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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 
Overall Participants Analyzed 
[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 
[1] Participants evaluable for this measure included only those who were current drinkers (36, 36, and 37 for each group, respectively).
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 


  Outcome Measures
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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