Trial Outcomes & Findings for Efficacy and Safety of Ramelteon Sublingual as Adjunctive Therapy for Maintenance Treatment of Bipolar I Disorder (NCT NCT01467713)

Last Updated: 2016-05-16

Results Overview

The time from randomization to relapse over 12 months double-blind treatment period as determined by the Principal Investigator (PI) or defined by any of the following criteria: depression \[Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥16\]; mania/hypomania \[Young Mania Rating Scale (YMRS) total score ≥14\]; mixed episode \[MADRS score ≥16 and YMRS total score ≥16\]; or, whether participant receives psychiatric hospitalization for bipolar disorder, electroconvulsive therapy (ECT) or any psychotropic medication change prescribed for the treatment of depression, mania/hypomania or mixed episodes.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

642 participants

Primary outcome timeframe

Randomization to Month 12 double-blind treatment period

Results posted on

2016-05-16

Participant Flow

Participants took part in the study at 100 investigative sites in Argentina, Chile, Colombia, Mexico and the United States from 21 December 2011 (first participants signed the informed consent form) to 26 March 2015.

Participants with a diagnosis of bipolar disorder were enrolled equally in 1 of 4 treatment groups, once a day placebo, Tak-375 SL (ramelteon) 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 9 months.	Ramelteon SL 0.1 mg Ramelteon SL 0.1 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.4 mg Ramelteon SL 0.4 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.8 mg Ramelteon SL 0.8 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.
Overall Study STARTED	164	164	160	154
Overall Study Safety Analysis Set: Received Treatment	163	164	159	154
Overall Study COMPLETED	62	60	58	45
Overall Study NOT COMPLETED	102	104	102	109

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 9 months.	Ramelteon SL 0.1 mg Ramelteon SL 0.1 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.4 mg Ramelteon SL 0.4 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.8 mg Ramelteon SL 0.8 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.
Overall Study Pretreatment Event or Adverse Event	9	4	6	5
Overall Study Major Protocol Deviation	2	4	4	1
Overall Study Lost to Follow-up	9	12	6	9
Overall Study Voluntary Withdrawal	18	14	21	20
Overall Study Study Termination	23	33	28	29
Overall Study Pregnancy	0	1	1	3
Overall Study Relapse	35	25	28	35
Overall Study Reason not Specified	6	11	8	7

Baseline Characteristics

Efficacy and Safety of Ramelteon Sublingual as Adjunctive Therapy for Maintenance Treatment of Bipolar I Disorder

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=164 Participants Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.1 mg n=164 Participants Ramelteon SL 0.1 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.4 mg n=160 Participants Ramelteon SL 0.4 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.8 mg n=154 Participants Ramelteon SL 0.8 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Total n=642 Participants Total of all reporting groups
Age, Continuous	44.21 years STANDARD_DEVIATION 12.224 • n=5 Participants	42.97 years STANDARD_DEVIATION 13.262 • n=7 Participants	42.93 years STANDARD_DEVIATION 11.666 • n=5 Participants	41.71 years STANDARD_DEVIATION 12.534 • n=4 Participants	42.98 years STANDARD_DEVIATION 12.440 • n=21 Participants
Age, Customized <=50 Years	109 participants n=5 Participants	105 participants n=7 Participants	113 participants n=5 Participants	112 participants n=4 Participants	439 participants n=21 Participants
Age, Customized >50 Years	55 participants n=5 Participants	59 participants n=7 Participants	47 participants n=5 Participants	42 participants n=4 Participants	203 participants n=21 Participants
Sex: Female, Male Female	96 Participants n=5 Participants	89 Participants n=7 Participants	92 Participants n=5 Participants	90 Participants n=4 Participants	367 Participants n=21 Participants
Sex: Female, Male Male	68 Participants n=5 Participants	75 Participants n=7 Participants	68 Participants n=5 Participants	64 Participants n=4 Participants	275 Participants n=21 Participants
Race/Ethnicity, Customized Hispanic or Latino	52 participants n=5 Participants	63 participants n=7 Participants	54 participants n=5 Participants	46 participants n=4 Participants	215 participants n=21 Participants
Race/Ethnicity, Customized Non-Hispanic and Non-Latino	112 participants n=5 Participants	101 participants n=7 Participants	106 participants n=5 Participants	108 participants n=4 Participants	427 participants n=21 Participants
Race/Ethnicity, Customized White	118 participants n=5 Participants	116 participants n=7 Participants	117 participants n=5 Participants	104 participants n=4 Participants	455 participants n=21 Participants
Race/Ethnicity, Customized Black	36 participants n=5 Participants	34 participants n=7 Participants	34 participants n=5 Participants	36 participants n=4 Participants	140 participants n=21 Participants
Race/Ethnicity, Customized Asian	1 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants	4 participants n=4 Participants	7 participants n=21 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	5 participants n=5 Participants	8 participants n=7 Participants	5 participants n=5 Participants	4 participants n=4 Participants	22 participants n=21 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 participants n=5 Participants	2 participants n=7 Participants	0 participants n=5 Participants	1 participants n=4 Participants	3 participants n=21 Participants
Race/Ethnicity, Customized Multiple	4 participants n=5 Participants	3 participants n=7 Participants	3 participants n=5 Participants	5 participants n=4 Participants	15 participants n=21 Participants
Region of Enrollment Argentina	16 participants n=5 Participants	19 participants n=7 Participants	18 participants n=5 Participants	13 participants n=4 Participants	66 participants n=21 Participants
Region of Enrollment Chile	13 participants n=5 Participants	10 participants n=7 Participants	12 participants n=5 Participants	11 participants n=4 Participants	46 participants n=21 Participants
Region of Enrollment Colombia	4 participants n=5 Participants	7 participants n=7 Participants	7 participants n=5 Participants	6 participants n=4 Participants	24 participants n=21 Participants
Region of Enrollment Mexico	9 participants n=5 Participants	12 participants n=7 Participants	8 participants n=5 Participants	10 participants n=4 Participants	39 participants n=21 Participants
Region of Enrollment United States	122 participants n=5 Participants	116 participants n=7 Participants	115 participants n=5 Participants	114 participants n=4 Participants	467 participants n=21 Participants
Height	168.65 cm STANDARD_DEVIATION 10.159 • n=5 Participants	168.56 cm STANDARD_DEVIATION 9.790 • n=7 Participants	167.49 cm STANDARD_DEVIATION 10.235 • n=5 Participants	168.47 cm STANDARD_DEVIATION 9.608 • n=4 Participants	168.30 cm STANDARD_DEVIATION 9.943 • n=21 Participants
Weight	87.04 kg STANDARD_DEVIATION 21.148 • n=5 Participants	87.52 kg STANDARD_DEVIATION 21.265 • n=7 Participants	88.68 kg STANDARD_DEVIATION 22.291 • n=5 Participants	85.71 kg STANDARD_DEVIATION 21.386 • n=4 Participants	87.25 kg STANDARD_DEVIATION 21.500 • n=21 Participants
Body Mass Index (BMI)	30.68 kg/m^2 STANDARD_DEVIATION 7.351 • n=5 Participants	30.66 kg/m^2 STANDARD_DEVIATION 6.382 • n=7 Participants	31.52 kg/m^2 STANDARD_DEVIATION 7.108 • n=5 Participants	30.11 kg/m^2 STANDARD_DEVIATION 6.702 • n=4 Participants	30.75 kg/m^2 STANDARD_DEVIATION 6.900 • n=21 Participants
Smoking Classification Participant Has Never Smoked	75 participants n=5 Participants	69 participants n=7 Participants	75 participants n=5 Participants	62 participants n=4 Participants	281 participants n=21 Participants
Smoking Classification Participant is a Current Smoker	56 participants n=5 Participants	68 participants n=7 Participants	58 participants n=5 Participants	63 participants n=4 Participants	245 participants n=21 Participants
Smoking Classification Participant is an Ex-smoker	33 participants n=5 Participants	27 participants n=7 Participants	27 participants n=5 Participants	29 participants n=4 Participants	116 participants n=21 Participants
Participant Drinking Status Has Never Drunk	68 participants n=5 Participants	70 participants n=7 Participants	65 participants n=5 Participants	58 participants n=4 Participants	261 participants n=21 Participants
Participant Drinking Status Ex-Drinker	47 participants n=5 Participants	50 participants n=7 Participants	48 participants n=5 Participants	41 participants n=4 Participants	186 participants n=21 Participants
Participant Drinking Status Current Drinker	49 participants n=5 Participants	43 participants n=7 Participants	47 participants n=5 Participants	55 participants n=4 Participants	194 participants n=21 Participants
Participant Drinking Status Missing	0 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	0 participants n=4 Participants	1 participants n=21 Participants
If Drinker, Amount Consumed <4 Drinks per Day	49 participants n=5 Participants	42 participants n=7 Participants	47 participants n=5 Participants	55 participants n=4 Participants	193 participants n=21 Participants
If Drinker, Amount Consumed >= 4 Drinks per Day	0 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	0 participants n=4 Participants	1 participants n=21 Participants
Does Participant Consume Caffeine? Yes	121 participants n=5 Participants	122 participants n=7 Participants	122 participants n=5 Participants	127 participants n=4 Participants	492 participants n=21 Participants
Does Participant Consume Caffeine? No	43 participants n=5 Participants	42 participants n=7 Participants	38 participants n=5 Participants	27 participants n=4 Participants	150 participants n=21 Participants

PRIMARY outcome

Timeframe: Randomization to Month 12 double-blind treatment period

Population: Full Analysis Set included all randomized participants who received at least 1 dose of study drug and had at least one valid post-baseline value for assessment of primary efficacy. Participants without relapse were censored.

Outcome measures

Outcome measures
Measure	Placebo n=157 Participants Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.1 mg n=162 Participants Ramelteon SL 0.1 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.4 mg n=154 Participants Ramelteon SL 0.4 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.8 mg n=149 Participants Ramelteon SL 0.8 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.
Time From Randomization to Any Relapse	248.3 Days Standard Error 8.11	287.7 Days Standard Error 8.83	253.1 Days Standard Error 7.52	223.9 Days Standard Error 7.60

SECONDARY outcome

Timeframe: Randomization to Month 12 double-blind treatment period

Relapse due to depression determined by any of the following criteria during the 12-month double-blind treatment period: PI judgment, MADRS ≥16, psychiatry hospitalization, ECT or any psychotropic medication change prescribed for the treatment of depressive episodes.

Outcome measures

Outcome measures
Measure	Placebo n=157 Participants Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.1 mg n=162 Participants Ramelteon SL 0.1 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.4 mg n=154 Participants Ramelteon SL 0.4 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.8 mg n=149 Participants Ramelteon SL 0.8 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.
Time From Randomization to Relapse Due to Depression	256.5 Days Standard Error 7.70	242.1 Days Standard Error 5.56	260.8 Days Standard Error 7.03	224.2 Days Standard Error 6.31

SECONDARY outcome

Timeframe: Randomization to Month 12 double-blind treatment period

Relapse due to mania/hypomania or mixed episode is determined by any of the following criteria: PI judgment, mania/hypomania \[YMRS ≥16\], mixed episode \[MADRS ≥16 and YMRS ≥16\], psychiatry hospitalization, ECT or any psychotropic medication change prescribed for the treatment of mania/hypomania or mixed episodes.

Outcome measures

Outcome measures
Measure	Placebo n=157 Participants Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.1 mg n=162 Participants Ramelteon SL 0.1 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.4 mg n=154 Participants Ramelteon SL 0.4 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.8 mg n=149 Participants Ramelteon SL 0.8 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.
Time From Randomization to Relapse Due to Mania/Hypomania or Mixed Episode	150.2 days Standard Error 1.60	319.3 days Standard Error 6.07	269.5 days Standard Error 3.69	255.5 days Standard Error 5.03

SECONDARY outcome

Timeframe: Randomization to Month 12 double-blind treatment period

The time from randomization to relapse event during the 12 month double-blind treatment period due to depression, determined by the PI judgement and/or a MADRS score ≥16. 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=157 Participants Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.1 mg n=162 Participants Ramelteon SL 0.1 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.4 mg n=154 Participants Ramelteon SL 0.4 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.8 mg n=149 Participants Ramelteon SL 0.8 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.
Time From Randomization to Relapse Due to Depression From PI Judgement and/or MADRS ≥16	265.0 days Standard Error 7.14	245.1 days Standard Error 5.22	262.5 days Standard Error 6.90	224.2 days Standard Error 6.31

SECONDARY outcome

Timeframe: Randomization to 12 Month double-blind treatment period

Relapse due to mania/hypomania is determined by the primary investigator (PI) judgement and/or a YMRS total score ≥16. YMRS is a 11 item scale with four items 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.

Outcome measures

Outcome measures
Measure	Placebo n=157 Participants Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.1 mg n=162 Participants Ramelteon SL 0.1 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.4 mg n=154 Participants Ramelteon SL 0.4 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.8 mg n=149 Participants Ramelteon SL 0.8 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.
Time From Randomization to Relapse Due to Mania/Hypomania	150.7 days Standard Error 1.60	328.8 days Standard Error 4.53	274.8 days Standard Error 2.20	263.3 days Standard Error 3.73

SECONDARY outcome

Timeframe: Randomization to Month 12 double-blind treatment period

Relapse due to Mixed episode is determined by PI judgement and/or MADRS score ≥16 and YMRS total score ≥16. MADRS is a 10-item scale that measures overall severity of depressive symptoms rated on a 7-point Likert scale from 0 (normal) to 6 (most abnormal) with a total score range from 0 to 60. 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). 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=157 Participants Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.1 mg n=162 Participants Ramelteon SL 0.1 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.4 mg n=154 Participants Ramelteon SL 0.4 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.8 mg n=149 Participants Ramelteon SL 0.8 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.
Time From Randomization to Relapse Due to Mixed Episode	147.6 days Standard Error 0.63	150.2 days Standard Error 1.53	96.0 days Standard Error 0.89	180.5 days Standard Error 2.31

SECONDARY outcome

Timeframe: Randomization to Month 12 double-blind treatment period

The time from randomization to relapse event during the 12 months double-blind treatment period due to psychiatric hospitalization for bipolar disorder.

Outcome measures

Outcome measures
Measure	Placebo n=157 Participants Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.1 mg n=162 Participants Ramelteon SL 0.1 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.4 mg n=154 Participants Ramelteon SL 0.4 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.8 mg n=149 Participants Ramelteon SL 0.8 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.
Time From Randomization to Relapse Due to Psychiatric Hospitalization for Bipolar Disorder	198.6 days Standard Error 2.29	34.8 days Standard Error 0.20	70.6 days Standard Error 0.52	251.3 days Standard Error 2.36

SECONDARY outcome

Timeframe: Randomization to Month 12 double-blind treatment period

The time from randomization to relapse event during the 12 month double-blind treatment period due to ECT.

Outcome measures

Outcome measures
Measure	Placebo n=157 Participants Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.1 mg n=162 Participants Ramelteon SL 0.1 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.4 mg n=154 Participants Ramelteon SL 0.4 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.8 mg n=149 Participants Ramelteon SL 0.8 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.
Time From Randomization to Relapse Due to Electroconvulsive Therapy (ECT) Administration	NA days Standard Error NA No relapses due to ECT.	NA days Standard Error NA No relapses due to ECT.	NA days Standard Error NA No relapses due to ECT.	NA days Standard Error NA No relapses due to ECT.

SECONDARY outcome

Timeframe: Randomization to Month 12 double-blind treatment period

The time from randomization to relapse event during the 12 month double-blind treatment period due to any psychotropic medication change prescribed for the treatment of depression, mania/hypomania or mixed episode(s).

Outcome measures

Outcome measures
Measure	Placebo n=157 Participants Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.1 mg n=162 Participants Ramelteon SL 0.1 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.4 mg n=154 Participants Ramelteon SL 0.4 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.8 mg n=149 Participants Ramelteon SL 0.8 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.
Time From Randomization to Relapse Due to Psychotropic Medication Change Prescribed for the Treatment of Depression, Mania/Hypomania or Mixed Episodes	197.8 days Standard Error 2.33	18.9 days Standard Error 0.13	257.9 days Standard Error 2.69	55.7 days Standard Error 0.46

SECONDARY outcome

Timeframe: Randomization to Month 12 double-blind treatment period

Population: Full Analysis Set included all randomized participants who received at least 1 dose of study drug and had at least one valid post-baseline value for assessment of primary efficacy.

The time from randomization to study withdrawal during the 12 month double-blind treatment period. Withdrawal includes pretreatment event/adverse event; liver function test abnormalities; major protocol deviation; lost to follow-up; voluntary withdrawal; study termination; pregnancy; lack of efficacy; participant has a depressive, mania/hypomania or mixed episode; is hospitalized for psychiatric reasons; receives electroconvulsive therapy for bipolar disorder; receives any psychotropic medication change prescribed for the treatment of depression, mania/hypomania or mixed episodes; or any other reason.

Outcome measures

Outcome measures
Measure	Placebo n=157 Participants Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.1 mg n=162 Participants Ramelteon SL 0.1 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.4 mg n=154 Participants Ramelteon SL 0.4 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.8 mg n=149 Participants Ramelteon SL 0.8 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.
Time From Randomization to Study Withdrawal for Any Reason	240.6 days Standard Error 11.44	226.8 days Standard Error 10.48	226.9 days Standard Error 10.88	208.7 days Standard Error 11.01

SECONDARY outcome

Timeframe: Baseline and Months 1, 2, 3, 4, 5, 6, 7, 8, 10 and 12

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

Q-LES-Q-SF is a self-administered 16-item questionnaire to assess the degree of enjoyment and satisfaction experienced by patients in various areas of daily functioning. It includes 30 items across five subscales (daily activities, clothing, diet/food habits, relationship, psychological well-being and distress), scored on a 6-point Likert scale with subscale and total score ranging from 0 (none) to 5 (all the time). For reporting purposes, the scores are reversed and higher scores reflect improved quality of life and positive changes relative to baseline indicate improved quality of life.

Outcome measures

Outcome measures
Measure	Placebo n=157 Participants Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.1 mg n=162 Participants Ramelteon SL 0.1 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.4 mg n=154 Participants Ramelteon SL 0.4 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.8 mg n=149 Participants Ramelteon SL 0.8 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.
Quality of Life, Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) Total Score Month 7 (n=115, 129, 121, 118)	67.0 percent of maximum total score Standard Deviation 16.80	70.4 percent of maximum total score Standard Deviation 15.98	69.7 percent of maximum total score Standard Deviation 15.80	65.8 percent of maximum total score Standard Deviation 17.61
Quality of Life, Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) Total Score Baseline (n=115, 129, 121, 118)	65.7 percent of maximum total score Standard Deviation 17.00	65.1 percent of maximum total score Standard Deviation 16.57	68.6 percent of maximum total score Standard Deviation 15.71	65.8 percent of maximum total score Standard Deviation 15.09
Quality of Life, Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) Total Score Month 1 (n=113, 127, 121, 118)	68.3 percent of maximum total score Standard Deviation 14.68	68.5 percent of maximum total score Standard Deviation 15.48	70.2 percent of maximum total score Standard Deviation 14.76	68.1 percent of maximum total score Standard Deviation 14.65
Quality of Life, Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) Total Score Month 2 (n=115, 128, 121, 118)	67.3 percent of maximum total score Standard Deviation 16.24	68.7 percent of maximum total score Standard Deviation 15.11	70.6 percent of maximum total score Standard Deviation 15.07	67.4 percent of maximum total score Standard Deviation 15.68
Quality of Life, Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) Total Score Month 3 (n=115, 129, 121, 118)	66.5 percent of maximum total score Standard Deviation 15.89	69.0 percent of maximum total score Standard Deviation 14.83	70.0 percent of maximum total score Standard Deviation 15.68	66.2 percent of maximum total score Standard Deviation 16.74
Quality of Life, Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) Total Score Month 4 (n=115, 129, 121, 118)	66.8 percent of maximum total score Standard Deviation 17.18	68.9 percent of maximum total score Standard Deviation 15.67	69.3 percent of maximum total score Standard Deviation 15.11	66.9 percent of maximum total score Standard Deviation 17.08
Quality of Life, Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) Total Score Month 5 (n=115, 129, 121, 118)	67.2 percent of maximum total score Standard Deviation 16.43	69.6 percent of maximum total score Standard Deviation 16.86	69.6 percent of maximum total score Standard Deviation 15.22	66.0 percent of maximum total score Standard Deviation 16.72
Quality of Life, Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) Total Score Month 6 (n=115, 129, 121, 118)	67.1 percent of maximum total score Standard Deviation 17.37	68.4 percent of maximum total score Standard Deviation 17.41	68.1 percent of maximum total score Standard Deviation 16.09	67.2 percent of maximum total score Standard Deviation 16.41
Quality of Life, Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) Total Score Month 8 (n=115, 129, 121, 118)	67.7 percent of maximum total score Standard Deviation 16.63	71.0 percent of maximum total score Standard Deviation 15.17	69.0 percent of maximum total score Standard Deviation 17.24	66.8 percent of maximum total score Standard Deviation 17.10
Quality of Life, Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) Total Score Month 10 (n=115, 129, 121, 118)	67.9 percent of maximum total score Standard Deviation 16.91	71.1 percent of maximum total score Standard Deviation 16.57	70.2 percent of maximum total score Standard Deviation 15.41	66.5 percent of maximum total score Standard Deviation 17.62
Quality of Life, Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) Total Score Month 12 (n=115, 129, 121, 118)	67.5 percent of maximum total score Standard Deviation 17.69	70.9 percent of maximum total score Standard Deviation 16.54	70.0 percent of maximum total score Standard Deviation 15.97	66.8 percent of maximum total score Standard Deviation 17.77

Adverse Events

Placebo

Serious events: 10 serious events

Other events: 55 other events

Deaths: 0 deaths

Ramelteon SL 0.1 mg

Serious events: 14 serious events

Other events: 47 other events

Deaths: 0 deaths

Ramelteon SL 0.4 mg

Serious events: 6 serious events

Other events: 49 other events

Deaths: 0 deaths

Ramelteon SL 0.8 mg

Serious events: 8 serious events

Other events: 50 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Placebo n=163 participants at risk Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.1 mg n=164 participants at risk Ramelteon SL 0.1 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.4 mg n=159 participants at risk Ramelteon SL 0.4 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.	Ramelteon SL 0.8 mg n=154 participants at risk Ramelteon SL 0.8 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.
Gastrointestinal disorders Diarrhoea	4.3% 7/163 • 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.	6.1% 10/164 • 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.	1.3% 2/159 • 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.	3.2% 5/154 • 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 Influenza	1.8% 3/163 • 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.	3.7% 6/164 • 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.	5.0% 8/159 • 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.	3.2% 5/154 • 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	6.7% 11/163 • 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.	3.7% 6/164 • 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.	6.3% 10/159 • 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.	8.4% 13/154 • 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 Upper respiratory tract infection	6.7% 11/163 • 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.	4.3% 7/164 • 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.	5.7% 9/159 • 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.	3.9% 6/154 • 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	8.0% 13/163 • 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.	8.5% 14/164 • 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.	8.8% 14/159 • 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% 10/154 • 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	5.5% 9/163 • 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.	3.7% 6/164 • 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.	4.4% 7/159 • 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.	9.7% 15/154 • 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 Insomnia	6.7% 11/163 • 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% 8/164 • 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.	6.3% 10/159 • 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.	4.5% 7/154 • 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