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

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ClinicalTrials.gov Identifier: NCT03287869
Recruitment Status : Completed
First Posted : September 19, 2017
Results First Posted : August 17, 2020
Last Update Posted : August 17, 2020
Sponsor:
Collaborator:
H. Lundbeck A/S
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.

Study Type Interventional
Study Design Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Bipolar I Disorder
Acute Mania
Intervention Drug: Brexpiprazole
Enrollment 381
Recruitment Details  
Pre-assignment Details 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
Hide 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) [1] 184 184
Completed 105 100
Not Completed 83 93
Reason Not Completed
Adverse Event             14             12
Lack of Efficacy             1             0
Lost to Follow-up             13             19
Non-Compliance With Study Drug             5             9
Progressive Disease             1             0
Protocol Deviation             2             1
Withdrawal by Subject             36             43
Early Closure of the Site             0             1
Physician Decision             5             5
Reason not Specified             6             3
[1]
Participants who received at least 1 dose of investigational medicinal product (IMP-brexpiprazole).
Arm/Group Title Prior Brexpiprazole Prior Placebo Total
Hide 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 Number of Baseline Participants 188 193 381
Hide Baseline Analysis Population Description
Enrolled Sample included all participants who signed an inform consent form (ICF) for the trial.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 188 participants 193 participants 381 participants
45.6  (11.0) 46.1  (11.5) 45.8  (11.2)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 188 participants 193 participants 381 participants
Female
97
  51.6%
92
  47.7%
189
  49.6%
Male
91
  48.4%
101
  52.3%
192
  50.4%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Race Number Analyzed 188 participants 193 participants 381 participants
White
129
  68.6%
146
  75.6%
275
  72.2%
Black or African American
52
  27.7%
47
  24.4%
99
  26.0%
American Indian or Alaska Native
3
   1.6%
0
   0.0%
3
   0.8%
Asian
2
   1.1%
0
   0.0%
2
   0.5%
Race-Other
2
   1.1%
0
   0.0%
2
   0.5%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Ethnicity Number Analyzed 188 participants 193 participants 381 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
   0.0%
2
   0.5%
1.Primary Outcome
Title Number of Participants With at Least One Treatment Emergent Adverse Event (TEAE) by Severity
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Sample included all participants who received at least 1 dose of IMP (brexpiprazole).
Arm/Group Title Prior Brexpiprazole Prior Placebo
Hide 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.
Overall Number of Participants Analyzed 184 184
Measure Type: Count of Participants
Unit of Measure: Participants
TEAE, Any grade
79
  42.9%
86
  46.7%
TEAE, Mild
60
  32.6%
68
  37.0%
TEAE, Moderate
31
  16.8%
29
  15.8%
TEAE, Severe
8
   4.3%
5
   2.7%
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
Hide 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 (%) Affected / at Risk (%)
Total   0/184 (0.00%)      0/184 (0.00%)    
Hide Serious Adverse Events
Prior Brexpiprazole Prior Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   11/184 (5.98%)      8/184 (4.35%)    
Cardiac disorders     
Acute Myocardial Infarction  1  0/184 (0.00%)  0 1/184 (0.54%)  1
Ear and labyrinth disorders     
Vertigo Positional  1  0/184 (0.00%)  0 1/184 (0.54%)  1
Gastrointestinal disorders     
Upper Gastrointestinal Haemorrhage  1  1/184 (0.54%)  1 0/184 (0.00%)  0
General disorders     
Chest Pain  1  0/184 (0.00%)  0 1/184 (0.54%)  1
Infections and infestations     
Cellulitis  1  1/184 (0.54%)  1 0/184 (0.00%)  0
Nervous system disorders     
Migraine  1  0/184 (0.00%)  0 1/184 (0.54%)  1
Psychiatric disorders     
Bipolar Disorder  1  0/184 (0.00%)  0 1/184 (0.54%)  1
Depression  1  3/184 (1.63%)  3 2/184 (1.09%)  2
Mania  1  5/184 (2.72%)  5 1/184 (0.54%)  1
Suicidal Behaviour  1  1/184 (0.54%)  1 0/184 (0.00%)  0
Suicidal Ideation  1  0/184 (0.00%)  0 1/184 (0.54%)  1
1
Term from vocabulary, MedDRA (22.0)
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Prior Brexpiprazole Prior Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   13/184 (7.07%)      26/184 (14.13%)    
Nervous system disorders     
Akathisia  1  8/184 (4.35%)  9 17/184 (9.24%)  17
Headache  1  5/184 (2.72%)  5 10/184 (5.43%)  12
1
Term from vocabulary, MedDRA (22.0)
Indicates events were collected by systematic assessment
As predefined in the protocol, there were no primary or secondary efficacy endpoints in this trial.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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
Layout table for Results Point of Contact information
Name/Title: Global Clinical Development
Organization: Otsuka Pharmaceutical Development & Commercialization, Inc.
Phone: 1-609-524-6788
EMail: clinicaltransparency@otsuka-us.com
Layout table for additonal information
Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier: NCT03287869    
Other Study ID Numbers: 331-201-00083
2017-002225-38 ( EudraCT Number )
First Submitted: August 24, 2017
First Posted: September 19, 2017
Results First Submitted: July 29, 2020
Results First Posted: August 17, 2020
Last Update Posted: August 17, 2020