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

A Multicenter, Randomized, Double-blind Trial of Brexpiprazole Versus Placebo for the Acute Treatment Manic Episodes, With or Without Mixed Features, Associated With Bipolar I Disorder

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.

Study Overview

• Status: Completed
• Conditions: Bipolar I Disorder; Manic Episode
• Intervention / Treatment: Drug: Brexpiprazole; Drug: Placebo

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).

• Study Type: Interventional
• Enrollment (Actual): 333
• Phase: Phase 3

Contacts and Locations

Study Locations

• Croatia
  • Rijeka, Croatia, 51000
    • Clinical Hospital Centre Rijeka
• Ukraine
  • Dnipro, Ukraine, 49005
    • Communal Institution "Dnipropetrovsk Regional Clinical Hospital named after I.I. Mechnikov
  • Kharkiv, Ukraine, 61068
    • SI ""Institute of Neurology, Psychiatry and Narcology of National Academy of Medical Sciences of Ukraine
  • Kherson, Ukraine, 73488
    • Communal Establishment "Kherson Regional Psychiatric Hospital" of Kherson Regional Council
  • Kyiv, Ukraine, 04080
    • Kyiv Regional Medical Incorporation "Psychiatry", Center for Novel Treatment and Rehabilitation of Psychotic Disorders
  • Lviv, Ukraine, 79021
    • Communal Institution of Lviv Regional Council "Lviv Regional Clinical Psychiatric Hospital", Department #20
  • Lviv, Ukraine, 79021
    • Communal Institution of Lviv Regional Council "Lviv Regional Clinical Psychiatric Hospital", Department #25
  • Oleksandrivka, Ukraine, 67513
    • Communal Establishment "Odesa Regional Psychiatric Hospital #2
  • Poltava, Ukraine, 36013
    • O.F. Maltsev Poltava Regional Psychiatric Hospital
  • Ternopil', Ukraine, 46027
    • Ternopil Regional Municipal Clinical Psychoneurolgical Hospital
  • Vinnytsia, Ukraine, 21005
    • Communal Establishment "Acad. O.I. Iushchenko Vinnytsia Regional Psychoneurologic Hospital"
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72211
      • Woodland International Research Group, LLC
    • Little Rock, Arkansas, United States, 72209
      • Atria Clinical Research
  • California
    • Bellflower, California, United States, 90706
      • CiTrials
    • Cerritos, California, United States, 90703
      • CNS Research Science Inc.
    • Long Beach, California, United States, 90813
      • Apostle Clinical Trials
    • San Diego, California, United States, 92102
      • CNRI-San Diego
    • San Diego, California, United States, 92103
      • Artemis Institute for Clinical Research
    • Santa Ana, California, United States, 92705
      • CiTrials
    • Torrance, California, United States, 90502
      • Collaborative Neuroscience Network, LLC
    • Yorba Linda, California, United States, 92886
      • Shreenath Clinical Service
  • Florida
    • Hialeah, Florida, United States, 33016
      • Galiz Research
    • Hollywood, Florida, United States, 33024
      • Research Centers of America LLC
    • Miami, Florida, United States, 33125
      • Optimus U Corporation
    • Miami Springs, Florida, United States, 33166
      • South Florida Research Phase I-IV
    • Orlando, Florida, United States, 32801
      • Meridien Research
  • Georgia
    • Decatur, Georgia, United States, 30030
      • iResearch Atlanta, LLC
  • Illinois
    • Chicago, Illinois, United States, 60640
      • Uptown Research Institute LLC
    • Winfield, Illinois, United States, 60190
      • Neuropsychiatric Research & Associates, LTD
  • Louisiana
    • Shreveport, Louisiana, United States, 71101
      • Louisiana Clinical Research
  • Missouri
    • Saint Louis, Missouri, United States, 63118
      • Arch Clinical Trials, LLC
    • Saint Louis, Missouri, United States, 63141
      • St Louis Clinical Trials LLC
  • New Jersey
    • Berlin, New Jersey, United States, 08009
      • Hassman Research Institute
  • New York
    • Jamaica, New York, United States, 11432
      • CNS Research Science, Inc.
  • North Carolina
    • Charlotte, North Carolina, United States, 28211
      • New Hope Clinical Research
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Department of Psychiatry and Behavorial Science
  • Texas
    • DeSoto, Texas, United States, 75115
      • Insite Clinical Research LLC
    • Richardson, Texas, United States, 75080
      • Pillar Clinical Research, LLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 (MINI) and a history of at least one 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 (WOCBP) 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 (IMP).
• 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, medications).
• 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 and 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.
• Participants 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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline In Young-Mania Rating Scale (YMRS) Score At 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 (MRMM).	Baseline, Week 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline In Clinical Global Impression-Bipolar (CGI-BP) Severity Score In Mania At 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.	Baseline, Week 3

Collaborators and Investigators

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Collaborators: H. Lundbeck A/S
• Investigators: Study Director: Matthew Leoni, M.D., Otsuka Pharmaceutical Development & Commercialization, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): September 19, 2017
• Primary Completion (Actual): January 22, 2019
• Study Completion (Actual): January 22, 2019

Study Registration Dates

• First Submitted: August 4, 2017
• First Submitted That Met QC Criteria: August 18, 2017
• First Posted (Actual): August 22, 2017

Study Record Updates

• Last Update Posted (Actual): February 11, 2020
• Last Update Submitted That Met QC Criteria: February 3, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Bipolar; Brexpiprazole; Manic episode
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Bipolar and Related Disorders; Bipolar Disorder; Mania; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Serotonin Agents; Dopamine Agonists; Dopamine Agents; Brexpiprazole
• Other Study ID Numbers: 331-201-00081

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD 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.
• IPD Sharing 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.
• IPD Sharing 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 clinicaltransparency@Otsuka-us.com
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No