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

This study has been terminated.
(Business Decision; Terminated due to futility, with no safety concerns (see below))
Sponsor:
Information provided by (Responsible Party):
Takeda
ClinicalTrials.gov Identifier:
NCT01677182
First received: August 29, 2012
Last updated: February 16, 2016
Last verified: February 2016
Results First Received: February 16, 2016  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Bipolar Disorder
Interventions: Drug: Ramelteon
Drug: Placebo

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups
  Description
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.

Participant Flow:   Overall Study
    Placebo     TAK-375SL 0.1 mg     TAK-375SL 0.4 mg  
STARTED     184     169     182  
COMPLETED     150     141     143  
NOT COMPLETED     34     28     39  
Adverse Event                 2                 1                 8  
Protocol Violation                 5                 1                 4  
Lost to Follow-up                 4                 0                 3  
Withdrawal by Subject                 7                 12                 10  
Study termination                 12                 9                 11  
Lack of Efficacy                 3                 0                 1  
Other reasons                 1                 5                 2  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Baseline analysis population included all randomized participants.

Reporting Groups
  Description
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.
Total Total of all reporting groups

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



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at Week 6   [ Time Frame: Baseline and Week 6 ]

2.  Secondary:   Change From Baseline in Young Mania Rating Scale (YMRS) Total Score at Week 6   [ Time Frame: Baseline and Week 6 ]

3.  Secondary:   Clinical Global Impression Scale-Improvement (CGI-I) Score   [ Time Frame: Week 6 ]

4.  Secondary:   Change From Baseline in Clinical Global Impression Scale-Severity (CGI-S) to Week 6   [ Time Frame: Baseline and Week 6 ]

5.  Secondary:   Change From Baseline in the Quick Inventory of Depressive Symptomatology - Self-Rated16 (QIDS-SR16) Total Score at Week 6   [ Time Frame: Baseline and Week 6 ]

6.  Secondary:   Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 6   [ Time Frame: Baseline and Week 6 ]

7.  Secondary:   Change From Baseline in Quality of Life, Enjoyment, and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) Total Score at Week 6   [ Time Frame: Baseline and Week 6 ]

8.  Secondary:   Percentage of Participants With MADRS Response   [ Time Frame: Week 6 ]

9.  Secondary:   Percentage of Participants With MADRS Remission   [ Time Frame: Week 6 ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information
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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 agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Medical Director
Organization: Takeda
phone: +1-877-825-3327
e-mail: clinicaltrialregistry@tpna.com



Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT01677182     History of Changes
Other Study ID Numbers: TAK-375SL_301
2012-001357-10 ( EudraCT Number )
U1111-1129-5184 ( Registry Identifier: WHO )
12/EM/0391 ( Registry Identifier: NRES )
Study First Received: August 29, 2012
Results First Received: February 16, 2016
Last Updated: February 16, 2016
Health Authority: United States: Food and Drug Administration
Russia: Pharmacological Committee, Ministry of Health
Ukraine: State Pharmacological Center - Ministry of Health
Romania: State Institute for Drug Control
Serbia and Montenegro: Agency for Drugs and Medicinal Devices
Bulgaria: Ministry of Health
United Kingdom: National Health Service
Czech Republic: State Institute for Drug Control
Germany: Federal Institute for Drugs and Medical Devices