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A Trial to Assess Brexpiprazole Versus Placebo for the Treatment of Acute Manic Episodes Associated With Bipolar I Disorder

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03259555
Recruitment Status : Completed
First Posted : August 23, 2017
Results First Posted : February 10, 2020
Last Update Posted : February 10, 2020
H. Lundbeck A/S
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.

Brief Summary:
To demonstrate the efficacy of brexpiprazole for the acute treatment of manic episodes, with or without mixed features, in participants with a diagnosis of bipolar I disorder.

Condition or disease Intervention/treatment Phase
Bipolar I Disorder Manic Episode Drug: Brexpiprazole Drug: Placebo Phase 3

Detailed Description:
A multicenter, randomized, double-blind trial of brexpiprazole versus placebo for the acute treatment of manic episodes, with or without mixed features, associated with bipolar I disorder. This study also demonstrated the safety and tolerability of brexpiprazole in the study population of males and females aged 18 to 65 years (inclusive, at time of consent).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 322 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Participants received a dose of brexpiprazole or placebo for a maximum of 21 days and were evaluated throughout the duration of the study.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Multicenter, Randomized, Double-blind Trial of Brexpiprazole Versus Placebo for the Acute Treatment of Manic Episodes, With or Without Mixed Features, Associated With Bipolar I Disorder
Actual Study Start Date : September 14, 2017
Actual Primary Completion Date : January 2, 2019
Actual Study Completion Date : January 2, 2019

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Brexpiprazole
Participants received a starting dose of 2 milligrams (mg)/day brexpiprazole from Days 1 to 3, followed by titration to 3 mg/day on Day 4. Participants may have been titrated (or re-titrated) to a higher dose of brexpiprazole, up to a maximum of 4 mg/day, based on treatment response and at the investigator's discretion anytime at Day 7 or thereafter. Participants who were unable to tolerate their current dose could have been titrated down to a minimum of 2 mg/day any time after Day 4.
Drug: Brexpiprazole
Brexpiprazole was administered orally with flexible dosing from 2 to 4 mg/day; titrated to a maximum of 4 mg/day for 3 weeks.

Placebo Comparator: Placebo
Matching placebo was administered in the same way as brexpiprazole to maintain the blind.
Drug: Placebo
Administered orally daily for 3 weeks.

Primary Outcome Measures :
  1. Change From Baseline In Young-Mania Rating Scale (YMRS) Score At Week 3 [ Time Frame: Baseline, Week 3 ]
    The YMRS was utilized to assess a participant's level of manic symptoms. It consists of 11 items: 1) elevated mood, 2) increased motor activity-energy, 3) sexual interest, 4) sleep, 5) irritability, 6) speech (rate and amount), 7) language-thought disorder, 8) content, 9) disruptive-aggressive behavior, 10) appearance, and 11) insight. Seven items are rated on a 0- to 4-scale, while four items (Items 5, 6, 8, and 9) are rated on a 0- to 8-scale with 0, 2, 4, 6, and 8 being the possible scores (twice the weight of the other items). For all items, 0 is the "best" rating and the highest score (4 or 8) is the 'worst' rating. The YMRS total score is the sum of ratings for all 11 items; therefore, possible total scores range from 0 to 60, with higher scores signifying more severe manic symptoms. Comparison between treatment groups was carried out using mixed-effect model repeated measure (MMRM).

Secondary Outcome Measures :
  1. Change From Baseline In Clinical Global Impression-Bipolar (CGI-BP) Severity Score In Mania At Week 3 [ Time Frame: Baseline, Week 3 ]
    The CGI-BP scale refers to the global impression of the participant with respect to bipolar disorder. The scale rates the participant's severity of illness (CGI-BP severity of illness: mania, depression, and overall bipolar illness) based on a 7-point scale: 1 = normal, not at all ill, 2 = minimally ill, 3 = mildly ill, 4 = moderately ill, 5 = markedly ill, 6 = severely ill, 7 = very severely ill.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Male or female participants, ages 18 to 65 years, inclusive, at the time of informed consent.
  • Participants willing to discontinue all prohibited medications to meet protocol-required washouts prior to and during the trial period.
  • Participants with a Diagnostic & Statistical Manual on Mental Disorders, 5th Edition (DSM-5) diagnosis of bipolar I disorder displaying an acute manic episode with or without mixed features requiring hospitalization. Diagnosis confirmed by the MINI International Neuropsychiatric Interview and a history of at least 1 previous manic episode with or without mixed features with manic symptoms of sufficient severity to require one of the following interventions: hospitalization or treatment with a mood stabilizer, or treatment with an antipsychotic agent. "Require" was defined as an intervention that occurred rather than one that was recommended.
  • Young-mania rating scale (YMRS) score of ≥24 at screening and baseline.

Exclusion Criteria:

  • Sexually active male or women of childbearing potential who did not agree to practice 2 different methods of birth control or remain abstinent during the trial and for 30 days after the last dose of investigational medicinal product.
  • Females who were breastfeeding and/or who had a positive pregnancy test result prior to receiving trial medication.
  • Participants considered unresponsive to clozapine or who were only responsive to clozapine.
  • Participants with a history of DSM-5 diagnosis other than bipolar I disorder, including schizophrenia, schizoaffective disorder, major depressive disorder, attention-deficit/hyperactivity disorder, delirium, dementia, amnestic, or other cognitive disorders. Also, participants with borderline, paranoid, histrionic, schizotypal, schizoid, or antisocial personality disorder. All other current diagnoses must have been discussed with the medical monitor.
  • Participants whose current manic episode had lasted for more than 4 weeks overall, or who had required hospitalization >21 days for the current acute episode at the time of the screening visit, excluding hospitalization for psychosocial reasons.
  • Participant with manic symptoms better accounted for by another general medical condition or direct physiological effect of substance (for example, medication).
  • Participants who have had electroconvulsive treatment within the past 2 months.
  • Participants with a positive drug screen for cocaine or other illicit drugs.
  • Abnormal laboratory test results, vital signs or electrocardiogram findings, unless based on investigator's judgment the findings are not medically significant or would not impact the safety of the participant or the interpretation of the trial results.
  • Rapid cyclers with more than 6 episodes in the previous year.
  • Participants with hypothyroidism or hyperthyroidism (unless condition has been stabilized with medications for at least the past 90 days) or an abnormal result for free thyroxine at screening.
  • Participants with uncontrolled hypertension or symptomatic hypotension or orthostatic hypotension.
  • Participant with epilepsy or history of seizures.
  • Participants who participated in a clinical trial within the last 60 days or who participated in more than 2 clinical trials within the past year.
  • Use of psychotropic medications (other than benzodiazepines) within 7 days of the baseline YMRS.
  • Participants who currently had clinically significant neurological, hepatic, renal, metabolic, hematological, immunological, cardiovascular, pulmonary, or gastrointestinal disorders.
  • Participants who received brexpiprazole in any prior clinical trial or currently taking commercially available brexpiprazole (Rexulti).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03259555

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Sponsors and Collaborators
Otsuka Pharmaceutical Development & Commercialization, Inc.
H. Lundbeck A/S
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Study Director: Matthew Leoni, M.D. Otsuka Pharmaceutical Development & Commercialization, Inc.
  Study Documents (Full-Text)

Documents provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:
Study Protocol  [PDF] December 21, 2017
Statistical Analysis Plan  [PDF] December 11, 2018

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Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc. Identifier: NCT03259555    
Other Study ID Numbers: 331-201-00080
First Posted: August 23, 2017    Key Record Dates
Results First Posted: February 10, 2020
Last Update Posted: February 10, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Anonymized Individual participant data (IPD) that underlie the results of this study will be shared with researchers to achieve aims pre-specified in a methodologically sound research proposal. Small studies with less than 25 participants are excluded from data sharing.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: Data will be available after marketing approval in global markets, or beginning 1-3 years following article publication. There is no end date to the availability of the data.
Access Criteria: Otsuka will share data on an Otsuka-owned remotely accessible data sharing platform with Python and R analytical software. Research requests should be directed to

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:
Manic episode
Additional relevant MeSH terms:
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Bipolar Disorder
Bipolar and Related Disorders
Mental Disorders
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Dopamine Agonists
Dopamine Agents