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

History of Changes

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

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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 ]

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2. Secondary:

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

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3. Secondary:

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

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4. Secondary:

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

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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 ]

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6. Secondary:

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

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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 ]

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8. Secondary:

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

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9. Secondary:

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

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Serious Adverse Events

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Other Adverse Events

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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:

	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.
	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.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: 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
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

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