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

Primary Purpose

Bipolar I Disorder, Manic Episode

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Brexpiprazole
Placebo
Sponsored by
Otsuka Pharmaceutical Development & Commercialization, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Bipolar I Disorder focused on measuring Brexpiprazole, Bipolar, Manic episode

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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).

Sites / Locations

  • Woodland International Research Group
  • Woodland Research Northwest, LLC
  • ProScience Research Group
  • Collaborative Neuroscience Network, LLC
  • Behavioral Research Specialists, LLC
  • Pacific Research Partners, LLC
  • NRC Research Institute
  • Asclepes Research Centers
  • Ci Trials
  • Sharp Vista Hospital
  • Galiz Research
  • Advanced Research Institute of Miami
  • Florida Behavioral Medicine
  • Optimus U Corporation
  • Behavioral Clinical Research, Inc.
  • Segal Trials
  • Radiant Research Inc.
  • Alexian Brothers Center for Psychiatric Research
  • CBH Health
  • Advanced Clinical Research Center, LLC
  • Richard H Weisler, MD, PA, and Associates
  • SP Research PLLC
  • Cutting Edge Research Group
  • Carolina Clinical Trials, Inc.
  • University of Texas at Austin
  • Community Clinical Research, Inc.
  • Pillar Clinical Research, LLC
  • Pillar Clinical Research, LLC
  • Mid Columbia Research
  • Mental Health Center Prof. Dr. Ivan Temkov - Burgas EOOD
  • State Psychiatry Hospital - Kardzhali
  • State Psychiatry Hospital Sv. Ivan Rilski
  • University Multiprofile Hospital for Active Treatment Sveti Georgi EAD
  • Mental Health Center - Ruse EOOD
  • University Multiprofile Hospital for Active Treatment Alexandrovska EAD
  • Multiprofile Hospital for Active Treatment - Targovishte AD
  • Mental Health Center - Veliko Tarnovo EOOD
  • Mental Health Center - Vratsa EOOD
  • Samodzielny Publiczny Psychiatryczny Zaklad Opieki Zdrowotnej im. Dr. Stanislawa Deresza w Choroszczy
  • Uniwersyteckie Centrum Kliniczne w Gdansku Klinika Psychiatrii Doroslych
  • NZOZ Centrum Medyczne HCP Sp. z o. o.
  • NZOZ Prywatna Klinika Psychiatryczna Inventiva
  • Clinic for Psychiatric Disorders Dr Laza Lazarevic
  • Clinical Center of Serbia
  • Clinical Hospital Center Dr Dragisa Misovic-Dedinje
  • Special Hospital for Psychiatric Diseases Kovin
  • Clinical Center Kragujevac
  • Clinical Center of Vojvodina

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Brexpiprazole

Placebo

Arm Description

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.

Matching placebo was administered in the same way as brexpiprazole to maintain the blind.

Outcomes

Primary Outcome Measures

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 (MMRM).

Secondary Outcome Measures

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.

Full Information

First Posted
August 4, 2017
Last Updated
February 3, 2020
Sponsor
Otsuka Pharmaceutical Development & Commercialization, Inc.
Collaborators
H. Lundbeck A/S
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1. Study Identification

Unique Protocol Identification Number
NCT03259555
Brief Title
A Trial to Assess Brexpiprazole Versus Placebo for the Treatment of Acute Manic Episodes Associated With Bipolar I Disorder
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
Study Type
Interventional

2. Study Status

Record Verification Date
February 2020
Overall Recruitment Status
Completed
Study Start Date
September 14, 2017 (Actual)
Primary Completion Date
January 2, 2019 (Actual)
Study Completion Date
January 2, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Otsuka Pharmaceutical Development & Commercialization, Inc.
Collaborators
H. Lundbeck A/S

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.
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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bipolar I Disorder, Manic Episode
Keywords
Brexpiprazole, Bipolar, Manic episode

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
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
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
322 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Brexpiprazole
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Matching placebo was administered in the same way as brexpiprazole to maintain the blind.
Intervention Type
Drug
Intervention Name(s)
Brexpiprazole
Intervention Description
Brexpiprazole was administered orally with flexible dosing from 2 to 4 mg/day; titrated to a maximum of 4 mg/day for 3 weeks.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Administered orally daily for 3 weeks.
Primary Outcome Measure Information:
Title
Change From Baseline In Young-Mania Rating Scale (YMRS) Score At Week 3
Description
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).
Time Frame
Baseline, Week 3
Secondary Outcome Measure Information:
Title
Change From Baseline In Clinical Global Impression-Bipolar (CGI-BP) Severity Score In Mania At Week 3
Description
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.
Time Frame
Baseline, Week 3

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Matthew Leoni, M.D.
Organizational Affiliation
Otsuka Pharmaceutical Development & Commercialization, Inc.
Official's Role
Study Director
Facility Information:
Facility Name
Woodland International Research Group
City
Little Rock
State/Province
Arkansas
ZIP/Postal Code
72211
Country
United States
Facility Name
Woodland Research Northwest, LLC
City
Rogers
State/Province
Arkansas
ZIP/Postal Code
72758
Country
United States
Facility Name
ProScience Research Group
City
Culver City
State/Province
California
ZIP/Postal Code
90230
Country
United States
Facility Name
Collaborative Neuroscience Network, LLC
City
Garden Grove
State/Province
California
ZIP/Postal Code
92845
Country
United States
Facility Name
Behavioral Research Specialists, LLC
City
Glendale
State/Province
California
ZIP/Postal Code
91206
Country
United States
Facility Name
Pacific Research Partners, LLC
City
Oakland
State/Province
California
ZIP/Postal Code
94607
Country
United States
Facility Name
NRC Research Institute
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Facility Name
Asclepes Research Centers
City
Panorama City
State/Province
California
ZIP/Postal Code
91402
Country
United States
Facility Name
Ci Trials
City
Riverside
State/Province
California
ZIP/Postal Code
92506
Country
United States
Facility Name
Sharp Vista Hospital
City
San Diego
State/Province
California
ZIP/Postal Code
92123
Country
United States
Facility Name
Galiz Research
City
Hialeah
State/Province
Florida
ZIP/Postal Code
33016
Country
United States
Facility Name
Advanced Research Institute of Miami
City
Homestead
State/Province
Florida
ZIP/Postal Code
33030
Country
United States
Facility Name
Florida Behavioral Medicine
City
Largo
State/Province
Florida
ZIP/Postal Code
33770
Country
United States
Facility Name
Optimus U Corporation
City
Miami
State/Province
Florida
ZIP/Postal Code
33125
Country
United States
Facility Name
Behavioral Clinical Research, Inc.
City
North Miami
State/Province
Florida
ZIP/Postal Code
33161
Country
United States
Facility Name
Segal Trials
City
North Miami
State/Province
Florida
ZIP/Postal Code
33161
Country
United States
Facility Name
Radiant Research Inc.
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30325
Country
United States
Facility Name
Alexian Brothers Center for Psychiatric Research
City
Hoffman Estates
State/Province
Illinois
ZIP/Postal Code
60169
Country
United States
Facility Name
CBH Health
City
Gaithersburg
State/Province
Maryland
ZIP/Postal Code
20877
Country
United States
Facility Name
Advanced Clinical Research Center, LLC
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63123
Country
United States
Facility Name
Richard H Weisler, MD, PA, and Associates
City
Raleigh
State/Province
North Carolina
ZIP/Postal Code
27609
Country
United States
Facility Name
SP Research PLLC
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73112
Country
United States
Facility Name
Cutting Edge Research Group
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73116
Country
United States
Facility Name
Carolina Clinical Trials, Inc.
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29407
Country
United States
Facility Name
University of Texas at Austin
City
Austin
State/Province
Texas
ZIP/Postal Code
78712
Country
United States
Facility Name
Community Clinical Research, Inc.
City
Austin
State/Province
Texas
ZIP/Postal Code
78754
Country
United States
Facility Name
Pillar Clinical Research, LLC
City
Garland
State/Province
Texas
ZIP/Postal Code
75042
Country
United States
Facility Name
Pillar Clinical Research, LLC
City
Richardson
State/Province
Texas
ZIP/Postal Code
75080
Country
United States
Facility Name
Mid Columbia Research
City
Richland
State/Province
Washington
ZIP/Postal Code
99352
Country
United States
Facility Name
Mental Health Center Prof. Dr. Ivan Temkov - Burgas EOOD
City
Burgas
ZIP/Postal Code
8000
Country
Bulgaria
Facility Name
State Psychiatry Hospital - Kardzhali
City
Kardzhali
ZIP/Postal Code
6600
Country
Bulgaria
Facility Name
State Psychiatry Hospital Sv. Ivan Rilski
City
Novi Iskar
ZIP/Postal Code
1282
Country
Bulgaria
Facility Name
University Multiprofile Hospital for Active Treatment Sveti Georgi EAD
City
Plovdiv
ZIP/Postal Code
4002
Country
Bulgaria
Facility Name
Mental Health Center - Ruse EOOD
City
Ruse
ZIP/Postal Code
7003
Country
Bulgaria
Facility Name
University Multiprofile Hospital for Active Treatment Alexandrovska EAD
City
Sofia
ZIP/Postal Code
1431
Country
Bulgaria
Facility Name
Multiprofile Hospital for Active Treatment - Targovishte AD
City
Targovishte
ZIP/Postal Code
7700
Country
Bulgaria
Facility Name
Mental Health Center - Veliko Tarnovo EOOD
City
Veliko Tarnovo
ZIP/Postal Code
5000
Country
Bulgaria
Facility Name
Mental Health Center - Vratsa EOOD
City
Vratsa
ZIP/Postal Code
3000
Country
Bulgaria
Facility Name
Samodzielny Publiczny Psychiatryczny Zaklad Opieki Zdrowotnej im. Dr. Stanislawa Deresza w Choroszczy
City
Choroszcz
ZIP/Postal Code
16-070
Country
Poland
Facility Name
Uniwersyteckie Centrum Kliniczne w Gdansku Klinika Psychiatrii Doroslych
City
Gdańsk
ZIP/Postal Code
80-952
Country
Poland
Facility Name
NZOZ Centrum Medyczne HCP Sp. z o. o.
City
Poznań
ZIP/Postal Code
61-485
Country
Poland
Facility Name
NZOZ Prywatna Klinika Psychiatryczna Inventiva
City
Tuszyn
ZIP/Postal Code
95-080
Country
Poland
Facility Name
Clinic for Psychiatric Disorders Dr Laza Lazarevic
City
Belgrade
ZIP/Postal Code
11000
Country
Serbia
Facility Name
Clinical Center of Serbia
City
Belgrade
ZIP/Postal Code
11000
Country
Serbia
Facility Name
Clinical Hospital Center Dr Dragisa Misovic-Dedinje
City
Belgrade
ZIP/Postal Code
11000
Country
Serbia
Facility Name
Special Hospital for Psychiatric Diseases Kovin
City
Kovin
ZIP/Postal Code
26220
Country
Serbia
Facility Name
Clinical Center Kragujevac
City
Kragujevac
ZIP/Postal Code
34000
Country
Serbia
Facility Name
Clinical Center of Vojvodina
City
Novi Sad
ZIP/Postal Code
21000
Country
Serbia

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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

Learn more about this trial

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

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