A Phase 3, 12-week, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy, Safety, and Tolerability of 2 Fixed Doses of Brexpiprazole in the Treatment of Alzheimer's Agitation

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01862640
• Collaborator: H. Lundbeck A/S (Industry)
• Enrollment: 433
• Locations: 85
• Arms: 3
• Actual Duration (Months): 44.1
• Patients Per Site: 5.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

To compare the efficacy of 2 fixed doses of brexpiprazole with placebo in participants with agitation associated with dementia of the Alzheimer's type.

Condition or Disease	Intervention/Treatment	Phase
Agitation Associated With; Alzheimer's Disease; Alzheimer's Type; Mental Disorder; Nervous System Diseases	Drug: Brexpiprazole, OPC-34712; Drug: Placebo Oral Tablet	Phase 3

Detailed Description

Behavioral symptoms, such as agitation, are core features in participants with Alzheimer's disease and related dementias and develop in the majority of dementia participants. The presence of agitation in participants with Alzheimer's disease places a significant burden not only on participants and their caregivers but also on the healthcare system.

This is a trial designed to assess the safety and efficacy of brexpiprazole in the treatment of participants with agitation associated with dementia of the Alzheimer's Type. The trial consists of a continuous 12-week double-blind treatment period with a 30-day follow-up. The trial population will include male and female participants between 55 and 90 years of age (inclusive) with a diagnosis of probable Alzheimer's disease, who are residing either in an institutionalized setting or in a non-institutionalized setting where the participant is not living alone.

Study Design

• Study Type: Interventional
• Actual Enrollment: 433 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 3, 12-week, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy, Safety, and Tolerability of 2 Fixed Doses of Brexpiprazole (OPC-34712) in the Treatment of Subjects With Agitation Associated With Dementia of the Alzheimer's Type
• Actual Study Start Date: Jul 11, 2013
• Actual Primary Completion Date: Mar 15, 2017
• Actual Study Completion Date: Mar 15, 2017

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Matching placebo once daily	Drug: Placebo Oral Tablet; Once-daily, tablets
Experimental: Brexpiprazole 1 mg Titrate up from 0.25 milligrams (mg)/day brexpiprazole to 1 mg/day brexpiprazole	Drug: Brexpiprazole, OPC-34712; Once-daily, tablets
Experimental: Brexpiprazole 2 mg Titrate up from 0.25 mg/day brexpiprazole to 2 mg/day brexpiprazole	Drug: Brexpiprazole, OPC-34712; Once-daily, tablets

Outcome Measures

Primary Outcome Measures

1. Change From Baseline In The Cohen-Mansfield Agitation Inventory (CMAI) Total Score After 12 Weeks Of Brexpiprazole Treatment [Baseline, Week 12/Early Termination (ET)]

   To compare the efficacy of 2 fixed doses (1 mg/day and 2 mg/day) of brexpiprazole with placebo in participants with agitation associated with dementia of the Alzheimer's type, by the assessment of CMAI after 12 weeks of treatment. The CMAI assesses the frequency of agitated behaviors in elderly persons, such as hitting, cursing, and restlessness. It consists of 29 items all rated on a 1 to 7 scale with 1 being the "best" rating and 7 being the "worst" rating. The minimum possible CMAI total score is 29, and the maximum possible CMAI total score is 203. A decrease in score indicates improvement in symptoms. To control the overall type I error at 0.05 level when making 2 comparisons of brexpiprazole doses versus placebo, statistical testing was carried out using a hierarchical testing procedure in the order of: 1) comparison of 2 mg/day brexpiprazole versus placebo, and 2) comparison of 1 mg/day brexpiprazole versus placebo.

Secondary Outcome Measures

1. Change From Baseline In The Clinical Global Impression-Severity Of Illness (CGI-S) Score, As Related To Symptoms Of Agitation After 12 Weeks Of Brexpiprazole Treatment [Baseline, Week 12/ET]

   To compare the efficacy of 2 fixed doses (1 mg/day and 2 mg/day) of brexpiprazole with placebo in participants with agitation associated with Alzheimer's dementia, by the assessment of CGI-S score after 12 weeks of treatment. The CGI-S was used to rate the severity of agitation. Scores were: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants. A decrease in score indicates improvement in symptoms.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 55 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male and female participants 55 to 90 years of age, inclusive, at the time of informed consent.

• Participants who are residing at their current location for at least 14 days before screening and are expected to remain at the same location for the duration of the trial.

• Participants with a diagnosis of probable Alzheimer's disease according to National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association.

• Participants with a Mini-Mental State Exam score of 5 to 22, inclusive, at screening and baseline visits.

• Participants with onset of symptoms of agitation at least 2 weeks prior to the screening visit.

• Participants with a score of ≥ 4 on the agitation/aggression item of the Neuropsychiatric Inventory-Nursing Home at the screening and baseline visits.

• Participants who require pharmacotherapy for treatment of agitation per the investigator's judgment, after an evaluation for reversible factors (for example, pain, infection, polypharmacy) and a trial of nonpharmacological intervention.

• Participants must have a previous magnetic resonance imaging or computed tomography of the brain, which was performed after the onset of symptoms of dementia, with findings consistent with the diagnosis of Alzheimer's disease.

Exclusion Criteria:

• Participants with dementia or other memory impairment not due to Alzheimer's disease

• Participants with a history of stroke, well-documented transient ischemic attack, pulmonary or cerebral embolism.

• Participants who currently have clinically significant neurological, hepatic, renal, metabolic, hematological, immunological, cardiovascular, pulmonary, gastrointestinal, or psychiatric disorders.

• Participants who have been diagnosed with an Axis I disorder (Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision criteria)

• Participants with uncontrolled hypertension

• Participants with uncontrolled insulin-dependent diabetes mellitus

• Participants with epilepsy or a history of seizures

• Participants considered in poor general health based on the investigator's judgment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Tuscaloosa	Alabama	United States	35404
2		Phoenix	Arizona	United States	85013
3		Bellflower	California	United States	90706
4		Costa Mesa	California	United States	92627
5		Downey	California	United States	90706
6		Orange	California	United States	92868
7		Redlands	California	United States	92373
8		Yorba Linda	California	United States	92886
9		Norwalk	Connecticut	United States	06851
10		Coconut Creek	Florida	United States	33024
11		Hialeah	Florida	United States	33012
12		Hialeah	Florida	United States	33013
13		Hialeah	Florida	United States	33018
14		Lauderhill	Florida	United States	33319
15		Miami Springs	Florida	United States	33166
16		Miami	Florida	United States	33122
17		Miami	Florida	United States	33126
18		Miami	Florida	United States	33136
19		Miami	Florida	United States	33137
20		Miami	Florida	United States	33145
21		Miami	Florida	United States	33161
22		Miami	Florida	United States	33174
23		Sarasota	Florida	United States	34239
24		Decatur	Georgia	United States	30033
25		Suwanee	Georgia	United States	30024
26		Weymouth	Massachusetts	United States	02190
27		Saint Louis	Missouri	United States	63128
28		Saint Louis	Missouri	United States	63141
29		Las Vegas	Nevada	United States	89148
30		Manchester	New Jersey	United States	08759
31		Mount Arlington	New Jersey	United States	07856
32		Toms River	New Jersey	United States	08755
33		Hickory	North Carolina	United States	28601
34		Oklahoma City	Oklahoma	United States	73118
35		Franklin	Tennessee	United States	37064
36		Bedford	Texas	United States	76022
37		Waukesha	Wisconsin	United States	53188
38		Rijeka		Croatia	57000
39		Zadar		Croatia	23000
40		Zagreb		Croatia	10000
41		Zagreb		Croatia	10090
42		Mittweida	Saxony	Germany	09648
43		Achim		Germany	28832
44		Berlin		Germany	12209
45		Bielefeld		Germany	33647
46		Bochum		Germany	44791
47		Hamburg		Germany	22083
48		Koln		Germany	50935
49		Ostfildern		Germany	73760
50		Westerstede		Germany	26655
51		Ekaterinburg		Russian Federation	620030
52		Samara		Russian Federation	443016
53		Saratov		Russian Federation	410060
54		St. Petersburg		Russian Federation	190000
55		St. Petersburg		Russian Federation	190005
56		St. Petersburg		Russian Federation	191119
57		St. Petersburg		Russian Federation	192019
58		St. Petersburg		Russian Federation	197341
59		St. Petersburg		Russian Federation	198510
60		Tonnel'nyy		Russian Federation	357034
61		Belgrade		Serbia	11000
62		Kovin		Serbia	26220
63		Kragujevac		Serbia	34000
64		Nis		Serbia	18000
65		Novi Knezevac		Serbia	23330
66		Novi Sad		Serbia	21000
67		Vrsac		Serbia	26300
68		Barcelona		Spain	08028
69		Getafe		Spain	28905
70		Girona		Spain	17190
71		Madrid		Spain	28034
72		Madrid		Spain	28040
73		Madrid		Spain	28049
74		Pamplona		Spain	31014
75		Salamanca		Spain	37003
76		Valencia		Spain	46010
77		Valencia		Spain	46026
78		Zamora		Spain	49021
79		Kharkiv		Ukraine	61068
80		Kherson		Ukraine	73488
81		Kiev		Ukraine	04080
82		Lviv		Ukraine	79021
83		Odessa		Ukraine	65006
84		Odessa		Ukraine	67513
85		Poltava		Ukraine	36013

Sponsors and Collaborators

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

Investigators

• Study Director: Eva Kohegyi, MD, Otsuka Pharmaceutical Development & Commercialization, Inc.

Study Documents (Full-Text)

• Study Protocol - Sep 10, 2015
• Statistical Analysis Plan - Mar 14, 2017

More Information

Publications

None provided.

• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• ClinicalTrials.gov Identifier: NCT01862640
• Other Study ID Numbers: 331-12-283
• First Posted: May 24, 2013
• Last Update Posted: Dec 31, 2020
• Last Verified: Dec 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.: OPC-34712; brexpiprazole; Dementia; Alzheimer's Disease; Cognitive Disorders; Agitation
• Additional relevant MeSH terms: Alzheimer Disease; Psychomotor Agitation; Nervous System Diseases; Mental Disorders; Brexpiprazole

Study Results

Participant Flow

Recruitment Details	Participants who met all the inclusion and none of the exclusion criteria were enrolled in this study. The study was conducted in 433 participants at 81 sites in 7 countries: Croatia, Germany, Serbia, Spain, Russia, Ukraine, and the United States.
Pre-assignment Detail	Participants attended a screening period ranging from 2 to 42 days. The purpose of the screening period was to determine the participant's eligibility and to washout prohibited concomitant pharmacotherapy prior to randomization.

Arm/Group Title	Brexpiprazole 0.5 mg/Day	Brexpiprazole 1 mg/Day	Brexpiprazole 2 mg/Day	Placebo
Arm/Group Description	All randomized participants received orally brexpiprazole 0.25 milligrams (mg)/day as a starting dose, which was up titrated to 0.5 mg/day. The investigational medicinal product (IMP) was administered once daily in the form of a tablet.	All randomized participants received orally brexpiprazole 0.25 mg/day as a starting dose, which was up titrated to 1 mg/day. The IMP was administered once daily in the form of a tablet.	All randomized participants received orally brexpiprazole 0.25 mg/day as a starting dose, which was up titrated to 2 mg/day. The IMP was administered once daily in the form of a tablet.	All randomized participants received orally brexpiprazole-matching Placebo. The Placebo was administered once daily in the form of a tablet.
Period Title: Overall Study
STARTED	20	137	140	136
COMPLETED	13	121	122	121
NOT COMPLETED	7	16	18	15

Baseline Characteristics

Arm/Group Title	Brexpiprazole 0.5 mg/Day	Brexpiprazole 1 mg/Day	Brexpiprazole 2 mg/Day	Placebo	Total
Arm/Group Description	All randomized participants received orally brexpiprazole 0.25 milligrams (mg)/day as a starting dose, which was up titrated to 0.5 mg/day. The investigational medicinal product (IMP) was administered once daily in the form of a tablet.	All randomized participants received orally brexpiprazole 0.25 mg/day as a starting dose, which was up titrated to 1 mg/day. The IMP was administered once daily in the form of a tablet.	All randomized participants received orally brexpiprazole 0.25 mg/day as a starting dose, which was up titrated to 2 mg/day. The IMP was administered once daily in the form of a tablet.	All randomized participants received orally brexpiprazole-matching Placebo. The Placebo was administered once daily in the form of a tablet.	Total of all reporting groups
Overall Participants	20	137	140	136	433
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	73.9 (9.1)	73.8 (8.8)	73.7 (8.1)	74.1 (8.0)	73.9 (8.3)
Sex: Female, Male (Count of Participants)
Female	12 60%	78 56.9%	79 56.4%	70 51.5%	239 55.2%
Male	8 40%	59 43.1%	61 43.6%	66 48.5%	194 44.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	1 0.7%	2 1.4%	1 0.7%	4 0.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	2 1.5%	5 3.6%	5 3.7%	12 2.8%
White	20 100%	134 97.8%	133 95%	130 95.6%	417 96.3%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline In The Cohen-Mansfield Agitation Inventory (CMAI) Total Score After 12 Weeks Of Brexpiprazole Treatment
Description	To compare the efficacy of 2 fixed doses (1 mg/day and 2 mg/day) of brexpiprazole with placebo in participants with agitation associated with dementia of the Alzheimer's type, by the assessment of CMAI after 12 weeks of treatment. The CMAI assesses the frequency of agitated behaviors in elderly persons, such as hitting, cursing, and restlessness. It consists of 29 items all rated on a 1 to 7 scale with 1 being the "best" rating and 7 being the "worst" rating. The minimum possible CMAI total score is 29, and the maximum possible CMAI total score is 203. A decrease in score indicates improvement in symptoms. To control the overall type I error at 0.05 level when making 2 comparisons of brexpiprazole doses versus placebo, statistical testing was carried out using a hierarchical testing procedure in the order of: 1) comparison of 2 mg/day brexpiprazole versus placebo, and 2) comparison of 1 mg/day brexpiprazole versus placebo.
Time Frame	Baseline, Week 12/Early Termination (ET)

Outcome Measure Data

Analysis Population Description

The modified intention-to-treat population consisted of all participants in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day, as doses lower than 1 mg/day were unlikely to be efficacious) and had a baseline and at least 1 post baseline evaluation for the CMAI total score.

Arm/Group Title	Brexpiprazole 2 mg/Day	Brexpiprazole 1 mg/Day	Placebo
Arm/Group Description	All randomized participants received orally brexpiprazole 0.25 mg/day as a starting dose, which was up titrated to 2 mg/day. The IMP was administered once daily in the form of a tablet.	All randomized participants received orally brexpiprazole 0.25 mg/day as a starting dose, which was up titrated to 1 mg/day. The IMP was administered once daily in the form of a tablet.	All randomized participants received orally brexpiprazole-matching Placebo. The Placebo was administered once daily in the form of a tablet.
Measure Participants	138	134	131
Least Squares Mean (Standard Error) [units on a scale]	-21.6 (1.32)	-17.6 (1.33)	-17.8 (1.34)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.0404
	Comments
	Method	Mixed-effect model repeated measure
	Comments
Method of Estimation	Estimation Parameter	Least square (LS) mean difference
	Estimated Value	-3.77
	Confidence Interval	(2-Sided) 95%; -7.38 to -0.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 1 mg/Day, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.9015
	Comments
	Method	Mixed-effect model repeated measure
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.23
	Confidence Interval	(2-Sided) 95%; -3.40 to 3.86
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline In The Clinical Global Impression-Severity Of Illness (CGI-S) Score, As Related To Symptoms Of Agitation After 12 Weeks Of Brexpiprazole Treatment
Description	To compare the efficacy of 2 fixed doses (1 mg/day and 2 mg/day) of brexpiprazole with placebo in participants with agitation associated with Alzheimer's dementia, by the assessment of CGI-S score after 12 weeks of treatment. The CGI-S was used to rate the severity of agitation. Scores were: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants. A decrease in score indicates improvement in symptoms.
Time Frame	Baseline, Week 12/ET

Outcome Measure Data

Analysis Population Description

The modified intention-to-treat population consisted of all participants in the randomized sample who took at least 1 dose of IMP (excluding 20 participants randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least 1 post baseline evaluation for the CMAI total score.

Arm/Group Title	Brexpiprazole 2 mg/Day	Brexpiprazole 1 mg/Day	Placebo
Arm/Group Description	All randomized participants received orally brexpiprazole 0.25 mg/day as a starting dose, which was up titrated to 2 mg/day. The IMP was administered once daily in the form of a tablet.	All randomized participants received orally brexpiprazole 0.25 mg/day as a starting dose, which was up titrated to 1 mg/day. The IMP was administered once daily in the form of a tablet.	All randomized participants received orally brexpiprazole-matching Placebo. The Placebo was administered once daily in the form of a tablet.
Measure Participants	138	134	131
Mean (Standard Deviation) [units on a scale]	-1.29 (1.05)	-1.04 (1.12)	-1.08 (0.89)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.1566
	Comments
	Method	Mixed-effect model repeated measure
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.16
	Confidence Interval	(2-Sided) 95%; -0.39 to 0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 1 mg/Day, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.4440
	Comments
	Method	Mixed-effect model repeated measure
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.09
	Confidence Interval	(2-Sided) 95%; -0.14 to 0.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events (AEs) were collected throughout the study (Baseline to Week 12/ET).
Adverse Event Reporting Description	Only participants who received at least 1 dose of study drug were analyzed for safety (Placebo N=135).
Arm/Group Title	Brexpiprazole 0.5 mg/Day		Brexpiprazole 1 mg/Day		Brexpiprazole 2 mg/Day		Placebo
Arm/Group Description	All randomized participants received orally brexpiprazole 0.25 milligrams (mg)/day as a starting dose, which was up titrated to 0.5 mg/day. The investigational medicinal product (IMP) was administered once daily in the form of a tablet.		All randomized participants received orally brexpiprazole 0.25 mg/day as a starting dose, which was up titrated to 1 mg/day. The IMP was administered once daily in the form of a tablet.		All randomized participants received orally brexpiprazole 0.25 mg/day as a starting dose, which was up titrated to 2 mg/day. The IMP was administered once daily in the form of a tablet.		All randomized participants received orally brexpiprazole-matching Placebo. The Placebo was administered once daily in the form of a tablet.
All Cause Mortality
	Brexpiprazole 0.5 mg/Day		Brexpiprazole 1 mg/Day		Brexpiprazole 2 mg/Day		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/20 (10%)		2/137 (1.5%)		1/140 (0.7%)		0/135 (0%)
Serious Adverse Events
	Brexpiprazole 0.5 mg/Day		Brexpiprazole 1 mg/Day		Brexpiprazole 2 mg/Day		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/20 (25%)		11/137 (8%)		13/140 (9.3%)		7/135 (5.2%)
Blood and lymphatic system disorders
Anaemia	0/20 (0%)		0/137 (0%)		1/140 (0.7%)		0/135 (0%)
Microcytic Anaemia	0/20 (0%)		0/137 (0%)		1/140 (0.7%)		0/135 (0%)
Gastrointestinal disorders
Duodenal Ulcer Haemorrhage	0/20 (0%)		0/137 (0%)		0/140 (0%)		1/135 (0.7%)
Pancreatitis	0/20 (0%)		1/137 (0.7%)		0/140 (0%)		0/135 (0%)
General disorders
Pyrexia	0/20 (0%)		1/137 (0.7%)		0/140 (0%)		0/135 (0%)
Infections and infestations
Bacterial Sepsis	0/20 (0%)		1/137 (0.7%)		0/140 (0%)		0/135 (0%)
Cellulitis	1/20 (5%)		0/137 (0%)		0/140 (0%)		0/135 (0%)
Clostridium Difficile Colitis	0/20 (0%)		1/137 (0.7%)		0/140 (0%)		0/135 (0%)
Encephalitis	1/20 (5%)		0/137 (0%)		0/140 (0%)		0/135 (0%)
Pneumonia	0/20 (0%)		0/137 (0%)		0/140 (0%)		1/135 (0.7%)
Urinary Tract Infection	0/20 (0%)		0/137 (0%)		4/140 (2.9%)		1/135 (0.7%)
Injury, poisoning and procedural complications
Fall	1/20 (5%)		0/137 (0%)		0/140 (0%)		0/135 (0%)
Humerus Fracture	1/20 (5%)		0/137 (0%)		0/140 (0%)		0/135 (0%)
Patella Fracture	0/20 (0%)		0/137 (0%)		0/140 (0%)		1/135 (0.7%)
Nervous system disorders
Cerebrovascular Accident	0/20 (0%)		1/137 (0.7%)		0/140 (0%)		0/135 (0%)
Dementia Alzheimer's Type	0/20 (0%)		1/137 (0.7%)		1/140 (0.7%)		0/135 (0%)
Epilepsy	0/20 (0%)		1/137 (0.7%)		0/140 (0%)		0/135 (0%)
Haemorrhage Intracranial	1/20 (5%)		0/137 (0%)		0/140 (0%)		0/135 (0%)
Lacunar Infarction	0/20 (0%)		1/137 (0.7%)		0/140 (0%)		0/135 (0%)
Psychomotor Hyperactivity	0/20 (0%)		0/137 (0%)		1/140 (0.7%)		0/135 (0%)
Seizure	0/20 (0%)		0/137 (0%)		0/140 (0%)		1/135 (0.7%)
Syncope	0/20 (0%)		1/137 (0.7%)		0/140 (0%)		1/135 (0.7%)
Transient Ischaemic Attack	0/20 (0%)		0/137 (0%)		0/140 (0%)		1/135 (0.7%)
Psychiatric disorders
Abnormal Behaviour	0/20 (0%)		1/137 (0.7%)		0/140 (0%)		0/135 (0%)
Agitation	1/20 (5%)		1/137 (0.7%)		1/140 (0.7%)		0/135 (0%)
Delusion	0/20 (0%)		1/137 (0.7%)		0/140 (0%)		0/135 (0%)
Intentional Self-Injury	0/20 (0%)		0/137 (0%)		0/140 (0%)		1/135 (0.7%)
Psychotic Disorder	0/20 (0%)		0/137 (0%)		1/140 (0.7%)		0/135 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic Obstructive Pulmonary Disease	1/20 (5%)		0/137 (0%)		1/140 (0.7%)		0/135 (0%)
Hypoxia	0/20 (0%)		0/137 (0%)		1/140 (0.7%)		0/135 (0%)
Obstructive Airways Disorder	0/20 (0%)		1/137 (0.7%)		0/140 (0%)		0/135 (0%)
Pneumonia Aspiration	0/20 (0%)		1/137 (0.7%)		0/140 (0%)		0/135 (0%)
Pulmonary Oedema	0/20 (0%)		0/137 (0%)		1/140 (0.7%)		0/135 (0%)
Vascular disorders
Venous Thrombosis Limb	0/20 (0%)		0/137 (0%)		1/140 (0.7%)		0/135 (0%)
Other (Not Including Serious) Adverse Events
	Brexpiprazole 0.5 mg/Day		Brexpiprazole 1 mg/Day		Brexpiprazole 2 mg/Day		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/20 (55%)		27/137 (19.7%)		43/140 (30.7%)		29/135 (21.5%)
Blood and lymphatic system disorders
Anaemia	1/20 (5%)		1/137 (0.7%)		2/140 (1.4%)		0/135 (0%)
Gastrointestinal disorders
Constipation	1/20 (5%)		1/137 (0.7%)		5/140 (3.6%)		1/135 (0.7%)
Salivary Hypersecretion	1/20 (5%)		0/137 (0%)		1/140 (0.7%)		0/135 (0%)
General disorders
Asthenia	1/20 (5%)		2/137 (1.5%)		3/140 (2.1%)		3/135 (2.2%)
Infections and infestations
Urinary Tract Infection	1/20 (5%)		2/137 (1.5%)		3/140 (2.1%)		1/135 (0.7%)
Injury, poisoning and procedural complications
Fall	1/20 (5%)		0/137 (0%)		3/140 (2.1%)		2/135 (1.5%)
Laceration	1/20 (5%)		1/137 (0.7%)		0/140 (0%)		0/135 (0%)
Investigations
Activated Partial Thromboplastin Time Prolonged	1/20 (5%)		0/137 (0%)		1/140 (0.7%)		0/135 (0%)
Alanine Aminotransferase Increased	1/20 (5%)		1/137 (0.7%)		0/140 (0%)		0/135 (0%)
Aspartate Aminotransferase Increased	1/20 (5%)		1/137 (0.7%)		0/140 (0%)		0/135 (0%)
Blood Alkaline Phosphatase Increased	1/20 (5%)		1/137 (0.7%)		0/140 (0%)		0/135 (0%)
Blood Creatine Phosphokinase Increased	2/20 (10%)		1/137 (0.7%)		1/140 (0.7%)		0/135 (0%)
Blood Insulin Decreased	1/20 (5%)		0/137 (0%)		0/140 (0%)		0/135 (0%)
Blood Lactate Dehydrogenase Increased	1/20 (5%)		1/137 (0.7%)		0/140 (0%)		0/135 (0%)
Electrocardiogram QT Prolonged	1/20 (5%)		3/137 (2.2%)		2/140 (1.4%)		1/135 (0.7%)
Gamma-Glutamyltransferase Increased	1/20 (5%)		0/137 (0%)		0/140 (0%)		0/135 (0%)
Metabolism and nutrition disorders
Vitamin B12 Deficiency	1/20 (5%)		0/137 (0%)		0/140 (0%)		0/135 (0%)
Nervous system disorders
Dizziness	0/20 (0%)		1/137 (0.7%)		8/140 (5.7%)		4/135 (3%)
Headache	0/20 (0%)		12/137 (8.8%)		13/140 (9.3%)		11/135 (8.1%)
Psychiatric disorders
Agitation	1/20 (5%)		2/137 (1.5%)		4/140 (2.9%)		4/135 (3%)
Insomnia	0/20 (0%)		7/137 (5.1%)		8/140 (5.7%)		6/135 (4.4%)
Paranoia	1/20 (5%)		0/137 (0%)		0/140 (0%)		0/135 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	1/20 (5%)		0/137 (0%)		0/140 (0%)		1/135 (0.7%)
Epistaxis	1/20 (5%)		0/137 (0%)		1/140 (0.7%)		0/135 (0%)
Skin and subcutaneous tissue disorders
Dermatitis Allergic	1/20 (5%)		0/137 (0%)		0/140 (0%)		0/135 (0%)
Ecchymosis	1/20 (5%)		0/137 (0%)		0/140 (0%)		0/135 (0%)
Vascular disorders
Hypertension	1/20 (5%)		1/137 (0.7%)		0/140 (0%)		3/135 (2.2%)
Orthostatic Hypotension	1/20 (5%)		0/137 (0%)		1/140 (0.7%)		0/135 (0%)

Limitations/Caveats

None reported

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.