Clinical Trial Results:
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
Summary
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EudraCT number |
2017-002190-20 |
Trial protocol |
HR |
Global end of trial date |
22 Jan 2019
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Results information
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Results version number |
v2(current) |
This version publication date |
29 Feb 2020
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First version publication date |
29 Dec 2019
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Other versions |
v1 |
Version creation reason |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
331-201-00081
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03257865 | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Otsuka Pharmaceutical Development & Commercialization, Inc.
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Sponsor organisation address |
2440 Research Boulevard, Rockville, MD, United States, 20850
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Public contact |
Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., +1-609 524-6788, clinicaltransparency@otsuka-us.com
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Scientific contact |
Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., +1-609 524-6788, clinicaltransparency@otsuka-us.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
10 Sep 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
22 Jan 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
22 Jan 2019
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
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.
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Protection of trial subjects |
This trial was conducted in accordance with International Council on Harmonisation (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which the trial was conducted.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
19 Sep 2017
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Croatia: 1
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Country: Number of subjects enrolled |
Ukraine: 93
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Country: Number of subjects enrolled |
United States: 239
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Worldwide total number of subjects |
333
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EEA total number of subjects |
1
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
333
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening 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. One participant randomized to brexpiprazole was not treated and excluded from the safety analysis set. | ||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||
Roles blinded |
Investigator, Subject | ||||||||||||||||||||||||||||||||||||
Blinding implementation details |
Treatment assignments were based on a computer-generated randomization code. Sponsor personnel, including those involved in monitoring, data management, and data analysis, did not have access to the treatment code during the trial.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Brexpiprazole | ||||||||||||||||||||||||||||||||||||
Arm description |
Brexpiprazole was administered orally with flexible dosing from 2 to 4 milligram (mg)/day; titrated to a maximum of 4 mg/day. | ||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Brexpiprazole
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Starting dose of 2 mg/day; titrated to a maximum of 4 mg/day. Adjustments could be made to dosing. Treatment duration was 3 weeks.
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Arm title
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Placebo | ||||||||||||||||||||||||||||||||||||
Arm description |
Matching placebo was administered orally in the same way as brexpiprazole to maintain the blind. | ||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Tablet taken daily for 3 weeks.
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Baseline characteristics reporting groups
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Reporting group title |
Brexpiprazole
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Reporting group description |
Brexpiprazole was administered orally with flexible dosing from 2 to 4 milligram (mg)/day; titrated to a maximum of 4 mg/day. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Matching placebo was administered orally in the same way as brexpiprazole to maintain the blind. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Brexpiprazole
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Reporting group description |
Brexpiprazole was administered orally with flexible dosing from 2 to 4 milligram (mg)/day; titrated to a maximum of 4 mg/day. | ||
Reporting group title |
Placebo
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Reporting group description |
Matching placebo was administered orally in the same way as brexpiprazole to maintain the blind. |
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End point title |
Change From Baseline In Young-Mania Rating Scale (YMRS) Score At Week 3 | ||||||||||||
End point 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).
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End point type |
Primary
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End point timeframe |
Baseline, Week 3
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Notes [1] - Participants who had analyzable data at the specified timepoint. [2] - Participants who had analyzable data at the specified timepoint. |
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Statistical analysis title |
Treatment Difference in YMRS | ||||||||||||
Comparison groups |
Brexpiprazole v Placebo
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Number of subjects included in analysis |
261
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.1011 | ||||||||||||
Method |
mixed-effect model repeated measure | ||||||||||||
Parameter type |
Treatment difference | ||||||||||||
Point estimate |
-1.62
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Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
-3.56 | ||||||||||||
upper limit |
0.32 |
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End point title |
Change From Baseline In Clinical Global Impression-Bipolar (CGI-BP) Severity Score In Mania At Week 3 | ||||||||||||
End point 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.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 3
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Notes [3] - Participants who had analyzable data at the specified timepoint. [4] - Participants who had analyzable data at the specified timepoint. |
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
From Day 1 (after dosing) through 6 weeks (3 weeks treatment, 3 weeks safety follow-up).
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.1
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Reporting groups
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Reporting group title |
Brexpiprazole
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Reporting group description |
Brexpiprazole was administered orally with flexible dosing from 2 to 4 milligram (mg)/day; titrated to a maximum of 4 mg/day. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Matching placebo was administered orally in the same way as brexpiprazole to maintain the blind. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 3% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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21 Dec 2017 |
• Remove an incorrect exclusion criteria of ≥ 30% decrease in YMRS between screening and baseline
• Add clarifying details on administration of the Clinical Global Impressions – Bipolar Scale assessment
• Add information on retesting participants with elevated lithium, valproate, or carbamazepine at screening
• Add information on use of anticholinergics
• Update the efficacy scales in the appendices to match the licensed versions currently available |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None |