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

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ClinicalTrials.gov Identifier: NCT03259555
Recruitment Status : Completed
First Posted : August 23, 2017
Results First Posted : February 10, 2020
Last Update Posted : February 10, 2020
Sponsor:
Collaborator:
H. Lundbeck A/S
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Bipolar I Disorder
Manic Episode
Interventions Drug: Brexpiprazole
Drug: Placebo
Enrollment 322
Recruitment Details  
Pre-assignment Details The trial population consisted of adult participants (18 to 65 years) diagnosed with bipolar I disorder displaying an acute manic episode with or without mixed features requiring hospitalization.
Arm/Group Title Brexpiprazole Placebo
Hide Arm/Group Description Brexpiprazole was administered orally with flexible dosing from 2 to 4 milligrams (mg)/day; titrated to a maximum of 4 mg/day. Matching placebo was administered orally in the same way as brexpiprazole to maintain the blind.
Period Title: Overall Study
Started 158 164
Received At Least 1 Dose of Study Drug [1] 158 163
Completed 124 134
Not Completed 34 30
Reason Not Completed
Adverse Event             6             4
Lack of Efficacy             6             4
Lost to Follow-up             0             2
Non-Compliance With Study Drug             1             0
Progressive Disease             0             2
Withdrawal by Subject             19             16
Physician Decision             1             2
Other             1             0
[1]
Randomized participants who received at least 1 dose of study drug were analyzed for safety.
Arm/Group Title Brexpiprazole Placebo Total
Hide Arm/Group Description Brexpiprazole was administered orally with flexible dosing from 2 to 4 milligrams (mg)/day; titrated to a maximum of 4 mg/day. Matching placebo was administered orally in the same way as brexpiprazole to maintain the blind. Total of all reporting groups
Overall Number of Baseline Participants 158 164 322
Hide Baseline Analysis Population Description
The baseline population consisted of all randomized participants.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 158 participants 164 participants 322 participants
43.4  (11.7) 44.5  (11.2) 44.0  (11.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 158 participants 164 participants 322 participants
Female
80
  50.6%
83
  50.6%
163
  50.6%
Male
78
  49.4%
81
  49.4%
159
  49.4%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 158 participants 164 participants 322 participants
Hispanic or Latino
16
  10.1%
22
  13.4%
38
  11.8%
Not Hispanic or Latino
141
  89.2%
141
  86.0%
282
  87.6%
Unknown
0
   0.0%
1
   0.6%
1
   0.3%
Ethnicity - Other
1
   0.6%
0
   0.0%
1
   0.3%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 158 participants 164 participants 322 participants
White
95
  60.1%
113
  68.9%
208
  64.6%
Black or African American
54
  34.2%
51
  31.1%
105
  32.6%
American Indian or Alaska Native
2
   1.3%
0
   0.0%
2
   0.6%
Asian
3
   1.9%
0
   0.0%
3
   0.9%
Native Hawaiian or Other Pacific Islander
2
   1.3%
0
   0.0%
2
   0.6%
Race - Other
2
   1.3%
0
   0.0%
2
   0.6%
1.Primary Outcome
Title Change From Baseline In Young-Mania Rating Scale (YMRS) Score At Week 3
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: all participants who received at least 1 dose of study drug and had a baseline value and at least 1 valid post-randomization efficacy evaluation for YMRS Total Score in the double-blind treatment phase at the specified timepoint.
Arm/Group Title Brexpiprazole Placebo
Hide Arm/Group Description:
Brexpiprazole was administered orally with flexible dosing from 2 to 4 milligrams (mg)/day; titrated to a maximum of 4 mg/day.
Matching placebo was administered orally in the same way as brexpiprazole to maintain the blind.
Overall Number of Participants Analyzed 124 134
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-10.6  (0.72) -10.8  (0.70)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Brexpiprazole, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.8797
Comments [Not Specified]
Method Mixed-effect Model Repeated Measure
Comments An "unstructured" covariance was used.
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 0.14
Confidence Interval (2-Sided) 95%
-1.74 to 2.03
Estimation Comments Comparison between treatment groups was carried out using MMRM, with study center, treatment group, visit, and treatment group-by-visit interaction as factor and baseline-by-visit interaction as a covariate. An "unstructured" covariance was used.
2.Secondary Outcome
Title Change From Baseline In Clinical Global Impression-Bipolar (CGI-BP) Severity Score In Mania At Week 3
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: all participants who received at least 1 dose of study drug and had a baseline value and at least 1 valid post-randomization efficacy evaluation for YMRS Total Score in the double-blind treatment phase at the specified timepoint.
Arm/Group Title Brexpiprazole Placebo
Hide Arm/Group Description:
Brexpiprazole was administered orally with flexible dosing from 2 to 4 milligrams (mg)/day; titrated to a maximum of 4 mg/day.
Matching placebo was administered orally in the same way as brexpiprazole to maintain the blind.
Overall Number of Participants Analyzed 124 134
Mean (Standard Deviation)
Unit of Measure: units on a scale
-1.12  (1.06) -1.21  (1.13)
Time Frame From Day 1 (after dosing) through 6 weeks (3 weeks treatment, 3 weeks safety follow-up).
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Brexpiprazole Placebo
Hide Arm/Group Description Brexpiprazole was administered orally with flexible dosing from 2 to 4 milligrams (mg)/day; titrated to a maximum of 4 mg/day. Matching placebo was administered orally in the same way as brexpiprazole to maintain the blind.
All-Cause Mortality
Brexpiprazole Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   0/158 (0.00%)      0/163 (0.00%)    
Hide Serious Adverse Events
Brexpiprazole Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   4/158 (2.53%)      1/163 (0.61%)    
Blood and lymphatic system disorders     
Thrombocytopenia  1  1/158 (0.63%)  1 0/163 (0.00%)  0
Infections and infestations     
Varicella  1  1/158 (0.63%)  1 0/163 (0.00%)  0
Nervous system disorders     
Akathisia  1  1/158 (0.63%)  1 0/163 (0.00%)  0
Dystonia  1  1/158 (0.63%)  1 0/163 (0.00%)  0
Psychiatric disorders     
Mania  1  1/158 (0.63%)  1 1/163 (0.61%)  1
1
Term from vocabulary, MedDra 21.1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 3%
Brexpiprazole Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   20/158 (12.66%)      24/163 (14.72%)    
Gastrointestinal disorders     
Constipation  1  2/158 (1.27%)  2 6/163 (3.68%)  6
Nausea  1  4/158 (2.53%)  4 5/163 (3.07%)  6
Nervous system disorders     
Akathisia  1  8/158 (5.06%)  8 2/163 (1.23%)  2
Headache  1  6/158 (3.80%)  8 11/163 (6.75%)  11
Psychiatric disorders     
Agitation  1  1/158 (0.63%)  1 5/163 (3.07%)  5
1
Term from vocabulary, MedDra 21.1
Indicates events were collected by systematic assessment
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: NCT03259555    
Other Study ID Numbers: 331-201-00080
First Submitted: August 4, 2017
First Posted: August 23, 2017
Results First Submitted: December 13, 2019
Results First Posted: February 10, 2020
Last Update Posted: February 10, 2020