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

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03257865
• Collaborator: H. Lundbeck A/S (Industry)
• Enrollment: 333
• Locations: 38
• Arms: 2
• Actual Duration (Months): 16.1
• Patients Per Site: 8.8
• Patients Per Site Per Month: 0.5

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Bipolar I Disorder; Manic Episode	Drug: Brexpiprazole; Drug: Placebo	Phase 3

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 333 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention 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.Participants received a dose of brexpiprazole or placebo for a maximum of 21 days and were evaluated throughout the duration of the study.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Sep 19, 2017
• Actual Primary Completion Date: Jan 22, 2019
• Actual Study Completion Date: Jan 22, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Brexpiprazole 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.	Drug: Brexpiprazole; Brexpiprazole was administered orally with flexible dosing from 2 to 4 mg/day; titrated to a maximum of 4 mg/day for 3 weeks.
Placebo Comparator: Placebo Matching placebo was administered in the same way as brexpiprazole to maintain the blind	Drug: Placebo; Administered orally daily for 3 weeks.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline In Young-Mania Rating Scale (YMRS) Score At Week 3 [Baseline, 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 (MRMM).

Secondary Outcome Measures

1. Change From Baseline In Clinical Global Impression-Bipolar (CGI-BP) Severity Score In Mania At Week 3 [Baseline, 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.

Eligibility Criteria

Criteria

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

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 (MINI) and a history of at least one 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 (WOCBP) 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 (IMP).

• 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, medications).

• 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 and 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.

• Participants 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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Atria Clinical Research	Little Rock	Arkansas	United States	72209
2	Woodland International Research Group, LLC	Little Rock	Arkansas	United States	72211
3	CiTrials	Bellflower	California	United States	90706
4	CNS Research Science Inc.	Cerritos	California	United States	90703
5	Apostle Clinical Trials	Long Beach	California	United States	90813
6	CNRI-San Diego	San Diego	California	United States	92102
7	Artemis Institute for Clinical Research	San Diego	California	United States	92103
8	CiTrials	Santa Ana	California	United States	92705
9	Collaborative Neuroscience Network, LLC	Torrance	California	United States	90502
10	Shreenath Clinical Service	Yorba Linda	California	United States	92886
11	Galiz Research	Hialeah	Florida	United States	33016
12	Research Centers of America LLC	Hollywood	Florida	United States	33024
13	South Florida Research Phase I-IV	Miami Springs	Florida	United States	33166
14	Optimus U Corporation	Miami	Florida	United States	33125
15	Meridien Research	Orlando	Florida	United States	32801
16	iResearch Atlanta, LLC	Decatur	Georgia	United States	30030
17	Uptown Research Institute LLC	Chicago	Illinois	United States	60640
18	Neuropsychiatric Research & Associates, LTD	Winfield	Illinois	United States	60190
19	Louisiana Clinical Research	Shreveport	Louisiana	United States	71101
20	Arch Clinical Trials, LLC	Saint Louis	Missouri	United States	63118
21	St Louis Clinical Trials LLC	Saint Louis	Missouri	United States	63141
22	Hassman Research Institute	Berlin	New Jersey	United States	08009
23	CNS Research Science, Inc.	Jamaica	New York	United States	11432
24	New Hope Clinical Research	Charlotte	North Carolina	United States	28211
25	University of Cincinnati Department of Psychiatry and Behavorial Science	Cincinnati	Ohio	United States	45219
26	InSite Clinical Research LLC	DeSoto	Texas	United States	75115
27	Pillar Clinical Research, LLC	Richardson	Texas	United States	75080
28	Clinical Hospital Centre Rijeka	Rijeka		Croatia	51000
29	Communal Institution "Dnipropetrovsk Regional Clinical Hospital named after I.I. Mechnikov	Dnipro		Ukraine	49005
30	SI ""Institute of Neurology, Psychiatry and Narcology of National Academy of Medical Sciences of Ukraine	Kharkiv		Ukraine	61068
31	Communal Establishment "Kherson Regional Psychiatric Hospital" of Kherson Regional Council	Kherson		Ukraine	73488
32	Kyiv Regional Medical Incorporation "Psychiatry", Center for Novel Treatment and Rehabilitation of Psychotic disorders	Kyiv		Ukraine	04080
33	Communal Institution of Lviv Regional Council "Lviv Regional Clinical Psychiatric Hospital", Department #20	Lviv		Ukraine	79021
34	Communal Institution of Lviv Regional Council "Lviv Regional Clinical Psychiatric Hospital", Department #25	Lviv		Ukraine	79021
35	Communal Establishment "Odesa Regional Psychiatric Hospital #2	Oleksandrivka		Ukraine	67513
36	O.F. Maltsev Poltava Regional Psychiatric Hospital	Poltava		Ukraine	36013
37	Ternopil Regional Municipal Clinical Psychoneurolgical Hospital	Ternopil'		Ukraine	46027
38	Communal Establishment "Acad. O.I. Iushchenko Vinnytsia Regional Psychoneurologic Hospital"	Vinnytsia		Ukraine	21005

Sponsors and Collaborators

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

Investigators

• Study Director: Matthew Leoni, M.D., Otsuka Pharmaceutical Development & Commercialization, Inc.

Study Documents (Full-Text)

• Study Protocol - Dec 21, 2017
• Statistical Analysis Plan - Dec 11, 2018

More Information

Publications

None provided.

• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• ClinicalTrials.gov Identifier: NCT03257865
• Other Study ID Numbers: 331-201-00081
• First Posted: Aug 22, 2017
• Last Update Posted: Feb 11, 2020
• Last Verified: Feb 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.: Brexpiprazole; Bipolar; Manic episode
• Additional relevant MeSH terms: Mania; Bipolar Disorder; Brexpiprazole

Study Results

Participant Flow

Pre-assignment Detail	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.

Arm/Group Title	Brexpiprazole	Placebo
Arm/Group Description	Brexpiprazole was administered orally with flexible dosing from 2 to 4 milligram (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	163	170
Received at Least 1 Dose of Study Drug	162	170
COMPLETED	128	135
NOT COMPLETED	35	35

Baseline Characteristics

Arm/Group Title	Brexpiprazole	Placebo	Total
Arm/Group Description	Brexpiprazole was administered orally with flexible dosing from 2 to 4 milligram (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 Participants	163	170	333
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	44.6 (10.7)	44.3 (12.0)	44.5 (11.4)
Sex: Female, Male (Count of Participants)
Female	85 52.1%	82 48.2%	167 50.2%
Male	78 47.9%	88 51.8%	166 49.8%
Race/Ethnicity, Customized (Count of Participants)
White	90 55.2%	102 60%	192 57.7%
Black or African American	70 42.9%	67 39.4%	137 41.1%
American Indian or Alaska Native	1 0.6%	0 0%	1 0.3%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Other Race	2 1.2%	1 0.6%	3 0.9%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	22 13.5%	17 10%	39 11.7%
Not Hispanic or Latino	140 85.9%	153 90%	293 88%
Other Ethnicity	1 0.6%	0 0%	1 0.3%

Outcome Measures

1. Primary Outcome

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 (MRMM).
Time Frame	Baseline, Week 3

Outcome Measure Data

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
Arm/Group Description	Brexpiprazole was administered orally with flexible dosing from 2 to 4 milligram (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.
Measure Participants	128	133
Least Squares Mean (Standard Error) [units on a scale]	-12.3 (0.73)	-10.7 (0.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.1011
	Comments
	Method	mixed-effect model repeated measure
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-1.62
	Confidence Interval	(2-Sided) 95%; -3.56 to 0.32
	Parameter Dispersion	Type: Value:
	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
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

Outcome Measure Data

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
Arm/Group Description	Brexpiprazole was administered orally with flexible dosing from 2 to 4 milligram (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.
Measure Participants	128	133
Mean (Standard Deviation) [units on a scale]	-1.31 (1.22)	-1.06 (1.09)

Adverse Events

Time Frame	From Day 1 (after dosing) through 6 weeks (3 weeks treatment, 3 weeks safety follow-up).
Arm/Group Title	Brexpiprazole		Placebo
Arm/Group Description	Brexpiprazole was administered orally with flexible dosing from 2 to 4 milligram (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 (%)	# Events	Affected / at Risk (%)	# Events
Total	0/162 (0%)		0/170 (0%)
Serious Adverse Events
	Brexpiprazole		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/162 (0%)		3/170 (1.8%)
Nervous system disorders
Epilepsy	0/162 (0%)	0	1/170 (0.6%)	1
Psychiatric disorders
Mania	0/162 (0%)	0	2/170 (1.2%)	2
Other (Not Including Serious) Adverse Events
	Brexpiprazole		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/162 (19.8%)		28/170 (16.5%)
Gastrointestinal disorders
Constipation	6/162 (3.7%)	6	5/170 (2.9%)	5
Nausea	2/162 (1.2%)	2	7/170 (4.1%)	8
Nervous system disorders
Akathisia	13/162 (8%)	14	4/170 (2.4%)	4
Dizziness	5/162 (3.1%)	5	1/170 (0.6%)	1
Headache	10/162 (6.2%)	12	18/170 (10.6%)	19
Psychiatric disorders
Insomnia	5/162 (3.1%)	6	2/170 (1.2%)	2

Limitations/Caveats

[Not Specified]

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.