TAK-375SL_301

Takeda

61 Aldwych, London, United Kingdom,  WC2B 4AE

Clinical Study Manager, Takeda Global Research & Development Centre (Europe) Ltd (TGRD), +44 203116 8000, clinicaloperations@tgrd.com

Clinical Study Manager, Takeda Global Research & Development Centre (Europe) Ltd (TGRD), +44 203116 8000, clinicaloperations@tgrd.com

No

No

No

Final

14 Sep 2015

No

Yes

03 Sep 2014

Yes

To evaluate the efficacy of TAK-375SL tablet 0.1 mg and 0.4 mg once daily at bedtime (QHS) compared with placebo as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS) after 6 weeks of treatment in subjects with acute depressive episodes associated with Bipolar 1 Disorder.

All study subjects were required to read and sign an Informed Consent Form.

29 Aug 2012

No

No

Poland: 10

United Kingdom: 1

Bulgaria: 88

Czech Republic: 24

Germany: 11

Romania: 24

Russian Federation: 34

Serbia: 67

Ukraine: 57

United States: 219

535

158

0

0

0

0

0

0

520

15

0

Overall Study (overall period)

Randomised - controlled

Yes

Placebo

Tablet

Sublingual use

TAK­375SL (ramelteon) placebo­matching tablet, sublingually, once daily for up to 6 weeks.

TAK-375SL

Ramelteon

Tablet

Sublingual use

TAK­375SL (ramelteon) 0.1 mg, tablet, sublingually, once daily for up to 6 weeks.

TAK-375SL

Ramelteon

Tablet

Sublingual use

TAK­375SL (ramelteon) 0.4 mg, tablet, sublingually, once daily for up to 6 weeks.

Placebo

TAK-375SL 0.1 mg

TAK-375SL 0.4 mg

Placebo

TAK-375SL 0.1 mg

TAK-375SL 0.4 mg

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. Full Analysis Set (FAS) included all randomized subjects 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.

Primary

Baseline and Week 6

Mixed Model Repeated Measures (MMRM) model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.

Placebo v TAK-375SL 0.1 mg

346

Pre-specified

0.8

2-sided

Standard error of the mean

0.98

MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.

Placebo v TAK-375SL 0.4 mg

355

Pre-specified

-0.4

2-sided

Standard error of the mean

0.97

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. FAS included all randomized subjects 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.

Secondary

Baseline and Week 6

MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.

Placebo v TAK-375SL 0.1 mg

346

Pre-specified

0.5

2-sided

Standard error of the mean

0.27

MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.

Placebo v TAK-375SL 0.4 mg

355

Pre-specified

-0.1

2-sided

Standard error of the mean

0.27

The CGI-I assesses the clinician’s impression of the subject’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. FAS included all randomized subjects 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.

Secondary

Week 6

MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.

Placebo v TAK-375SL 0.1 mg

288

Pre-specified

0

2-sided

Standard error of the mean

0.12

MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.

Placebo v TAK-375SL 0.4 mg

292

Pre-specified

-0.2

2-sided

Standard error of the mean

0.12

The CGI-S assesses the clinician’s impression of the subject’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). FAS included all randomized subjects 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.

Secondary

Baseline and Week 6

MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.

Placebo v TAK-375SL 0.1 mg

346

Pre-specified

0.1

2-sided

Standard error of the mean

0.12

MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.

Placebo v TAK-375SL 0.4 mg

355

Pre-specified

0

2-sided

Standard error of the mean

0.12

The 16-item QIDS-SR16 version is a widely used validated scale designed to assess the severity of depressive symptoms. The subject 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. FAS included all randomized subjects 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.

Secondary

Baseline and Week 6

MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.

Placebo v TAK-375SL 0.1 mg

346

Pre-specified

0.8

2-sided

Standard error of the mean

0.51

MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.

Placebo v TAK-375SL 0.4 mg

355

Pre-specified

-0.1

2-sided

Standard error of the mean

0.51

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. FAS included all randomized subjects 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.

Secondary

Baseline and Week 6

MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.

Placebo v TAK-375SL 0.1 mg

346

Pre-specified

0.6

2-sided

Standard error of the mean

0.7

MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.

Placebo v TAK-375SL 0.4 mg

355

Pre-specified

0.3

2-sided

Standard error of the mean

0.7

Q-LES-Q-SF is a self-administered, widely used 16-item questionnaire to assess the degree of enjoyment and satisfaction experienced by subjects 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 subjects 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. FAS included all randomized subjects 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.

Secondary

Baseline and Week 6

MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.

Placebo v TAK-375SL 0.1 mg

346

Pre-specified

-0.8

2-sided

Standard error of the mean

1.64

MMRM model with baseline by week interaction, pooled center, week, treatment, baseline, and week by treatment interaction as factors was used for the analysis.

Placebo v TAK-375SL 0.4 mg

355

Pre-specified

0.1

2-sided

Standard error of the mean

1.63

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

Secondary

Week 6

Odds ratio, 95% confidence intervals and p-values are analyzed from logistic regression with explanatory variables for treatment and baseline MADRS total score.

Placebo v TAK-375SL 0.1 mg

346

Pre-specified

0.998

2-sided

Odds ratio, 95% confidence intervals and p-values are analyzed from logistic regression with explanatory variables for treatment and baseline MADRS total score.

Placebo v TAK-375SL 0.4 mg

355

Pre-specified

0.886

2-sided

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

Secondary

Week 6

Odds ratio, 95% confidence intervals and p-values are analyzed from logistic regression with explanatory variables for treatment and baseline MADRS total score.

Placebo v TAK-375SL 0.1 mg

346

Pre-specified

0.978

2-sided

Odds ratio, 95% confidence intervals and p-values are analyzed from logistic regression with explanatory variables for treatment and baseline MADRS total score.

Placebo v TAK-375SL 0.4 mg

355

Pre-specified

0.865

2-sided

Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 30 days 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 subject or observed by the investigator was recorded, irrespective of the relation to study treatment.

17.0

Placebo

TAK-375SL 0.1 mg

TAK-375SL 0.4 mg