A Trial to Evaluate the Safety and Tolerability of Brexpiprazole in the Treatment of Participants With Bipolar I Disorder.

Sponsor
Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT03287869
Collaborator
H. Lundbeck A/S (Industry)
381
73
1
21.2
5.2
0.2

Study Details

Study Description

Brief Summary

This study evaluated the safety and evaluate the safety and tolerability of open-label brexpiprazole (2 - 4 mg/day, with a starting dose of 2 mg/day) for the treatment of adult subjects with bipolar I disorder. All participants received a starting dose of brexpiprazole.

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

While the availability of atypical antipsychotics had increased the therapeutic options available, there remains a need for safer and more effective therapies in the treatment of manic and depressive episodes of bipolar I disorder. Brexpiprazole's specific receptor activity profile likely correlates with its established efficacy in schizophrenia and major depressive disorder, and may prove to be an effective target for the treatment of acute mania of bipolar I disorder.

Study Design

Study Type:
Interventional
Actual Enrollment :
381 participants
Intervention Model:
Parallel Assignment
Intervention Model Description:
Group composed of eligible rollover participants who completed one of the double-blind, phase 3 efficacy trials (331-201-00080 (NCT03259555) or 331-201-00081 (NCT03257865)).Group composed of eligible rollover participants who completed one of the double-blind, phase 3 efficacy trials (331-201-00080 (NCT03259555) or 331-201-00081 (NCT03257865)).
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Multicenter, Open-label Trial to Evaluate the Safety and Tolerability of Brexpiprazole in the Treatment of Subjects With Bipolar I Disorder
Actual Study Start Date :
Oct 24, 2017
Actual Primary Completion Date :
Jul 31, 2019
Actual Study Completion Date :
Jul 31, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: Brexpiprazole

Brexpiprazole was administered in participants orally with flexible dosing from 2 mg/day from Days 1 to 3 regardless of treatment assignment in the previous double-blind trial, 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 tablets
Other Names:
  • OPC-34712
  • Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With at Least One Treatment Emergent Adverse Event (TEAE) by Severity [From Day 1 (after dosing) through 29 weeks (26 weeks treatment, 3 weeks safety follow-up)]

      An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. AEs severity were graded on a 3-point scale as: 1 = mild; discomfort noticed, but no disruption to daily activity, 2 = moderate; discomfort sufficient to reduce or affect normal daily activity, and 3 = severe; inability to work or perform normal daily activity.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 65 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No

    Inclusion Criteria (rollover participants from 331-201-00080 & 331-201-00081 trials)

    • Participants remaining in hospital at the Day 21 visit of trial 331-201-00080 or 331-201-00081 were permitted to enroll in the 331-201-00083 trial at the week 3 visit of the double-blind trial if they were planned to be discharged from the hospital before the week 1 visit of trial 331-201-0083. Participants not discharged by the week 1 visit of trial 331-201-0083 were withdrawn.

    • Participants who, in the opinion of the investigator, could potentially benefit from administration of oral brexpiprazole for the treatment of bipolar I disorder and who completed 3 weeks of post-randomization treatment in Trial 331-201-00080 & Trial 331-201-00081.

    Exclusion Criteria (rollover participants from 331-201-00080 & 331-201-00081 trials)

    • Participants with a major protocol violation during the course of their participation in the double-blind phase 3 trials (331-201-00080 or 331-201-00081).

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Woodland International Research Group Little Rock Arkansas United States 72211
    2 Woodland Research Northwest, LLC Rogers Arkansas United States 72758
    3 Citrials Inc. Bellflower California United States 90706
    4 Radiant Research Cerritos California United States 90703
    5 ProScience Research Group Culver City California United States 90230
    6 Collaborative Neuroscience Network, LLC Garden Grove California United States 92845
    7 Behavioral Research Specialists, LLC Glendale California United States 91206
    8 Apostle Clinical Trials Long Beach California United States 90813
    9 Pacific Research Partners, LLC Oakland California United States 94607
    10 NRC Research Institute Orange California United States 92868
    11 Asclepes Research Centers, PC Panorama City California United States 91402
    12 CI Trials Riverside California United States 92705
    13 CNRI-San Diego San Diego California United States 92102
    14 Artemis Institute for Clinical Research San Diego California United States 92103
    15 Sharp Mesa Vista Hospital San Diego California United States 92123
    16 CI Trials Santa Ana California United States 92705
    17 Collaborative Neuroscience Network, LLC Torrance California United States 90502
    18 Shreenath Clinical Service Yorba Linda California United States 92886
    19 Optimus U Corp Coral Gables Florida United States 33134
    20 Segal Trials Fort Lauderdale Florida United States 33308
    21 Galiz Research Hialeah Florida United States 33016
    22 Research Centers of America, LLC Hollywood Florida United States 33024
    23 Florida Behavioral Medicine Largo Florida United States 33770
    24 University of South Florida Board of Trustees Tampa Florida United States 33613
    25 iResearch Atlanta, LLC Decatur Georgia United States 30030
    26 Alexian Brothers Center for Psychiatric Research Hoffman Estates Illinois United States 60169
    27 NeuroPsychiatric Research Winfield Illinois United States 60190
    28 Louisiana Clinical Research Shreveport Louisiana United States 71101
    29 CBH Health Gaithersburg Maryland United States 20877
    30 St. Charles Psychiatric Associates Saint Charles Missouri United States 63304
    31 Arch Clinical Trials, LLC Saint Louis Missouri United States 63118
    32 St. Louis Clinical Trials Saint Louis Missouri United States 63141
    33 Hassman Research Institute, LLC Berlin New Jersey United States 08009
    34 Clinical Trials of America-NC, LLC Hickory North Carolina United States 28601
    35 Richard H Weisler, MD PA Associates Raleigh North Carolina United States 27609
    36 SP Research PLLC Oklahoma City Oklahoma United States 73112
    37 Cutting Edge Research Group Oklahoma City Oklahoma United States 73116
    38 Community Clinical Research, Inc. Austin Texas United States 78754
    39 InSite Clinical Research DeSoto Texas United States 75115
    40 North Texas Clinical Trials Fort Worth Texas United States 76104
    41 Pillar Clinical Research LLC Garland Texas United States 75042
    42 Pillar Clinical Research, LLC Richardson Texas United States 75080
    43 Core Clinical Research Everett Washington United States 98201
    44 Mid Columbia Research Richland Washington United States 99352
    45 Mental Health Center Prof. Dr. Ivan Temkov - Burgas EOOD, Department for Treatment of Emergency Psychiatric Condition Burgas Bulgaria 8000
    46 State Psychiatry Hospital - Kardzhali,Third Male Department, First Female Department Kardzhali Bulgaria 6600
    47 State Psychiatry Hospital Sv. Ivan Rilski, First Male department, First Female Department Novi Iskar Bulgaria 1282
    48 University Multiprofile Hospital for Active Treatment Sveti Georgi EAD, Clinic of Psychiatry Plovdiv Bulgaria 4002
    49 "Mental Health Centre-Ruse" EOOD, Male department for persons with severe mental disorders, Female department for persons with severe mental disorders Ruse Bulgaria 7003
    50 University Multiprofile Hospital for Active Treatment -Alexandrovska EAD, Clinic of Psychiatry, First Department of Psychiatry Sofia Bulgaria 1431
    51 Multiprofile Hospital for Active Treatment - Targovishte AD, Department of Psychiatry Targovishte Bulgaria 7700
    52 Mental Health Center - Veliko Tarnovo EOOD, Department of Psychiatry for Active Treatment of Persons with Severe Mental Disorders Veliko Tarnovo Bulgaria 5000
    53 Mental Health Center - Vratsa EOOD, Department of Psychiatry Vratsa Bulgaria 3000
    54 CHC Rijeka-Clinic for Psychiatrics Rijeka Croatia 51000
    55 Poliklinika Neuron /Polyclinic Neuron Zagreb Croatia 10000
    56 Indywidualna Specjalistyczna Praktyka Lekarska Wieslaw Jerzy Cubala GdaƄsk Poland 80-438
    57 NZOZ Prywatna Klinika Psychiatryczna Inventiva Tuszyn Poland 95-080
    58 CHC Dr Dragisa Misovic Belgrade Serbia 11000
    59 Clinic for Psychiatric Disorders, Dr Laza Lazarevic Belgrade Serbia 11000
    60 Clinic for Psychiatry Belgrade Serbia 11000
    61 Specialized Hospital for Psychiatry Diseases Kovin Kovin Serbia 26220
    62 Clinical Center Kragujevac, Clinic of Psychiatry Kragujevac Serbia 34000
    63 Klinika za psihijariju, Klinicki Centar Vojvodine Novi Sad Serbia 21000
    64 Regional Clinical Hospital n.a I.I. Mechnicov Dnipro Ukraine 49005
    65 SI of Neurology Psychiatry and Narcology NAMS Kharkiv Ukraine 61068
    66 Kherson Regional Psychiatric Hospital Kherson Ukraine 73488
    67 Kyiv Regional Medical Incorporation Psychiatry Kyiv Ukraine 04080
    68 CI of LOR Lviv Regional Clinical Psychiatric Hospital, Department #25 Lviv Ukraine 79021
    69 Communal Institution of Lviv Regional Council "Lviv Regional Clinical Psychiatric Hospital", department #20 Lviv Ukraine 79021
    70 Odesa Regional Psychiatric Hospital 2 Odesa Ukraine 67513
    71 Maltsev Regional Clinical Psychiatric Hospital Poltava Ukraine 36013
    72 Ternopil Regional Municipal Clinical Psychoneurological Hospital Ternopil' Ukraine 46027
    73 O.I. Yushenko Vinnitsa Regional Clinic Vinnitsa Ukraine 21018

    Sponsors and Collaborators

    • Otsuka Pharmaceutical Development & Commercialization, Inc.
    • H. Lundbeck A/S

    Investigators

    None specified.

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Otsuka Pharmaceutical Development & Commercialization, Inc.
    ClinicalTrials.gov Identifier:
    NCT03287869
    Other Study ID Numbers:
    • 331-201-00083
    • 2017-002225-38
    First Posted:
    Sep 19, 2017
    Last Update Posted:
    Aug 17, 2020
    Last Verified:
    Aug 1, 2020
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    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.
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail The study included participants who completed 3-week double-blind treatment in studies 331-201-00080 (NCT03259555)/331-201-00081 (NCT03257865) and, who in the investigator's judgment, could potentially benefit to receive brexpiprazole in this study. Data was summarized as per the treatment received in the previous studies.
    Arm/Group Title Prior Brexpiprazole Prior Placebo
    Arm/Group Description Brexpiprazole was administered in participants orally with flexible dosing from 2 mg/day from Days 1 to 3 regardless of treatment assignment in the previous double-blind trial, 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. Participants who received brexpiprazole in the double-blind treatment period in previous studies were included in this group. Brexpiprazole was administered in participants orally with flexible dosing from 2 mg/day from Days 1 to 3 regardless of treatment assignment in the previous double-blind trial, 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. Participants who received placebo in the double-blind treatment period in previous studies were included in this group.
    Period Title: Overall Study
    STARTED 188 193
    Analyzed For Safety (Safety Sample) 184 184
    COMPLETED 105 100
    NOT COMPLETED 83 93

    Baseline Characteristics

    Arm/Group Title Prior Brexpiprazole Prior Placebo Total
    Arm/Group Description Brexpiprazole was administered in participants orally with flexible dosing from 2 mg/day from Days 1 to 3 regardless of treatment assignment in the previous double-blind trial, 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. Participants who received brexpiprazole in the double-blind treatment period in previous studies were included in this group. Brexpiprazole was administered in participants orally with flexible dosing from 2 mg/day from Days 1 to 3 regardless of treatment assignment in the previous double-blind trial, 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. Participants who received placebo in the double-blind treatment period in previous studies were included in this group. Total of all reporting groups
    Overall Participants 188 193 381
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    45.6
    (11.0)
    46.1
    (11.5)
    45.8
    (11.2)
    Sex: Female, Male (Count of Participants)
    Female
    97
    51.6%
    92
    47.7%
    189
    49.6%
    Male
    91
    48.4%
    101
    52.3%
    192
    50.4%
    Race/Ethnicity, Customized (Count of Participants)
    White
    129
    68.6%
    146
    75.6%
    275
    72.2%
    Black or African American
    52
    27.7%
    47
    24.4%
    99
    26%
    American Indian or Alaska Native
    3
    1.6%
    0
    0%
    3
    0.8%
    Asian
    2
    1.1%
    0
    0%
    2
    0.5%
    Race-Other
    2
    1.1%
    0
    0%
    2
    0.5%
    Race/Ethnicity, Customized (Count of Participants)
    Hispanic or Latino
    21
    11.2%
    24
    12.4%
    45
    11.8%
    Not Hispanic or Latino
    165
    87.8%
    169
    87.6%
    334
    87.7%
    Ethnicity-Other
    2
    1.1%
    0
    0%
    2
    0.5%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With at Least One Treatment Emergent Adverse Event (TEAE) by Severity
    Description An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. AEs severity were graded on a 3-point scale as: 1 = mild; discomfort noticed, but no disruption to daily activity, 2 = moderate; discomfort sufficient to reduce or affect normal daily activity, and 3 = severe; inability to work or perform normal daily activity.
    Time Frame From Day 1 (after dosing) through 29 weeks (26 weeks treatment, 3 weeks safety follow-up)

    Outcome Measure Data

    Analysis Population Description
    Safety Sample included all participants who received at least 1 dose of IMP (brexpiprazole).
    Arm/Group Title Prior Brexpiprazole Prior Placebo
    Arm/Group Description Brexpiprazole was administered in participants orally with flexible dosing from 2 mg/day from Days 1 to 3 regardless of treatment assignment in the previous double-blind trial, 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. Participants who received brexpiprazole in the double-blind treatment period in previous studies were included in this group. Brexpiprazole was administered in participants orally with flexible dosing from 2 mg/day from Days 1 to 3 regardless of treatment assignment in the previous double-blind trial, 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. Participants who received placebo in the double-blind treatment period in previous studies were included in this group.
    Measure Participants 184 184
    TEAE, Any grade
    79
    42%
    86
    44.6%
    TEAE, Mild
    60
    31.9%
    68
    35.2%
    TEAE, Moderate
    31
    16.5%
    29
    15%
    TEAE, Severe
    8
    4.3%
    5
    2.6%

    Adverse Events

    Time Frame From Day 1 (after dosing) through 29 weeks (26 weeks treatment, 3 weeks safety follow-up)
    Adverse Event Reporting Description Safety Sample included all participants who received at least 1 dose of IMP.
    Arm/Group Title Prior Brexpiprazole Prior Placebo
    Arm/Group Description Brexpiprazole was administered in participants orally with flexible dosing from 2 mg/day from Days 1 to 3 regardless of treatment assignment in the previous double-blind trial, 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. Participants who received brexpiprazole in the double-blind treatment period in previous studies were included in this group. Brexpiprazole was administered in participants orally with flexible dosing from 2 mg/day from Days 1 to 3 regardless of treatment assignment in the previous double-blind trial, 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. Participants who received placebo in the double-blind treatment period in previous studies were included in this group.
    All Cause Mortality
    Prior Brexpiprazole Prior Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/184 (0%) 0/184 (0%)
    Serious Adverse Events
    Prior Brexpiprazole Prior Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 11/184 (6%) 8/184 (4.3%)
    Cardiac disorders
    Acute Myocardial Infarction 0/184 (0%) 0 1/184 (0.5%) 1
    Ear and labyrinth disorders
    Vertigo Positional 0/184 (0%) 0 1/184 (0.5%) 1
    Gastrointestinal disorders
    Upper Gastrointestinal Haemorrhage 1/184 (0.5%) 1 0/184 (0%) 0
    General disorders
    Chest Pain 0/184 (0%) 0 1/184 (0.5%) 1
    Infections and infestations
    Cellulitis 1/184 (0.5%) 1 0/184 (0%) 0
    Nervous system disorders
    Migraine 0/184 (0%) 0 1/184 (0.5%) 1
    Psychiatric disorders
    Bipolar Disorder 0/184 (0%) 0 1/184 (0.5%) 1
    Depression 3/184 (1.6%) 3 2/184 (1.1%) 2
    Mania 5/184 (2.7%) 5 1/184 (0.5%) 1
    Suicidal Behaviour 1/184 (0.5%) 1 0/184 (0%) 0
    Suicidal Ideation 0/184 (0%) 0 1/184 (0.5%) 1
    Other (Not Including Serious) Adverse Events
    Prior Brexpiprazole Prior Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 13/184 (7.1%) 26/184 (14.1%)
    Nervous system disorders
    Akathisia 8/184 (4.3%) 9 17/184 (9.2%) 17
    Headache 5/184 (2.7%) 5 10/184 (5.4%) 12

    Limitations/Caveats

    As predefined in the protocol, there were no primary or secondary efficacy endpoints in this trial.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Sponsor reserves the right to review results publications prior to public release and can delay such publications for a period greater than 60 days but no more than 120 days from the date that the publication is submitted to the Sponsor for review. Sponsor can require changes to the publication to protect Sponsor's intellectual property rights and/or confidential information and reserves the right to limit publication timing and scope of data published based on the number of study locations.

    Results Point of Contact

    Name/Title Global Clinical Development
    Organization Otsuka Pharmaceutical Development & Commercialization, Inc.
    Phone 1-609-524-6788
    Email clinicaltransparency@otsuka-us.com
    Responsible Party:
    Otsuka Pharmaceutical Development & Commercialization, Inc.
    ClinicalTrials.gov Identifier:
    NCT03287869
    Other Study ID Numbers:
    • 331-201-00083
    • 2017-002225-38
    First Posted:
    Sep 19, 2017
    Last Update Posted:
    Aug 17, 2020
    Last Verified:
    Aug 1, 2020