoked	84 participants n=5 Participants	75 participants n=7 Participants	79 participants n=5 Participants	238 participants n=4 Participants
Smoking Classification Current Smoker	75 participants n=5 Participants	70 participants n=7 Participants	82 participants n=5 Participants	227 participants n=4 Participants
Smoking Classification Ex-smoker	25 participants n=5 Participants	24 participants n=7 Participants	21 participants n=5 Participants	70 participants n=4 Participants
Subject Drinking Status Had Never Drunk	97 participants n=5 Participants	92 participants n=7 Participants	109 participants n=5 Participants	298 participants n=4 Participants
Subject Drinking Status Ex-Drinker	51 participants n=5 Participants	41 participants n=7 Participants	36 participants n=5 Participants	128 participants n=4 Participants
Subject Drinking Status Current Drinker	36 participants n=5 Participants	36 participants n=7 Participants	37 participants n=5 Participants	109 participants n=4 Participants
Amount of Alcohol Consumed if Current Drinker < 4 drinks per day	36 participants n=5 Participants	36 participants n=7 Participants	37 participants n=5 Participants	109 participants n=4 Participants
Amount of Alcohol Consumed if Current Drinker >= 4 drinks per day	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	0 participants n=4 Participants
Consumption of Caffeine Consumer	140 participants n=5 Participants	128 participants n=7 Participants	144 participants n=5 Participants	412 participants n=4 Participants
Consumption of Caffeine Not a consumer	44 participants n=5 Participants	41 participants n=7 Participants	38 participants n=5 Participants	123 participants n=4 Participants
Psychiatric History for response to Lithium treatment for Bipolar 1 Disorder Failed to Respond	7 participants n=5 Participants	7 participants n=7 Participants	7 participants n=5 Participants	21 participants n=4 Participants
Psychiatric History for response to Lithium treatment for Bipolar 1 Disorder Responded	101 participants n=5 Participants	92 participants n=7 Participants	100 participants n=5 Participants	293 participants n=4 Participants
Psychiatric History for response to Lithium treatment for Bipolar 1 Disorder Not Applicable	69 participants n=5 Participants	63 participants n=7 Participants	68 participants n=5 Participants	200 participants n=4 Participants
Psychiatric History for response to Lithium treatment for Bipolar 1 Disorder Unknown	7 participants n=5 Participants	7 participants n=7 Participants	7 participants n=5 Participants	21 participants n=4 Participants
Psychiatric History for response to Valproic Acid Treatment of Bipolar 1 Disorder Failed to Respond	6 participants n=5 Participants	8 participants n=7 Participants	9 participants n=5 Participants	23 participants n=4 Participants
Psychiatric History for response to Valproic Acid Treatment of Bipolar 1 Disorder Responded	133 participants n=5 Participants	124 participants n=7 Participants	136 participants n=5 Participants	393 participants n=4 Participants
Psychiatric History for response to Valproic Acid Treatment of Bipolar 1 Disorder Not Applicable	35 participants n=5 Participants	29 participants n=7 Participants	27 participants n=5 Participants	91 participants n=4 Participants
Psychiatric History for response to Valproic Acid Treatment of Bipolar 1 Disorder Unknown	10 participants n=5 Participants	8 participants n=7 Participants	10 participants n=5 Participants	28 participants n=4 Participants
Female Reproductive Status Postmenopausal	44 participants n=5 Participants	30 participants n=7 Participants	34 participants n=5 Participants	108 participants n=4 Participants
Female Reproductive Status Surgically Sterile	20 participants n=5 Participants	14 participants n=7 Participants	12 participants n=5 Participants	46 participants n=4 Participants
Female Reproductive Status Child-Bearing Potential	55 participants n=5 Participants	54 participants n=7 Participants	62 participants n=5 Participants	171 participants n=4 Participants
Female Reproductive Status Not applicable (male participants)	65 participants n=5 Participants	71 participants n=7 Participants	74 participants n=5 Participants	210 participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline and Week 6

Population: 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.

Outcome measures

Outcome measures
Measure	Placebo n=179 Participants TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.1 mg n=167 Participants TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.4 mg n=176 Participants TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.
Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at Week 6 Baseline (n= 179, 167, 176)	30.8 units on scale Standard Error 0.28	30.2 units on scale Standard Error 0.29	30.4 units on scale Standard Error 0.29
Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at Week 6 Change at Week 6 (n= 149, 139, 143)	-14.7 units on scale Standard Error 0.69	-14.0 units on scale Standard Error 0.71	-15.1 units on scale Standard Error 0.70

SECONDARY outcome

Timeframe: Baseline and Week 6

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=179 Participants TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.1 mg n=167 Participants TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.4 mg n=176 Participants TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.
Change From Baseline in Young Mania Rating Scale (YMRS) Total Score at Week 6 Baseline (n= 179, 167, 176)	4.4 units on a scale Standard Error 0.16	4.3 units on a scale Standard Error 0.16	4.4 units on a scale Standard Error 0.16
Change From Baseline in Young Mania Rating Scale (YMRS) Total Score at Week 6 Change at Week 6 (n= 149, 139, 143)	-1.4 units on a scale Standard Error 0.19	-0.9 units on a scale Standard Error 0.20	-1.5 units on a scale Standard Error 0.20

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=149 Participants TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.1 mg n=139 Participants TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.4 mg n=143 Participants TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.
Clinical Global Impression Scale-Improvement (CGI-I) Score	2.5 units on a scale Standard Error 0.08	2.5 units on a scale Standard Error 0.09	2.3 units on a scale Standard Error 0.09

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Placebo n=179 Participants TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.1 mg n=167 Participants TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.4 mg n=176 Participants TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.
Change From Baseline in Clinical Global Impression Scale-Severity (CGI-S) to Week 6 Baseline (n= 179, 167, 176)	4.5 units on a scale Standard Error 0.04	4.5 units on a scale Standard Error 0.04	4.5 units on a scale Standard Error 0.04
Change From Baseline in Clinical Global Impression Scale-Severity (CGI-S) to Week 6 Change at Week 6 (n= 149, 139, 143)	-1.4 units on a scale Standard Error 0.08	-1.3 units on a scale Standard Error 0.09	-1.4 units on a scale Standard Error 0.08

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=179 Participants TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.1 mg n=167 Participants TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.4 mg n=176 Participants TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.
Change From Baseline in the Quick Inventory of Depressive Symptomatology - Self-Rated16 (QIDS-SR16) Total Score at Week 6 Baseline (n= 178, 167, 176)	14.8 units on a scale Standard Error 0.26	14.5 units on a scale Standard Error 0.27	14.2 units on a scale Standard Error 0.26
Change From Baseline in the Quick Inventory of Depressive Symptomatology - Self-Rated16 (QIDS-SR16) Total Score at Week 6 Change at Week 6 (n= 148, 139, 143)	-7.2 units on a scale Standard Error 0.36	-6.4 units on a scale Standard Error 0.38	-7.3 units on a scale Standard Error 0.37

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=179 Participants TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.1 mg n=167 Participants TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.4 mg n=176 Participants TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.
Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 6 Change at Week 6 (n= 148, 139, 143)	-6.8 units on a scale Standard Error 0.51	-6.2 units on a scale Standard Error 0.52	-6.4 units on a scale Standard Error 0.51
Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 6 Baseline (n= 174, 163, 172)	18.1 units on a scale Standard Error 0.43	17.1 units on a scale Standard Error 0.44	15.9 units on a scale Standard Error 0.43

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=179 Participants TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.1 mg n=167 Participants TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.4 mg n=176 Participants TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.
Change From Baseline in Quality of Life, Enjoyment, and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) Total Score at Week 6 Baseline (n= 174, 163, 172)	38.3 percentage of total possible score Standard Error 0.93	38.8 percentage of total possible score Standard Error 0.95	41.0 percentage of total possible score Standard Error 0.93
Change From Baseline in Quality of Life, Enjoyment, and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) Total Score at Week 6 Change at Week 6 (n= 148, 139, 143)	15.6 percentage of total possible score Standard Error 1.19	14.7 percentage of total possible score Standard Error 1.22	15.7 percentage of total possible score Standard Error 1.21

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=179 Participants TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.1 mg n=167 Participants TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.4 mg n=176 Participants TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.
Percentage of Participants With MADRS Response	43.6 percentage of participants	43.1 percentage of participants	40.3 percentage of participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=179 Participants TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.1 mg n=167 Participants TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.4 mg n=176 Participants TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.
Percentage of Participants With MADRS Remission	26.8 percentage of participants	26.9 percentage of participants	24.4 percentage of participants

Adverse Events

Placebo

Serious events: 1 serious events

Other events: 18 other events

Deaths: 0 deaths

TAK-375SL 0.1 mg

Serious events: 0 serious events

Other events: 14 other events

Deaths: 0 deaths

TAK-375SL 0.4 mg

Serious events: 5 serious events

Other events: 10 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=184 participants at risk TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.1 mg n=169 participants at risk TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.4 mg n=182 participants at risk TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.
Infections and infestations Cellulitis	0.00% 0/184 • 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. 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% 0/169 • 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. 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.	0.55% 1/182 • 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. 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 Pyelonephritis	0.00% 0/184 • 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. 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% 0/169 • 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. 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.	0.55% 1/182 • 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. 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% 0/184 • 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. 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% 0/169 • 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. 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.	0.55% 1/182 • 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. 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 Hypomania	0.00% 0/184 • 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. 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% 0/169 • 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. 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.	0.55% 1/182 • 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. 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	0.00% 0/184 • 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. 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% 0/169 • 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. 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.	0.55% 1/182 • 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. 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 Psychiatric symptom	0.54% 1/184 • 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. 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% 0/169 • 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. 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% 0/182 • 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. 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=184 participants at risk TAK-375SL (ramelteon) placebo-matching tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.1 mg n=169 participants at risk TAK-375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.	TAK-375SL 0.4 mg n=182 participants at risk TAK-375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.
Nervous system disorders Headache	9.8% 18/184 • 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. 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.	8.3% 14/169 • 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. 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% 10/182 • 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. 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

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