Clinical trial NCT03594123
Conditions: Alzheimer's Disease
Keywords: Agitation
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Start date: 2018-10-11; Completion date: 2022-09-19
Enrollment: 259 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Active treatment extension study of the 331-14-213 trial, to assess the long-term safety and tolerability of oral brexpiprazole as treatment in adult participants with agitation associated with dementia of the Alzheimer's type (AAD).

Detailed description:

Arms: arm 1: Participants who received brexpiprazole in a previous double-blind phase 3 study (Trial 331-14-213 {NCT03548584}), received the same dose of brexpiprazole \[2 or 3 milligrams (mg)\], once daily (QD), orally, as they received during the previous study, for up to 12 weeks with dose adjustment. arm 2: Participants who received placebo in a previous double-blind phase 3 study (Trial 331-14-213 {NCT03548584}), received brexpiprazole following a titration schedule, to gradually increase their dose from 0.5 mg QD, in the starting to 2 or 3 mg QD, orally, for up to 12 weeks with dose adjustment.
Interventions: intervention 1: Brexpiprazole intervention 2: Brexpiprazole
Intervention descriptions: intervention 1: 2 or 3 mg tablet intervention 2: 0.5 to 3 mg tablet

Protocol documents:
Prot_000.pdf: 
Table of Contents
Table of Contents..........................................................................................................
1
Study 331-201-00182 Protocol Amendment 3; 22 Sep 2020.......................................
2
Study 331-201-00182 Addendum For Clinical Protocol; Version No 3.0....................
83
Clinical Study Report 331-201-00182
16.1.1 Protocol and Protocol Amendments
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Confidential - Proprietary Information
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Version 4.0, 22 Sep 2020
Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigational Medicinal Product
OPC-34712
CLINICAL PROTOCOL
A 12-week, Multicenter, Active-treatment Extension Trial to Evaluate the Safety and 
Tolerability of Brexpiprazole in the Treatment of Subjects With Agitation Associated 
With Dementia of the Alzheimer’s Type
Protocol No. 331-201-00182
IND No. 115960
EudraCT No. 2018-002783-88
CONFIDENTIAL – PROPRIETARY INFORMATION
Clinical Development Phase: 
3
Sponsor:
Otsuka Pharmaceutical
Development & Commercialization, Inc.
2440 Research Boulevard
Rockville, Maryland 20850, United States
Immediately Reportable Event 
Syneos Health Pharmacovigilance & Drug 
Safety
Issue Date:
18 Jun 2018
Amendment 1:
26 Jun 2020
Amendment 2:
06 Aug 2020
Amendment 3:
22 Sep 2020
Version No.:
4.0
Clinical Study Report 331-201-00182
16.1.1 Protocol and Protocol Amendments
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Trial Conduct for COVID-19
All procedures and assessments in this protocol are to be followed to the fullest extent 
possible. The sponsor, in coordination with the site, investigator(s), and medical monitor, 
will continuously monitor and evaluate the benefits and risks to subject participation in 
the clinical trial as it relates to coronavirus disease 2019 (COVID-19). If any protocol-
specified activities were not able to be performed, or cannot be performed due to 
COVID-19 considerations, refer to the COVID-19 Addendum for the appropriate 
measures to be followed.  Appropriate measures may include replacing in-person visits 
with virtual visits (phone or video) as deemed necessary by the investigator to ensure 
subject safety and maintain protocol requirements. 
Clinical Study Report 331-201-00182
16.1.1 Protocol and Protocol Amendments
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Protocol Synopsis 
Name of Sponsor:  Otsuka Pharmaceutical
Development & Commercialization, Inc.
Name of Investigational Medicinal Product:  
Brexpiprazole (OPC-34712)
Protocol No.:  331-201-00182
IND No.:  115960
EudraCT No.:  2018-002783-88
Protocol Title:
A 12-week, Multicenter, Active-treatment Extension Trial to 
Evaluate the Safety and Tolerability of Brexpiprazole in the 
Treatment of Subjects With Agitation Associated With 
Dementia of the Alzheimer’s Type
Clinical Phase/Trial 
Type:
3/Safety extension
Treatment Indication: Agitation associated with dementia of the Alzheimer’s type 
(AAD)
Objectives: 
Primary: To assess the long-term safety and tolerability of oral 
brexpiprazole as treatment in adult subjects with AAD.
 
Trial Design:
This is a multicenter, active-treatment extension trial designed 
to assess the long-term safety and tolerability of oral 
brexpiprazole (2 and 3 mg/day) as treatment in adults with 
AAD.  Enrollment into the trial will consist of eligible subjects 
who completed the 12-week treatment in the double blind, 
phase 3 efficacy Trial 331-14-213.  In addition, subjects who 
are early terminated from Trial 331-14-213, if the trial is 
terminated due to overwhelming efficacy from the interim 
analysis, may be offered entry into this trial.
The trial will be organized as follows:
Screening/baseline:  Subjects who completed Week 12 of the 
double-blind trial and had no substantial protocol deviations 
will be screened for eligibility at the last visit of the 
double-blind trial (ie, Week 12 or ET, if the trial is terminated, 
visit of Trial 331-14-213).  Subjects will sign a separate 
informed consent form (ICF) for participation in Trial 331-
201-00182 before any procedures specific to the extension trial 
are performed.  The assessments from the last visit of the 
double-blind trial will serve as the baseline measures for Trial 
331-201-00182 for any assessment that is not unique to the 
extension trial.  Medical history will be updated, if necessary.
Clinical Study Report 331-201-00182
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Trial Design 
(continued):
Active Extension Treatment:  Eligible subjects from 
Trial 331-14-213 will receive 12 weeks of daily treatment with 
brexpiprazole (target doses of 2 or 3 mg/day) in 
Trial 331-201-00182.  Visits will occur at the end of Weeks 1, 
2, 6, and 12.  
Follow-up:  All subjects, whether they complete the trial or are 
withdrawn prematurely for any reason, will be followed up for 
a safety evaluation 30 (+ 2) days after the last dose of 
investigational medicinal product (IMP) during a clinic visit at 
either the investigator’s site or residential facility, as 
applicable.  If a clinic visit is not possible, the subject should 
be assessed by telephone contact with the subject and a 
caregiver.  For all subjects who terminate early from the trial, 
all attempts will be made to collect mortality data by telephone 
contact with the subject’s caregiver at Week 16 (relative to 
baseline visit).
Subject Population:
The trial population for Trial 331-201-00182 will include 
rollover subjects who have completed 12 weeks of 
post-randomization treatment in the double-blind, phase 3 
efficacy Trial 331-14-213, and who are living in either an 
institutionalized setting, or in a non-institutionalized setting 
where they are not living alone.  In both the institutionalized 
and non-institutionalized settings, the subject must have a 
caregiver who can spend a minimum of 2 hours per day for 
4 days per week with them in order to assess changes in the 
condition of the subject.  
In addition, subjects who are early terminated from 
Trial 331-14-213, if the trial is terminated due to 
overwhelming efficacy from the interim analysis, may be 
offered entry into this trial.
Clinical Study Report 331-201-00182
16.1.1 Protocol and Protocol Amendments
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Inclusion/Exclusion 
Criteria: 
Key inclusion criteria are described under Subject Population 
in this synopsis.  Subjects must meet the inclusion criteria at 
the screening/baseline visit, which is also the last visit in Trial 
331-14-213.
Key exclusion criteria include the following:

Subjects who, in the opinion of the investigator, medical 
monitor, or sponsor, should not participate in the trial.

Subjects with a substantial protocol violation during the 
course of their participation in the double-blind 
Trial 331-14-213.  Lesser violations such as occasional 
visits outside of the acceptable window or a missing blood 
draw will not exclude a subject from participation in 
Trial 331-201-00182; however, continual lack of 
compliance with the visit schedule, trial assessments, or 
treatment regimen in the prior double-blind trial would be 
considered a substantial violation that would result in 
exclusion from Trial 331-201-00182.  The medical monitor 
should be contacted if the investigator is unsure of a 
subject’s eligibility.
Trial Sites: 
All trial centers will have participated as sites in Trial 
331-14-213.  
Clinical Study Report 331-201-00182
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Investigational 
Medicinal Product, 
Dose, Dosage 
regimen, Treatment 
period, Formulation, 
Mode of 
Administration:
The IMP will be supplied as brexpiprazole tablets.  Each dose 
will be supplied in blister cards containing sufficient tablets for 
7 (+2) days.  When accessed by the site, the eSource method 
will assign specific blister card number(s) to be dispensed to a 
subject.
All subjects will receive brexpiprazole at target doses of either 
2 or 3 mg/day.
To preserve the blind in Trial 331-14-213, all doses in Trial 
331-201-00182 will remain blinded.  Subjects randomized to 
the 2 mg/day and 3 mg/day doses of brexpiprazole in 
Trial 331-14-213 will begin treatment on these same doses in 
the active-treatment extension Trial 331-201-00182.  All 
subjects who received placebo in Trial 331-14-213 will receive 
active drug in Trial 331-201-00182.
For subjects who may be offered entry into this trial as a result 
of early termination of Trial 331-14-213 due to overwhelming 
efficacy from the interim analysis, treatment in Trial 331-201-
00182 will begin based on randomization and last visit 
completed in Trial 331-14-213. Subjects who received placebo 
in Trial 331-14-213 will receive active drug in 
Trial 331-201-00182.  Subjects randomized to brexpiprazole 
and who completed the titration schedule in Trial 331-14-213 
(ie, completed Week 4 visit in 331-14-213) will begin 
treatment on the same dose in this trial.  Subjects randomized 
to brexpiprazole and who have not completed the titration 
schedule will restart drug in Trial 331-201-00182 dependent 
on the point in the titration scheme for Trial 331-14-213 that 
early termination occurred.
All doses of brexpiprazole will be taken orally once daily, 
preferably in the morning, and will be administered without 
regard to meals.  Brexpiprazole should be taken at 
approximately the same time each day.
Trial Assessments:
Safety:  Adverse event (AE) reporting, clinical laboratory tests, 
electrocardiograms (ECGs), vital signs, physical and 
neurological examinations, body weight, body mass index, 
Mini-Mental State Examination (MMSE), Simpson Angus 
Scale (SAS) total score, Abnormal Involuntary Movement 
Scale (AIMS) Movement Rating Score, and Barnes Akathisia 
Rating Scale (BARS) Global Score, and Sheehan Suicidality 
Tracking Scale (Sheehan-STS).
 
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Criteria for 
Evaluation:
Primary outcome variable:  The primary outcome variable is 
the frequency and severity of AEs (safety and tolerability of 
brexpiprazole).
 
 
 
Statistical Methods:
The primary safety analysis is the frequency and severity of 
AEs.  All AEs will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term.  The 
incidence of the following events will be summarized 
descriptively:

Treatment-emergent AEs (TEAEs)

TEAEs by severity

Potentially drug-related TEAEs (per investigator)

TEAEs with an outcome of death

Serious TEAEs

TEAEs leading to discontinuation of the IMP
Safety and tolerability will be also evaluated by clinically 
significant changes in: physical examinations, neurological 
examinations, vital sign measurements, body weight, clinical 
laboratory tests, and electrocardiograms.  Other safety 
variables will include the Mini Mental State Examination 
(MMSE) score and assessments of suicidality and 
extrapyramidal symptoms.
Descriptive statistics will be provided for each endpoint, and 
will be summarized at each trial visit using the observed cases 
(OC) dataset.  Baseline is defined as the last available 
measurement prior to the first dose of IMP in the 
active-treatment extension trial.
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Trial Duration:
Individual participation for subjects who complete the trial will 
consist of a 12-week treatment period and a 30-day follow-up 
period.  All subjects will be followed up at a clinic visit or via 
telephone contact 30 (+ 2) days after the last dose of the IMP.  
In addition, for all subjects who terminate early from the trial, 
all attempts will be made to collect mortality data by telephone 
contact with the subject’s caregiver at Week 16 (relative to 
baseline visit).
Clinical Study Report 331-201-00182
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Table of Contents 
Trial Conduct for COVID-19.......................................................................2
Protocol Synopsis...........................................................................................3
Table of Contents ..........................................................................................9
List of In-text Tables...................................................................................13
List of In-text Figures .................................................................................14
List of Appendices .......................................................................................15
List of Abbreviations and Definitions of Terms .......................................16
1
Introduction........................................................................................18
2
Trial Rationale and Objectives .........................................................21
2.1
Trial Rationale...................................................................................................21
2.2
Dosing Rationale...............................................................................................22
2.3
Trial Objectives.................................................................................................22
3
Trial Design.........................................................................................22
3.1
Type/Design of Trial .........................................................................................22
3.2
Trial Treatments ................................................................................................26
3.3
Trial Population.................................................................................................27
3.3.1
Caregiver/Caretaker Requirements.................................................................27
3.3.1.1
Non-institutionalized Subjects ....................................................................27
3.3.1.2
Institutionalized Subjects ............................................................................27
3.3.2
Description of Population...............................................................................28
3.4
Eligibility Criteria .............................................................................................28
3.4.1
Informed Consent ...........................................................................................28
3.4.1.1
Determinations of Capacity ........................................................................28
3.4.1.2
Documentation of Informed Consent..........................................................29
3.4.2
Inclusion Criteria ............................................................................................30
3.4.3
Exclusion Criteria...........................................................................................31
3.5
Outcome Variables............................................................................................31
3.5.1
Primary Outcome Variable.............................................................................31
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3.5.3
Safety Outcomes.............................................................................................32
3.6
Trial Procedures ................................................................................................32
3.6.1
Schedule of Assessments................................................................................35
3.6.1.1
Screening/Baseline......................................................................................35
3.6.1.2
Weeks 1, 2, and 6........................................................................................35
3.6.1.3
End of Treatment (Week 12 or ET) ............................................................36
3.6.1.4
Follow-up....................................................................................................36
3.6.2.1
Cohen-Mansfield Agitation Inventory........................................................37
3.6.2.2
Clinical Global Impression Severity of Illness (CGI-S) .............................37
3.6.3
Prior and Concomitant Medications...............................................................37
3.6.4
Safety Assessments.........................................................................................38
3.6.4.1
Adverse Events ...........................................................................................38
3.6.4.2
Clinical Laboratory Assessments................................................................38
3.6.4.3
Physical and Neurological Examination and Vital Signs ...........................40
3.6.4.3.1
Physical Examinations.............................................................................40
3.6.4.3.2
Neurological Examinations .....................................................................40
3.6.4.3.3
Vital Signs ...............................................................................................41
3.6.4.4
Electrocardiogram Assessments .................................................................41
3.6.4.5
Other Safety Assessments...........................................................................42
3.6.4.5.1
Simpson Angus Scale..............................................................................42
3.6.4.5.2
Abnormal Involuntary Movement Scale .................................................42
3.6.4.5.3
Barnes Akathisia Rating Scale ................................................................43
3.6.4.5.4
Sheehan Suicidality Tracking Scale ........................................................43
3.6.4.5.5
Mini-Mental State Examination ..............................................................43
3.6.5
End of Trial.....................................................................................................44
3.7
Stopping Rules, Withdrawal Criteria, and Procedures......................................44
3.7.1
Entire Trial......................................................................................................44
3.7.2
Individual Site.................................................................................................44
3.7.3
Individual Subject Discontinuation ................................................................44
3.7.3.1
Treatment Discontinuation..........................................................................44
3.7.3.2
Documenting Reasons for Treatment Discontinuation...............................44
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7.6
Safety Analysis..................................................................................................58
7.6.1
Adverse Events...............................................................................................58
7.6.2
Clinical Laboratory Data ................................................................................59
7.6.3
Physical/Neurological Examination and Vital Sign Measurements Data ......59
7.6.4
Electrocardiogram Data..................................................................................59
7.6.5
Other Safety Data ...........................................................................................60
8
Management of Investigational Medicinal Product........................60
9
Records Management ........................................................................62
9.1
Source Documents.............................................................................................62
10
Quality Control and Quality Assurance...........................................65
10.1
Monitoring.........................................................................................................65
10.2
Auditing.............................................................................................................65
11
Ethics and Responsibility...................................................................66
12
Confidentiality....................................................................................66
13
Amendment Policy .............................................................................67
14
Publication Authorship Requirements.............................................67
15
References ...........................................................................................69
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List of In-text Figures
Figure 3.1-1
Trial Design Schematic..................................................................25
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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
5-HT
Serotonin
5-HT1A
Serotonin type 1A receptor
5-HT2A
Serotonin type 2A receptor
AAD
Agitation in Alzheimer’s dementia
ADHD
Attention-deficit/hyperactivity disorder
AE
Adverse event
AIMS
Abnormal Involuntary Movement Scale
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BARS
Barnes Akathisia Rating Scale
BMI
Body mass index
bpm
Beats per minute
CGI-S
Clinical Global Impression Severity of Illness
CMAI
Cohen-Mansfield Agitation Inventory
CNS
Central nervous system
COVID-19
Coronavirus disease 2019
CRF
Case report form
CYP
Cytochrome P450
D
Dopamine
D2
Dopamine type 2
ECG
Electrocardiogram
eICF
Electronic informed consent form
EPS
Extrapyramidal symptoms
ET
Early termination
FDA
Food and Drug Administration
GABA
Gamma-aminobutyric acid
GCP
Good Clinical Practice
HbA1c
Glycosylated hemoglobin
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
ICMJE
International Committee of Medical Journal Editors
ID
Identification
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
IND
Investigational New Drug
IPA
International Psychogeriatric Association
IRB
Institutional review board
IRE
Immediately reportable event
MDD
Major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
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MMSE
Mini-Mental State Examination
MTD
Maximum tolerated dose
OC
Observed-case
OPC
Otsuka Pharmaceutical Company, Ltd.
PK
Pharmacokinetic
PTSD
Post-traumatic stress disorder
PQC
Product Quality Complaint
QTc
Corrected QT interval
QTcF
QT interval corrected for heart rate by Fridericia’s formula
QTcN
QT interval corrected for heart rate by the FDA Neuropharm Division 
formula
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Simpson Angus Scale
Sheehan-STS
Sheehan Suicidality Tracking Scale
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal range
US
United States
WOCBP
Women of childbearing potential
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1
Introduction
It is currently estimated that 5.4 million Americans have Alzheimer’s disease, and future 
projections estimate that, due to an increase in the aging population, there will be 
approximately 13.8 million Americans with Alzheimer’s disease by 2050.1,2  Fourteen 
percent of people aged 71 and older in the United States (US) have dementia and 
Alzheimer's disease accounts for an estimated 60% to 80% of cases.1,3 
Neuropsychiatric symptoms, including agitation, are common features of Alzheimer’s 
disease and related dementias.  Over the course of the disease, nearly all patients with 
Alzheimer’s dementia will likely experience neuropsychiatric symptoms.4  Although 
agitation has a long history of being recognized as an important clinical feature of 
Alzheimer’s disease, a widely recognized definition has been lacking in the literature 
until recently.  In 2015, the provisional International Psychogeriatric Association (IPA) 
definition of agitation limited to patients with cognitive impairment was developed and 
requires: a) evidence of emotional distress; (b) one of 3 observable types of 
behaviors-excessive motor activity, verbal aggression, or physical aggression; (c) that the 
behavior causes excess disability; and (d) that the behaviors cannot be solely attributable 
to a suboptimal care environment or other disorder such as a psychiatric illness, a medical 
illness, or effects of a substance.5 
Agitation can be present from the early stages and throughout the course of Alzheimer’s 
disease, and symptoms usually become more consequential as the disease progresses.  
Agitation in Alzheimer’s dementia (AAD) has been associated with more rapid cognitive 
decline and progression to severe dementia, loss of independence, and earlier death.6,7  
Agitation is a leading cause of institutionalization for patients with Alzheimer’s 
dementia; within care facilities, 40% to 60% of patients with Alzheimer’s disease exhibit 
symptoms of agitation with and without aggression.8  The presence of agitation in 
subjects with Alzheimer’s dementia places a significant burden not only on subjects and 
their caregivers but also on the healthcare system.  Additionally, aggressive behaviors 
such as combativeness, destroying property, and being a danger to oneself and others are 
significant predictors of time to nursing home placement.9 
Currently, there are no approved treatments in the US for the management of agitation in 
patients with Alzheimer’s disease.  In other countries, treatment for the indication is 
restricted to the treatment of persistent aggression for a short period of time.  Without 
approved labeling, at best in current clinical practice, clinicians rely on guidelines when 
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prescribing pharmaceutical treatments for patients with AAD.10,11,12  Proven effective, 
tolerable, and safe treatment is essential in addressing this serious unmet need.
Brexpiprazole (OPC-34712, and Lu AF41156) was discovered by Otsuka Pharmaceutical 
Company, Ltd. (OPC) and is being codeveloped by Otsuka and H. Lundbeck A/S 
(Lundbeck).  While the precise mechanism of action of brexpiprazole in treating 
psychiatric conditions is unknown, the efficacy of brexpiprazole is believed to be 
mediated by a combination of high affinity interactions with multiple monoaminergic 
receptors.  Brexpiprazole is a serotonin (5-HT)-dopamine (D) activity modulator that is a 
partial agonist at 5-HT1A and D2 receptors, and an antagonist at serotonin 5-HT2A and 
noradrenaline α1B/2C receptors, all with similar subnanomolar potencies.  The 5-HT1A/D2 
receptor partial agonist activity in combination with 5-HT2A and α1B/2C receptor 
antagonism of brexpiprazole may correlate with antipsychotic and antidepressant 
efficacy, reduced impulsive behavior, and cognitive improvement.  Additionally, it is 
hypothesized that the partial agonist and antagonist activities of brexpiprazole at multiple 
serotonergic, dopaminergic and noradrenergic receptor systems may have a therapeutic 
benefit in the treatment of AAD.
Refer to the Investigator’s Brochure (IB) for more detailed information about the 
investigational medicinal product (IMP).13 
1.1
Nonclinical Data
A complete description of the available efficacy and safety pharmacology data from 
nonclinical studies, including pharmacokinetic (PK) and toxicology studies in different 
animal species can be found in the current IB.13 
1.2
Clinical Data
Currently, brexpiprazole is approved in the US for use in adult patients for the treatment 
of schizophrenia, and for the use as an adjunctive therapy to antidepressants for the 
treatment of major depressive disorder (MDD), and in Canada and Australia in adult 
patients for the treatment of schizophrenia.  Additionally, the current clinical 
development program is designed to show safety and efficacy of brexpiprazole for the 
treatment of the following indications: treatment of adult post-traumatic stress disorder 
(PTSD), bipolar mania, adolescent schizophrenia, and the treatment of AAD.13 
As of 17 Apr 2017, the brexpiprazole clinical development program consisted of a total 
of 68 clinical trials conducted in North America, Latin America, Europe, and Asia 
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(60 completed and 8 ongoing).  This includes 61 trials conducted under US 
Investigational New Drug (IND) Applications (54 completed and 7 ongoing) for 
schizophrenia, adjunctive treatment of MDD, adjunctive treatment of 
attention-deficit/hyperactivity disorder (ADHD), AAD, or PTSD; and 7 non-US IND 
trials (6 completed and 1 ongoing) in either South Korea or Japan conducted in healthy 
subjects and subjects with schizophrenia.13 
Please refer to the IB for a detailed summary of available clinical data.13 
1.3
Known and Potential Risks and Benefits
As of 30 Apr 2017, at least 8978 subjects have been exposed to a dose of brexpiprazole 
across the phase 2/3 completed trials for AAD, schizophrenia, MDD, ADHD, and PTSD, 
including 3249 subjects who have been exposed to brexpiprazole for at least 6 months 
and 1809 subjects who have been exposed for at least 1 year.
Data from clinical trials completed to date indicate that the maximum tolerated dose 
(MTD) of brexpiprazole in healthy adult subjects is 6 mg after single-dose administration 
and 2 mg after once-daily, multiple-dose (14 days) administration.  The MTD of 
brexpiprazole in subjects with schizophrenia, MDD, or ADHD has not been established.  
Within the 3 indications with completed trials, data from completed multiple-dose 
phase 1 clinical trials indicate brexpiprazole is tolerated at multiple oral doses up to 
12 mg/day in subjects with schizophrenia or schizoaffective disorder, up to 4 mg/day as 
adjunctive therapy in adult subjects with MDD or ADHD, and up to 3 mg/day as 
adjunctive therapy in elderly subjects (70 to 85 years of age) with MDD.  
Preliminary data from the 2 completed phase 3 trials (Trials 331-12-283 and 331-12-284) 
in subjects with AAD indicate brexpiprazole is safe and well tolerated, with no new 
safety signals identified in this elderly population.  There was a low incidence of 
treatment-emergent adverse events (TEAEs) associated with extrapyramidal symptoms 
(EPS) (5.8% brexpiprazole versus 4.0% placebo), weight increased (1.4% brexpiprazole 
versus 0.7% placebo), somnolence/sedation (3.7% brexpiprazole versus 2.2% placebo), 
falls (1.6% brexpiprazole versus 2.9% placebo), cardiovascular events (5.1% 
brexpiprazole versus 2.9% placebo), cerebrovascular events (0.7% brexpiprazole versus 
0.4% placebo), and mortality (1.4% brexpiprazole versus 0.4% placebo).  Overall, the 
TEAEs associated with mortality do not appear to support a relationship with the IMP.  
Results from the 2 completed phase 3 trials in subjects with AAD (Trial 331-12-283 and 
Trial 331-12-284) showed that brexpiprazole doses up to 2 mg/day are safe and well 
tolerated in this population.
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Please refer to the IB for a summary of available nonclinical and clinical safety data.13 
2
Trial Rationale and Objectives
2.1
Trial Rationale
Data from the 2 completed phase 3 trials (Trials 331-12-283 and 331-12-284) indicate 
efficacy of brexpiprazole 2 mg/day in the treatment of subjects with AAD.  The primary 
endpoint of mean change in Cohen-Mansfield Agitation Inventory (CMAI) total score 
from baseline to Week 12 in the fixed-dose trial (Trial 331-12-283) showed brexpiprazole 
2 mg/day was statistically significantly superior to placebo (p < 0.05).  The lower dose 
group, 1 mg/day brexpiprazole, did not show any meaningful separation relative to 
placebo (p > 0.05).  In the flexible-dose trial (Trial 331-12-284), the brexpiprazole 0.5 to 
2 mg/day group (mean dose 1.54 mg/day) did not show statistically significant 
superiority relative to placebo on the CMAI total score at Week 12 (p > 0.05), but 
showed numerical improvement at each visit starting at Week 6, the first time point at 
which subjects who received the 2 mg/day dose could be evaluated.  Additionally, 
post-hoc analyses of subjects who had their dose titrated to 2 mg/day brexpiprazole (or 
equivalent placebo) in the flexible dose trial (Trial 331-12-284) supported the efficacy of 
brexpiprazole 2 mg/day. 
The sponsors met with the Food and Drug Administration (FDA) to discuss results of the 
2 completed phase 3 trials of brexpiprazole for the treatment AAD (Trials 331-12-283 
and 331-12-284).
 
  
Trial 331-14-213 was designed to confirm the 
, safety, and tolerability of 
brexpiprazole 2 mg/day compared with placebo, as well as to provide information about 
the
, safety, and tolerability of brexpiprazole at 3 mg/day.  In a subsequent 
meeting with the FDA to discuss the proposed design for Trial 331-14-213, the FDA also 
recommended conducting an extension trial to investigate the long-term safety of 
brexpiprazole in subjects with AAD.
The proposed, 12-week, multicenter, active-treatment extension trial will be conducted to 
evaluate the long-term safety and tolerability of brexpiprazole for the treatment of 
subjects with AAD.  This would result in 24 weeks (6 months) of continuous exposure 
for subjects who had received brexpiprazole in the double-blind, placebo-controlled 
Trial 331-14-213. 
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2.2
Dosing Rationale
The 2 mg/day dose of brexpiprazole to be used in Trial 331-14-213 is included based on 
its separation from placebo on the primary endpoint, change from baseline in CMAI total 
score, in Trial 331-12-283, and its demonstrated safety and tolerability, and is therefore 
considered the minimum effective dose.  The 3 mg/day dose is included to explore the 
, safety, and tolerability of a higher dose of brexpiprazole, as recommended by 
the FDA.
2.3
Trial Objectives
Primary:
To assess the long-term safety and tolerability of oral brexpiprazole as 
treatment in adult subjects with AAD.
 
3
Trial Design
3.1
Type/Design of Trial
This is a multicenter, active-treatment extension trial designed to assess the long-term 
safety and tolerability of oral brexpiprazole (2 and 3 mg/day) as treatment in adults with 
AAD.  Enrollment into the trial will consist of eligible subjects who completed the 
12-week treatment in the double-blind, phase 3 efficacy Trial 331-14-213.  In addition, 
subjects who are early terminated from Trial 331-14-213, if the trial is terminated due to 
overwhelming efficacy from the interim analysis, may be offered entry into this trial.
The trial will be organized as follows:
Screening/baseline:  Subjects who completed Week 12 of the double-blind trial and had 
no substantial protocol deviations will be screened for eligibility at the last visit of the 
double-blind trial (ie, Week 12 or ET, if the trial is terminated, visit of Trial 331-14-213).  
Subjects will sign a separate informed consent form (ICF) for participation in 
Trial 331-201-00182 before any procedures specific to the extension trial are performed.  
The assessments from the last visit of the double-blind trial will serve as the baseline 
measures for Trial 331-201-00182 for any assessment that is not unique to the extension 
trial.  Medical history will be updated, if necessary.
Active Extension Treatment:  Eligible subjects from Trial 331-14-213 will receive 
12 weeks of daily treatment with brexpiprazole (target doses of 2 or 3 mg/day) in 
Trial 331-201-00182.  Visits will occur at the end of Weeks 1, 2, 6, and 12.  
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Follow-up:  All subjects, whether they complete the trial or are withdrawn prematurely 
for any reason, will be followed up for a safety evaluation 30 (+ 2) days after the last 
dose of IMP during a clinic visit at either the investigator’s site or residential facility, as 
applicable.  If a clinic visit is not possible, the subject should be assessed by telephone 
contact with the subject and a caregiver.  For all subjects who terminate early from the 
trial, all attempts will be made to collect mortality data by telephone contact with the 
subject’s caregiver at Week 16 (relative to baseline visit).
See Figure 3.1-1 for a schematic of the trial design.  See Table 3.6-1 for the Schedule of 
Assessments. 
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aStarting at week 4, 1 dose decrease can occur at any time (scheduled or unscheduled visits)  until the end of the trial.  In addition, one dose increase can occur 
but only at the Week 6 scheduled visit.  For subjects who may be offered entry into this trial as a result of early termination due to overwhelming efficacy 
from the 331-14-213 interim analysis, treatment in Trial 331-201-00182 will begin based on randomization and last visit completed in Trial 331-14-213. 
Subjects who received placebo in Trial 331-14-213 will receive active drug in Trial 331-201-00182.  Subjects randomized to brexpiprazole and who 
completed the titration schedule in Trial 331-14-213 (ie, completed Week 4 visit in 331-14-213) will begin treatment on the same dose in this trial.  Subjects 
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randomized to brexpiprazole and who have not completed the titration schedule will restart drug in Trial 331-201-00182 dependent on the point in the titration 
scheme for Trial 331-14-213 that early termination occurred.
bFor subjects who may be offered entry into this trial as a result of early termination of Trial 331-14-213 due to overwhelming efficacy from the interim analysis, 
the Screening/Baseline will occur at the last visit of the double-blind trial (ie, ET visit of Trial 331-14-213).  
Figure 3.1-1
Trial Design Schematic
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3.2
Trial Treatments
All subjects will receive target doses of 2 or 3 mg/day brexpiprazole in Trial 331-201-
00182; these doses were those studied in Trial 331-14-213.  
To preserve the blind in Trial 331-14-213, all doses in Trial 331-201-00182 will remain 
blinded.  The first dose taken in Trial 331-201-00182 should be taken one day after the 
Week 12 or ET, if the trial is terminated due to overwhelming efficacy from the interim 
analysis, visit of Trial 331-14-213 so that treatment continues without interruption.  
Subjects randomized to the 2 mg/day and 3 mg/day doses of brexpiprazole in Trial 
331-14-213 will begin treatment on these same doses in the active-treatment extension 
Trial 331-201-00182.  All subjects who received placebo in Trial 331-14-213 will receive 
active drug (ie, brexpiprazole) in Trial 331-201-00182.
For subjects who may be offered entry into this trial as a result of early termination of 
Trial 331-14-213 due to overwhelming efficacy from the interim analysis, treatment in 
Trial 331-201-00182 will begin based on randomization and last visit completed in 
Trial 331-14-213. Subjects who received placebo in Trial 331-14-213 will receive active 
drug in Trial 331-201-00182.  Subjects randomized to brexpiprazole and who completed 
the titration schedule in Trial 331-14-213 (ie, completed Week 4 visit in 331-14-213) will 
begin treatment on the same dose in this trial.  Subjects randomized to brexpiprazole and 
who have not completed the titration schedule will restart drug in Trial 331-201-00182 
dependent on the point in the titration scheme for Trial 331-14-213 that early termination 
occurred.
All subjects will receive target doses of 2 or 3 mg/day brexpiprazole during the trial.  
Dose adjustments are allowed during the trial.  Starting at week 4, one dose decrease can 
occur at any time (scheduled or unscheduled visits) until the end of the trial.  In addition, 
one dose increase is permitted but only at the Week 6 scheduled visit.  Subjects who 
require an additional dose increase or decrease will be discontinued from the trial.  
Timing of dose adjustments as outlined above is summarized in the table below.
Dosing Adjustments
Visit
Decreasea
Increase
Week 6
Permitted
Permitted
Unscheduled (week 4 or anytime thereafter)
Permitted
Not Permitted
aStarting at week 4, 1 dose decrease can occur at any time (scheduled or unscheduled visits) until the 
end of the trial.  
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All doses of brexpiprazole will be taken orally once daily, preferably in the morning, and 
will be administered without regard to meals, and should be taken at approximately the 
same time each day.  
3.3
Trial Population
3.3.1
Caregiver/Caretaker Requirements
3.3.1.1
Non-institutionalized Subjects
In a non-institutionalized setting, the subject’s caretaker is the person who lives with and 
cares for the subject on a regular basis.  For example, caring for a subject on a regular 
basis may include the following activities:  assisting with dispensing of IMP; observing 
the subject’s general medical condition, including nutrition and hydration intake; 
reducing the chance of fall; and assisting the subject if emergency medical care is needed 
by contacting appropriate emergency services, the subject’s primary physician, or the 
principal investigator, whatever is warranted or associated with providing custodial care.  
The caretaker may be supported in providing care to the subject by a professional(s), 
friend(s), or family member(s).
For purposes of this trial, the subject’s caregiver is defined as the person who has 
sufficient contact to describe the subject’s symptoms, and has direct observation of the 
subject’s behavior in order to participate in the interview for the CMAI and other 
applicable trial assessments.  The caregiver identified during the screening period for 
Trial-331-14-213 can continue to function as the caregiver for the extension trial.  The 
caregiver should acknowledge and agree to undertake all the tasks designated by this 
protocol at the time of the informed consent process.  The caregiver role in the 
non-institutionalized setting may or may not be fulfilled by the same individual who 
fulfills the role of caretaker depending on the circumstances of the subject.  The 
minimum level of contact between the caregiver and the subject is 2 hours per day for 
4 days per week.  The caregiver is the person who should accompany the subject to all 
visits where the CMAI is administered unless other arrangements are made and approved 
by the sponsor.  Starting at screening/baseline, there should be no changes in living 
situation (eg, room) to ensure the same pre-trial routine is maintained.
3.3.1.2
Institutionalized Subjects
In the institutionalized setting, there is only one role defined and that is the role of 
caregiver.  A caregiver in the institutionalized setting is an individual who has sufficient 
contact to describe the subject’s symptoms and who has direct observation of the 
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subject’s behavior in order to participate in the interview for the CMAI and other 
applicable trial assessments.  The caregiver identified during the screening period for 
Trial-331-14-213 can continue to function as the caregiver for the extension trial.  The 
caregiver should acknowledge and agree to undertake all the tasks designated by this 
protocol at the time of the informed consent process.  The identified caregiver can be a 
staff member of the institutionalized setting or another individual (eg, family member, 
family friend, hired professional caregiver) who meets the caregiver requirements.  The 
recommended minimum level of contact between the caregiver and the subject is 2 hours 
per day for 4 days per week.  Starting at screening, there should be no changes in living 
situation (eg, room) to ensure the same pre-trial routine is maintained.
3.3.2
Description of Population
The trial population for Trial 331-201-00182 will include rollover subjects who have 
completed 12 weeks of post-randomization treatment in the double-blind, phase 3 
efficacy Trial 331-14-213, and who are living in either an institutionalized setting, or in a 
non-institutionalized setting where they are not living alone.  In both the institutionalized 
and non-institutionalized settings, the subject must have a caregiver who can spend a 
minimum of 2 hours per day for 4 days per week with them in order to assess changes in 
the condition of the subject.  
In addition, subjects who are early terminated from Trial 331-14-213, if the trial is 
terminated due to overwhelming efficacy from the interim analysis, may be offered entry 
into this trial.
3.4
Eligibility Criteria
3.4.1
Informed Consent
3.4.1.1
Determinations of Capacity
The investigator must assess the capacity of the subject to provide informed consent 
during the screening period and throughout the course of the trial.  This assessment will 
be made in accordance with the investigator’s standard practice.  Once these 
determinations are made by the investigator, the following options for obtaining informed 
consent from or on behalf of the subject must be followed:

If the subject is deemed capable by the investigator, informed consent will be 
obtained from the subject prior to the initiation of any trial protocol-required 
procedures.  In such cases, acknowledgement from the subject’s legally acceptable 
representative (an individual, or judicial or other body, authorized under applicable 
law to consent to the subject’s participation in the clinical trial on behalf of that 
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prospective subject) will also be obtained, if required, in accordance with state or 
local regulations prior to initiation of any trial protocol-required procedures.

If the subject is deemed incapable by the investigator of providing consent (eg, 
subjects with severe dementia), informed consent will be obtained from the subject’s 
legally acceptable representative prior to initiation of any trial protocol required 
procedures.  In such cases, assent from the subject, if possible, will be confirmed in 
accordance with state or local regulations prior to the initiation of any trial protocol-
required procedures.

If the subject cannot provide assent, and does not dissent, then the consent of the 
legally acceptable representative is sufficient unless otherwise required by the 
governing ethics body or applicable state or local regulations.

If the subject dissents, then the subject is not eligible for participation in the trial.

If the subject initially provided assent at trial entry, but subsequently dissents to 
participate in the trial, the subject will be early terminated from the trial.

If the subject was initially deemed capable of providing informed consent but is no 
longer deemed so, informed consent must be obtained from the subject’s legally 
acceptable representative, and assent from the subject, if possible, will be confirmed 
in accordance with state or local regulations prior to the initiation or continuation of 
any trial protocol-required procedures.
3.4.1.2
Documentation of Informed Consent
In support of the site’s standard process for administering informed consent, this trial will 
also utilize an electronic informed consent form (eICF) as a tool within applicable 
regions and sites.  The eICF utilizes the institutional review board (IRB)-approved, 
site-specific ICF to offer subjects an enhanced platform to review and understand their 
rights as a research subject as well as required trial procedures.  When possible, sites will 
have subjects review and sign the eICF prior to starting any trial procedures; however if 
local regulations does not allow for use of the electronic format, subjects may continue in 
the trial utilizing the standard paper signature process.
Informed consent will be freely obtained from all subjects (or their guardian or legally 
acceptable representative, as applicable for local laws).  The ICF will be approved by the 
same IRB or independent ethics committee (IEC) that approves this protocol.
Each ICF will comply with the International Council for Harmonisation (ICH) Good 
Clinical Practice (GCP) Guideline14 and local regulatory requirements.  The investigator 
will ensure that the sponsor reviews and authorizes any site-specific ICF used in the trial 
prior to submission to the IRB or IEC.
Investigators may discuss trial availability and the possibility for entry with a potential 
subject without first obtaining consent.  However, informed consent must be obtained and 
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documented before initiation of any procedures that are performed solely for the purpose 
of determining eligibility for this trial, including withdrawal from current medication(s).
Potential subjects are free to refuse entry into the trial, or withdraw from the trial at any 
time, without justification, and there will be no consequences to their further care.
Prospective trial participants will be provided with controlled access to the ICF 
application by trial site staff.  When the trial site staff and the participant agree that the 
participant has enough information to make an informed decision to participate, the 
participant will sign in the ICF application and a date and timestamp will be applied to 
the signature.  The subject will be given a printed, signed copy of the ICF.  Any other 
parties required by the IRB or IEC (trial site staff, witnesses, or legally authorized 
representative [Section 3.4.1.1]) are also required to sign and these signatures will be 
stored with the ICF in accordance with the ICH GCP Guideline and local regulatory 
requirements or guidelines.  These signatures cannot be altered, removed, or copied.
If the subject or subject’s legally acceptable representative is unable to read or sign due to 
physical limitations, an impartial witness should be present during the entire informed 
consent discussion.  After the subject’s legally acceptable representative and subject 
orally consent and have signed, if capable, the witness should sign and personally date 
the consent or assent form attesting that the information is accurate and that the subject’s 
legally acceptable representative and subject understand and have freely given consent.
The informed consent and any other information provided to the subject and the subject’s 
legally acceptable representative should be revised whenever important new information 
becomes available that is relevant to the consent, and should receive IRB or IEC approval 
prior to use.  The investigator (or qualified designee) should fully inform the subject and 
the subject’s legally acceptable representative of all pertinent aspects of the trial and of 
any new information relevant to the willingness of the subject and the subject’s legally 
acceptable representative to continue participation in the trial.  This communication 
should be documented.
Subjects may be asked to sign additional ICFs if the protocol is amended and the changes 
to the protocol result in additional information that needs to be provided to the subjects, 
so that they can make a knowledgeable and voluntary decision on trial participation.
3.4.2
Inclusion Criteria
Subjects are required to meet the inclusion criteria presented in Table 3.4.2-1.
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Table 3.4.2-1
Inclusion Criteria
1.
The investigator must assess the capacity of the subject to provide informed consent prior to 
enrollment.  Once this determination is made by the investigator, the options for obtaining 
informed consent from or on behalf of the subject must be followed as provided in the protocol.
2.
Subjects who completed 12 weeks of post-randomization treatment in Trial 331-14-213.  In 
addition, subjects who are early terminated from Trial 331-14-213, if the trial is terminated due to 
overwhelming efficacy from the interim analysis, may be offered entry into this trial.
3.
Institutionalized subjects with an identified caregiver who has sufficient contact (minimum of 2 
hours per day for 4 days per week) to describe the subject’s symptoms and has direct observation 
of the subject’s behavior.  The identified caregiver can be a staff member of the institutionalized 
setting or another individual (eg, family member, family friend, hired professional caregiver) who 
meets the caregiver requirements.
Non-institutionalized subjects may not be living alone and must have an identified caregiver who 
has sufficient contact (minimum of 2 hours per day for 4 days per week) to describe the subject’s 
symptoms and has direct observation of the subject’s behavior.
4.
Subjects who are able to satisfactorily comply with the protocol requirements.
3.4.3
Exclusion Criteria
Subjects will be excluded if they meet any of the exclusion criteria in Table 3.4.3-1.
Table 3.4.3-1
Exclusion Criteria
1.
Subjects who, in the opinion of the investigator, medical monitor, or sponsor, should not participate 
in the trial.
2.
Subjects with a substantial protocol violation during the course of their participation in the double-
blind Trial 331-14-213.  Lesser violations such as occasional visits outside of the acceptable 
window or a missing blood draw will not exclude a subject from participation in Trial 331-201-
00182; however, continual lack of compliance with the visit schedule, trial assessments, or 
treatment regimen in the prior double-blind trial would be considered a substantial violation that 
would result in exclusion from Trial 331-201-00182.  The medical monitor should be contacted if 
the investigator is unsure of a subject’s eligibility.
3.5
Outcome Variables
3.5.1
Primary Outcome Variable
The primary outcome variable is the frequency and severity of adverse events (AEs; 
safety and tolerability of brexpiprazole).
 
 
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3.5.3
Safety Outcomes
In addition to AEs, safety variables to be examined in this trial will include 
physical/neurological examinations, vital sign measurements, body weight, waist 
circumference, clinical laboratory tests (hematology, serum chemistry [including 
prolactin], urinalysis, and pregnancy tests), electrocardiograms (ECGs), the Simpson 
Angus Scale (SAS), the Abnormal Involuntary Movement Scale (AIMS), the Barnes 
Akathisia Rating Scale (BARS), and the Sheehan Suicidality Tracking Scale 
(Sheehan-STS).
Mean change from baseline and the incidence of potentially clinically relevant abnormal 
values will be calculated for vital sign measurements, body weight, routine laboratory 
tests (including prolactin), and ECG parameters.  Mean change from baseline will be 
calculated for glycosylated hemoglobin (HbA1c), waist circumference, and body mass 
index (BMI; derived programmatically from body weight and height measurements 
[height values will be obtained in Trial 331-14-213]).  A central ECG service will be 
utilized to review all ECGs in order to standardize interpretations for the safety analysis.  
EPS will be evaluated by calculating mean change from baseline on the SAS, AIMS, and 
BARS.  The Sheehan-STS will be used to assess and classify reported suicidal behavior.  
By-patient listings of physical examination findings will be reviewed as a further 
assessment of safety.
3.6
Trial Procedures
The time from enrollment of the first subject to the last subject’s last trial visit will be 
approximately 3 years, of which approximately 2.5 years are allotted for rollover of 
subjects from Trial 331-14-213.  Individual participation for subjects who complete the 
trial will consist of a 12-week treatment period and a 30-day follow-up period.  All 
subjects will be followed up at a clinic visit or via telephone contact 30 (+ 2) days after 
the last dose of the IMP.  In addition, for all subjects who terminate early from the trial, 
all attempts will be made to collect mortality data by telephone contact with the subject’s 
caregiver (relative to baseline visit).
Trial assessment time points are summarized in Table 3.6-1.
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Table 3.6-1
Schedule of Assessments
Visit
Assessment
Screening/Baselinea
Week
1
(±2 days)
Week
2
(±2 days)
Week
6
(±2 days)
Week
12 or ET
(±2 days)
Follow-
upb
(+2 days)
Week 16c
ENTRANCE and HISTORY
Informed consent
X
Inclusion and exclusion criteria
X
SAFETY
Physical examination
X
X
Neurological examination
X
X
Vital signs
X
X
X
X
X
Body weight
X
X
Clinical laboratory tests (hematology, serum 
chemistry, urinalysis)
X
X
Prolactin
X
X
HbA1c
X
X
Urine pregnancy test (women of childbearing 
potential only)
X
X
ECG
X
X
MMSE
X
X
Sheehan-STS
X
X
Extrapyramidal symptoms scales (SAS, AIMS, 
BARS)
X
X
X
Adverse events
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
Mortality assessment
Xc
OTHER PROCEDURES
IMP dispensing
X
X
X
X
IMP accountability
X
X
X
X
X
ET = early termination; MMSE = Mini-Mental State Examination.
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aScreening for Trial 331-201-00182 occurs simultaneously with baseline, which will be the same day as the Week 12, or ET visit if the trial is terminated due 
to overwhelming efficacy from the interim analysis, of Trial 331-14-213.  
bAll subjects, whether they complete the trial or are withdrawn prematurely for any reason, will be followed up for a safety evaluation 30 (+ 2) days after the 
last dose of IMP during a clinic visit at either the investigator’s site or residential facility, if applicable.  If a clinic visit is not possible, the subject should be 
assessed by telephone contact with the subject and a caregiver.  
cFor all subjects who terminate early from the trial, all attempts will be made to collect mortality data by telephone contact with the subject’s caregiver at 
Week 16 (relative to baseline visit).
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3.6.1
Schedule of Assessments
3.6.1.1
Screening/Baseline
Screening for rollover subjects occurs simultaneously with baseline at the Week 12 or 
ET, if the trial is terminated, visit of Trial 331-14-213 (see Table 3.6-1).  Rollover 
subjects entering Trial 331-201-00182 must sign the ICF for the active-treatment trial 
before any procedures specific to Trial 331-201-00182 can be performed.  Subjects will 
retain the same subject identification (ID) number assigned in the double-blind, phase 3 
Trial 331-14-213.  Screening/baseline values will be derived from the Week 12 or ET 
visit of Trial 331-14-213 for the following assessments:  CMAI, CGI-S, SAS, AIMS, 
BARS, Sheehan-STS, physical/neurological examination, waist circumference, vital 
signs, ECG, and clinical laboratory tests.  The only additional procedures to be performed 
for rollover subjects at screening/baseline of the active-treatment trial are as follows:

Inclusion/exclusion criteria for Trial 331-201-00182 will be reviewed to ensure the 
subject’s eligibility.

Medical history will be updated, if necessary.

Concomitant medications will be reviewed to ensure that the subject is not receiving 
any prohibited medications.

Brexpiprazole will be dispensed to the subject.

AE recording will begin with the signing of the ICF for Trial 331-201-00182.

The subject will take the first dose of the IMP the day after the baseline visit.  The 
subject should take the IMP at approximately the same time each day, preferably in 
the morning, without regard to meals.
3.6.1.2
Weeks 1, 2, and 6
All subjects will be evaluated at Weeks 1 and 2.  Visits are to occur within ± 2 days of 
the target visit date.  All required evaluations will be performed as described in the 
Schedule of Assessments (Table 3.6-1).  The following should also be noted:

The investigator must determine if there have been any changes to the prior 
assessment of the subject’s capacity to provide informed consent.  If changes have 
been made, refer to the instructions detailed in Section 3.4.1.1.

IMP accountability will be performed.

The subject will start taking the IMP from the assigned blister card the day after the 
clinic visit.  The subject should take the IMP at approximately the same time each 
day, preferably in the morning, without regard to meals.
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3.6.1.3
End of Treatment (Week 12 or ET)
All required evaluations will be performed as described in the Schedule of Assessments 
(Table 3.6-1). The Week 12 visit signifies the end of treatment with IMP for all subjects.  
Therefore, all subjects will undergo a complete evaluation at Week 12 (± 2 days).  In 
addition, Week 12 or early termination (ET) evaluations are to be completed for any 
subject withdrawn from the trial at any time, if possible.  If a subject is withdrawn, every 
effort will be made to complete all of the Week 12 or ET evaluations prior to 
administering any additional medications for the treatment of agitation or other 
prohibited medications.  The following should be noted:

Final IMP accountability will be performed.
3.6.1.4
Follow-up
All required assessments will be performed as described in the Schedule of Assessments 
(Table 3.6-1). All subjects, whether they complete the trial or are withdrawn prematurely 
for any reason, will be followed up for a safety evaluation 30 (+ 2) days after the last 
dose of IMP during a clinic visit at either the investigator’s site or residential facility, as 
applicable.  If a clinic visit is not possible, the subject should be assessed by telephone 
with the subject and a caregiver.  All AEs and concomitant medications will be recorded.
For all subjects who terminate early from the trial, all attempts will be made to collect 
mortality data by telephone contact with the subject’s caregiver at Week 16.
 
  
 
 
 
 
 
 
 
 
 
 
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3.6.2.1
Cohen-Mansfield Agitation Inventory
The CMAI was developed to assess the frequency of agitated behaviors in elderly 
persons and was originally used in nursing home residents.  It consists of 29 agitated 
behaviors that are further categorized into distinct agitation syndromes, also known as 
CMAI factors of agitation.15  As initially described by Cohen-Mansfield15 and outlined in 
the Instruction Manual for the CMAI16 these distinct agitation syndromes include:  
aggressive behavior, physically nonaggressive behavior, and verbally agitated behavior.
All CMAI interviews will be recorded.  Regular quality reviews of CMAI audio 
recordings will be performed in order to verify the quality of the CMAI interview and 
accuracy of scoring.  The process for data oversight will be outlined in the Operations 
Manual.
3.6.2.2
Clinical Global Impression Severity of Illness (CGI-S)
The severity of agitation for each subject will be rated using the CGI-S.17  To perform 
this assessment, the investigator (or designee) will answer the following question: 
“Considering your total clinical experience with this particular population, how mentally 
ill (as related to agitation) is the subject at this time?”  Response choices are 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 subjects.
3.6.3
Prior and Concomitant Medications
The investigator will record all medications and therapies taken by the subject from the 
time of signing of informed consent for Trial 331-201-00182 through the end of the 
evaluation period (defined as the time period during which subjects are evaluated for 
primary or secondary objectives) on the eSource.  Details of prohibited and restricted 
medications are provided in Section 4.1.  The investigator will record all medications and 
therapies taken by the subject for treatment of an AE or which caused an AE until the end 
of the trial (defined as the last date of contact or date of final contact attempt) on the 
eSource.
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3.6.4
Safety Assessments
3.6.4.1
Adverse Events
Refer to Section 5, Reporting of Adverse Events.
3.6.4.2
Clinical Laboratory Assessments
A central laboratory designated by the sponsor will be used for all laboratory testing 
required during the trial.  The central laboratory should be used for all laboratory testing 
whenever possible (including unscheduled and follow up, if needed).  In cases where an 
immediate result is required for a particular laboratory test, the sample should be divided 
and sent to both a local laboratory and the designated central laboratory.  Subjects should 
be fasting for a minimum of 8 hours prior to the blood draws, if possible.  Vital sign 
measurements and ECG assessments should be completed before any blood samples are 
collected.  Additional urine and blood samples may be collected for further evaluation of 
safety as warranted by the investigator’s judgment.  Reports from the central laboratory 
will be retained electronically within the lab vendor's online portal and assessed by the 
investigator or qualified designee for clinical significance within eSource.
The clinical laboratory assessments are described in Table 3.6.4.2-1.
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Table 3.6.4.2-1
Clinical Laboratory Assessments
Hematology
White blood cell count with differential
Red blood cell count
Hematocrit
Hemoglobin
Platelet count
Urinalysis
pH
Specific gravity
Protein
Ketones
Glucose
Blood
Microscopic exam (performed only if any part of 
the urinalysis is not negative)
Serum Chemistry
Alkaline phosphatase
Alanine aminotransferase
Aspartate aminotransferase
Blood urea nitrogen
Creatine phosphokinase
Creatinine
Total bilirubin
Triglycerides
Cholesterol (total, low-density and high-density 
lipoproteins)
Calcium
Chloride
Glucose
Insulin
Sodium
Potassium
Total protein
Uric acid
Gamma glutamyltransferase
Prolactin
Albumin
Additional Tests
Urine pregnancy (women of childbearing potential)a
HbA1c
aAll positive urine pregnancy test results must be confirmed by a serum test.  Subjects with a positive 
serum pregnancy test result at screening must not be enrolled and subjects with a positive serum 
pregnancy test result during the trial must discontinue treatment and be withdrawn from the trial.
The total volume of blood to be collected during the trial will be documented in the ICF.
Pregnancy tests can be performed at any point during the trial if pregnancy is suspected.  
An additional pregnancy test will be conducted in women of childbearing potential 
(WOCBP) at the Week 12 or ET visit.
Any value outside the normal range will be flagged for the attention of the investigator 
who must indicate whether or not a flagged value is of clinical significance.  If one or 
more values are questionable, the test(s) may be repeated.  If the result of any test (or 
repeat test, if done) is indicated as clinically significant in the samples taken during the 
screening period, the subject will NOT be enrolled into the trial without the permission of 
the medical monitor.  In addition, unscheduled laboratory tests should be performed if 
clinically significant abnormalities are observed.  Unscheduled laboratory tests may be 
repeated at any time at the discretion of the investigator for appropriate medical care.  
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3.6.4.3
Physical and Neurological Examination and Vital Signs
3.6.4.3.1
Physical Examinations
A complete physical examination will be performed at baseline and will consist of 
measurement of waist circumference and a review of the following body systems:  head, 
eyes, ears, nose, and throat; thorax; abdomen; urogenital; extremities; neurological (see 
Section 3.6.4.3.2); and skin and mucosa.  Waist circumference will be measured at each 
physical examination (baseline and Week 12/ET), using the provided measuring tape.  
The following procedures will aid in the standardization of these measurements:

The subject should be minimally clothed (ie, lightweight clothing; no heavy 
overgarments).

Waist circumference should be recorded before a subject’s meal and at approximately 
the same time at each visit.

Measurement will be accomplished by locating the upper hip bone and the top of the 
right iliac crest and placing a weighted measuring tape in a horizontal plane around 
the abdomen at the level of the crest.  Before reading the tape measure, the assessor 
should assure that the tape is snug, but does not compress the skin, and is parallel to 
the floor.  The measurement is to be made at the end of a normal exhalation.18
The investigator (or designee) is responsible for performing the physical examination.  If 
the appointed designee is to perform the physical examination, he or she must be 
permitted by local regulations and his or her name must be included on the delegation of 
authority log.  Whenever possible, the same individual should perform all physical 
examinations.  Any condition present at the post-treatment physical examination that was 
not present at the baseline examination should be documented as an AE and followed to a 
satisfactory conclusion.
3.6.4.3.2
Neurological Examinations
A detailed neurological examination will be performed by a physician at baseline and 
Week 12/ET, and as needed during the trial for new onset neurological symptoms.  The 
neurological examination will consist of an evaluation of the subject’s mental status, 
cranial nerves, motor system (eg, motor strength, muscle tone, reflexes), cerebellar 
system (eg, coordination), gait and station, and sensory system.
The physician is responsible for performing the neurological examination and must be 
included on the delegation of authority log.  Whenever possible, the same physician 
should perform all neurological examinations.  Any condition present at the 
post-treatment neurological examination that was not present at the baseline examination 
and that is determined to be an AE should be documented as an AE and followed to a 
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satisfactory conclusion.  If new potentially clinically relevant neurological signs or 
symptoms are identified, referral to a neurologist is recommended.
3.6.4.3.3
Vital Signs
Vital sign measurements will include body weight, body temperature, systolic blood 
pressure, diastolic blood pressure, and heart rate.  The following guidelines will aid in the 
standardization of body weight measurements:

The same scale should be used to weigh a given subject each time, if possible.

Scales should be calibrated and reliable; scales should be at zero just prior to each 
subject’s weigh-in session.

A subject should void prior to being weighed and be minimally clothed (ie, no shoes 
or heavy overgarments).

Weight should be recorded before a subject’s meal and at approximately the same 
time at each visit (screening, baseline, Week 12 or ET).
Blood pressure and heart rate measurements will be made in the supine, sitting, and 
standing positions.  The supine measurements will be performed first, followed by sitting, 
and finally standing.  Blood pressure and heart rate measurements in the supine position 
should be taken after the subject has been lying for at least 5 minutes.  The sitting and 
standing measurements should be taken within 1 to 3 minutes of changing positions.  
Vital signs scheduled at the same visit as blood samples are to be completed before blood 
is drawn.
 
3.6.4.4
Electrocardiogram Assessments
Standard 12-lead ECGs will be recorded at the visits specified in Table 3.6-1.  Any ECGs 
scheduled for the same visit as blood samples are to be completed before blood is drawn.  
Electrocardiogram recordings will be obtained after the subject has been supine and at 
rest for at least 5 minutes.  Additional 12-lead ECGs may be obtained at the investigator’s 
discretion and should always be obtained if the subject is terminated early.  The ECG 
results will be evaluated at the investigational site to determine the subject’s eligibility 
and to monitor safety during the trial.  The principal investigator (or qualified designee) 
will review, sign, and date each ECG reading, noting whether or not any abnormal results 
are of clinical significance.  The ECG will be repeated if any results are considered to be 
clinically significant.  A central ECG service will be used for reading all ECGs in order 
to standardize interpretations for the safety analysis.
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Please consult the medical monitor in case of questions.
3.6.4.5
Other Safety Assessments
3.6.4.5.1
Simpson Angus Scale
The SAS19 consists of a list of 10 symptoms of Parkinsonism (gait, arm dropping, 
shoulder shaking, elbow rigidity, wrist rigidity, head rotation, glabella tap, tremor, 
salivation, and akathisia).  Each item will be rated on a 5-point scale, with a score of zero 
representing absence of symptoms and a score of 4 representing a severe condition.  The 
SAS total score is the sum of the scores for all 10 items.  Propranolol is not permitted 
within 12 hours of scale administration (see Section 4.1).  Investigators are encouraged to 
delay scale administration until the required time frame has elapsed, if at all possible.  
However, if delaying administration of the scale is not feasible, the SAS should still be 
administered and the use of the medication documented, including a notation of the drug 
name, dose, and time of administration on the eSource.
3.6.4.5.2
Abnormal Involuntary Movement Scale
The AIMS17 assessment consists of 10 items describing symptoms of dyskinesia.  Facial 
and oral movements (items 1 through 4), extremity movements (items 5 and 6), and trunk 
movements (item 7) will be observed unobtrusively while the subject is at rest (eg, in the 
waiting room), and the investigator will also make global judgments on the subject’s 
dyskinesias (items 8 through 10).  Each item will be rated on a 5-point scale, with a score 
of zero representing absence of symptoms (for item 10, no awareness), and a score of 4, 
indicating a severe condition (for item 10, awareness, severe distress).  For this scale, the 
subject is to be sitting on a hard, firm chair.  In addition, the AIMS includes 2 yes or no 
questions that address the subject’s dental status.  Propranolol is not permitted within 
12 hours of scale administration (see Section 4.1).  Investigators are encouraged to delay 
scale administration until the required time frame has elapsed, if at all possible.  
However, if delaying administration of the scale is not feasible, the AIMS should still be 
administered and the use of the medication documented, including a notation of the drug 
name, dose, and time of administration on the eSource.  The AIMS Movement Rating 
Score is defined as the sum of items 1 through 7 (ie, items 1 through 4, facial and oral 
movements; items 5 and 6, extremity movements; and item 7, trunk movements).
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3.6.4.5.3
Barnes Akathisia Rating Scale
The BARS20 consists of 4 items related to akathisia:  objective observation of akathisia 
by the investigator, subjective feelings of restlessness by the subject, subjective distress 
due to akathisia, and global clinical assessment of akathisia.  The first 3 items will be 
rated on a 4-point scale, with a score of zero representing absence of symptoms and a 
score of 3 representing a severe condition.  The global clinical evaluation will be made on 
a 6-point scale, with zero representing absence of symptoms and a score of 5 representing 
severe akathisia.  To complete this scale, subjects will be observed while they are seated 
and then standing for a minimum of 2 minutes in each position.  Symptoms observed in 
other situations (eg, while engaged in neutral conversation or engaged in other activity) 
may also be rated.  Subjective phenomena are to be elicited by direct questioning.  
Propranolol is not permitted within 12 hours of scale administration (see Section 4.1).  
Investigators are encouraged to delay scale administration until the required time frame 
has elapsed, if at all possible.  However, if delaying administration of the scale is not 
feasible, the BARS should still be administered and the use of the medication 
documented, including a notation of the drug name, dose, and time of administration on 
the eSource.  The BARS global score is defined as the global clinical assessment of 
akathisia.
3.6.4.5.4
Sheehan Suicidality Tracking Scale
Suicidality will be monitored during the trial using the Sheehan-STS.21  The 
Sheehan-STS is a prospective scale that assesses treatment-emergent suicidal thoughts 
and behaviors.  Each item of the Sheehan-STS is scored on a 5-point Likert scale (0 = not 
at all; 1 = a little; 2 = moderate; 3 = very; and 4 = extremely).  The Sheehan-STS can be 
analyzed as individual item scores, suicidal ideation subscale score, suicidal behavior 
subscale score, or total score.  The “Screening” Sheehan-STS form was completed at the 
screening visit of the double-blind Trial 331-14-213 to determine eligibility.  The “Since 
Last Visit” Sheehan-STS form will be completed baseline and Week 12/ET during 
Trial 331-201-00182.  The medical monitor should be contacted if a score of 3 or 4 on 
any one question 3 through 6 or 11 or a score of 2 or higher on any one questions 1a, 7 
through 10, or 12, or 18, or if suicide results in death.
3.6.4.5.5
Mini-Mental State Examination
The Mini-Mental State Examination (MMSE)22 is a brief practical test for assessing 
cognitive dysfunction.  The test consists of 5 sections (orientation, registration, attention 
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and calculation, recall, and language) and has a total possible score of 30.  The MMSE is 
completed at baseline and Week 12 or ET.
3.6.5
End of Trial
The end of trial date is defined as the last date of contact or the date of final contact 
attempt from the post-treatment follow-up eSource page for the last subject completing or 
withdrawing from the trial.
3.7
Stopping Rules, Withdrawal Criteria, and Procedures
3.7.1
Entire Trial
If the sponsor terminates or suspends the trial for any reason, prompt notification will be 
given to investigators, IRBs/IECs, and regulatory authorities in accordance with 
regulatory requirements.
3.7.2
Individual Site
Individual trial site participation may be discontinued by the sponsor, the investigator, or 
the IRB/IEC if judged to be necessary for medical, safety, regulatory, ethical or other 
reasons consistent with applicable laws, regulations, and GCP.  The investigator will 
notify the sponsor promptly if the trial is terminated by the investigator or the IRB/IEC at 
the site.
3.7.3
Individual Subject Discontinuation
3.7.3.1
Treatment Discontinuation
After entry into Trial 331-201-00182, a subject may stop treatment permanently for a 
variety of reasons.  Treatment discontinuations may be initiated by a subject who is not 
satisfied with treatment or may become medically necessary due to AEs, required 
treatment with a disallowed medication or therapy, or other issues, as determined by the 
investigator.  However, each investigator must comprehensively review the 
circumstances and offer the subject options for continued treatment to the degree possible 
as described in Section 3.7.3.4.  Refer to the Schedule of Assessments (Table 3.6-1) for a 
description of follow-up procedures.
3.7.3.2
Documenting Reasons for Treatment Discontinuation
If a subject discontinues the trial prematurely, the reason must be fully evaluated and 
recorded appropriately in eSource.  If the subject is being withdrawn because of an AE, 
the AE should be indicated as the reason for withdrawal.
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Subjects meeting any of the following criteria must be withdrawn from the trial:

Occurrence of any AE, intercurrent illness, or abnormality in a laboratory assessment 
that, in the opinion of the investigator, warrants the subject’s permanent withdrawal 
from the trial

Treatment with a prohibited concomitant medication other than the use of appropriate 
medications for the treatment of AEs under direction of the investigator, unless 
allowed after discussion with and approval by the medical monitor

Subject noncompliance, defined as refusal or inability to adhere to the trial schedule 
or procedures (see Section 3.11, Subject Compliance)

At the request of the subject, caregiver, legally acceptable representative, investigator, 
sponsor, or regulatory authority

Subject becomes pregnant (see Section 5.5)

Subject cannot tolerate the assigned dose of brexpiprazole

Subject develops clinically significant agitation per investigator’s judgment that 
cannot be adequately treated with allowed medications and poses a potential safety 
risk to the subject or others

Subject is lost to follow-up
The medical monitor should be contacted if the Sheehan-STS score is 3 or 4 on any one 
question 3 through 6 or 11 or if the Sheehan-STS score is 2 or higher on any one 
questions 1a, 7 through 10, or 12, or 18, or if suicide results in death.
Subjects withdrawn prior to Week 12 must complete the Week 12 or ET evaluations at 
the time of withdrawal.  In addition, all subjects who withdraw prematurely from the trial 
will be assessed 30 (+ 2) days after the last dose of the IMP for evaluation of safety.  This 
assessment can be accomplished at a clinic visit at either the investigator’s site or 
residential facility, as applicable.  If a clinic visit is not possible, the subject should be 
assessed by telephone contact with the subject and a caregiver.  In addition, for all 
subjects who terminate early from the trial, all attempts will be made to collect mortality 
data by telephone contact with the subject’s caregiver at Week 16.  Three attempts will be 
made to contact the subject's caregiver by telephone; in the event the site is unable to 
reach the subject's caregiver by telephone, the site will attempt to contact the subject's 
caregiver via certified mail or an alternative similar method where appropriate.
Meeting a screening exclusion criterion postrandomization does not require an automatic 
discontinuation of the subject.  The investigator should assess the change for clinical 
significance, determine if an AE should be reported, and make a determination of subject 
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continuation based on subject safety.  The investigator will consult with the medical 
monitor to determine subject continuation in the trial.
3.7.3.3
Withdrawal of Consent
All subjects have the right to withdraw their consent from further participation in the trial 
at any time without prejudice.  Subjects cannot withdraw consent for use of data already 
collected as part of the trial, but only for future participation.  The investigator can also 
discontinue a subject’s participation in the trial at any time if medically necessary.  
Unless the subject provides their written withdrawal of consent or there is other written 
documentation by the investigator confirming the subject’s verbal intent to completely 
withdraw from the trial, subjects should be followed for all protocol-specified evaluations 
and assessments, if possible.
Complete withdrawal of consent requires a subject’s refusal of ALL of the following 
methods of follow up (these methods of follow up will also be noted in the trial ICF):

Participation in all follow-up procedures specified in the protocol (whether in-clinic, 
by telephone, or by an in-home visit).

Participation in a subset of protocol specified follow-up procedures (by a frequency 
schedule and method, as agreed by subject and staff).

Contact of the subject by trial personnel, even if only by telephone, to assess current 
medical condition, and obtain necessary medical or laboratory reports relevant to the 
trial’s objectives.

Contact of alternative person(s) who have been designated in source records as being 
available to discuss the subject’s medical condition, even if only by telephone, mail, 
or e-mail (eg, family, spouse, partner, legal representative, friend, neighbor, or 
physician).

Access to medical information from alternative sources (eg, hospital or clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, social media sources).
Withdrawal of consent is a critical trial event and therefore should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent.  
The reasons for a subject’s intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial.  
A subject may initially express their desire to discontinue IMP administration, which is 
not equivalent to a complete withdrawal of consent for further participation (see 
Section 3.7.3.1).  A subject may, however, indicate that further trial participation is 
creating a burden on their work or social schedule.  Therefore, the investigator should 
follow the procedures outlined in Section 3.7.3.2 to determine if the subject can continue 
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participation in the trial if modifications to his or her treatment or Schedule of 
Assessments can be accommodated.  Only subjects who withdraw their permission for all 
of the above degrees of follow-up are considered to have completely withdrawn their 
consent to participate in the trial.
3.7.3.4
Procedures to Encourage Continued Trial Participation
In all cases of impending IMP discontinuation or consent withdrawal, investigators will 
be instructed to meet and discuss with the subject their options of continuing in the trial, 
preferably on therapy.  The investigator should ensure understanding and documentation 
of the reasons for the subject’s desire to withdraw consent.
3.8
Screen Failures
A screen failure subject is one from whom informed consent is obtained and is 
documented in writing (ie, subject signs an ICF), but who is not started on treatment.  For 
the purposes of this trial, treatment begins with the first dose of brexpiprazole in 
Trial 331-201-00182.  Rollover subjects who do not qualify for Trial 331-201-00182 at 
the last visit of Trial 331-14-213 may not be rescreened.  
3.9
Definition of Completed Subjects
The treatment period is defined as the time period during which subjects are evaluated for 
primary and/or secondary objectives of the trial irrespective of whether or not the subject 
actually consumed all doses of the IMP.  Subjects who are evaluated at the last scheduled 
visit during the treatment period will be defined as trial completers.  For purposes of this 
trial, subjects who complete the Week 12 visit will be defined as trial completers.
3.10
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted on or before the Week 12 visit during the treatment 
period, who do not have a known reason for discontinuation (eg, withdrew consent or 
AE), and for whom a survival status at the end of the trial cannot be determined will be 
classified as “lost to follow-up” as the reason for discontinuation.  Survival status can be 
determined from a variety of sources, either by obtaining acceptable documentation for 
death (ie, death certificate, medical records, public records, statement by a family 
member or primary care physician) or acceptable documentation for life (ie, direct 
contact with the subject, medical records, successful telephone contact with the subject, 
statement by a family member or primary care physician, or public records).
The site will make 3 documented attempts to contact the subject by telephone and in the 
event the site is unable to reach the subject by telephone, the site will attempt to contact 
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the subject via certified mail or an alternative similar method, where appropriate, before 
assigning a “lost to follow-up” status.
3.11
Subject Compliance 
Responsible trial personnel will dispense the IMP (ie, brexpiprazole) according to the 
visits outlined in the Schedule of Assessments (Table 3.6-1).  Accountability and 
compliance verification should be documented in the subject’s trial records. 
The importance of taking the IMP as directed should be emphasized at all trial visits.  If 
poor compliance continues (eg, dosing errors resulting in overall compliance less than 
80% or greater than 120%), discontinuation of the subject from the trial should be 
considered in consultation with the medical monitor.
3.12
Protocol Deviations
In the event of a significant deviation from the protocol due to an emergency, accident, or 
mistake (eg, violation of informed consent process, IMP dispensing or subject dosing 
error, treatment assignment error, subject enrolled in violation of eligibility criteria or 
concomitant medication criteria), the investigator or designee will contact the sponsor’s 
designee (medical monitor) at the earliest possible time.  The investigator and sponsor’s 
designee will come as quickly as possible to a joint decision regarding the subject’s 
continuation in the trial.  This decision will be documented by the investigator and the 
sponsor’s designee, and reviewed by the site monitor.
4
Restrictions
4.1
Prohibited Medications
Concomitant medications taken by subjects who are rolling over into 
Trial-331-201-00182 from Trial 331-14-213 should be reviewed for the prohibited 
medications listed in Table 4.1-1.  Any subject taking a prohibited concomitant 
medication should not be enrolled in Trial 331-201-00182.  
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Table 4.1-1
List of Restricted and Prohibited Medications
All other psychotropic agents not listed in the below table are prohibited
Medication
During the Active Drug Treatment Period
1.
Medications to treat Alzheimer’s disease 
(cholinesterase inhibitors, memantine, or 
other cognitive enhancers)
Subject should remain on the same dose throughout 
the duration of the trial, except when medically 
indicated due to a change in the underlying medical 
condition.
Antipsychotics
Prohibited
2.
Clozapine
Prohibited
3.
Antidepressants
Subject should remain on the same dose throughout 
the duration of the trial, except when medically 
indicated due to a change in the underlying medical 
condition.
Antidepressant medications that are CYP2D6 or 
CYP3A4 inhibitors are prohibited.
4.
Mood stabilizers (such as lithium, 
valproate, carbamazepine)
Prohibited
5.
Anticonvulsants
Prohibited
6.
Benzodiazepines
Prohibited
7.
Non-benzodiazepine sleep agentsa
If a bedtime dose of a sleep agent for insomnia was 
taken on a regular basis during Trial 331-14-213, a 
stable dose of the sleep agent may be continued as 
needed during the trial.  If a sleep agent was not 
previously taken and needs to be initiated, medication 
should be limited to a maximum dose of 5 mg/day of 
zolpidem (or equivalent).
8.
Opioid analgesics
Prohibited unless permission is obtained from the 
medical monitor.  Permission for opioid use may be 
considered for a documented and clinically 
appropriate indication (eg, episodic pain condition, 
tooth extraction) if prescribed at a medically 
appropriate dose and frequency.
9.
Anticholinergics for treatment of 
extrapyramidal symptoms
Prohibited
10.
Propranololb
For treatment of akathisia or tremor:  maximum dose 
of 20 mg, 3 times daily (total of 60 mg/day).  For 
treatment of heart disease: may remain on stable 
pretrial doses as needed throughout the trial, as long 
as the total dose does not exceed 60 mg/day.
Propranolol must not be administered within 12 hours 
prior to the efficacy and safety scales. 
11.
Varenicline
Prohibited
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Table 4.1-1
List of Restricted and Prohibited Medications
All other psychotropic agents not listed in the below table are prohibited
Medication
During the Active Drug Treatment Period
12.
Medications to treat other medical 
conditions, such as hypertension, 
hypercholesterolemia, etc., and anti-
platelet agents
Subject should remain on the same dose throughout 
the duration of the trial, except when medically 
indicated due to a change in the underlying medical 
condition.
Initiation of a new medication treatment for a medical 
condition may be allowed throughout the duration of 
the trial if medically indicated due to a change in the 
subject’s underlying medical condition and not 
otherwise prohibited (ie, CYP interaction).  
Consultation with the medical monitor is encouraged 
in this case.
13.
Nutritional supplements and 
nonprescription herbal preparations with 
CNS effects (eg, St. John’s wort, omega-3 
fatty acids, kava extracts, GABA 
supplements, etc)
Prohibited
14.
CYP2D6 inhibitors or CYP3A4 inhibitors 
and inducers (see Table 4.1-2)
Prohibited
CNS = central nervous system; CYP = cytochrome P450; GABA = gamma-aminobutyric acid.
aFor the non-benzodiazepine sleep aids, site personnel should only utilize one of the listed medications 
that are approved for this indication in their respective countries and the country-specific prescribing 
information is to be used to determine the maximum allowable daily dose for the treatment of 
insomnia.
bPropranolol must not be administered within 12 hours prior to scheduled efficacy and safety scales, 
including EPS scales.  Investigators are encouraged to delay scale administration until 12 hours have 
elapsed, if at all possible.  However, if delaying administration of efficacy and safety scales is not 
feasible, the scales should still be administered and the use of propranolol documented, including a 
notation of the drug name, dose, and time of administration on the eSource.
Table 4.1-2
Selected CYP2D6 Inhibitors and CYP3A4 
Inhibitors and Inducers
Type
Examples (Generic Names)
CYP2D6 Inhibitors
Celecoxib, chloroquine, chlorpheniramine, clemastine, clomipramine, 
diphenhydramine, duloxetine, fluoxetinea, halofantrine, hydroxyzine, 
methadone, moclobemide, paroxetine, pyrilamine, quinidine, terbinafine, 
tripelennamine
CYP3A4 Inhibitors
Amiodarone, amprenavir, aprepitant, chloramphenicol, cimetidine, 
clarithromycin, clotrimazole (if used orally), delavirdine, diltiazem, 
erythromycin, fluconazole, fluvoxamine, indinavir, itraconazole, ketoconazole, 
nefazodone, nelfinavir, quinupristin/dalfopristin, ritonavir, saquinavir, 
troleandomycin, verapamil
CYP3A4 Inducers
Carbamazepine, dexamethasone, efavirenz, nevirapine, oxcarbazepine, 
phenobarbital, phenytoin, primidone, rifampin, St. John’s wort, troglitazone
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aFluoxetine requires a 28-day washout prior to randomization.
4.2
Other Restrictions
The following restrictions apply:

Subjects should not undergo any elective medical procedure without prior 
consultation with the investigator.  An elective procedure (minor surgery, dental 
surgery, orthopedic surgery, etc.) that might require hospitalization or general 
anesthesia should be deferred until after the trial whenever clinically appropriate.

Consumption of grapefruit, grapefruit products, Seville oranges, or Seville orange 
products within 72 hours prior to the first dose of IMP and during the trial is 
prohibited.

Subjects should refrain from drinking alcoholic beverages or using illicit drugs during 
participation in the trial.

The investigator may request a blood or urine drug screen or blood alcohol test at any 
time during the trial if there is a suspicion of illicit drug use.
Treatment with other investigational agents is not permitted during the trial.
New onset nonpharmacological interventions for the treatment of agitation are not 
permitted during the double-blind treatment period.  Subjects who have been treated with 
nonpharmacological interventions prior to trial entry may continue these therapies during 
the double-blind treatment period.
5
Reporting of Adverse Events
5.1
Definitions
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  Adverse events would not include information recorded 
as medical history at screening for pre-planned procedures for which the underlying 
condition was known and no worsening occurred.  An adverse reaction is any untoward 
and unintended response to an IMP related to any dose administered.
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE.  For the purpose of IND safety reporting, “reasonable possibility” 
means there is evidence to suggest a causal relationship between the IMP and the AE.  
Suspected adverse reaction implies a lesser degree of certainty about causality.
A serious AE (SAE) includes any event that results in any of the following outcomes:
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
Death

Life-threatening; ie, the subject was, in the opinion of the investigator, at immediate 
risk of death from the event as it occurred.  It does not include an event that, had it 
occurred in a more severe form, might have caused death.

Persistent or significant incapacity or disability or substantial disruption of the ability 
to conduct normal life functions.

Requires in-patient hospitalization or prolongs hospitalization.

Hospitalization itself should not be reported as an SAE; whenever possible the 
reason for the hospitalization should be reported.

Hospitalizations or prolonged hospitalizations for social admissions (ie, those 
required for reasons of convenience or other non-medical need) are not 
considered SAEs.

Congenital anomaly or birth defect.

Other medically significant events that, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above; eg, allergic bronchospasm requiring 
intensive treatment in an emergency room or home, blood dyscrasias or convulsions 
that do not result in hospitalization, or the development of drug dependency or drug 
abuse.
Nonserious AEs are all AEs that do not meet the criteria for a "serious" AE.
Immediately Reportable Event (IRE):

Any SAE.

Any AE related to occupational exposure.

Potential serious hepatotoxicity (see Section 5.4).

Pregnancies are also defined as IREs.  Although normal pregnancy is not an AE, it 
will mandate IMP discontinuation and must be reported on an IRE form to the 
sponsor.  Pregnancy will only be documented on the AE eSource if there is an 
abnormality or complication.
Clinical Laboratory Test Value Changes:  It is the investigator’s responsibility to review 
the results of all laboratory tests as they become available.  This review will be 
documented by the investigator’s dated signature on the laboratory report.  For each 
abnormal laboratory test result, the investigator needs to ascertain if this is an abnormal 
(ie, clinically significant) change from baseline for that individual subject.  This 
determination, however, does not necessarily need to be made the first time an abnormal 
value is observed.  The investigator may repeat the laboratory test or request additional 
tests to verify the results of the original laboratory tests.  If this laboratory value is 
considered medically relevant by the investigator (subject is symptomatic, requiring 
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corrective treatment or further evaluation), or if the laboratory value leads to 
discontinuation, or fulfills a seriousness criterion, this is considered an AE. 
Severity:  Adverse events will be graded on a 3-point scale and reported as indicated on 
the eSource.  The intensity of an adverse experience is defined as follows:
1 = Mild:
Discomfort noticed, but no disruption to daily activity.
2 = Moderate:
Discomfort sufficient to reduce or affect normal daily activity.
3 = Severe:
Inability to work or perform normal daily activity.
IMP Causality:  Assessment of causal relationship of an AE to the use of the IMP is 
defined as follows:
Related: 
There is a reasonable possibility of a temporal and causal 
relationship between the IMP and the AE.
Not Related: 
There is no temporal or causal relationship between the IMP and 
the AE.
5.2
Eliciting and Reporting Adverse Events
Adverse events will be recorded, starting after the ICF has been signed.  The investigator 
will periodically assess subjects for the occurrence of AEs.  To avoid bias in eliciting 
AEs, subjects should be asked the non-leading question: “How have you felt since your 
last visit?”  All AEs (serious and nonserious) reported by the subject must be recorded on 
the source documents and eSource provided by the sponsor.  All AE (including SAEs) 
collection is to begin after a subject has signed the ICF.
Use medical terminology in AE reporting.  Adverse events should be reported as a single 
unifying diagnosis whenever possible or, in the absence of a unifying diagnosis, as 
individual signs or symptoms.  Exacerbation or disease progression should be reported as 
an AE only if there are unusual or severe clinical features that were not present, or 
experienced earlier, or not expected based on the course of the condition.
In addition, the sponsor must be notified immediately by telephone, fax, or e-mail of any 
IREs according to the procedure outlined below, in Section 5.3.  Special attention should 
be paid to recording hospitalization and concomitant medications.
5.3
Immediately Reportable Events 
The investigator must immediately report after either the investigator or site personnel 
become aware of any SAE, potential serious hepatotoxicity, or confirmed pregnancy, by 
telephone, fax, or e-mail to the sponsor using the contact information on the cover page 
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of this protocol.  An IRE form must be completed and sent per the instructions in the 
Operations Manual.  (Please note that the IRE form is NOT the AE eSource.)
Subjects experiencing SAEs should be followed clinically until their health has returned 
to baseline status, or until all parameters have returned to normal or have otherwise been 
explained.  It is expected that the investigator will provide or arrange appropriate 
supportive care for the subject and will provide prompt updates on the subject’s status to 
the sponsor.
5.4
Potential Serious Hepatotoxicity
For a subject who experiences an elevation in aspartate transaminase or alanine 
transaminase that is  3 times the upper limit of normal range (ULN), a total bilirubin 
level should also be evaluated.  If the total bilirubin is  2 times the ULN, complete an 
IRE form with all values listed and also report as an AE on the eSource.
5.5
Pregnancy
Women of childbearing potential (WOCBP) are defined as female subjects for whom 
menstruation has started and who are not documented as sterile (ie, have had a bilateral 
oophorectomy or hysterectomy or who have been postmenopausal for at least 
12 months).
For WOCBP and for men who are sexually active, there must be a documented 
agreement that the subject or their partner will take effective measures (ie, double-barrier 
method) to prevent pregnancy during the course of the trial and for 30 days after the last 
dose of IMP.  Unless the subject is sterile (ie, women who have had a bilateral 
oophorectomy or hysterectomy or who have been postmenopausal for at least 
12 consecutive months; or men who have had a bilateral orchidectomy) or remains 
abstinent, 2 of the following precautions must be used:  vasectomy, tubal ligation, vaginal 
diaphragm, intrauterine device, birth control pills, birth control depot injection, birth 
control implant, condom with spermicide, or sponge with spermicide.  Any single method 
of birth control, including vasectomy and tubal ligation, may fail, leading to pregnancy.
Before enrolling WOCBP in this clinical trial, investigators must review the below 
guidelines about trial participation with all WOCBP.  The topics should generally 
include:

General information

ICF

Pregnancy prevention information
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
Drug interactions with hormonal contraceptives

Contraceptives in current use

Guidelines for the follow-up of a reported pregnancy
Before trial enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy.  The subject must sign an ICF stating that the above-mentioned risk factors 
and the consequences were discussed with her.
A urine or serum pregnancy test for human chorionic gonadotropin will be performed at 
screening on all WOCBP.  If a urine test is performed and is positive, the investigator 
will follow up with a confirmatory serum test.
During the trial, all WOCBP should be instructed to contact the investigator immediately 
if they suspect they might be pregnant (eg, missed or late menstrual cycle).
If a subject is suspected to be pregnant before she receives IMP, the IMP administration 
must be withheld until the results of serum pregnancy tests are available.  If the 
pregnancy is confirmed, the subject must not receive the IMP and must not be enrolled in 
the trial.  If pregnancy is suspected while the subject is taking IMP, the IMP must be 
withheld immediately until the result of the pregnancy test is known.  If pregnancy is 
confirmed, the IMP will be permanently discontinued in an appropriate manner and the 
subject will be withdrawn from the trial.
The investigator must immediately notify the sponsor of any pregnancy associated with 
IMP exposure during the trial and for 30 days after the last dose of IMP, and record the 
event on the IRE form and forward it to the sponsor.  The sponsor will forward 
Pregnancy Surveillance Form(s) for monitoring the outcome of the pregnancy.
Protocol-required procedures for trial discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies).  Other appropriate 
pregnancy follow-up procedures should be considered, if indicated.  In addition, the 
investigator must report to the sponsor, on appropriate Pregnancy Surveillance Form(s), 
follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome.  Infants will be followed for a minimum of 6 months from the date of 
birth.
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5.6
Follow-up of Adverse Events
5.6.1
Follow-up of Nonserious Adverse Events
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE eSource with the current status (ongoing or resolved or recovered) noted.  All 
nonserious events that are ongoing at the last scheduled contact will be recorded as 
ongoing on the eSource.  For any AE having been identified throughout the trial, during 
analysis, additional relevant medical history information may be requested by the sponsor 
to further ascertain causality (including, but not limited to, information such as 
risk-related behavior, family history and occupation).
5.6.2
Follow-up of Serious Adverse Events and Immediately 
Reportable Events
This trial requires that subjects be actively monitored for SAEs and IREs up to 30 days 
after the last dose of IMP is administered.
Serious AEs and nonserious IREs that are identified or ongoing at the last scheduled 
contact must be recorded as such on the AE eSource page.  If updated information (eg, 
resolved status) on SAE or IRE status becomes available after a subject’s last scheduled 
contact (up to last in-clinic visit for the entire trial), this must be reported to the sponsor 
and recorded on the AE eSource page, according to the appropriate reporting procedures.  
The investigator will follow SAEs until the events are resolved, stabilized, or the subject 
is lost to follow-up or has died.  Resolution means that the subject has returned to the 
baseline state of health and stabilized means that the investigator does not expect any 
further improvement or worsening of the subject’s condition.  The investigator will 
continue to report any significant follow-up information to the sponsor up to the point the 
event has resolved or stabilized, or the subject is lost to follow-up or has died.
5.6.3
Follow-up and Reporting of Serious Adverse Events and 
Immediately Reportable Events Occurring after Last Scheduled 
Contact
Any new SAEs or IREs reported to the investigator which occur after the last scheduled 
contact and are determined by the investigator to be reasonably associated with the use of 
the IMP, should be reported to the sponsor.  This may include SAEs or IREs that are 
captured on follow-up telephone contact or at any other time point after the defined trial 
period.  The investigator should follow SAEs or IREs identified after the defined trial 
period and continue to report any significant follow-up information to the sponsor until 
the events are resolved or stabilized, or the subject is lost to follow-up or has died.
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5.6.4
Follow-up Mortality Assessment
For all subjects who terminate early from the trial, all attempts will be made to collect 
mortality data by telephone contact with the subject’s caregiver at Week 16.  Three 
attempts will be made to contact the subject's caregiver by telephone; in the event the site 
is unable to reach the subject's caregiver by telephone, the site will attempt to contact the 
subject's caregiver via certified mail or an alternative similar method where appropriate.
6
Pharmacokinetic Analysis
No pharmacokinetic analysis is planned.
7
Statistical Analysis
7.1
Sample Size
The sample size is not based on statistical power considerations.  The trial population will 
be derived from eligible subjects who rollover from the double-blind phase 3 
Trial 331-14-213.  
7.2
Datasets for Analysis
The following datasets are defined for this trial:
Safety Sample:  comprised of those subjects who sign an ICF for the trial and receive at 
least one dose of brexpiprazole in Trial 331-201-00182.
Efficacy Sample:  comprises those subjects in the Safety Sample who have at least one 
postbaseline efficacy evaluation.
The observed case (OC) dataset will consist of the actual observations recorded at each 
visit and will be used to present summaries per trial week.
7.3
Handling of Missing Data
Since this trial is planned as an extension trial with safety as the primary objective and no 
reference arm is planned, there is no pre-specified primary efficacy estimand.  All 
efficacy evaluations are exploratory and no formal sensitivity analysis is planned. 
All efficacy summaries will be presented based on the OC dataset, which is defined in 
Section 7.2.
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7.4
Primary and Secondary Outcome Analyses
7.4.1
Primary Outcome Analysis
The primary safety analysis is the frequency and severity of AEs (see Section 7.6.1).  
Descriptive statistics will be provided for each endpoint, and will be summarized at each 
trial visit using the OC dataset.  Baseline is defined as the last available measurement 
prior to the first dose of IMP in the active-treatment extension trial.
7.5
Analysis of Demographic and Baseline Characteristics
Baseline demographic characteristics including age, race, ethnicity, gender, weight, 
height (from Trial 331-14-213), and BMI will be summarized by descriptive statistics 
(frequency, mean, median, standard deviation, maximum, minimum, and percentage 
when applicable).  These summaries will be presented for the Safety Sample.
7.6
Safety Analysis
Standard safety variables to be analyzed include AEs, clinical laboratory tests, vital signs, 
ECGs, body weight, waist circumference, and BMI.  In addition, data from the following 
safety scales will be evaluated:  SAS, AIMS, BARS, and Sheehan-STS.  Safety analysis 
will be conducted based on the safety dataset.  In general, baseline of a safety variable is 
defined as the last observation of the variable before taking the first dose of brexpiprazole 
during Trial 331-201-00182, unless specified otherwise.  Details of safety analysis will be 
provided in the statistical analysis plan (SAP).
7.6.1
Adverse Events
All AEs will be coded by system organ class and Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term.  The incidence of the following events will be 
summarized descriptively:

TEAEs

TEAEs by severity

TEAEs potentially causally related to the IMP (per investigator)
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
TEAEs with an outcome of death

Serious TEAEs

TEAEs leading to discontinuation of the IMP 
A TEAE is defined as an AE that starts after the first dose of IMP in the extension trial or 
an AE that is reported at baseline and increases in intensity or becomes serious or trial 
drug-related or results in death, discontinuation, interruption, or reduction of IMP.
7.6.2
Clinical Laboratory Data
Summary statistics for changes from baseline in the routine clinical laboratory 
measurements, prolactin concentrations, and HbA1c will be provided.  In addition, 
potentially clinically significant results in laboratory tests identified using prospectively 
defined criteria will be summarized.
7.6.3
Physical/Neurological Examination and Vital Sign Measurements 
Data
By-patient listings will be provided for physical and neurological examinations.  
Summary statistics for changes from baseline in vital sign measurements will be 
provided.  Potentially clinically significant results in vital sign measurements will also be 
summarized.
7.6.4
Electrocardiogram Data 
Mean change from baseline will be summarized by visit.  Incidence of clinically relevant 
changes will be calculated for ECG parameters and summarized by visit.
The analysis of QT and corrected QT interval (QTc) data from 3 consecutive complexes 
(representing 3 consecutive heart beats) will be measured to determine average values.  
The following QT corrections will be used:

QTcB is the length of the QT interval corrected for heart rate by the Bazett’s formula:  
QTcB = QT/(RR)0.5

QTcF is the length of the QT interval corrected for heart rate by the Fridericia’s 
formula:  QTcF = QT/(RR)0.33

QTcN is the length of the QT interval corrected for heart rate by the FDA 
Neuropharm Division formula:  QTcN = QT/(RR)0.37
Results will be summarized by visit.
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7.6.5
Other Safety Data
Change from baseline in scores for the MMSE score will be summarized descriptively.  
The analyses will be based on the OC dataset of the Safety Sample.
The suicidality (eg, Sheehan-STS) will be summarized based on the OC dataset of the 
Safety Sample.  Details will be described in SAP.
8
Management of Investigational Medicinal Product
For full details on IMP management, please refer to the Brexpiprazole IB.13
8.1
Packaging and Labeling
Trial medication will be provided to the investigators and the persons designated by the 
investigator(s) or institution(s) by the sponsor or designated agent.  The IMP will be 
supplied as active brexpiprazole tablets.  Each dose will be supplied as blister cards 
containing sufficient tablets for 7 (+2) days.  When accessed by the site, the eSource 
method will assign specific blister card number(s) to be dispensed to a subject.
Each blister card of brexpiprazole used in the trial will be given an identifying number 
and will be labeled to clearly disclose the blister card number, site number (to be filled in 
by the site staff or investigator), subject ID (to be filled in by the site staff or 
investigator), subject’s initials or other unique identifier (to be filled in by the site staff or 
investigator), compound ID, protocol number, the sponsor's name and address, 
instructions for use, route of administration, and appropriate precautionary statements.  
Once a blister card has been assigned to a subject, it cannot be dispensed to another 
subject.
8.2
Storage
The IMP will be stored in a securely locked cabinet or enclosure.  Access will be limited 
to investigators and their designees.  Neither investigators nor any designees may provide 
IMP to any subject not participating in this protocol.
The IMP will be stored at ambient conditions as per the clinical label on the IMP.  The 
clinical site staff will ensure that the temperature log is maintained in the drug storage 
area and that the temperature is recorded at least once each working day.  The clinical site 
staff will maintain a temperature log in the IMP storage area recording the temperature at 
least once each working day.
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8.3
Accountability
The investigator or designee must maintain an inventory record of IMP received, 
dispensed, administered, and returned.
8.4
Returns and Destruction
Previously dispensed blister cards are to be returned at each visit and subjects will start 
taking the IMP from the new blister card the day after the clinic visit.  Upon completion 
or termination of the trial, all used IMP containers, unused IMP, and partially used IMP 
must be returned to the sponsor or a designated agent, or destroyed at the trial site(s).  
The IMP may only be destroyed by the trial site(s), if approved by the sponsor and if the 
IMP destruction meets all local regulations.
All IMP returned to the sponsor must be accompanied by appropriate documentation and 
be identified by protocol number with trial site number on the outermost shipping 
container.  Returned supplies should be in the original containers (eg, subject kits).  The 
assigned trial monitor will facilitate the return or destruction of used IMP containers, 
unused IMP, and partially-used IMP.
8.5
Reporting of Product Quality Complaints
A Product Quality Complaint (PQC) is any written, electronic, or verbal communication 
by a healthcare professional, consumer, subject, medical representative, Competent 
Authority, regulatory agency, partner, affiliate or other third party that alleges 
deficiencies or dissatisfaction related to identity, quality, labeling, packaging, reliability, 
safety, durability, tampering, counterfeiting, theft, effectiveness or performance of a drug 
product or medical device after it is released for distribution.  Examples include, but are 
not limited to, communications involving:

Failure or malfunction of a product to meet any of its specifications

Incorrect or missing labeling

Packaging issues (eg, damaged, dirty, crushed, missing product)

Blister defects (eg, missing, empty blisters)

Product defect (eg, odor, chipped, broken, embossing illegible)

Loss or theft of product
8.5.1
Eliciting and Reporting Product Quality Complaints
The investigator or designee must record all PQCs identified through any means from the 
receipt of the IMP from the sponsor, or sponsor’s designee, through and including 
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reconciliation and up to destruction, including subject dosing.  The investigator or 
designee must notify the sponsor (or sponsor’s designee) by e-mail or telephone within 
24 hours of becoming aware of the PQC according to the procedure outlined below.

Online:  Send information required for reporting purposes (listed below) to 

Phone:  
Identification of a PQC by the subject should be reported to the site investigator, who 
should then follow one of the reporting mechanisms above.
8.5.2
Information Required for Reporting Purposes

Description of compliant

Reporter ID (eg, subject, investigator, site, etc.)

Reporter contact information (eg, address, phone number, e-mail address)

ID of material (product and compound name, coding)

Clinical protocol reference (number or trial name)

Dosage form and strength (if known)

Pictures (if available)

Availability for return
8.5.3
Return Process
Indicate during the report of the PQC if the complaint sample is available for return.  If 
complaint sample is available for return, return it in the product retrieval package, which 
will be provided by the sponsor.
It must be documented in the site accountability record that a complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation.
8.5.4
Assessment/Evaluation
Assessment and evaluation of PQCs will be handled by the sponsor.
9
Records Management
9.1
Source Documents
Source documents are defined as the results of original observations and activities of a 
clinical investigation.  Source documents will include but are not limited to progress 
notes, electronic data, screening logs, and recorded data from automated instruments.  All 
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source documents pertaining to this trial will be maintained by the investigators and made 
available for direct inspection by authorized persons.
Investigator(s) and institution(s) will permit trial-related monitoring, audits, IRB and IEC 
review, and regulatory inspection(s) by providing direct access to source data and 
documents by authorized persons as defined in the ICF.  In all cases, subject 
confidentiality must be maintained in accordance with local regulatory requirements.
9.2
Data Collection
During each subject’s visit to the clinic, a clinician participating in the trial will record 
progress notes to document all significant observations.  At a minimum, these notes will 
contain:

Documentation of the informed consent process, including any revised consents;

Documentation of the investigator’s decision to enroll the subject into the trial, the 
review of all inclusion and exclusion criteria prior to IMP administration, and 
confirmation of the subject’s actual participation in the trial;

The date of the visit and the corresponding Visit or Day in the trial schedule;

General subject status remarks, including any significant medical findings.  The 
severity, frequency, duration, action taken, and outcome of any AEs and the 
investigator's assessment of relationship to IMP must also be recorded;

Any changes in concomitant medications or dosages;

A general reference to the procedures completed; 

The signature (or initials) and date of each clinician (or designee) who made an entry 
in the progress notes.
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as 
described above.
Source documents and source data will be captured electronically in this trial, and will 
meet the same fundamental elements of data quality (eg, attributable, legible, 
contemporaneous, original, and accurate) as paper records.  These data will be collected 
into a system that is fully validated.  Changes to the data will be captured by an automatic 
audit trail.
The trial site will be given a tablet to directly record subject data and clinical 
observations on electronic forms.  Designated trial site staff will not be given access to 
the system until they have been appropriately trained.  Information to be originally 
captured and reviewed electronically shall include details of the subject visit and the 
protocol required assessments performed as a part of these visits, medical history, AEs, 
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and concomitant medications.  Because this trial is using an electronic source record as 
the original point of data capture, there is no additional data entry step for the trial site for 
data collected directly into the application – rather, the electronic source record directly 
populates the trial database.
Some data may be captured via paper and then entered into the eSource system.  These 
and any other data treated in this manner will be source data verified by the trial clinical 
research associate, and the location of the source data (ie, eSource, paper, or a local 
electronic system) will be documented before the trial start.  Any changes to information 
in paper source documents will be initialed and dated on the day the change is made by a 
trial site staff member authorized to make the change.  Changes will be made by striking 
a single line through erroneous data (so as not to obliterate the original data), and clearly 
entering the correct data (eg, wrong data right data). If the reason for the change is not 
apparent, a brief explanation for the change will be written in the source documentation 
by the clinician.
Another exception will be safety laboratory or central ECG data, where the official 
source documentation will be considered the report issued by the analyzing laboratory.
Remote monitoring of the original electronic source records will take place, however 
on-site monitoring inspections will continue to take place in order to review data entry of 
source documentation directly captured on paper and transcribed into the system, to 
ensure protocol adherence, to assess trial site operational capabilities and to perform 
other monitoring activities that cannot be performed remotely.
At the end of the trial, the investigator must certify that the data entered into the eSource 
application are complete and accurate.  After database lock, the investigator will receive 
an electronic copy of the subject data.
9.3
File Management at the Trial Site
The investigator will ensure that the trial site file is maintained in accordance with 
Section 8 of the ICH GCP Guideline E6 and as required by applicable local regulations.  
The investigator and institution will take measures to prevent accidental or premature 
destruction of these documents.
9.4
Records Retention at the Trial Site
Regulatory requirements for the archival of records for this trial necessitate that 
participating investigators maintain detailed clinical data for the longest of the following 
3 periods:
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
A period of at least 2 years after the date on which approval to market the drug is 
obtained (or if IMP development is discontinued, the date regulatory authorities were 
notified of discontinuation); OR

A period of at least 3 years after the sponsor notifies the investigator that the final 
report has been filed with regulatory authorities.

Longer, region-specific storage requirements, if applicable.
The investigator must not dispose of any records relevant to this trial without either 
(1) written permission from the sponsor or (2) provision of an opportunity for sponsor to 
collect such records.  The investigator will be responsible to maintain adequate and 
accurate electronic or hard copy source documents of all observations and data generated 
during this trial including any data clarification forms received from the sponsor.  Such 
documentation is subject to inspection by the sponsor and relevant regulatory authorities.  
If the investigator withdraws from the trial (eg, due to relocation or retirement), all trial-
related records should be transferred to a mutually agreed-upon designee within a 
sponsor-specified timeframe.  Notice of such transfer will be given to the sponsor in 
writing.
10
Quality Control and Quality Assurance 
10.1
Monitoring
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, the ICH E6 GCP: Consolidated Guidance, and 
applicable regulatory requirements and local laws.  As part of a concerted effort to fulfill 
these obligations (maintain current personal knowledge of the progress of the trial), the 
sponsor's monitors will visit the site during the trial, as well as communicate frequently 
via telephone, e-mail, and written communications.  In addition, all investigators and 
clinical site personnel will undergo initial and ongoing training for this particular trial, 
and this training will be clearly documented.
10.2
Auditing
The sponsor's Quality Assurance Unit (or representative) may conduct trial site audits.  
Audits will include, but are not limited to, IMP supply, presence of required documents, 
the informed consent process, and comparison of eSource with source documents.  The 
investigator agrees to participate with audits.
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Regulatory authorities may inspect the investigator site during or after the trial.  The 
investigator will cooperate with such inspections and will contact the sponsor 
immediately if such an inspection occurs.
11
Ethics and Responsibility
This trial must be conducted in compliance with the protocol, ICH GCP Guideline (E6), 
international ethical principles derived from the Declaration of Helsinki and Council for 
International Organizations of Medical Science guidelines, and applicable local laws and 
regulations.  Each trial site will seek approval/favorable opinion by an IRB or IEC 
according to regional requirements, and the investigator will provide that documentation 
to the sponsor.  The IRB/IEC will evaluate the ethical, scientific and medical 
appropriateness of the trial.  Further, in preparing and handling eSource, the investigator, 
sub-investigator and their staff will take measures to ensure adequate care in protecting 
subject privacy.  To this end, a subject number and subject ID code will be used to 
identify each subject.
Financial aspects, subject insurance and the publication policy for the trial will be 
documented in the agreement between the sponsor and the investigator.
12
Confidentiality
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission.  Subject confidentiality requirements of the region(s) where the trial 
is conducted will be met.  However, authorized regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy the records, 
consistent with local requirements.  All IMPs, subject bodily fluids, or other materials 
collected shall be used solely in accordance with this protocol, unless otherwise agreed to 
in writing by the sponsor.
Subjects will be identified only by unique subject numbers in eSource.  If further subject 
ID is required, subjects’ full names may be made known to a regulatory agency or other 
authorized officials if necessary, subject to local regulations.
Per country regulations, if subject initials cannot be collected, another unique identifier 
will be used.  Their full names may, however, be made known to a regulatory agency or 
other authorized officials if necessary.
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13
Amendment Policy
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval/favorable opinion by the IRB/IEC.  Any 
permanent change to the protocol, whether an overall change or a change for specific trial 
site(s), must be handled as a protocol amendment.  Any amendment will be written by the 
sponsor.  Each amendment will be submitted to the IRB/IEC, as required by local 
regulations.  Except for “administrative” or “non-substantial” amendments, investigators 
will wait for IRB/IEC approval/favorable opinion of the amended protocol before 
implementing the change(s).  Administrative amendments are defined as having no effect 
on the safety of subjects, conduct or management of the trial, trial design, or the quality 
or safety of IMP(s) used in the trial.  A protocol change intended to eliminate an apparent 
immediate hazard to subjects should be implemented immediately after agreement by the 
sponsor and investigator, followed by IRB/IEC notification within local applicable 
timelines.  The sponsor will submit protocol amendments to the applicable regulatory 
agencies within local applicable timelines.
When the IRB/IEC, investigators, or the sponsor concludes that the protocol amendment 
substantially alters the trial design or increases the potential risk to the subject, the 
currently approved ICF will require similar modification.  In such cases, after 
approval/favorable opinion of the new ICF by the IRB/IEC, repeat informed consent will 
be obtained from subjects enrolled in the trial before expecting continued participation 
and before the amendment-specified changes in the trial are implemented.
14
Publication Authorship Requirements
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 
criteria (http://www.icmje.org/recommendations).  According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met:
1. Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND
2. Drafting the work or revising it critically for important intellectual content; AND
3. Final approval of the version to be published; AND
4. Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.
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All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors.
Investigators or other trial participants who do not qualify for authorship may be 
acknowledged in publications resulting from the trial.  By agreeing to participate in the 
trial, investigators or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct.
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Appendix 4
Protocol Amendment(s)/Administrative Change(s)
Amendment Number: 1 
Issue Date: 26 Jun 2020 
PURPOSE: 
The purpose of this protocol amendment is to introduce a COVID-19 Addendum for any 
protocol-specified activities that are not able to be performed or cannot be performed due 
to COVID-19 considerations. Refer to the COVID-19 Addendum for the appropriate 
measures to be followed. Wording was added to state that subjects who are early 
terminated from Trial 331-14-213, if the trial is terminated due to overwhelming efficacy 
from the interim analysis, may be offered entry into this trial. Additional minor edits were 
made to the protocol.
BACKGROUND: 
These changes to clinical trial protocol 331-201-00182, originally issued on 18 Jun 2018, 
were made to introduce a COVID-19 Addendum, specify that measurements for height 
will be taken from Trial 331-14-213, and to specify that subjects who are early 
terminated from Trial 331-14-213 due to trial termination may be enrolled into this trial.
MODIFICATIONS TO PROTOCOL:
Description of Change
Rationale for Change
Sections Affected by Change
Added that subjects who are 
early terminated from 
Trial 331-14-213, if the trial 
is terminated due to 
overwhelming efficacy from 
the interim analysis, may be 
offered entry into this trial.
Week 12 visit of 
Trial 331-14-213 was 
changed to Week 12 or ET, if 
the trial is terminated, visit of 
Trial 331-14-213.
Trial 331-14-213 may be ended 
early if overwhelming efficacy 
is shown in the interim analysis.
Protocol Synopsis
Section 3.1 Type/Design of Trial
Figure 3.1-1 Trial Design Schematic
Section 3.2 Trial Treatments
Section 3.3.2 Description of 
Population
Table 3.4.2-1 Inclusion Criteria
Table 3.6-1 Schedule of 
Assessments (footnotes)
Section 3.6.1 Schedule of 
Assessments
Randomization for subjects 
from Trial 331-14-213 was 
specified. 
To provide additional details 
regarding rollover subjects.
Protocol Synopsis
Section 3.2 Trial Treatments
Specified that measurements 
for height will be taken from 
Trial 331-14-213.
To specify where height data 
will be obtained.
Section 3.5.3 Safety Outcomes
Section 7.5 Analysis of 
Demographic and Baseline 
Characteristics
Clinical Study Report 331-201-00182
16.1.1 Protocol and Protocol Amendments
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Description of Change
Rationale for Change
Sections Affected by Change
Minor formatting changes.
Correction of typographical 
errors and formatting.
Throughout document.
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
A complete redline version of this amendment showing all changes from the previous 
version will be produced and will be available upon final approval of this amendment. 
Clinical Study Report 331-201-00182
16.1.1 Protocol and Protocol Amendments
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Amendment Number: 2 
Issue Date: 06 Aug 2020
PURPOSE: 
The purpose of this protocol amendment is to remove wording that was added with 
amendment 1 to state that subjects who are early terminated from Trial 331-14-213, if the 
trial is terminated following the interim analysis, may be offered entry into this trial. 
BACKGROUND: 
The changes to clinical trial protocol 331-201-00182, originally issued on 18 Jun 2018, 
and amended 26 Jun 2020, were made to remove language stating that subjects who are 
early terminated from Trial 331-14-213 (the parent trial) due to trial termination may be 
enrolled into this trial. Due to feedback from the FDA on protocol 331-14-213, the parent 
trial is expected to conclude with a total enrollment of roughly 255 or roughly 
330 subjects. The decision to stop at 255 or 330 subjects will be determined by the results 
of an interim analysis. The changes from amendment 1 of protocol 331-201-00182 did 
not go into effect and the amendment was not distributed to sites or IRBs. Since 
amendment 1 was finalized, signed, and distributed externally to vendors, the protocol is 
being formally amended. 
Additionally, an addendum describing COVID-19-related trial procedures was included 
in amendment 1.
MODIFICATIONS TO PROTOCOL:
Description of Change
Rationale for Change
Sections Affected by Change
Deleted language stating that 
subjects who are early 
terminated from 
Trial 331-14-213, if the trial 
is terminated due to 
overwhelming efficacy from 
the interim analysis, may be 
offered entry into this trial.
Language no longer needed due 
to FDA feedback on the parent 
protocol, 331-14-213.
Protocol Synopsis
Section 3.1 Type/Design of Trial
Figure 3.1-1 Trial Design Schematic
Section 3.2 Trial Treatments
Section 3.3.2 Description of 
Population
Table 3.4.2-1 Inclusion Criteria
Table 3.6-1 Schedule of 
Assessments (footnotes)
Section 3.6.1.1 Screening/Baseline
Deleted details regarding 
treatment assignment for 
subjects from Trial 331-14-
213. 
Language no longer needed.
Protocol Synopsis
Figure 3.1-1 Trial Design Schematic
Section 3.2 Trial Treatments
Clinical Study Report 331-201-00182
16.1.1 Protocol and Protocol Amendments
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ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
A complete redline version of this amendment showing all changes from the previous 
version will be produced and will be available upon final approval of this amendment. 
Clinical Study Report 331-201-00182
16.1.1 Protocol and Protocol Amendments
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Amendment Number: 3 
Issue Date: 22 Sep 2020 
PURPOSE: 
The purpose of this protocol amendment is to state that subjects who are early terminated 
from Trial 331-14-213, if the trial is terminated due to overwhelming efficacy from the 
interim analysis, may be offered entry into this trial. Additional minor edits were made to 
the protocol.
BACKGROUND: 
These changes to clinical trial protocol 331-201-00182, originally issued on 18 Jun 2018, 
and amended 26 Jun 2020 and 06 Aug 2020, were made to specify that subjects who are 
early terminated from Trial 331-14-213 because of trial termination due to overwhelming 
efficacy from the interim analysis may be enrolled into this trial.
MODIFICATIONS TO PROTOCOL:
Description of Change
Rationale for Change
Sections Affected by Change
Added that subjects who are 
early terminated from 
Trial 331-14-213, if the trial 
is terminated due to 
overwhelming efficacy from 
the interim analysis, may be 
offered entry into this trial.
Week 12 visit of 
Trial 331-14-213 was 
changed to Week 12 or ET, if 
the trial is terminated, visit of 
Trial 331-14-213.
Trial 331-14-213 may be ended 
early based on the results from 
the interim analysis.
Protocol Synopsis
Section 3.1 Type/Design of Trial
Figure 3.1-1 Trial Design Schematic
Section 3.2 Trial Treatments
Section 3.3.2 Description of 
Population
Table 3.4.2-1 Inclusion Criteria
Table 3.6-1 Schedule of 
Assessments (footnote a)
Section 3.6.1.1 Screening/Baseline
Enrollment for subjects from 
Trial 331-14-213 was 
specified. 
To provide additional details 
regarding rollover subjects.
Protocol Synopsis
Figure 3.1-1 Trial Design 
Schematic.
Section 3.2 Trial Treatments
Minor formatting changes.
Correction of typographical 
errors and formatting.
Throughout document.
Clinical Study Report 331-201-00182
16.1.1 Protocol and Protocol Amendments
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ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
A complete redline version of this amendment showing all changes from the previous 
version will be produced and will be available upon final approval of this amendment. 
The COVID-19 addendum to this protocol was also updated accordingly.
Clinical Study Report 331-201-00182
16.1.1 Protocol and Protocol Amendments
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Agreement
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator's Brochure) and agree that it contains all the ethical, legal and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor's (or designee's) Clinical Trial Agreement.
I will provide copies of the protocol to all physicians, nurses, and other professional personnel to 
whom I delegate trial responsibilities. I will discuss the protocol with them to ensure that they are 
sufficiently informed regarding the investigational new drug, brexpiprazole, the concurrent 
medications, the efficacy and safety parameters and the conduct of the trial in general. I am 
aware that this protocol must be approved by the Institutional Review Board (IRB) or receive a 
favorable opinion by the Independent Ethics Committee (IEC)responsible for such matters in the 
clinical trial facility where brexpiprazole will be tested prior to commencement of this trial. I agree 
to adhere strictly to the attached protocol (unless amended in the manner set forth in the 
sponsor's Clinical Trial Agreement, at which time I agree to adhere strictly to the protocol as 
amended).
I understand that this IRB- or IEC-approved protocol will be submitted to the appropriate 
regulatory authority/ies by the sponsor. I agree that clinical data entered on case report forms by 
me and my staff will be utilized by the sponsor in various ways, such as for submission to 
governmental regulatory authorities and/or in combination with clinical data gathered from other 
research sites, whenever applicable. I agree to allow sponsor and designee monitors and 
auditors full access to all medical records at the research facility for subjects screened or enrolled 
in the trial.
I agree to await IRB/IEC approval before implementation of any substantial amendments to this 
protocol. If, however, there is an immediate hazard to subjects, I will implement the amendment 
immediately, and provide the information to the IRB/IEC within the required local applicable 
timelines. Administrative changes to the protocol will be transmitted to the IRB/IEC for 
informational purposes only, if required by local regulations.
I agree to provide all subjects with informed consent forms, as required by the applicable 
regulations and by ICH guidelines. I agree to report to the sponsor any adverse experiences in 
accordance with the terms of the sponsor's Clinical Trial Agreement and the relevant regional 
regulation(s) and guideline(s). I further agree to provide all required information regarding 
financial certification or disclosure to the sponsor for all investigators and sub-investigators in 
accordance with the terms of the relevant regional regulation(s). I understand that participation in 
the protocol involves a commitment to publish the data from this trial in a cooperative publication 
before publication of efficacy and safety results on an individual basis may occur, and I consent to 
be acknowledged in any such cooperative publications that result.
____________________________
_____________________________
___________
Principal Investigator Print Name
Signature
Date
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This page is a manifestation of an electronically captured signature
SIGNATURE PAGE
Document Name: Protocol 331-201-00182 Amendment 3
Document Number:
Document Version: 5.0
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:min) -
UTC timezone
Clinical Approval
22-Sep-2020
13:49:15
Biostatistics Approval
22-Sep-2020
13:36:10
Clinical Study Report 331-201-00182
16.1.1 Protocol and Protocol Amendments
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Version 3.0, 22 Sep 2020
Otsuka Pharmaceutical Development & Commercialization, Inc
Investigational Medicinal Product
OPC-34712
ADDENDUM FOR CLINICAL PROTOCOL FOR TRIAL 331-201-00182
A 12-week, Multicenter, Active-treatment Extension Trial to Evaluate the Safety and 
Tolerability of Brexpiprazole in the Treatment of Subjects With Agitation Associated 
With Dementia of the Alzheimer’s Type 
IND No. 115960
EudraCT No. 2018-002783-88
CONFIDENTIAL – PROPRIETARY INFORMATION
Clinical Development Phase:
3
Sponsor:
Otsuka Pharmaceutical Development & 
Commercialization, Inc
2440 Research Boulevard
Rockville, Maryland 20850
Immediately Reportable Event 
Syneos Health Pharmacovigilance & Drug 
Safety
Issue Date:
26 Jun 2020
Amendment 1:
06 Aug 2020
Amendment 2:
22 Sep 2020
Version No.:
3.0
Clinical Study Report 331-201-00182
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Trial Conduct for COVID-19
All procedures and assessments in Protocol 331-201-00182 are to be followed to the 
fullest extent possible. The sponsor, in coordination with the site, investigator(s), 
and medical monitor, will continuously monitor and evaluate the benefits and risks 
to subject participation in the clinical trial as it relates to coronavirus disease 2019 
(COVID-19). If any protocol-specified activities were not able to be performed, or 
cannot be performed due to COVID-19 considerations, the appropriate measures to 
be followed are provided in this document.
Note: The changes from amendment 1 of protocol 331-201-00182 (including version 1 of 
this COVID-19 addendum) did not go into effect and the amendment and COVID-19 
addendum were not distributed to sites or IRBs. Since amendment 1 and COVID-19 
addendum version 1 were finalized, signed, and distributed externally to vendors, the 
documents were formally amended.
Clinical Study Report 331-201-00182
16.1.1 Protocol and Protocol Amendments
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Table of Contents
Trial Conduct for COVID-19.......................................................................2
Table of Contents ..........................................................................................3
List of In-text Tables.....................................................................................4
List of In-text Figures ...................................................................................5
List of Abbreviations and Definitions of Terms .........................................6
1
Trial 331-201-00182 COVID-19 Protocol Summary.........................7
1.1
Trial Design Schematic .......................................................................................7
1.2
Schedule of Assessments ....................................................................................9
2
General Considerations .....................................................................11
2.1
Telemedicine .....................................................................................................11
2.2
Reconsent ..........................................................................................................11
2.3
Protocol Deviations...........................................................................................11
2.4
Guidance to Record Adverse Events and Discontinuations Due to 
COVID-19.........................................................................................................12
2.5
Statistical Analyses ...........................................................................................12
2.6
Clinical Outcomes.............................................................................................12
3
Trial Population..................................................................................13
3.1
Inclusion Criteria...............................................................................................13
3.2
Exclusion Criteria..............................................................................................13
4
Trial Procedures.................................................................................13
4.1
Safety Assessments ...........................................................................................13
4.1.1
Vital Signs ......................................................................................................13
4.1.2
Pregnancy .......................................................................................................14
5
IMP......................................................................................................14
Clinical Study Report 331-201-00182
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List of In-text Tables
Table 1.2-1
COVID-19 Impact Schedule of Assessments..................................9
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List of In-text Figures
Figure 1.1-1
COVID-19 Impact Trial Design Schematic ....................................8
Clinical Study Report 331-201-00182
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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
AE
Adverse event
AIMS
Abnormal Involuntary Movement Scale
BARS
Barnes Akathisia Rating Scale
CGI-S
Clinical Global Impression Severity of Illness
CMAI
Cohen-Mansfield Agitation Inventory
COVID-19
Coronavirus disease 2019
CRO
Clinical research organization
EC
Ethics committee
ECG
Electrocardiogram
ET
Early termination
EudraCT
European Clinical Trial Data Base
IMP
Investigational medicinal product
IND
Investigational New Drug
IRB
Institutional review board
MMSE
Mini-Mental State Examination
SAE
Serious adverse event
SAS
Simpson Angus Scale
Sheehan-STS
Sheehan Suicidality Tracking Scale
WOCBP
Women of childbearing potential
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1
Trial 331-201-00182 COVID-19 Protocol Summary
1.1
Trial Design Schematic
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aStarting at Week 4, one dose decrease can occur at any time (scheduled or unscheduled visits) until the end of the trial. In addition, one dose increase can 
occur but only at the Week 6 scheduled visit. For subjects who may be offered entry into this trial as a result of early termination due to overwhelming 
efficacy from the 331-14-213 interim analysis, treatment in Trial 331-201-00182 will begin based on randomization and last visit completed in Trial 331-14-
213. Subjects who received placebo in Trial 331-14-213 will receive active drug in Trial 331-201-00182.  Subjects randomized to brexpiprazole and who 
completed the titration schedule in Trial 331-14-213 (ie, completed Week 4 visit in 331-14-213) will begin treatment on the same dose in this trial.  Subjects 
randomized to brexpiprazole and who have not completed the titration schedule will restart drug in Trial 331-201-00182 dependent on the point in the titration 
scheme for Trial 331-14-213 that early termination occurred.
bFor subjects who may be offered entry into this trial as a result of early termination of Trial 331-14-213 due to overwhelming efficacy from the interim analysis, 
the Screening/Baseline will occur at the last visit of the double-blind trial (ie, ET visit of Trial 331-14-213).  
Figure 1.1-1
COVID-19 Impact Trial Design Schematic
Clinical Study Report 331-201-00182
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1.2
Schedule of Assessments
Table 1.2-1
COVID-19 Impact Schedule of Assessments
Visit
Assessment
Screening/Baselinea
Week
1b
(±2 days)
Week
2b
(±2 days)
Week
6b
(±2 days)
Week
12 or 
ETb,c
(±2 days)
Follow-
upd
(+2 days)
Week 16e
ENTRANCE and HISTORY
Informed consent
X
Inclusion and exclusion criteria
X
SAFETY
Physical examination
X
Xf
Neurological examination
X
Xf
Vital signs
X
X
X
X
X
Body weight
X
X
Clinical laboratory tests (hematology, serum 
chemistry, urinalysis)
X
Xf
Prolactin
X
Xf
HbA1c
X
Xf
Urine pregnancy test (women of childbearing 
potential only)
X
X
ECG
X
Xf
MMSE
X
X
Sheehan-STS
X
X
Extrapyramidal symptoms scales (SAS, AIMS, 
BARS)
X
Xg
Xg
Adverse events
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
Clinical Study Report 331-201-00182
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Table 1.2-1
COVID-19 Impact Schedule of Assessments
Visit
Assessment
Screening/Baselinea
Week
1b
(±2 days)
Week
2b
(±2 days)
Week
6b
(±2 days)
Week
12 or 
ETb,c
(±2 days)
Follow-
upd
(+2 days)
Week 16e
Mortality assessment
Xe
OTHER PROCEDURES
IMP dispensingh
X
X
X
X
IMP accountability
X
X
X
X
X
AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating Scale;
 
 ECG = electrocardiogram; ET = early termination; IMP = investigational medicinal product; MMSE = Mini-Mental 
State Examination; SAS = Simpson Angus Score; Sheehan-STS = Sheehan Suicidality Tracking Scale.
aScreening for Trial 331-201-00182 occurs simultaneously with baseline, which will be the same day as the Week 12 or ET visit if the trial is terminated due 
to overwhelming efficacy from the interim analysis, visit of Trial 331-14-213. The screening/baseline visit must occur in the clinic. 
bThe Week 1, 2, 6, and 12 visits may be completed virtually.
cSubjects must be early terminated if 1. the subject tests positive for COVID-19 or 2. is presumed positive with COVID-19 or 3. the caregiver tests positive 
for COVID-19 and another caregiver cannot be identified. Subjects who miss an assessment due to a visit performed virtually (eg, clinical laboratory tests, 
ECGs) may continue in the trial based on the investigator’s clinical assessment and judgement.
dAll subjects, whether they complete the trial or are withdrawn prematurely for any reason, will be followed up for a safety evaluation 30 (+ 2) days after the 
last dose of IMP during a clinic visit at either the investigator’s site or residential facility, if applicable. If a clinic visit is not possible, the subject should be 
assessed by telephone contact with the subject and a caregiver. 
eFor all subjects who terminate early from the trial, all attempts will be made to collect mortality data by telephone contact with the subject’s caregiver at 
Week 16 (relative to baseline visit).
fAssessment is not obligatory if the visit is virtual.
gIf the visit is performed virtually, the BARS and AIMS can be performed using vidoconference. The SAS cannot be completed remotely.
hFor the Weeks 1, 2 and 6 visits, if the visit is performed virtually, alternative methods for dispensing IMP to the subject can be performed, if allowed by 
country guidances and regulations, eg, use of courier or curbside pickup.
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2
General Considerations
2.1
Telemedicine
All procedures and assessments in the protocol should be followed to the fullest extent 
possible. However, telemedicine can be used in cases where the site, subject and/or 
caregiver requests a virtual visit be performed due to COVID-19 conditions. Guidance 
will be provided to sites on whether use of phone is acceptable, or if video is required. 
Sites will be instructed to attempt to standardize collection via phone or video depending 
on the requirements of the trial to minimize confusion and risk of errors of utilizing 
varying collection strategies. All applicable country-by-country guidances and local 
regulations will be followed when implementing telemedicine options.
Note: If a trial-wide virtual visit mandate is declared due to COVID-19, virtual visit 
guidance is not applicable for hospitalized subjects where the investigator is also the 
subject’s physician. Subjects who meet this description can continue in-person visits.
2.2
Reconsent
In cases where there is an immediate need to reconsent subjects and the subject and/or 
caregiver are unable to attend an in-clinic visit due to COVID-19 conditions, either paper 
reconsent or remote eConsent, in regions where remote capacity exists, are acceptable. 
Sites are to contact the clinical research organization (CRO) to discuss the options and 
agree to best approach for the site.  
The investigator must continue to determine if there have been any changes to the prior 
assessment of the subject’s capacity to provide informed consent. If changes have been 
made, refer to the instructions in the protocol (Section 3.4.1.1).
2.3
Protocol Deviations
Protocol deviations that occurred as a direct result of the COVID-19 pandemic and prior 
to a site’s local regulatory agency and investigational review board/ethics commitee 
(IRB/EC) approval of this addendum, must be recorded in eSource.  A “direct result” is 
defined as being due to actual COVID-19 illness, or as a result of quarantine, social 
distancing, or site closures. The flexibility in procedures due to COVID-19 conditions 
allowed per this addendum (eg, virtual visits, missed assessments due to virtual visit, 
alternative investigational medicinal product [IMP] dispensation to subject), will not be 
be considered protocol deviations following IRB/EC approval of this addendum. All 
other deviations will follow the normal deviation process described in the protocol and 
should not be entered proactively by sites.
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2.4
Guidance to Record Adverse Events and Discontinuations Due to 
COVID-19
If a subject tests positive OR is presumed positive with COVID-19, the subject must be 
discontinued from the trial, and an adverse event (AE) of “Coronovirus Infection” OR 
“Coronavirus Positive Test Result” will be entered on the AE page of the eSource. A 
positive test result or a presumed positive subject is not automatically a serious adverse 
event (SAE), unless an SAE criterion is met (eg, hospitalization).
If a subject discontinues due to COVID-19 either because they test positive OR are 
presumed positive with COVID-19, then the primary reason for discontinuation should be 
reported as “Adverse Event” and indicate the AE number in the “Specify the reason for 
discontinuation” space that corresponds with the AE of “Coronavirus Infection” OR 
“Coronavirus Positive Test Result.”
If a subject discontinues due to COVID-19 for reasons other than the subject testing 
positive OR being presumed positive with COVID-19 (eg, quarantine, fear of infection), 
then the primary reason for discontinuation should be reported as “Other.” Be sure to 
specify the reason as “COVID-19” followed by the reason ensuring that the prefix of the 
description includes “COVID-19.” Do note that the reason “Other” should be selected 
even if the subject decides to withdraw consent or if the investigator decides to withdraw 
the subject due to COVID-19 concerns.
In case a caregiver is COVID-19 positive and another caregiver is available to continue 
the trial, the situation should be discussed with the medical monitor to determine 
continuation in the trial on a case-by-case basis. If there is no other caregiver, the subject 
needs to be early terminated from the trial.
2.5
Statistical Analyses
Any impact of COVID-19 on the planned statistical analyses for the trial will be 
described in the final statistical analysis plan.
2.6
Clinical Outcomes
To decrease variability, sites should attempt to standardize the method of administration 
for a scale for an individual subject and across all subjects in the trial. Assessments 
should be administered by the same qualified/trained rater who rated the subject 
previously; if this is not possible due to staff availability and/or technological limitations, 
discuss relevant information with previous raters to obtain clinical context (note that, per 
protocol, raters must be trained/qualified to conduct assessments in all cases). Raters 
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should conduct all assessments for that visit during the same remote session, where 
possible.
Please refer to Virtual and Remote Visit Overview and Virtual Visit Instructions for 
Clinical Sites for modification of administration methods for remote visits.
3
Trial Population
3.1
Inclusion Criteria
No changes are required to the inclusion criteria due to COVID-19. However, if there is a 
future restriction on face-to-face visits and virtual visits are mandated due to COVID-19, 
then hospitalized subjects who are currently enrolled in the parent Trial 331-14-213 
where the investigator is also the subject’s physician can rollover into the 331-201-00182 
trial.
3.2
Exclusion Criteria
No changes are required to the exclusion criteria due to COVID-19.
4
Trial Procedures
If a virtual visit is conducted due to COVID-19 conditions, there are some assessments 
that can not be performed (eg, laboratory collections, electrocardiogram [ECG], Simpson 
Angus Scale [SAS]). Please refer to the Virtual and Remote Visit Overview and Virtual 
Visit Instructions for Clinical Sites for modification of administration methods for remote 
visits. 
4.1
Safety Assessments
4.1.1
Vital Signs
Blood pressure, heart rate, weight, and temperature will all be measured as described in 
the protocol at the timepoints defined in this COVID-19 Addendum Schedule of 
Assessments (Table 1.2-1) with the following considerations: 

If blood pressure measurements cannot be collected for 2 consecutive visits, the 
medical monitor should be contacted for guidance.

Subjects and caregivers will be asked to use their own collection device, if available, 
until devices can be provided.
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
Where possible, site staff will remotely supervise the collection of measurements via 
video or guide by telephone, if video is not possible, on the appropriate visits.

Subjects and caregivers will be instructed to be as consistent as possible regarding the 
time of day the measurement is taken, and to notify the site staff of the measurement 
results via telephone, or other means, on the appropriate visits.

Site staff will be instructed to record the measurement in eSource, and if there are 
believed to be any errors, inconsistencies, or safety concerns with the reported home 
measurement, the medical monitor should be notified.

Site staff will instruct the subjects to follow the procedures in the protocol for blood 
pressure and heart rate collection, but specify that the supine and standing positions 
for blood pressure are necessary, while the sitting position is less important. If sitting 
position is not collected, it should be documented as a COVID-19 protocol deviation 
(see Section 2.3).
4.1.2
Pregnancy
Pregnancy tests will be performed as described in the protocol at the timepoints defined 
in this COVID-19 Addendum Schedule of Assessments (Table 1.2-1) with the following 
changes: 

For planned visits that require a pregnancy test for women of childbearing potential 
(WOCBP), the site will provide the necessary tests and instructions so the test may be 
performed at home;

Applicable subjects will perform a pregnancy test at the timepoints defned in 
Table 1.2-1, ensuring a date- and time-stamped picture or video of the result is taken, 
followed by notification to the site staff of the results via telephone, or other means, 
on the appropriate visits. Subjects will also provide the site staff with the date- and 
time-stamped picture/video.

If negative, site to inform subject to proceed with dosing (if applicable).

If positive, the site must instruct the subject to immediately stop taking IMP (if 
applicable), and the site will refer to the Pregnancy section of the protocol for 
appropriate immediately reportable event reporting.
5
IMP
Given the ongoing COVID-19 restrictions, clinical sites are permitted to transport IMP 
directly to subjects via courier, if allowed by country guidances and regulations. 
Alternately, curbside pick-up by the caregiver is permitted.
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Server Date
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Biostatistics Approval
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SAP_001.pdf: 
Table of Contents
Table of Contents.............................................................................................................
1
Statistical Analysis Plan - 22 April 2022.........................................................................
2
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Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigational New Drug
Brexpiprazole (OPC-34712)
A 12-week, Multicenter, Active-treatment Extension Trial to Evaluate the Safety and 
Tolerability of Brexpiprazole in the Treatment of Subjects With Agitation Associated With 
Dementia of the Alzheimer’s Type
Protocol No. 331-201-00182
IND No. 115960
EudraCT No. 2018-002783-88
Statistical Analysis Plan
Version: Final 
Date: April 22, 2022
CONFIDENTIAL – PROPRIETARY INFORMATION
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Otsuka Pharmaceutical Development & Commercialization, Inc.


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Table of Contents
Table of Contents ..........................................................................................2
List of Abbreviations and Definitions of Terms .........................................4
1
Introduction..........................................................................................5
2
Study Objectives...................................................................................5
3
Trial Details ..........................................................................................5
3.1
Study Design .......................................................................................................5
3.2
Trial Treatments ..................................................................................................9
4
Sample Size and Power Justification..................................................9
5
Data Sets for Analysis and Missing Data ...........................................9
5.1
Data Sets for Analysis.........................................................................................9
5.2
Handling of Missing Data .................................................................................10
6
Study Conduct ....................................................................................10
6.1
Subject Disposition, Completion Rate and Reasons for Discontinuation.........10
6.2
Treatment Compliance ......................................................................................11
6.3
Protocol Deviation.............................................................................................11
7
Baseline Characteristics.....................................................................11
7.1
Baseline Definition............................................................................................11
7.2
Demographic Characteristics ............................................................................11
7.3
Baseline Psychiatric Evaluations.......................................................................11
8.1
COVID-19 Related Supplementary Analyses...................................................12
9
Safety Analysis....................................................................................12
9.1
Adverse Events..................................................................................................13
9.2
Clinical Laboratory Tests..................................................................................14


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9.2.1
Change from Baseline in Lab Tests................................................................14
9.2.2
Potentially Clinically Relevant Values...........................................................15
9.2.3
Potentially Liver Injury Related Laboratory Test...........................................15
9.3
Physical and Neurological Examination and Vital Signs..................................16
9.4
12-Lead ECG.....................................................................................................16
9.5
Simpson-Angus Scale, Abnormal Involuntary Movement Scale, and Barnes 
Akathisia Rating Scale ......................................................................................17
9.6
Mini-Mental State Examination........................................................................17
9.7
Suicidality Data.................................................................................................17
9.8
Concomitant Medications .................................................................................18
9.9
Extent of Exposure............................................................................................18
10
Conventions.........................................................................................18
10.1
Study Visit Windows ........................................................................................18
10.2
Scales: Rules for Scoring and Handling of Missing Data.................................19
10.2.1
Cohen-Mansfield Agitation Inventory............................................................19
10.2.2
Clinical Global Impression-Severity of Illness Scale.....................................20
10.2.3
Simpson-Angus Scale.....................................................................................21
10.2.4
Abnormal Involuntary Movement Scale ........................................................21
10.2.5
Barnes Akathisia Rating Scale........................................................................21
10.2.6
Sheehan Suicidality Tracking Scale ...............................................................21
10.2.7
Mini-Mental State Examination .....................................................................22
11
References ...........................................................................................23


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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
AAD
Agitation in Alzheimer’s dementia
AE
Adverse event
AIMS
Abnormal Involuntary Movement Scale
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BARS
Barnes Akathisia Rating Scale
BMI
Body mass index
CGI-S
Clinical Global Impression - Severity
CRF
Case Report Form
CMAI 
Cohen-Mansfield Agitation Inventory
DBP
Diastolic blood pressure
ECG
Electrocardiogram
EPS
Extrapyramidal symptoms
ET
Early termination
FDA
(United States) Food and Drug Administration
HbA1c
Glycosylated hemoglobin
HDL
High density lipoprotein
IAF
Informed assent form
ICF
Informed consent form
ID
Identification
IMP
Investigational medicinal product
IRE
Immediately reportable event
LDL
Low density lipoprotein
LOCF
MedDRA
Last Observation Carried Forward
Medical Dictionary for Regulatory Activities
OPDC
Otsuka Pharmaceutical Development and Commercialization, Inc.
PE
Physical examination
QD
Once Daily
QTc
Corrected QT interval
QTcF
QT interval as corrected for heart rate by Fridericia’s formula
SAE
Serious adverse event
SAS
Simpson Angus Scale
SAS®
Statistical Analysis System®
SAP
Statistical Analysis Plan
SCS
Summary of Clinical Safety
SOC
System Organ Class
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal


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1
Introduction
This statistical analysis plan (SAP) expands the statistical section of the protocol 
331-201-00182 and documents in detail the statistical methodologies and data analysis 
algorithms and conventions to be applied to the analysis and reporting of the safety and 
tolerability data collected in the study.  All amendments to the protocol have been taken into 
consideration in developing this SAP. 
2
Study Objectives
Primary: To assess the long-term safety and tolerability of oral brexpiprazole as treatment in   
adult subjects with AAD. 
 
   
3
Trial Details
3.1
Study Design
This is a multicenter, active-treatment extension trial designed to assess the long-term safety 
and tolerability of oral brexpiprazole (2 and 3 mg/day) as treatment in adults with AAD.  
Enrollment into the trial will consist of eligible subjects who completed the 12-week 
treatment in the double-blind, phase 3 efficacy Trial 331-14-213.  
The trial will be organized as follows:
Screening/baseline:  Subjects who completed Week 12 of the double-blind trial and had no 
substantial protocol deviations will be screened for eligibility at the last visit of the 
double-blind trial (ie, Week 12 or ET, if the trial is terminated, visit of Trial 331-14-213).  
Subjects will sign a separate informed consent form (ICF) for participation in 
Trial 331-201-00182 before any procedures specific to the extension trial are performed.  The 
assessments from the last visit of the double-blind trial will serve as the baseline measures for 
Trial 331-201-00182 for any assessment that is not unique to the extension trial.  Medical 
history will be updated, if necessary.
Active Extension Treatment:  Eligible subjects from Trial 331-14-213 will receive 12 weeks 
of daily treatment with brexpiprazole (target doses of 2 or 3 mg/day) in Trial 331-201-00182.  
Visits will occur at the end of Weeks 1, 2, 6, and 12.  
Follow-up:  All subjects, whether they complete the trial or are withdrawn prematurely for 
any reason, will be followed up for a safety evaluation 30 (+ 2) days after the last dose of IMP 


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during a clinic visit at either the investigator’s site or residential facility, as applicable.  If a 
clinic visit is not possible, the subject should be assessed by telephone contact with the 
subject and a caregiver.  For all subjects who terminate early from the trial, all attempts will 
be made to collect mortality data by telephone contact with the subject’s caregiver at Week 16 
(relative to baseline visit).
See Figure 3.1-1 for a schematic of the trial design.   


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aStarting at week 4, 1 dose decrease can occur at any time (scheduled or unscheduled visits) until the end of the trial.  In addition, one dose increase can occur 
but only at the Week 6 scheduled visit. Subjects who received placebo in Trial 331-14-213 will receive active drug in Trial 331-201-00182.  Subjects 
randomized to brexpiprazole and who completed the titration schedule in Trial 331-14-213 (ie, completed Week 4 visit in 331-14-213) will begin treatment on 
the same dose in this trial.  Subjects randomized to brexpiprazole and who have not completed the titration schedule will restart drug in Trial 331-201-00182 
dependent on the point in the titration scheme for Trial 331-14-213 that early termination occurred.


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bFor subjects who may be offered entry into this trial as a result of early termination of Trial 331-14-213 due to overwhelming efficacy from the interim analysis, 
the Screening/Baseline will occur at the last visit of the double-blind trial (ie, ET visit of Trial 331-14-213).  
Figure 3.1-1
Trial Design Schematic


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3.2
Trial Treatments
All subjects will receive target doses of 2 or 3 mg/day brexpiprazole in Trial 331-201-00182; 
these doses were those studied in Trial 331-14-213.  
To preserve the blind in Trial 331-14-213, all doses in Trial 331-201-00182 will remain 
blinded.  The first dose taken in Trial 331-201-00182 should be taken one day after the Week 
12.  
Subjects randomized to the 2 mg/day and 3 mg/day doses of brexpiprazole in Trial 
331-14-213 will begin treatment on these same doses in the active-treatment extension Trial 
331-201-00182.  All subjects who received placebo in Trial 331-14-213 will receive active 
drug (ie, brexpiprazole) in Trial 331-201-00182.
All subjects will receive target doses of 2 or 3 mg/day brexpiprazole during the trial.  Dose 
adjustments are allowed during the trial.  Starting at week 4, one dose decrease can occur at 
any time (scheduled or unscheduled visits) until the end of the trial.  In addition, one dose 
increase is permitted but only at the Week 6 scheduled visit.  Subjects who require an 
additional dose increase or decrease will be discontinued from the trial.  Timing of dose 
adjustments as outlined above is summarized in the table below.
Dosing Adjustments
Visit
Decreasea
Increase
Week 6
Permitted
Permitted
Unscheduled (week 4 or anytime thereafter)
Permitted
Not Permitted
aStarting at week 4, 1 dose decrease can occur at any time (scheduled or unscheduled visits) until the end of 
the trial.  
All doses of brexpiprazole will be taken orally once daily, preferably in the morning, and will 
be administered without regard to meals, and should be taken at approximately the same time 
each day.
4
Sample Size and Power Justification
The sample size is not based on statistical power considerations.  The trial population will be 
derived from eligible subjects who rollover from the double-blind phase 3 Trial 331-14-213.  
5
Data Sets for Analysis and Missing Data 
5.1
Data Sets for Analysis
To adequately describe the statistical analyses and reporting, three analysis populations are 
defined as follows. 


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
Enrolled Sample: comprises all subjects who sign an ICF for the trial and are enrolled 
into the trial.   

Safety Sample: comprised of those subjects who sign an ICF for the trial and receive 
at least one dose of brexpiprazole in Trial 331-201-00182.

Efficacy Sample: comprises all subjects in the Safety Sample who have a baseline 
assessment and at least one post-baseline assessment for CMAI (Cohen-Mansfield 
Agitation Inventory) total score. 
5.2
Handling of Missing Data
In order to assess the sensitivity of results due to missing data, 2 types of analyses will be 
performed:  last observation carried forward (LOCF) and observed cases (OC). The OC 
dataset will consist of the actual observations recorded at each visit.  The LOCF dataset will 
include data recorded at a scheduled visit, ie, all OC data, or, if no observation is recorded at 
that visit, data will be carried forward from the previously scheduled visit.  Baseline data will 
not be carried forward to impute missing values for the LOCF dataset. The OC dataset will be 
used for analyses at each trial visit and the LOCF dataset will be used for analyses at the last 
visit.  
6
Study Conduct
6.1
Subject Disposition, Completion Rate and Reasons for Discontinuation
Subject disposition will be summarized for the Enrolled Sample by parent study treatment 
group and overall. 
Subject completion rate and reasons for discontinuation will be summarized for the Enrolled 
Sample by parent study treatment group and overall. 
The above summaries will be repeated in subject subgroups as defined by gender (Female and 
Male), age group (< 65; ≥ 65 and < 75; or ≥ 75), race (white or other), geographical region 
(North America or other), and dementia severity (severe, moderate, and mild), where 
dementia severity will be defined based on Mini Mental State Examination (MMSE) score at 
baseline as follows:

Severe: MMSE score ≤ 12

Moderate: MMSE score > 12 and ≤ 18

Mild: MMSE score > 18




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8.1
COVID-19 Related Supplementary Analyses 
Summary statistics for mean and mean change from baseline in CMAI total score, by trial 
visit and at the last visit (i.e., Week 12/ET) and by visit type (face-to-face vs. remote) based 
on the Efficacy Sample will be provided by parent study treatment group for rollover subjects 
and overall. 
9
Safety Analysis
The primary safety endpoint analysis is the frequency and severity of AEs in the open-label 
treatment phase (see Section 9.1). Other standard safety variables to be analyzed include 
clinical laboratory tests, vital signs, body weight, waist circumference, BMI, 12-lead 
electrocardiograms (ECGs), and physical examinations. In addition, data from the following 
safety scales will be evaluated: MMSE score, assessments of suicidality (eg, Sheehan-STS), 
and extrapyramidal symptoms (EPS; eg, the Simpson-Angus Scale, abnormal involuntary 
movement scale [AIMS], and Barnes Akathisia Rating Scale [BARS]).  
Safety analyses will be conducted based on the Safety Sample, and summary statistics will be 
provided by parent study treatment group and overall, unless otherwise specified. 
The long-term 24 weeks (6 months) safety analysis for subjects who received brexpiprazole in 
the parent trial 331-14-213 will be described in the SAP for the Summary of Clinical Safety 
(SCS) for Agitation in Alzheimer’s dementia (AAD) and the results will be presented in the 
SCS.
Unless otherwise specified, in general, analysis of safety data will be performed on observed 
case and for last visit.


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9.1
Adverse Events
All adverse events will be coded by System Organ Class (SOC) and Preferred Term (PT) 
according to the Medical Dictionary for Regulatory Activities (MedDRA). AEs that are sex-
specific, eg, ovarian cancer, will have their incidence rates evaluated for the specific sex.
Treatment-emergent AEs (TEAEs) are defined as AEs with an onset date on or after the first 
dose of IMP. In more detail, TEAEs are all adverse events which started after start of IMP; or 
if the event was continuous from baseline and was worsening, serious, study drug related, or 
resulted in death, discontinuation, interruption or reduction of study therapy. Adverse events 
occurring up to 30 days after the last day of IMP will be included in the summary tables. 
The incidence of the following events in the open-label treatment phase will be tabulated by 
treatment group and overall using the Safety Sample:
a) Treatment-emergent AEs (TEAEs)
b) TEAEs by severity
c) TEAEs potentially causally related to the IMP
d) TEAEs with an outcome of death
e) Serious TEAEs
f)
TEAEs leading to discontinuation of the IMP 
The above summaries (b), (e) and (f) will also be prepared for TEAEs potentially causally 
related to the IMP.
In addition, incidence of TEAE during the open-label treatment phase of at least 5% by SOC 
and PT will be provided.
Incidence of TEAEs by SOC and PT will be summarized for sex, race, age and region 
subgroups.
Extrapyramidal symptoms (EPS)-related AEs will be grouped into five categories.
1) Dystonic Events, which include blepharospasm, cervical spasm, clumsiness, dystonia, 
dystonic tremor, emprosthotonus, essential tremor, facial spasm, fumbling, gait inability, head 
titubation, intention tremor, Meige's syndrome, muscle contractions involuntary, muscle 
spasms, muscle spasticity, muscle tightness, muscle tone disorder, musculoskeletal stiffness, 
myotonia, nuchal rigidity, oculogyration, oesophageal spasm, opisthotonos, opisthotonus, 
oromandibular dystonia, oropharyngeal spasm, pharyngeal dystonia, pleurothotonus, risus 


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sardonicus, spasmodic dysphonia, tongue spasm, torticollis, torticollis psychogenic, trismus, 
uvular spasm;
2) Parkinsonian Events, which include action tremor, akinesia, asterixis, bradykinesia, 
bradyphrenia, cogwheel rigidity, dysphonia, fine motor skill dysfunction, freezing 
phenomenon, gait disturbance, gait festinating, hypertonia, hypokinetic dysarthria, laryngeal 
tremor, masked facies, micrographia, mobility decreased, muscle rigidity, on and off 
phenomenon, parkinsonian crisis, parkinsonian gait, parkinsonian rest tremor, parkinsonism, 
parkinsonism hyperpyrexia syndrome, parkinsons disease, parkinson's disease,
parkinson's 
disease psychosis, postural reflex impairment, postural tremor, propulsive gait, reduced facial 
expression, resting tremor, tremor, walking disability;
3) Akathisia Events, which include akathisia, extrapyramidal disorder, hyperkinesia, 
movement disorder, psychomotor hyperactivity, and restlessness;
4) Dyskinetic Events, which include abnormal involuntary movement scale, athetosis, 
ballismus, buccoglossal syndrome, chorea, choreoathetosis, chronic tic disorder, complex tic, 
dopamine dysregulation syndrome, drooling, dyskinesia, dyskinesia oesophageal, grimacing, 
motor dysfunction, muscle twitching, nodding of head, oculogyric crisis, pharyngeal 
dyskinesia, protrusion tongue, provisional tic disorder, rabbit syndrome, respiratory 
dyskinesia, secondary tic, tardive dyskinesia, tic;
5) Residual Events, which include huntingtons disease and myoclonus.
Unless otherwise specified, in general, analysis of safety data will be performed on observed 
case and for last visit.
Unless otherwise specified, in general, analysis of safety data will be performed on observed 
case and for last visit.
9.2
Clinical Laboratory Tests
9.2.1 Change from Baseline in Lab Tests
Summary statistics for mean and mean change from baseline in the routine clinical laboratory 
measurements, prolactin concentrations, coagulation parameters (prothrombin time, activated 
partial thromboplastin time, and international normalized ratio), HbA1c, and thyroid-
stimulating hormone will be provided by parent study treatment and by visit.


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9.2.2 Potentially Clinically Relevant Values
In addition, the incidence of treatment-emergent PCR values identified using prospectively 
defined criteria
 for laboratory tests will be summarized by parent study 
treatment group.  A listing of PCRs by subject and by test will be provided.
9.2.3 Potentially Liver Injury Related Laboratory Test
Total bilirubin level will be checked for any subjects with increased alanine transaminase 
(ALT) or aspartate transaminase (AST) levels greater or equal to three times the upper normal 
limits (or baseline).
Liver injury related laboratory test results will be summarized for subjects who met following 
criteria for Safety Sample during the open-label treatment period.  The corresponding listing 
will be provided as well.

AST or ALT ≥ 3 × upper limit of normal (ULN) and 

T_Bili ≥ 2 × ULN 
 
 
 
 
   
 


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9.3
Physical and Neurological Examination and Vital Signs
Physical and neurological examination findings will be listed by subject.
Summary statistics for change from baseline in vital signs, body weight, BMI, and waist 
circumference will be provided by parent study treatment group.
In addition, the incidence of treatment-emergent PCR values identified using prospectively 
defined criteria
 for vital signs and body weight will be summarized by parent 
study treatment group.  Listing of PCRs by subject and by test will be provided.
9.4
12-Lead ECG
Summary statistics for change from baseline in ECG parameters will be provided by parent 
study treatment group and by visit.
In addition, the incidence of treatment-emergent PCR values identified using prospectively 
defined criteria for ECG will be summarized by parent study treatment group.  Listing of 
PCRs by subject and by test will be provided.
For the analysis of QT and QTc, data from three consecutive complexes (representing three 
consecutive heart beats) will be measured to determine average values.  The following QT 
corrections will be used for reporting purposes in the clinical study report:

QTcB is the length of the QT interval corrected for heart rate by the Bazett formula: 
QTcB=QT/(RR)0.5

QTcF is the length of the QT interval corrected for heart rate by the Fridericia 
formula: QTcF=QT/(RR)0.33

QTcN is the length of the QT interval corrected for heart rate by the FDA Neuropharm 
Division formula:  QTcN = QT/(RR)0.37
Categorical changes in ECG parameters during the open-label treatment period will be 
summarized based on the criteria in Table 9.4-1.


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Table 9.4-1
Categorical Change Criteria in QT/QTc Parameters
Classification
Category
Criteria 
QT
New onset (≥ 450 msec for men 
or ≥ 470 msec for women)
New onset in QT means a subject who 
attains a cut off value during treatment 
period but not at baseline.
QTca
New onset (≥ 450 msec for men 
or ≥ 470 msec for women)
New onset in QTc means a subject who 
attains a cut-off value during treatment 
period but not at baseline.
New onset (≥ 450 msec for men 
or ≥ 470 msec for women) and > 10% 
increase
New onset and > 10% increase in QTc 
means a subject who attains a cut off 
value and > 10% increase during 
treatment period but not at baseline
New onset (> 500 msec)
New onset (> 500 msec) in QTc means a 
subject who attains a value > 500 msec 
during treatment period but not at 
baseline.
Increase 30 - 60 msec
Increase from baseline 
value > 30 and ≤ 60 msec in QTc
Increase > 60 msec
Increase from baseline value > 60 msec in 
QTc
a QTc categorical change criteria apply to QTcB, QTcF and QTcN.
9.5
Simpson-Angus Scale, Abnormal Involuntary Movement Scale, and 
Barnes Akathisia Rating Scale
The mean change from baseline in SAS, AIMS, and BARS scales for trial visits during the 
open-label treatment phase using the Safety Sample will be summarized by descriptive 
statistics. In addition, incidence of BARS Global Clinical Assessment of Akathisia during the 
open-label treatment phase by severity category will be provided. Descriptive statistics will be 
summarized at each visit using the OC data set and at the last visit (Week 12/ET) using the 
LOCF data set.
9.6
Mini-Mental State Examination
The mean changes from baseline in MMSE for trial visits during the open-label treatment 
phase will be summarized by descriptive statistics. Descriptive statistics will be summarized 
at each visit using the OC data set and at the last visit (Week 12/ET) using the LOCF data set.
9.7
Suicidality Data
The mean changes from baseline in Sheehan-STS individual item scores, suicidal ideation 
subscale score, suicidal behavior subscale score, or total score for trial visits during the open-
label treatment phase using the Safety Sample will be summarized by descriptive statistics. 
Descriptive statistics will be summarized at each visit using the OC data set and at the last 


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visit (Week 12/ET) using the LOCF data set.Incidence of treatment emergent suicidal 
ideation, suicidal behavior will be summarized by treatment, and overall.
9.8
Concomitant Medications
Number and proportion of subjects taking concomitant medications prior to IMP, during the 
open-label treatment period, and after IMP are tabulated by drug classification using the 
World Health Organization drug dictionary.
9.9
Extent of Exposure
The start date of open-label IMP will be the first day of open-label IMP dosing.  The number 
and percentage of subjects who receive open-label IMP will be presented by week and by 
parent study treatment group.  Each dosing week will be based on the actual week; i.e., Day 1 
to 7 in Week 1, Day 8 to 14 in Week 2, etc.  This summary will be performed on the Safety 
Sample.
The number and percentage of completers will be presented by week and by parent study 
treatment group.
The mean daily dosage will be summarized by week and parent study treatment group using 
descriptive statistics.  The mean daily dosage per subject per week will be determined for 
each week of the trial.  This will be calculated by dividing the sum of individual total doses by 
the number of days in the week interval.  The summary will contain for each parent study 
treatment group the number of subjects receiving open-label IMP, and the mean and range of 
the mean daily dose for each week. 
10 Conventions
10.1 Study Visit Windows
Trial visit windows will be used to map visits using trial day intervals.  This visit window 
convention applies to tables and listings for all efficacy and safety scales (CMAI, CGI-S, 
SAS, AIMS, BARS, MMSE and Sheehan-STS).  This derived trial window variable will be 
named as WEEK and will be footnoted.  In listings it will be listed along with the case report 
form (CRF) trial visit.
Table 10.1-1 below shows classifications for trial day intervals in the open-label treatment 
period.  The variable “target day” is defined using the number of days since the start of open-
label brexpiprazole dosing.  The first day of open-label brexpiprazole dosing is defined as 
“Day 1”.  If more than one observation falls within a particular trial day interval, then the last 
observation within that interval is used.  Evaluations occurring more than 7 days after the last 


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open-label brexpiprazole dosing date will not be mapped into study visit windows and will be 
excluded from the analysis.
Table 10.1-1   Mapping of the Analysis Visit for the Open-label Treatment Period
Analysis Visit
Target Study Day a per Protocol
Study Day Intervala  (endpoint inclusive)
Day 1 
1
1 
Week 1
7 
2 to 10
Week 2
14 
11 to 28
Week 6
42 
29 to 63
Week 12
84 
64 to 91
a Relative to the first day of IMP in the open-label treatment period.
b Evaluations occurring more than seven days after the last dosing date of IMP in the open-label treatment 
period will be excluded from the efficacy analyses.
The preceding algorithm ensures that all observations collected at an ET visit or any other 
unscheduled visit will be mapped to an analysis visit.  In instances where multiple 
observations (of same parameter on the same subject) fall into one study day interval, all 
values of the multiple observations in the study interval will be included for listings, but only 
the last observation will be used for the by-visit analysis or summary. 
10.2
Scales: Rules for Scoring and Handling of Missing Data 
10.2.1
Cohen-Mansfield Agitation Inventory
The CMAI 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 CMAI total score is the sum of ratings for all 29 items.  The 
possible total scores are from 29 to 203.  The CMAI total score will be unevaluable if less 
than 24 of the 29 items are recorded.  If 24 to 28 of the 29 items are recorded, the total score 
will be the mean of the recorded items multiplied by 29 and then rounded to the first decimal 
place.
Factor 1: Aggressive behavior: Hitting (including self), kicking, scratching, grabbing onto 
people, pushing, hurt self or other (cigarette, hot water, etc.), throwing things, cursing or 
verbal aggression, spitting (include at meals), tearing things or destroying property, 
screaming, biting.
Criteria for agitated status based on Factor 1: 

at least one aggressive behavior occurring at a frequency of at least 4; or

at least two aggressive behaviors occurring at a frequency of at least 3; or

at least three aggressive behaviors occurring at a frequency of at least 2;


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Factor 2: Physically nonaggressive behavior: Pace, aimless wandering, trying to get to a 
different place, general restlessness, inappropriate dress or disrobing, handling things 
inappropriately, performing repetitious mannerisms.
Criteria for agitated status based on Factor 2: 

at least one physically nonaggressive behavior occurring at a frequency of at least 5; 
or

at least two physically nonaggressive behavior occurring at a frequency of at least 4; 
or

at least three physically nonaggressive behavior occurring at a frequency of at least 3; 
or

at least four physically nonaggressive behavior occurring at a frequency of at least 2;
Factor 3: Verbally agitated behavior: Complaining, constant unwarranted request for 
attention or help, repetitious sentences or questions, negativism.
Criteria for agitated status based on Factor 3: 

at least one verbally agitated behavior occurring at a frequency of at least 5; or

at least two verbally agitated behavior occurring at a frequency of at least 4; or

at least three verbally agitated behavior occurring at a frequency of at least 3; or

at least four verbally agitated behavior occurring at a frequency of at least 2;
Factor 4: Hiding things, hoarding things.
The following items are not included in factors derivation1: Intentional Falling; Making 
Verbal Sexual Advances; Making Physical Sexual Advances; Strange Noises (weird laughter 
or crying); Eating or Drinking Inappropriate Substances.
10.2.2
Clinical Global Impression-Severity of Illness Scale
The severity of agitation for each subject will be rated using the Clinical Global Impression-
Severity of Illness Scale (CGI-S).  To perform this assessment, the investigator (or designee) 
will answer the following question: “Considering your total clinical experience with this 
particular population, how mentally ill (as related to agitation) is the subject at this time?”  
Response choices are 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 subjects.  The score 0 (not assessed) will be set to missing.  The CGI-S is 
therefore a 7-point scale from 1 through 7.


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10.2.3
Simpson-Angus Scale
The Simpson-Angus Scale is a rating scale used to measure EPS.  The Simpson-Angus Scale 
is a 10-item scale, with each item rated from 0 to 4, with 0 being normal and 4 being the 
worst.  The Simpson-Angus Scale total score is the sum of ratings for all 10 items, with 
possible total scores from 0 to 40.  The Simpson-Angus Scale total score will be un-evaluable 
if less than 8 of the 10 items are recorded.  If 8 or 9 of the 10 items are recorded, the total 
score will be the mean of the recorded items multiplied by 10 and then rounded to the first 
decimal place.
10.2.4
Abnormal Involuntary Movement Scale
The AIMS is a 12-item scale.  The first 10 items are rated from 0 to 4 (0 = best, 4 = worst).  
An item score of 0, depending on the item, either means: no abnormal involuntary movement 
(AIM), or no incapacitation due to AIM, or no awareness of AIM.  An item score of 4 either 
means: severe AIM, or severe incapacitation due to AIM, or being aware of, and severe 
distress caused by AIM.  Items 11 and 12, related to dental status, have dichotomous 
responses, 0 = no and 1 = yes.  The AIMS total score is the sum of the ratings for the first 
seven items.  The possible total scores are from 0 to 28.  The AIMS total score will be un-
evaluable if less than 6 of the first 7 items are recorded.  If 6 of the items are recorded, then 
the total score will be the mean of the recorded items multiplied by 7 and then rounded to the 
first decimal place.
10.2.5
Barnes Akathisia Rating Scale
Barnes Akathisia Rating Scale (BARS) will be used to assess the presence and severity of 
akathisia.  This scale consists of 4 items.  Only the 4th item, the Global Clinical Assessment 
of Akathisia, will be evaluated in this trial.  This item is rated on a 6-point scale, with 0 being 
best (absent) and 5 being worst (severe akathisia).
10.2.6
Sheehan Suicidality Tracking Scale
Suicidality will be monitored during the trial using the Sheehan-STS.  The Sheehan-STS is a 
prospective scale that assesses treatment-emergent suicidal thoughts and behaviors.  Each 
item of the Sheehan-STS is scored on a 5-point Likert scale (0 = not at all; 1 = a little; 
2 = moderate; 3 = very; and 4 = extremely).  The Sheehan-STS can be analyzed as individual 
item scores, suicidal ideation subscale score, suicidal behavior subscale score, or total score.  
The trial will use the “Screening” and “Since Last Visit” version of the scale.  The 
“Screening” Sheehan-STS form will be completed at the screening visit to determine 
eligibility.  Any subject with evidence of serious risk of suicide based on the Sheehan-STS, ie, 


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a score of 3 or 4 on any one question 2 through 6 or 11 or a score of 2 or higher on any one 
questions 1a, 7 through 10, or 12, or who, in the opinion of the investigator, present a serious 
risk of suicide should be excluded from the trial.  The “Since Last Visit” Sheehan-STS form 
will be completed at all other visits.  The medical monitor should be contacted if a score of 
3 or 4 on any one question 3 through 6 or 11 or a score of 2 or higher on any one questions 1a, 
7 through 10, or 12, or 18, or if suicide results in death.
10.2.7
Mini-Mental State Examination
The MMSE is a brief practical test for assessing cognitive dysfunction.  The test consists of 
5 sections (orientation, registration, attention and calculation, recall, and language) and has a 
total possible score of 30.  The MMSE is used for screening subjects and is also to be 
completed at Week 12/ET.
The MMSE is a 19-item scale.  Items 1 to 10, 15, and 17 to 19 are rated on a scale from 
0 to 1, item 14 is rated on a 0 to 2 scale, items 11, 13 and 16 are rated on a scale from 0 to 3, 
and Item 12 is rated on a scale from 0 to 5.  Low scores are the worst, high scores are the best.  
The MMSE total score is calculated by adding the individual item scores.  The possible range 
for the MMSE total score is from 0 to 30.  If the maximum total of the missing items could 
contribute more than 6 points to the total score then the total score will be set to missing.  
Otherwise, a mean non-missing items score will be calculated by summing the non-missing 
items and dividing them by the maximum score possible from the non-missing items.  For 
missing items with possible scores from 0 to 1, the mean score will be imputed for each 
missing item.  If item 14 is missing, two times this mean will be imputed for item 14.  If items 
11, 13, or 16 are missing three times this mean for will be imputed each missing item.  If item 
12 is missing 5 times then this mean will be imputed for item 12.  After all by-item 
imputation has been done, the individual item scores will be added and this sum will be 
rounded to the first decimal place to arrive at an imputed total score.  In other terms, the 
MMSE total score is simply the mean non-missing items score multiplied by 30, and then 
rounded to the first decimal place.


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11
References
1
Rabinowitz J, Davidson M, Paul De Deyn P, Katz I, Brodaty H, Cohen-Mansfield J. 
Factor Analysis of the Cohen-Mansfield Agitation Inventory in Three Large Samples of 
Nursing Home Patients With Dementia and Behavioral Disturbance. Am J Geriatr 
Psychiatry. 2005;13(11):991-8.


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