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

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ClinicalTrials.gov Identifier: NCT01467700
Recruitment Status : Terminated (Business Decision; No Safety Concerns)
First Posted : November 9, 2011
Results First Posted : May 16, 2016
Last Update Posted : May 16, 2016
Sponsor:
Information provided by (Responsible Party):
Takeda

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Acute Depressive Episode
Interventions Drug: Ramelteon SL
Drug: Placebo
Enrollment 490
Recruitment Details 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.
Pre-assignment Details 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.
Arm/Group Title Placebo Ramelteon SL 0.1 mg Ramelteon SL 0.4 mg Ramelteon SL 0.8 mg
Hide Arm/Group Description 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, tablets, SL, once daily (QD), every night at bedtime for up to 8 weeks. Ramelteon SL 0.4 mg, tablets, SL, once daily, every night at bedtime for up to 8 weeks. Ramelteon SL 0.8 mg tablets, SL, once daily, every night at bedtime for up to 8 weeks.
Period Title: Overall Study
Started 115 128 124 123
Safety Set - Received Treatment 115 127 124 123
Completed 86 100 97 96
Not Completed 29 28 27 27
Reason Not Completed
Pretreatment Event or Adverse Event             6             4             2             3
Major Protocol Deviation             3             3             2             3
Lost to Follow-up             6             5             2             3
Voluntary Withdrawal             5             7             6             2
Study Termination             6             5             10             7
Pregnancy             0             1             1             0
Lack of Efficacy             2             0             2             1
Reason not Specified             1             3             2             8
Arm/Group Title Placebo Ramelteon SL 0.1 mg Ramelteon SL 0.4 mg Ramelteon SL 0.8 mg Total
Hide Arm/Group Description 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, tablets, SL, once daily (QD), every night at bedtime for up to 8 weeks. Ramelteon SL 0.4 mg, tablets, SL, once daily, every night at bedtime for up to 8 weeks. Ramelteon SL 0.8 mg tablets, SL, once daily, every night at bedtime for up to 8 weeks. Total of all reporting groups
Overall Number of Baseline Participants 115 128 124 123 490
Hide Baseline Analysis Population Description
All randomized participants.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 115 participants 128 participants 124 participants 123 participants 490 participants
44.95  (10.867) 43.01  (11.998) 42.96  (13.211) 43.97  (10.243) 43.69  (11.646)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 115 participants 128 participants 124 participants 123 participants 490 participants
<=50 Years 85 92 88 97 362
>50 Years 30 36 36 26 128
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 115 participants 128 participants 124 participants 123 participants 490 participants
<=65 years 111 126 119 121 477
>65 Years 4 2 5 2 13
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 115 participants 128 participants 124 participants 123 participants 490 participants
Female
74
  64.3%
71
  55.5%
78
  62.9%
69
  56.1%
292
  59.6%
Male
41
  35.7%
57
  44.5%
46
  37.1%
54
  43.9%
198
  40.4%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 115 participants 128 participants 124 participants 123 participants 490 participants
Hispanic or Latino 36 38 35 37 146
Non-Hispanic and Non-Latino 79 90 89 86 344
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 115 participants 128 participants 124 participants 123 participants 490 participants
White 76 81 85 79 321
Black 29 42 32 38 141
Asian 3 0 2 0 5
American Indian or Alaska Native 5 3 0 4 12
Native Hawaiian or Other Pacific Islander 1 0 1 1 3
Multiple 1 2 4 1 8
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 115 participants 128 participants 124 participants 123 participants 490 participants
United States 85 97 95 94 371
Argentina 12 11 11 11 45
Chile 5 5 6 3 19
Colombia 3 3 1 3 10
Mexico 10 12 11 12 45
Height  
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 115 participants 128 participants 124 participants 123 participants 490 participants
166.93  (10.345) 169.00  (9.937) 167.22  (9.677) 168.15  (10.590) 167.85  (10.139)
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 115 participants 128 participants 124 participants 123 participants 490 participants
85.44  (20.034) 87.58  (21.555) 85.09  (20.873) 86.69  (21.535) 86.22  (20.989)
Body Mass Index (BMI)   [1] 
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 115 participants 128 participants 124 participants 123 participants 490 participants
30.62  (6.778) 30.63  (7.254) 30.37  (6.808) 30.61  (6.825) 30.56  (6.904)
[1]
Measure Description: BMI is calculated using the weight collected at the first screening visit: BMI=weight(kg)/[height(m)]^2.
Smoking Classification  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 115 participants 128 participants 124 participants 123 participants 490 participants
Participant Has Never Smoked 47 55 49 45 196
Participant is a Current Smoker 50 58 58 58 224
Participant is an Ex-smoker 18 15 17 20 70
Participant Drinking Status  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 115 participants 128 participants 124 participants 123 participants 490 participants
Has Never Drunk 52 41 45 49 187
Ex-Drinker 25 36 28 37 126
Current Drinker 22 34 33 25 114
Missing 16 17 18 12 63
If Drinker, Amount Consumed   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 115 participants 128 participants 124 participants 123 participants 490 participants
< 4 drinks per day 22 34 33 25 114
>= 4 drinks per day 0 0 0 0 0
[1]
Measure Description: Only participants with drinking status Current Drinker are accounted for: N=22, 34, 33, 25 in each treatment arm, respectively.
Does Participant Consume Caffeine?  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 115 participants 128 participants 124 participants 123 participants 490 participants
Yes 77 84 83 81 325
No 22 27 23 30 102
Missing 16 17 18 12 63
1.Primary Outcome
Title Change From Baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score at Week 6
Hide Description 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.
Time Frame Baseline and Week 6
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Placebo Ramelteon SL 0.1 mg Ramelteon SL 0.4 mg Ramelteon SL 0.8 mg
Hide Arm/Group Description:
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, tablets, SL, once daily (QD), every night at bedtime for up to 8 weeks.
Ramelteon SL 0.4 mg, tablets, SL, once daily, every night at bedtime for up to 8 weeks,
Ramelteon SL 0.8 mg tablets, SL, once daily, every night at bedtime for up to 8 weeks.
Overall Number of Participants Analyzed 93 109 101 103
Least Squares Mean (Standard Error)
Unit of Measure: score on a scale
-14.5  (0.94) -14.4  (0.89) -11.8  (0.91) -14.8  (0.91)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Ramelteon SL 0.1 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.518
Comments P-values were from an MMRM model with baseline*week, pooled center, week, treatment, baseline, and week*treatment as factors in the analysis.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 0.1
Confidence Interval (2-Sided) 98%
-2.9 to 3.1
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.28
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Ramelteon SL 0.4 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.979
Comments P-values were from an MMRM model with baseline*week, pooled center, week, treatment, baseline, and week*treatment as factors in the analysis.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 2.6
Confidence Interval (2-Sided) 98%
-0.4 to 5.7
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.29
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Ramelteon SL 0.8 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.400
Comments P-values were from an MMRM model with baseline*week, pooled center, week, treatment, baseline, and week*treatment as factors in the analysis.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.3
Confidence Interval (2-Sided) 99%
-3.7 to 3.0
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.29
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Change From Baseline in Quality of Life, Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF) Short Form Total Score at Week 6
Hide Description 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.
Time Frame Baseline and Week 6
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Placebo Ramelteon SL 0.1 mg Ramelteon SL 0.4 mg Ramelteon SL 0.8 mg
Hide Arm/Group Description:
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, tablets, SL, once daily (QD), every night at bedtime for up to 8 weeks.
Ramelteon SL 0.4 mg, tablets, SL, once daily, every night at bedtime for up to 8 weeks,
Ramelteon SL 0.8 mg tablets, SL, once daily, every night at bedtime for up to 8 weeks.
Overall Number of Participants Analyzed 82 95 85 93
Least Squares Mean (Standard Error)
Unit of Measure: percent of maximum score on a scale
8.4  (1.67) 13.1  (1.56) 9.2  (1.61) 14.8  (1.57)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Ramelteon SL 0.1 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.017
Comments P-values were from an MMRM model with baseline*week, pooled center, week, treatment, baseline, and week*treatment as factors in the analysis.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 4.7
Confidence Interval (2-Sided) 98%
-0.5 to 9.9
Parameter Dispersion
Type: Standard Error of the mean
Value: 2.22
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Ramelteon SL 0.4 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.361
Comments P-values were from an MMRM model with baseline*week, pooled center, week, treatment, baseline, and week*treatment as factors in the analysis.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 0.8
Confidence Interval (2-Sided) 98%
-4.5 to 6.1
Parameter Dispersion
Type: Standard Error of the mean
Value: 2.25
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Ramelteon SL 0.8 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.002
Comments P-values were from an MMRM model with baseline*week, pooled center, week, treatment, baseline, and week*treatment as factors in the analysis.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 6.4
Confidence Interval (2-Sided) 99%
0.6 to 12.1
Parameter Dispersion
Type: Standard Error of the mean
Value: 2.23
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Percentage of Participants With MADRS Response at Week 6, With Response Defined as a ≥ 50% Decrease in the MADRS Total Score From Baseline
Hide Description 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.
Time Frame Baseline and Week 6
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Placebo Ramelteon SL 0.1 mg Ramelteon SL 0.4 mg Ramelteon SL 0.8 mg
Hide Arm/Group Description:
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, tablets, SL, once daily (QD), every night at bedtime for up to 8 weeks.
Ramelteon SL 0.4 mg, tablets, SL, once daily, every night at bedtime for up to 8 weeks,
Ramelteon SL 0.8 mg tablets, SL, once daily, every night at bedtime for up to 8 weeks.
Overall Number of Participants Analyzed 93 109 101 103
Measure Type: Number
Unit of Measure: percentage of participants
45.2 50.5 47.5 52.4
4.Secondary Outcome
Title Change From Baseline in Young Mania Rating Scale (YMRS) Total Score at Week 6
Hide Description 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.
Time Frame Baseline and Week 6
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Placebo Ramelteon SL 0.1 mg Ramelteon SL 0.4 mg Ramelteon SL 0.8 mg
Hide Arm/Group Description:
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, tablets, SL, once daily (QD), every night at bedtime for up to 8 weeks.
Ramelteon SL 0.4 mg, tablets, SL, once daily, every night at bedtime for up to 8 weeks,
Ramelteon SL 0.8 mg tablets, SL, once daily, every night at bedtime for up to 8 weeks.
Overall Number of Participants Analyzed 93 109 101 103
Least Squares Mean (Standard Error)
Unit of Measure: score on a scale
-0.9  (0.35) -0.8  (0.33) -0.7  (0.34) -0.4  (0.34)
5.Secondary Outcome
Title Clinical Global Impression Scale-Improvement (CGI-I) Score at Week 6
Hide Description 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.
Time Frame 6 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Placebo Ramelteon SL 0.1 mg Ramelteon SL 0.4 mg Ramelteon SL 0.8 mg
Hide Arm/Group Description:
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, tablets, SL, once daily (QD), every night at bedtime for up to 8 weeks.
Ramelteon SL 0.4 mg, tablets, SL, once daily, every night at bedtime for up to 8 weeks,
Ramelteon SL 0.8 mg tablets, SL, once daily, every night at bedtime for up to 8 weeks.
Overall Number of Participants Analyzed 93 109 101 102
Least Squares Mean (Standard Error)
Unit of Measure: score on a scale
2.6  (0.10) 2.6  (0.10) 2.8  (0.10) 2.6  (0.10)
6.Secondary Outcome
Title Change From Baseline in Clinical Global Impression Scale-Severity (CGI-S) at Week 6
Hide Description 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.
Time Frame Baseline and Week 6
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Placebo Ramelteon SL 0.1 mg Ramelteon SL 0.4 mg Ramelteon SL 0.8 mg
Hide Arm/Group Description:
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, tablets, SL, once daily (QD), every night at bedtime for up to 8 weeks.
Ramelteon SL 0.4 mg, tablets, SL, once daily, every night at bedtime for up to 8 weeks,
Ramelteon SL 0.8 mg tablets, SL, once daily, every night at bedtime for up to 8 weeks.
Overall Number of Participants Analyzed 93 109 101 103
Least Squares Mean (Standard Error)
Unit of Measure: score on a scale
-1.3  (0.11) -1.3  (0.10) -1.1  (0.10) -1.3  (0.10)
7.Secondary Outcome
Title Percentage of Participants With MADRS Remission at Week 6, With Remission Defined as a MADRS Total Score ≤10
Hide Description 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.
Time Frame Week 6
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Placebo Ramelteon SL 0.1 mg Ramelteon SL 0.4 mg Ramelteon SL 0.8 mg
Hide Arm/Group Description:
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, tablets, SL, once daily (QD), every night at bedtime for up to 8 weeks.
Ramelteon SL 0.4 mg, tablets, SL, once daily, every night at bedtime for up to 8 weeks,
Ramelteon SL 0.8 mg tablets, SL, once daily, every night at bedtime for up to 8 weeks.
Overall Number of Participants Analyzed 93 109 101 103
Measure Type: Number
Unit of Measure: percentage of participants
30.1 36.7 31.7 35.9
8.Secondary Outcome
Title Change From Baseline in the Quick Inventory of Depressive Symptomatology - Self-Rated16 (QIDS-SR16) Total Score at Week 6
Hide Description 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.
Time Frame Baseline and Week 6
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Placebo Ramelteon SL 0.1 mg Ramelteon SL 0.4 mg Ramelteon SL 0.8 mg
Hide Arm/Group Description:
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, tablets, SL, once daily (QD), every night at bedtime for up to 8 weeks.
Ramelteon SL 0.4 mg, tablets, SL, once daily, every night at bedtime for up to 8 weeks,
Ramelteon SL 0.8 mg tablets, SL, once daily, every night at bedtime for up to 8 weeks.
Overall Number of Participants Analyzed 66 82 78 78
Least Squares Mean (Standard Error)
Unit of Measure: score on a scale
-6.1  (0.59) -6.2  (0.54) -4.3  (0.54) -6.2  (0.55)
9.Secondary Outcome
Title Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 6
Hide Description 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.
Time Frame Baseline and Week 6
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Placebo Ramelteon SL 0.1 mg Ramelteon SL 0.4 mg Ramelteon SL 0.8 mg
Hide Arm/Group Description:
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, tablets, SL, once daily (QD), every night at bedtime for up to 8 weeks.
Ramelteon SL 0.4 mg, tablets, SL, once daily, every night at bedtime for up to 8 weeks,
Ramelteon SL 0.8 mg tablets, SL, once daily, every night at bedtime for up to 8 weeks.
Overall Number of Participants Analyzed 92 109 100 102
Least Squares Mean (Standard Error)
Unit of Measure: score on a scale
-5.1  (0.71) -6.8  (0.66) -4.1  (0.67) -5.7  (0.68)
Time Frame Approximately 30 days after the last dose of study drug (up to 12 Weeks)
Adverse Event Reporting Description At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
 
Arm/Group Title Placebo Ramelteon SL 0.1 mg Ramelteon SL 0.4 mg Ramelteon SL 0.8 mg
Hide Arm/Group Description 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, tablets, SL, once daily (QD), every night at bedtime for up to 8 weeks. Ramelteon SL 0.4 mg, tablets, SL, once daily, every night at bedtime for up to 8 weeks. Ramelteon SL 0.8 mg tablets, SL, once daily, every night at bedtime for up to 8 weeks.
All-Cause Mortality
Placebo Ramelteon SL 0.1 mg Ramelteon SL 0.4 mg Ramelteon SL 0.8 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Ramelteon SL 0.1 mg Ramelteon SL 0.4 mg Ramelteon SL 0.8 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   4/115 (3.48%)   5/127 (3.94%)   3/124 (2.42%)   1/123 (0.81%) 
Injury, poisoning and procedural complications         
Toxicity to various agents  1  1/115 (0.87%)  0/127 (0.00%)  0/124 (0.00%)  0/123 (0.00%) 
Pregnancy, puerperium and perinatal conditions         
Abortion spontaneous  1  0/115 (0.00%)  1/127 (0.79%)  0/124 (0.00%)  0/123 (0.00%) 
Psychiatric disorders         
Suicidal ideation  1  3/115 (2.61%)  4/127 (3.15%)  0/124 (0.00%)  1/123 (0.81%) 
Bipolar I disorder  1  0/115 (0.00%)  0/127 (0.00%)  2/124 (1.61%)  0/123 (0.00%) 
Depression  1  0/115 (0.00%)  0/127 (0.00%)  1/124 (0.81%)  0/123 (0.00%) 
Depressive symptom  1  1/115 (0.87%)  0/127 (0.00%)  0/124 (0.00%)  0/123 (0.00%) 
Mania  1  1/115 (0.87%)  0/127 (0.00%)  0/124 (0.00%)  0/123 (0.00%) 
Respiratory, thoracic and mediastinal disorders         
Asthma  1  0/115 (0.00%)  0/127 (0.00%)  1/124 (0.81%)  0/123 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (17.1)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Ramelteon SL 0.1 mg Ramelteon SL 0.4 mg Ramelteon SL 0.8 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   10/115 (8.70%)   17/127 (13.39%)   19/124 (15.32%)   19/123 (15.45%) 
Gastrointestinal disorders         
Dry mouth  1  1/115 (0.87%)  2/127 (1.57%)  8/124 (6.45%)  5/123 (4.07%) 
Infections and infestations         
Nasopharyngitis  1  2/115 (1.74%)  7/127 (5.51%)  2/124 (1.61%)  6/123 (4.88%) 
Nervous system disorders         
Headache  1  8/115 (6.96%)  3/127 (2.36%)  6/124 (4.84%)  6/123 (4.88%) 
Somnolence  1  0/115 (0.00%)  7/127 (5.51%)  5/124 (4.03%)  5/123 (4.07%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (17.1)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Name/Title: Medical Director, Clinical Science
Organization: Takeda
Phone: +1-877-825-3327
Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT01467700     History of Changes
Other Study ID Numbers: TAK-375SL_201
U1111-1122-7380 ( Registry Identifier: WHO )
First Submitted: November 4, 2011
First Posted: November 9, 2011
Results First Submitted: April 8, 2016
Results First Posted: May 16, 2016
Last Update Posted: May 16, 2016