Efficacy and Safety of Ramelteon Sublingual as Adjunctive Therapy for Maintenance Treatment of Bipolar I Disorder

NCT01467713 | Terminated Phase 3 Results

• 2 other identifiers: TAK-375SL_203U1111-1124-4675
• Study Type: interventional
• Target: 642
• Locations: 5 countries
• Sites: 156

Brief Summary

The purpose of this study is to determine the efficacy and safety of ramelteon, once nightly before bedtime (QHS), sublingual (SL), in the maintenance treatment of Bipolar I Disorder in adult patients.

Conditions

Bipolar Disorder

Keywords

Drug Therapy

Outcome Measures

Primary Outcomes (1)

• Time From Randomization to Any Relapse

  The time from randomization to relapse over 12 months double-blind treatment period as determined by the Principal Investigator (PI) or defined by any of the following criteria: depression \[Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥16\]; mania/hypomania \[Young Mania Rating Scale (YMRS) total score ≥14\]; mixed episode \[MADRS score ≥16 and YMRS total score ≥16\]; or, whether participant receives psychiatric hospitalization for bipolar disorder, electroconvulsive therapy (ECT) or any psychotropic medication change prescribed for the treatment of depression, mania/hypomania or mixed episodes.

  Randomization to Month 12 double-blind treatment period

Secondary Outcomes (10)

• Time From Randomization to Relapse Due to Depression

  Randomization to Month 12 double-blind treatment period

• Time From Randomization to Relapse Due to Mania/Hypomania or Mixed Episode

  Randomization to Month 12 double-blind treatment period

• Time From Randomization to Relapse Due to Depression From PI Judgement and/or MADRS ≥16

  Randomization to Month 12 double-blind treatment period

• Time From Randomization to Relapse Due to Mania/Hypomania

  Randomization to 12 Month double-blind treatment period

• Time From Randomization to Relapse Due to Mixed Episode

  Randomization to Month 12 double-blind treatment period

Study Arms (4)

Placebo

PLACEBO COMPARATOR

Ramelteon SL placebo-matching, tablets, sublingual (SL) \[dissolved under the tongue\], once daily, every night at bedtime for up to 9 months.

Drug: Placebo

Ramelteon SL 0.1 mg

EXPERIMENTAL

Ramelteon SL 0.1 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.

Drug: Ramelteon SL

Ramelteon SL 0.4 mg

EXPERIMENTAL

Ramelteon SL 0.4 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.

Drug: Ramelteon SL

Ramelteon SL 0.8 mg

EXPERIMENTAL

Ramelteon SL 0.8 mg, tablets, sublingual, once daily, every night at bedtime for up to 9 months.

Drug: Ramelteon SL

Interventions

Ramelteon SL DRUG

Ramelteon sublingual (SL) tablets

Also known as: TAK-375SL

Ramelteon SL 0.1 mg; Ramelteon SL 0.4 mg; Ramelteon SL 0.8 mg

Placebo DRUG

Ramelteon sublingual (SL) placebo-matching tablets

Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
• 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.
• The participant suffers from bipolar I disorder, according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria and is confirmed by the Structured Clinical Interview for DSM Disorders (SCID).
• The participant is a man or woman aged between 18 and 75 years, inclusive.
• The participant has an identified caregiver or person responsible (e.g. family member, spouse, case worker or nurse at a residential living (facility) that is considered reliable by the investigator.
• The most recent mood episode (depression, mania, mixed episode) is within the past 9 months from screening.
• The participant has been in remission in the opinion of the principal investigator (PI) for at least 8 weeks prior to baseline from their most recent mood episode.
• The participant has a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≤12 at the Screening and Baseline visits.
• The participant has a Young Mania Rating Scale (YMRS) score of ≤10 both at the Screening and Baseline visits.
• The participant has a Clinical Global Impression Scale - Severity (CGI-S) score of ≤2 at the Screening and Baseline visits.
• Hamilton Rating Scale for Anxiety (HAM-A) score is ≤21 at Screening and Baseline visits.
• The participant's medications for bipolar I disorder are stable i.e., no dose adjustment has been made for at least 8 weeks prior to the randomization
• 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.
• A female participant of childbearing potential who is sexually active with a non sterilized male partner 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.

You may not qualify if:

• The participant has received any investigational compound \<30 days before Screening or 5 half-lives prior to Screening.
• The participant has ever received ramelteon in a previous clinical study or has ever used ramelteon.
• 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 (eg, spouse, parent, child, sibling) or may consent under duress.
• The participant has one or more of the following:
• Any current psychiatric disorder which is the primary focus of treatment other than bipolar I disorder as defined in the DSM-IV-TR, as assessed by the SCID.
• Current or history of: schizophrenia or any other psychotic disorder, including major depression with psychotic features, bipolar depression with psychotic features (with the exception of psychosis associated with a manic or mixed episode), obsessive-compulsive disorder (OCD), 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 (excluding nicotine or caffeine) as defined in the DSM-IV-TR that has not been in full and sustained remission for at three months from the day of screening (Participant must also have negative urine drug screen at Screening and Baseline; only exception is for benzodiazepines and opiates provided the participant has a valid prescription).
• Current diagnosis or history of alcohol or other substance dependence (excluding nicotine or caffeine) as defined in the DSM-IV-TR that has not been in full and sustained remission for at six months from the day of screening.(Participant must also have negative urine drug screen at Screening and Baseline; only exception is for benzodiazepines and opiates provided the participant has a valid prescription).
• Presence or history of a clinically significant neurological disorder (including epilepsy) as determined by the investigator.
• 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.
• The participant experienced the first episode of mood disorder after the age of 65 years.
• The participant is on any other medications other than antidepressants (except fluvoxamine), mood stabilizers (lithium, valproate, lamotrigine), or atypical antipsychotics (risperidone, lithium and/or valproate, the levels should be in the specified range: lithium (serum levels up to 1.2 mEq/L); valproate (serum levels up to 125 mcg/ml) at screening.
• The participant has received electroconvulsive therapy, vagal nerve stimulation, or repetitive transcranial magnetic stimulation within 6 months prior to Screening.

Sponsors & Collaborators

• Takeda: lead

Study Sites (156)

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Birmingham, Alabama, United States

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Dothan, Alabama, United States

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Muscle Shoals, Alabama, United States

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Phoenix, Arizona, United States

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Little Rock, Arkansas, United States

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Bellflower, California, United States

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Costa Mesa, California, United States

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Garden Grove, California, United States

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Harbor City, California, United States

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Huntington Park, California, United States

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Irvine, California, United States

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Lomita, California, United States

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Long Beach, California, United States

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Los Angeles, California, United States

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Murrieta, California, United States

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National City, California, United States

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Oceanside, California, United States

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Orange, California, United States

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Paramount, California, United States

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Rancho Cucamonga, California, United States

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Redondo Beach, California, United States

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Riverside, California, United States

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Sacramento, California, United States

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San Diego, California, United States

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San Jose, California, United States

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San Ramon, California, United States

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Sherman Oaks, California, United States

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Torrance, California, United States

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Wildomar, California, United States

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Colorado Springs, Colorado, United States

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Denver, Colorado, United States

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Norwalk, Connecticut, United States

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Washington D.C., District of Columbia, United States

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Clearwater, Florida, United States

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Coral Gables, Florida, United States

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Coral Springs, Florida, United States

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Edgewater, Florida, United States

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Hialeah, Florida, United States

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Jacksonville, Florida, United States

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Leesburg, Florida, United States

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Miami, Florida, United States

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Miami Beach, Florida, United States

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Miami Lakes, Florida, United States

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Orange City, Florida, United States

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Orlando, Florida, United States

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Pembroke Pines, Florida, United States

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Plantation, Florida, United States

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Port Charlotte, Florida, United States

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Saint Cloud, Florida, United States

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Tampa, Florida, United States

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Vero Beach, Florida, United States

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Atlanta, Georgia, United States

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Dunwoody, Georgia, United States

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East Point, Georgia, United States

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Smyrna, Georgia, United States

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Suwanee, Georgia, United States

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Honolulu, Hawaii, United States

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Chicago, Illinois, 60610, United States

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Chicago, Illinois, United States

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Gurnee, Illinois, 60610, United States

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Libertyville, Illinois, United States

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Skokie, Illinois, United States

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Brownsburg, Indiana, United States

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Manhattan, Kansas, United States

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Topeka, Kansas, United States

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Wichita, Kansas, United States

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Elizabethtown, Kentucky, United States

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Lexington, Kentucky, United States

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Paducah, Kentucky, United States

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Mandeville, Louisiana, United States

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Metairie, Louisiana, United States

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Baltimore, Maryland, United States

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Boston, Massachusetts, United States

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Fall River, Massachusetts, United States

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Bloomfield Hills, Michigan, United States

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Detroit, Michigan, United States

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Kalamazoo, Michigan, United States

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Flowood, Mississippi, United States

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Hazelwood, Missouri, United States

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Saint Charles, Missouri, United States

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St Louis, Missouri, United States

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Washington, Missouri, United States

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Lincoln, Nebraska, United States

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Las Vegas, Nevada, United States

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Cherry Hill, New Jersey, United States

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Albuquerque, New Mexico, United States

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Brooklyn, New York, United States

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Cedarhurst, New York, United States

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Fresh Meadows, New York, United States

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New York, New York, United States

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Rochester, New York, United States

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Staten Island, New York, United States

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Charlotte, North Carolina, United States

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Columbiana, North Carolina, United States

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Durham, North Carolina, United States

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Greensboro, North Carolina, United States

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Raleigh, North Carolina, United States

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Salisbury, North Carolina, United States

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Wilmington, North Carolina, United States

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Fargo, North Dakota, United States

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Cincinnati, Ohio, United States

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Cleveland, Ohio, United States

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Dayton, Ohio, United States

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Franklin, Ohio, United States

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Oklahoma City, Oklahoma, United States

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Portland, Oregon, United States

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Allentown, Pennsylvania, United States

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Duncansville, Pennsylvania, United States

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Harleysville, Pennsylvania, United States

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McMurray, Pennsylvania, United States

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Media, Pennsylvania, United States

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Philadelphia, Pennsylvania, United States

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Pittsburgh, Pennsylvania, United States

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Lincoln, Rhode Island, United States

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Columbia, South Carolina, United States

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Greer, South Carolina, United States

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Old Point Station, South Carolina, United States

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Clarksville, Tennessee, United States

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Knoxville, Tennessee, United States

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Memphis, Tennessee, United States

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Austin, Texas, United States

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Bellaire, Texas, United States

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Corpus Christi, Texas, United States

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Dallas, Texas, United States

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Irving, Texas, United States

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Nassau Bay, Texas, United States

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Plano, Texas, United States

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San Antonio, Texas, United States

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Bountiful, Utah, United States

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Newport News, Virginia, United States

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Norfolk, Virginia, United States

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Richmond, Virginia, United States

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Virginia Beach, Virginia, United States

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Kirkland, Washington, United States

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Richland, Washington, United States

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Seattle, Washington, United States

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Clarksburg, West Virginia, United States

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Milwaukee, Wisconsin, United States

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Buenos Aires, Argentina

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Córdoba, Argentina

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Mendoza, Argentina

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Santa Fe, Argentina

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Antofagasta, Chile

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Arauco, Chile

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Elqui, Chile

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Santiago, Chile

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Bello, Antioquia, Colombia

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Antioquia, Colombia

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Barranquilla, Colombia

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Bogotá, Colombia

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Mexicali, Estado de Baja California, Mexico

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León, Guanajuato, Mexico

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Mexico City, Mexico City, Mexico

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Monterrey, Nuevo León, Mexico

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Mérida, Yucatán, Mexico

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México, Mexico

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Related Publications (1)

• Mahableshwarkar AR, Calabrese JR, Macek TA, Budur K, Adefuye A, Dong X, Hanson E, Sachs GS. Efficacy and safety of sublingual ramelteon as an adjunctive therapy in the maintenance treatment of bipolar I disorder in adults: A phase 3, randomized controlled trial. J Affect Disord. 2017 Oct 15;221:275-282. doi: 10.1016/j.jad.2017.06.044. Epub 2017 Jun 20.

  PMID: 28662460 DERIVED

Related Links

• Rozerem Package Insert

MeSH Terms

Conditions

Bipolar Disorder

Condition Hierarchy (Ancestors)

Bipolar and Related Disorders; Mood Disorders; Mental Disorders

Results Point of Contact

• Title: Medical Director, Clinical Science
• Organization: Takeda

trialdisclosures@takeda.com

1-877-825-3327

Study Officials

• Medical Director Clinical Science

  Takeda

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 4, 2011
• First Posted: November 9, 2011
• Study Start: December 1, 2011
• Primary Completion: March 1, 2015
• Study Completion: March 1, 2015
• Last Updated: May 16, 2016
• Results First Posted: May 16, 2016

Record last verified: 2016-04

Locations

CO (4); US (138); CL (4); AR (4); ME (6)