Clinical trial NCT01467700: Efficacy and Safety of Ramelteon Sublingual in Adult Patients With Acute Depressive Episodes Associated With Bipolar I Disorder
Official title: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Once a Day, TAK-375 (Ramelteon) Tablet for Sublingual Administration (TAK-375SL Tablet) in the Treatment of Acute Depressive Episodes Associated With Bipolar I Disorder in Adult Patients Who Are on Lithium and/or Valproate
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Acute Depressive Episode
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2011-11-09
Enrollment: 490
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine the efficacy and safety of Ramelteon, once daily (QD), sublingual (SL), in adult participants with acute depressive episodes associated with Bipolar I disorder.

Detailed description: Ramelteon sublingual formulation is being developed by Takeda Pharmaceutical Company Limited for maintenance therapy of Bipolar I disorder.

Participants will be seen twice during the first week of treatment, weekly during the first 2 weeks of treatment and then every 2 weeks up to the end of the 8-week treatment period. Participants who complete the 8-week treatment period will have a follow-up visit approximately seven days after the last visit. A safety follow-up phone call will be made 30 days after completion of the 8-week treatment period.

Based on the recommendation of the Independent Data Monitoring Committee which determined that the study data had met pre-determined criteria for futility, Takeda has made a decision to terminate the study. No safety concerns were identified by the Independent Data Monitoring Committee

Eligibility criteria: Inclusion Criteria:

1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.
3. The participant is a man or woman aged between 18 and 75 years, inclusive.
4. The participant suffers from Bipolar I Disorder, Most Recent Episode Depressed as the primary diagnosis according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria (classification code 296.5x) and confirmed by the Structured Clinical Interview for DSM Disorders (SCID).
5. The reported duration of the current Major Depressive Episode (MDE) is at least four weeks and less than 6 months.
6. The participant has a Young Mania Rating Scale (YMRS) score of ≤10 both at the Screening and Baseline visits.
7. The participant has a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥24 at the Screening and Baseline Visits.
8. The participant has a Clinical Global Impression Scale - Severity (CGI-S) score of ≥4 at the Screening and Baseline Visits.
9. Hamilton Rating Scale for Anxiety (HAM-A) score is ≤21 at Screening and Baseline visits.
10. The participant has a lithium and/or valproate levels within therapeutic range (0.6 - 1.2 mEq/L for lithium or 50-125 mcg/ml for valproate) at screening. If the patient does not have a lithium and/or valproate level within therapeutic range at screening, they must have a lithium and/or valproate levels within the therapeutic range between Day - 15 to Day -30 of screening.
11. A female participant of childbearing potential who is sexually active and agrees to use routinely adequate contraception from signing of informed consent throughout the duration of the study and for 30 days after the last dose.
12. A male participant who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception from signing of informed consent through the duration of the study and for 30 days after the last dose.

Exclusion Criteria:

1. The participant has received any investigational compound \<30 days before Screening or 5 half-lives prior to Screening.
2. The participant has received ramelteon in a previous clinical study or has ever used ramelteon.
3. The participant is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (e.g., spouse, parent, child, sibling) or may consent under duress.
4. The participant has one or more of the following:

   * Any current psychiatric disorder other than Bipolar I Disorder, Most Recent Episode Depressed as defined in the DSM-IV-TR, as assessed by the SCID.
   * Current or history of: schizophrenia, unipolar depression with psychotic features, bipolar depression with psychotic features, any other psychotic disorder (with the exception of psychosis associated with a manic episode), mental retardation, organic mental disorders, or mental disorders due to a general medical condition as defined in the DSM-IV-TR.
   * Current diagnosis or history of alcohol or other substance abuse or dependence (excluding nicotine or caffeine) as defined in the DSM-IV-TR that has not been in full and sustained remission for at least one year from the day of screening. (Participant must also have negative urine drug screen prior to Baseline).
   * Presence or history of a clinically significant neurological disorder (including epilepsy).
   * Neurodegenerative disorder (Alzheimer disease, Parkinson disease, multiple sclerosis, Huntington disease, etc).
   * Any Axis II disorder that might compromise the study.
   * History of Rapid Cycling Bipolar Disorder: Patients who have more than 8 episodes of mood disorder per year.
5. The participant experienced the first episode of mood disorder after the age of 65 years.
6. The current depressive symptoms of the participant are considered by the investigator to have been resistant to 2 adequate treatment trials with any of the mood stabilizers (specifically started to treat the current depressive episode) and/or antidepressant medications of at least 6 weeks duration each.
7. The participant is on any other psychotropic medications except for lithium (serum levels 0.8 to mEq/L) or valproate (serum levels 50 to 125 mcg/ml) at the Screening visit.
8. The participant is on lithium and/or valproate for less than 30 days prior to screening.
9. If the participant is on antidepressant medications and/or antipsychotic medications (used as a mood stabilizer) and the patient is considered appropriate by the PI, these medications must be washed out for at least 2 weeks prior to the Screening visit.
10. The participant has received electroconvulsive therapy, vagal nerve stimulation, or repetitive transcranial magnetic stimulation within 6 months prior to Screening.
11. The participant has started receiving formal cognitive or behavioral therapy, systematic psychotherapy within 30 days prior to screening or plans to initiate such therapy during the study.
12. The participant has a significant risk of suicide according to the investigator's clinical judgment or has a score ≥ 5 on item 10 (suicidal thoughts) of the MADRS or has made a suicide attempt in the previous 6 months.
13. The participant has taken or is anticipated that the participant will take at least 1 of the disallowed concomitant medications.
14. The participant has a clinically significant unstable illness, for example hepatic impairment or renal insufficiency, or a cardiovascular, pulmonary, gastrointestinal, endocrine, neurological, rheumatologic, immunologic, hematological, infectious, dermatological disorder or metabolic disturbance as determined by Investigator.
15. The participant has a history or current diagnosis of Fibromyalgia, Chronic Fatigue Syndrome, Chronic Pain Syndrome or Sleep apnea.
16. The participant has a previous history of cancer that had been in remission for less than 5 years prior to the first dose of study medication. This criterion does not include those participants with basal cell or stage I squamous cell carcinoma of the skin.
17. The participant has 1 or more laboratory value outside the normal range, based on the blood or urine samples taken at the Screening Visit, that are considered by the investigator to be clinically significant; or the participant has any of the following values at the Screening Visit:

    * A serum creatinine value \>1.5 times the upper limits of normal (xULN).
    * A serum total bilirubin value \>1.5 xULN.
    * A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value \>2 xULN.
18. The participant has glycosylated hemoglobin (HbA1C) ≥7% at baseline and no prior diagnosis of diabetes and/or treatment for diabetes. NOTE: Participants with known diabetes are not excluded.
19. The participant has a thyroid stimulating hormone (TSH) value outside the normal range at the Screening Visit that is deemed clinically significant by the investigator. If TSH is outside the normal range, a free T4 will be obtained.
20. The participant has clinically significant abnormal vital signs as determined by the investigator.
21. The participant has an abnormal electrocardiogram (ECG) as determined by the central reader and confirmed as clinically significant by the investigator.
22. The participant has a disease or takes medication that, in the opinion of the investigator, could interfere with the assessments of safety, tolerability, or efficacy.
23. The participant, in the opinion of the investigator, is unlikely to comply with the clinical study protocol or is unsuitable for any reason.

Primary outcomes:
measure: Change From Baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score at Week 6
timeFrame: Baseline and Week 6
Secondary outcomes:
measure: Change From Baseline in Quality of Life, Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF) Short Form Total Score at Week 6
timeFrame: Baseline and Week 6
measure: Percentage of Participants With MADRS Response at Week 6, With Response Defined as a ≥ 50% Decrease in the MADRS Total Score From Baseline
timeFrame: Baseline and Week 6
measure: Change From Baseline in Young Mania Rating Scale (YMRS) Total Score at Week 6
timeFrame: Baseline and Week 6
measure: Clinical Global Impression Scale-Improvement (CGI-I) Score at Week 6
timeFrame: 6 Weeks
measure: Change From Baseline in Clinical Global Impression Scale-Severity (CGI-S) at Week 6
timeFrame: Baseline and Week 6
measure: Percentage of Participants With MADRS Remission at Week 6, With Remission Defined as a MADRS Total Score ≤10
timeFrame: Week 6
measure: Change From Baseline in the Quick Inventory of Depressive Symptomatology - Self-Rated16 (QIDS-SR16) Total Score at Week 6
timeFrame: Baseline and Week 6
measure: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 6
timeFrame: Baseline and Week 6
Other outcomes:
Locations:
city: Birmingham
country: United States
state: Alabama
city: Dothan
country: United States
state: Alabama
city: Muscle Shoals
country: United States
state: Alabama
city: Phoenix
country: United States
state: Arizona
city: Fayetteville
country: United States
state: Arkansas
city: Little Rock
country: United States
state: Arkansas
city: Bellflower
country: United States
state: California
city: Costa Mesa
country: United States
state: California
city: Garden Grove
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state: California
city: Harbor City
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state: California
city: Huntington Park
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state: California
city: Irvine
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state: California
city: Lomita
country: United States
state: California
city: Long Beach
country: United States
state: California
city: Los Angeles
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state: California
city: Murrieta
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state: California
city: National City
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state: California
city: Oceanside
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state: California
city: Orange
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state: California
city: Paramount
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state: California
city: Rancho Cucamonga
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city: Redondo Beach
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city: Sacramento
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city: San Diego
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city: San Jose
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city: San Ramon
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state: California
city: Sherman Oaks
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state: California
city: Torrance
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state: California
city: Wildomar
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state: California
city: Colorado Springs
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state: Colorado
city: Denver
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state: Colorado
city: Norwalk
country: United States
state: Connecticut
city: Washington
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state: District of Columbia
city: Clearwater
country: United States
state: Florida
city: Coral Gables
country: United States
state: Florida
city: Coral Springs
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state: Florida
city: Edgewater
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state: Florida
city: Hialeah
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state: Florida
city: Jacksonville
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state: Florida
city: Leesburg
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state: Florida
city: Miami Beach
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state: Florida
city: Miami Lakes
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state: Florida
city: Miami
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state: Florida
city: Orange City
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city: Orlando
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city: Pembroke Pines
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city: Plantation
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city: Port Charlotte
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city: Saint Cloud
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city: Tampa
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state: Florida
city: Vero Beach
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state: Florida
city: Atlanta
country: United States
state: Georgia
city: Dunwoody
country: United States
state: Georgia
city: East Point
country: United States
state: Georgia
city: Smyrna
country: United States
state: Georgia
city: Suwanee
country: United States
state: Georgia
city: Honolulu
country: United States
state: Hawaii
city: Chicago
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state: Illinois
city: Chicago
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state: Illinois
city: Gurnee
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city: Hoffman Estates
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city: Libertyville
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city: Skokie
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state: Illinois
city: Brownsburg
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state: Indiana
city: Manhattan
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city: Topeka
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city: Wichita
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state: Kansas
city: Elizabethtown
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state: Kentucky
city: Lexington
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city: Paducah
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city: Mandeville
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state: Louisiana
city: Metairie
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state: Louisiana
city: Baltimore
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state: Maryland
city: Boston
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state: Massachusetts
city: Fall River
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city: Bloomfield Hills
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state: Michigan
city: Detroit
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state: Michigan
city: Kalamazoo
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state: Michigan
city: Flowood
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state: Mississippi
city: Hazelwood
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state: Missouri
city: St Louis
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city: St. Charles
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city: Washington
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state: Missouri
city: Lincoln
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state: Nebraska
city: Las Vegas
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state: Nevada
city: Cherry Hill
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state: New Jersey
city: Albuquerque
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state: New Mexico
city: Brooklyn
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state: New York
city: Cedarhurst
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city: Fresh Meadows
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city: Rochester
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city: Staten Island
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state: New York
city: Charlotte
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state: North Carolina
city: Columbiana
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state: North Carolina
city: Durham
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state: North Carolina
city: Greensboro
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state: North Carolina
city: Raleigh
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city: Salisbury
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state: North Carolina
city: Wilmington
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state: North Carolina
city: Fargo
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state: North Dakota
city: Cincinnati
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state: Ohio
city: Cleveland
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city: Dayton
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city: Franklin
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city: Oklahoma City
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state: Oklahoma
city: Portland
country: United States
state: Oregon
city: Allentown
country: United States
state: Pennsylvania
city: Duncansville
country: United States
state: Pennsylvania
city: Harleysville
country: United States
state: Pennsylvania
city: McMurray
country: United States
state: Pennsylvania
city: Media
country: United States
state: Pennsylvania
city: Philadelphia
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state: Pennsylvania
city: Pittsburgh
country: United States
state: Pennsylvania
city: Lincoln
country: United States
state: Rhode Island
city: Columbia
country: United States
state: South Carolina
city: Greer
country: United States
state: South Carolina
city: Indian Land
country: United States
state: South Carolina
city: Clarksville
country: United States
state: Tennessee
city: Knoxville
country: United States
state: Tennessee
city: Memphis
country: United States
state: Tennessee
city: Austin
country: United States
state: Texas
city: Bellaire
country: United States
state: Texas
city: Corpus Christi
country: United States
state: Texas
city: Dallas
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state: Texas
city: Houston
country: United States
state: Texas
city: Irving
country: United States
state: Texas
city: Nassau Bay
country: United States
state: Texas
city: Plano
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: Bountiful
country: United States
state: Utah
city: Newport News
country: United States
state: Virginia
city: Norfolk
country: United States
state: Virginia
city: Richmond
country: United States
state: Virginia
city: Virginia Beach
country: United States
state: Virginia
city: Kirkland
country: United States
state: Washington
city: Richland
country: United States
state: Washington
city: Seattle
country: United States
state: Washington
city: Clarksburg
country: United States
state: West Virginia
city: Milwaukee
country: United States
state: Wisconsin
city: Buenos Aires
country: Argentina
city: Cordoba
country: Argentina
city: Mendoza
country: Argentina
city: Santa Fe
country: Argentina
city: Antofagasta
country: Chile
city: Arauco
country: Chile
city: Elqui
country: Chile
city: Santiago
country: Chile
city: Bello
country: Colombia
state: Antioquia
city: Antioquia
country: Colombia
city: Barranquilla
country: Colombia
city: Bogotá
country: Colombia
city: Mexicali
country: Mexico
state: Baja California
city: Mexico
country: Mexico
state: DF
city: Leon
country: Mexico
state: Guanajuato
city: Monterrey
country: Mexico
state: Nuevo Leon
city: San Lucas
country: Mexico
state: Tepetlacalco
city: Merida
country: Mexico
state: Yucatan
city: Mexico
country: Mexico
city: San Luis Potosi
country: Mexico
Study officials:
affiliation: Takeda
name: Medical Director Clinical Science
role: STUDY_DIRECTOR
References: