Conditions: Agitation Associated With Alzheimer's Dementia Alzheimer Dementia
Keywords: Agitation
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 345
Healthy volunteers: no

Brief summary:
This study compares the efficacy of 2 doses of brexpiprazole with placebo in participants with agitation associated with dementia of the Alzheimer's type.

Detailed description:
This is a phase 3, 12-week, multicenter, randomized, double-blind, placebo-controlled, fixed-dose trial designed to assess the efficacy, safety, and tolerability of brexpiprazole compared with placebo. The trial consists of a 12-week double-blind treatment period with a 30 day follow-up. The trial population will include male and female participants between 55 and 90 years of age (inclusive) with a diagnosis of probable Alzheimer's disease, who are residing either in an institutionalized setting or in a non-institutionalized setting where the participant is not living alone. This trial will analyze data gathered from approximately 330 participants at multiple countries. Participants may also be eligible to enter an active treatment extension trial.

Arms:
arm 1: Participants followed a titration schedule, to gradually increase their dose from 0.5 milligrams per day (mg/day) in the starting to 2 mg/day from Day 15. Participants continued to receive brexpiprazole 2 milligrams (mg), once daily until Week 12. arm 2: Participants followed a titration schedule, to gradually increase their dose from 0.5 mg/day in the starting to 3 mg/day from Day 29. Participants continued to receive brexpiprazole 3 mg, once daily until Week 12. arm 3: Participants received matching placebo, once daily for 12 weeks.

Interventions: intervention 1: Brexpiprazole intervention 2: Placebo
Intervention descriptions: intervention 1: Oral tablets intervention 2: Oral tablets

Protocol document:
Prot_000.pdf: 
Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigational Medicinal Product
OPC-34712
REVISED CLINICAL PROTOCOL
A Phase 3, 12-Week, Multicenter, Randomized, Double-blind, Placebo-controlled, 
2-Arm, Fixed-dose Trial to Evaluate the Efficacy, Safety, and Tolerability of 
Brexpiprazole (OPC-34712) in the Treatment of Subjects With Agitation Associated 
With Dementia of the Alzheimer’s Type
Protocol No. 331-14-213
IND No. 115960
EudraCT No. 2017-003940-19
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:
23 Feb 2018
Amendment 1:
03 Dec 2019
Amendment 2:
06 Aug 2020
Amendment 3:
14 Sep 2020
Version No.:
4.0


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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 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.  


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Protocol Synopsis
Name of Sponsor:  Otsuka Pharmaceutical
Development & Commercialization, Inc.
Name of Investigational Medicinal Product:  
Brexpiprazole (OPC-34712)
Protocol No.:  331-14-213
IND No.:  115960
EudraCT No.:  2017-003940-19
Protocol Title:
A Phase 3, 12-Week, Multicenter, Randomized, Double-blind, 
Placebo-controlled, 2-Arm, Fixed-dose Trial to Evaluate the 
Efficacy, Safety, and Tolerability of Brexpiprazole (OPC-
34712) in the Treatment of Subjects With Agitation Associated 
With Dementia of the Alzheimer’s Type
Clinical Phase/Trial 
Type:
3/Therapeutic confirmatory
Treatment 
Indication:
Agitation associated with dementia of the Alzheimer’s type
Objective(s):
Primary:  To confirm the efficacy of brexpiprazole compared 
with placebo in subjects with agitation in Alzheimer’s dementia 
(AAD)
Secondary:  To evaluate the safety and tolerability of 
brexpiprazole compared with placebo in subjects with AAD
Trial Design:
This is a phase 3, 12-week, multicenter, randomized, 
double-blind, placebo-controlled, fixed-dose trial designed to 
assess the efficacy, safety, and tolerability of brexpiprazole 
compared with placebo.  Subjects will be randomized in a 2:1 
ratio to brexpiprazole or placebo.  Within the brexpiprazole 
arm, subjects will be further randomized in a 1:2 ratio to 
2 mg/day or 3 mg/day, to explore the efficacy, safety, and 
tolerability of 2 mg/day and 3 mg/day brexpiprazole versus 
placebo.  The randomization will be stratified by site.
Currently, there are no approved treatments in the United States 
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 (6 weeks). Proven effective, tolerable, and safe 
treatment is essential in addressing this serious unmet need.
The trial consists of a 2- to 42-day screening period, a 12-week 
double-blind treatment period, and a 30-day post-treatment 
safety follow-up period.  In addition, for all subjects who 
terminate early from the trial, attempts will be made to collect 


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data on mortality status by telephone contact with the subject’s 
caregiver at Week 16.
This trial will be monitored by an independent Data Monitoring 
Committee (DMC).  The DMC will periodically monitor safety 
based on a predetermined schedule.  In addition, an interim 
analysis of efficacy data is planned during the course of the 
trial, and will be performed by the independent DMC.  The 
sponsor will remain blinded to the observed results of the 
interim analysis, and will only receive recommendations as per 
the interim analysis plan and DMC Charter.
The trial is organized as follows:
Screening Period
The screening period will range from 2 days up to 42 days, with 
the goal of completing all screening activities within 30 days, if 
possible, and will begin when the informed consent form (ICF) 
is signed, prior to the initiation of any procedures.  The 
screening period may be extended after discussion with and 
approval by the medical monitor.  An eSource method will be 
used to obtain an identification number for each subject with 
documented consent.
The purpose of the screening period is to determine the 
subject’s eligibility and to washout prohibited concomitant 
pharmacotherapy prior to randomization.
External quality oversight methods will be used by Clinical 
Surveillance & Training (CST) and the Independent 
Adjudication Panel to promote appropriate subject enrollment.
In addition, starting at screening and continuing throughout the 
12-week double-blind treatment period, the subject’s behavior 
will be logged into a diary by the caregiver or facility staff.  
This diary will be sent to CST on a routine basis in order to 
corroborate information recorded on the Cohen-Mansfield 
Agitation Inventory (CMAI).


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12-Week, Double-blind Treatment Period
Based on a randomization scheme, eligible subjects will be 
randomized in a 2:1 ratio to one of the following 2 treatment 
groups:

Brexpiprazole (further randomized in a 1:2 ratio to 
2 mg/day or 3 mg/day)

Placebo
Subjects will follow a titration schedule, depending upon their 
assigned treatment group, to gradually increase their dose of the 
investigational medicinal product (IMP) to their assigned target 
dose as follows:
The first dose of IMP (brexpiprazole or placebo) will be 
administered on the day after the baseline visit (ie, Day 1) and 
ending on Week 12 or early termination (ET; the last day of the 
treatment period).
Subjects unable to tolerate their assigned dose of brexpiprazole 
(or matching placebo) will be withdrawn from the trial.  
Down-titration is not allowed at any time during the trial.  If a 
subject is withdrawn or discontinues prematurely before 
Week 12, 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.
Subjects will be evaluated at baseline and at Weeks 2, 4, 6, 8, 
10, and 12 during the double-blind treatment period.  
Trial-related efficacy and safety assessments will be performed 
as outlined in the Schedule of Assessments.
Subjects who complete the 12-week double-blind treatment 
period of Trial 331-14-213 may be eligible to enter a 12-week 
open-label extension trial.


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If this trial is terminated early due to overwhelming efficacy 
from the interim analysis, subjects in this trial at the time may 
be offered entry into the open-label extension trial 
(Trial 331-201-00182) if they choose to participate.
Follow-up Period
All subjects, with the exception of those entering the optional 
open-label extension trial, 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.
Subject Population:
The trial population will include male and female subjects 
between 55 and 90 years of age (inclusive), 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.  All subjects must have a diagnosis 
of probable Alzheimer’s disease according to the National 
Institute of Neurological and Communicative Disorders and 
Stroke and the Alzheimer’s Disease and Related Disorders 
Association (NINCDS-ADRDA) criteria, have a Mini-Mental 
State Examination (MMSE) score between 5 and 22 (inclusive), 
meet the criteria for the provisional International 
Psychogeriatric Association (IPA) consensus definition of 
agitation in patients with cognitive disorders, and meet 
additional predetermined blinded eligibility criteria to which 
the site clinical investigators will remain blinded (described in a 
separate blinded protocol addendum that will not be accessible 
to the site clinical investigators).  (The provisional IPA 
definition is limited to patients with cognitive impairment 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.)


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All trial visits will take place as a clinic visit at either the 
investigator’s site or residential facility, as applicable.  All 
attempts should be made to maintain the subject’s normal 
routine with regard to physician appointments and overnight 
accommodations.  Subjects who at any point during the 
double-blind treatment period transfer from an institutionalized 
setting to a non-institutionalized setting, or vice versa, will be 
withdrawn from the trial.  Individual circumstances that fall 
outside this general convention (eg, short-term hospitalization) 
should be discussed with the medical monitor in order to 
determine appropriateness to proceed.  In case of a short-term 
hospitalization, a determination of the subject’s eligibility to 
stay in the trial must be made based on the subject’s safety by 
the investigator and medical monitor.  A subject in an 
institutionalized setting may receive supervised day passes at 
the discretion of the investigator and may also receive 
supervised overnight passes at the discretion of the investigator 
as long as such overnight stays are part of the subject’s normal 
routine.
Inclusion/Exclusion 
Criteria: 
Key inclusion criteria are described under Subject Population in 
this synopsis.  Subjects must meet the inclusion criteria at both 
screening and baseline.
Key exclusion criteria include the following:

Subjects with dementia or other memory impairment not 
due to Alzheimer’s disease, such as mixed or vascular 
dementia, dementia with Lewy bodies, Parkinson’s disease 
dementia, frontotemporal dementia, substance-induced 
dementia, human immunodeficiency virus-dementia, 
traumatic brain injury, normal pressure hydrocephalus, or 
any other specific non-Alzheimer’s-type dementia; subjects 
with a diagnosis of Down syndrome.

Subjects with a previous magnetic resonance imaging 
(MRI)/computed tomography (CT) scan of the brain, which 
was performed after the onset of the symptoms of 
dementia, with findings consistent with a clinically 
significant central nervous system disease other than 
Alzheimer’s disease, such as vascular changes (eg, cortical 
stroke, multiple infarcts), space-occupying lesion (eg, 
tumor), or other major structural brain disease.  

Subjects with a history of stroke, well-documented transient 
ischemic attack, or pulmonary or cerebral embolism.

Subjects with delirium or history of delirium within the 


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30 days prior to the screening visit.

Subjects who have received high-dose antipsychotics 
exceeding the equivalent of ≥ 3 mg of risperidone (eg, ≥ 5 
mg of haloperidol, ≥ 375 mg quetiapine, ≥ 10 mg 
olanzapine, or local equivalent) within 90 days prior to 
screening.

Subjects who have received multiple antipsychotic 
medications simultaneously for a period of > 7 days within 
90 days prior to screening.

Subjects with evidence of serious risk of suicide based on 
the Sheehan Suicidality Tracking Scale (Sheehan-STS), ie, 
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.

Subjects considered in poor general health based on the 
investigator’s judgment.  Examples include subjects who 
have a recent clinically significant weight loss, chronic 
dehydration or hypovolemia, poor fluid or nutritional 
intake, or a recent clinically significant infection, as per the 
investigator’s judgment.
Trial Site(s): 
The trial is expected to enroll subjects at approximately 80 sites 
worldwide.
Investigational 
Medicinal 
Product(s), Dose, 
Dosage regimen, 
Treatment period, 
Formulation, Mode 
of Administration:
The IMP will be supplied as brexpiprazole tablets or matching 
placebo 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.
After a 2- to 42-day screening period, eligible subjects will be 
randomized in a 2:1 ratio to brexpiprazole or placebo.  Within 
the brexpiprazole arm, subjects will be further randomized in a 
1:2 ratio to 2 mg/day or 3 mg/day.
The total duration of double-blind treatment will be 12 weeks 
for all randomized subjects.
Neither the investigator nor the subject will be aware of the 
treatment assignment.  All doses of brexpiprazole and matching 
placebo will be taken orally once daily, preferably in the 
morning, and will be administered without regard to meals.  
Brexpiprazole (or matching placebo) should be taken at 
approximately the same time each day.


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Trial Assessments:
Efficacy:  CMAI, Clinical Global Impression Severity of Illness 
(CGI-S) scale, Clinical Global Impression Improvement of 
Illness (CGI-I) scale,
 
 
.
Pharmacokinetic (PK),
 
The PK samples for 
determination of brexpiprazole will be collected at the baseline 
visit and at the Week 8 and Week 12 or ET trial visits, at the 
same time as the sample collection for the clinical laboratory 
tests. 
 
 
Safety:  Adverse event (AE) reporting, clinical laboratory tests, 
electrocardiograms (ECGs), vital signs, physical and 
neurological examinations, body weight, body mass index, 
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-STS.
Screening/Other:  Hachinski Ischemic Scale and 
NINCDS-ADRDA.


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Criteria for 
Evaluation:
Primary Efficacy Endpoint:
The primary efficacy endpoint is the change from baseline to 
Week 12 in the CMAI total score.
Key Secondary Efficacy Endpoint:
The key secondary efficacy endpoint is the change from 
baseline to Week 12 in the CGI-S score, as related to agitation.
Secondary Efficacy Endpoints:

Change from baseline to Week 12 in CMAI subscale scores 
(aggressive behavior, physically nonaggressive behavior, 
verbally agitated behavior)

Change from baseline in CMAI total score for each trial 
visit during the double-blind treatment period

Change from baseline in CGI-S for each trial visit during 
the double-blind treatment period

CGI-I score at each trial visit during the double-blind 
treatment period 

CMAI-based responder analysis as described in the 
statistical analysis plan (SAP)

CGI-I responder analysis as described in the SAP
 
 
 


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Safety Endpoints:
Safety and tolerability will be evaluated by reports of AEs, 
clinically significant changes in: physical examinations, 
neurological examinations, vital signs, body weight, waist 
circumference, clinical laboratory tests, and ECGs. Change 
from baseline in body mass index (derived programmatically 
from body weight and height measurements) will be 
summarized.  Other safety variables will include the MMSE 
score and assessments of suicidality (Sheehan-STS), and 
extrapyramidal symptoms (SAS, AIMS, and BARS).
Pharmacokinetic/Pharmacodynamic Endpoints:
Plasma concentrations will be determined for brexpiprazole and 
descriptive statistics will be calculated.  Concentrations of 
metabolites of brexpiprazole that are not identified in the 
protocol may also be determined, if needed. No formal 
statistical comparisons are planned.  Additional population or 
PK or pharmacodynamic modeling may be performed as a 
separate analysis by combining data from this trial with data 
from all other trials.
Statistical Methods:
Descriptive statistics will be provided for all efficacy and safety 
variables in general.  Continuous variables will be summarized 
by tabulations of mean, median, range, and standard deviation.  
Tabulations of frequency distributions will be provided for 
categorical variables.  The primary endpoint will be analyzed 
using a mixed-effect model repeated measures (MMRM) 
model.  The model will include fixed-class effect terms for 
treatment, trial site, visit week, and an interaction term of 
treatment by visit week and include the interaction term of 
baseline values of CMAI total score by visit week as a 
covariate.  The primary efficacy outcome measure is the mean 
change from baseline to Week 12 in the CMAI total score.  The 
primary statistical comparison of interest is brexpiprazole 
versus placebo.  The null hypothesis of this comparison is that 
there is no difference between the brexpiprazole treatment 
group and placebo in change from baseline to Week 12 in 
CMAI total score.  Details of sensitivity analyses under the 
assumption of missing not at random will be provided in the 
SAP.
The key secondary efficacy variable is the change from baseline 
to Week 12 in the CGI-S score, as related to agitation.  It will 
be analyzed by the same statistical methodology specified for 
the analysis of the primary efficacy variable.


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Trial Duration:
The trial is planned to randomize approximately 330 subjects at 
maximum.  There will be one interim analysis when 
approximately the first 255 subjects have completed the 
12-week trial or discontinued early.  Depending on the result of 
the interim analysis, the trial may stop at the conclusion of the 
interim analysis, or proceed to the final analysis at the 
maximum sample size of approximately 330 subjects.   The 
time from enrollment of the first subject to the last (330th) 
subject’s last trial visit will be approximately 4.0 years, of 
which approximately 3.75 years are allotted for recruitment of 
subjects.  Enrollment timelines could be shortened, as the trial 
may stop at the interim analysis based on the interim analysis 
result.
If this trial is terminated early due to overwhelming efficacy 
from the interim analysis, subjects in this trial at the time may 
be offered entry into the open-label extension trial 
(Trial 331-201-00182) if they choose to participate.
Individual participation for subjects who complete the trial will 
range from 16 to 22 weeks, consisting of a 2- to 42-day 
screening period, a 12-week double-blind treatment period, and 
a 30-day follow-up period.  All subjects, with the exception of 
those entering the optional open-label extension trial, whether 
they complete the trial or are withdrawn prematurely for any 
reason, 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.


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Table of Contents
Trial Conduct for COVID-19.......................................................................2
Protocol Synopsis...........................................................................................3
Table of Contents ........................................................................................13
List of In-text Tables...................................................................................19
List of In-text Figures .................................................................................20
List of In-text Appendices...........................................................................21
List of Abbreviations and Definitions of Terms .......................................22
1
Introduction........................................................................................25
1.1
Nonclinical Data................................................................................................26
1.2
Clinical Data......................................................................................................26
1.3
Known and Potential Risks and Benefits ..........................................................27
2
Trial Rationale and Objectives .........................................................28
2.1
Trial Rationale...................................................................................................28
2.2
Dosing Rationale...............................................................................................28
2.3
Trial Objectives.................................................................................................29
3
Trial Design.........................................................................................29
3.1
Type/Design of Trial .........................................................................................29
3.2
Trial Treatments ................................................................................................34
3.3
Trial Population.................................................................................................35
3.3.1
Caregiver/Caretaker Requirements.................................................................36
3.3.1.1
Non-institutionalized Subjects ....................................................................36
3.3.1.2
Institutionalized Subjects ............................................................................36
3.3.2
Number of Subjects and Description of Population .......................................37
3.3.3
Subject Selection and Numbering ..................................................................37
3.4
Eligibility Criteria .............................................................................................37
3.4.1
Informed Consent ...........................................................................................37
3.4.1.1
Determinations of Capacity ........................................................................37
3.4.1.2
Documentation of Informed Consent..........................................................38
3.4.2
Inclusion Criteria ............................................................................................40


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3.4.3
Exclusion Criteria...........................................................................................41
3.5
Endpoints...........................................................................................................44
3.5.1
Primary Endpoint............................................................................................44
3.5.1.1
Primary Efficacy Endpoint..........................................................................44
3.5.2
Secondary Endpoints ......................................................................................44
3.5.2.1
Key Secondary Efficacy Endpoint..............................................................44
3.5.2.2
Secondary Efficacy Endpoints....................................................................44
3.5.4
Safety Endpoints.............................................................................................45
3.5.5
Pharmacokinetic/Pharmacodynamic Endpoints .............................................46
3.6
Measures to Minimize/Avoid Bias....................................................................46
3.6.1
Randomization................................................................................................46
3.7
Trial Procedures ................................................................................................46
3.7.1
Schedule of Assessments................................................................................51
3.7.1.1
Screening.....................................................................................................51
3.7.1.2
Baseline (Day 0)..........................................................................................52
3.7.1.3
Double-blind Treatment Period ..................................................................52
3.7.1.3.1
Weeks 2, 4, 6, 8, and 10 ..........................................................................52
3.7.1.4
End of Treatment (Week 12) ......................................................................52
3.7.1.5
Follow-up....................................................................................................53
3.7.2
Efficacy Assessments .....................................................................................53
3.7.2.1
Cohen-Mansfield Agitation Inventory........................................................54
3.7.2.2
Clinical Global Impression Severity of Illness (CGI-S) .............................54
3.7.2.3
Clinical Global Impression Improvement of Illness (CGI-I)......................54
 
3.7.3
Other Assessments..........................................................................................56
3.7.3.1
National Institute of Neurological and Communicative Disorders and 
Stroke and the Alzheimer’s Disease and Related Disorders 
Association..................................................................................................56


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3.7.3.2
Hachinski Ischemic Scale (Rosen Modification)........................................56
3.7.3.3
Magnetic Resonance Imaging/Computed Tomography Scan of the 
Brain............................................................................................................56
3.7.3.4
International Psychogeriatric Association ..................................................56
3.7.4
Prior and Concomitant Medications...............................................................57
3.7.5
Safety Assessments.........................................................................................57
3.7.5.1
Adverse Events ...........................................................................................57
3.7.5.2
Clinical Laboratory Assessments................................................................58
3.7.5.3
Physical and Neurological Examination and Vital Signs ...........................60
3.7.5.3.1
Physical Examinations.............................................................................60
3.7.5.3.2
Neurological Examinations .....................................................................61
3.7.5.3.3
Vital Signs ...............................................................................................61
3.7.5.4
Electrocardiogram Assessments .................................................................62
3.7.5.5
Other Safety Assessments...........................................................................63
3.7.5.5.1
Simpson Angus Scale..............................................................................63
3.7.5.5.2
Abnormal Involuntary Movement Scale .................................................64
3.7.5.5.3
Barnes Akathisia Rating Scale ................................................................64
3.7.5.5.4
Sheehan Suicidality Tracking Scale ........................................................65
3.7.5.5.5
Mini-Mental State Examination ..............................................................65
3.7.6
Pharmacokinetic
Assessments .........................................65
3.7.6.1
Pharmacokinetic Assessments ....................................................................65
3.7.6.1.1
Pharmacokinetic Blood Samples.............................................................65
3.7.7
End of Trial.....................................................................................................67
3.7.8
Independent Data Monitoring Committee......................................................67
3.7.9
Independent Adjudication Panel and Clinical Surveillance Team .................67
3.8
Stopping Rules, Withdrawal Criteria, and Procedures......................................68
3.8.1
Entire Trial or Treatment Arm(s) ...................................................................68
3.8.2
Individual Site.................................................................................................68
3.8.3
Individual Subject Discontinuation ................................................................68


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3.8.3.1
Treatment Discontinuation..........................................................................68
3.8.3.2
Documenting Reasons for Treatment Discontinuation...............................68
3.8.3.3
Withdrawal of Consent ...............................................................................70
3.8.3.4
Procedures to Encourage Continued Trial Participation.............................71
3.9
Screen Failures ..................................................................................................71
3.10
Definition of Completed Subjects.....................................................................71
3.11
Definition of Subjects Lost to Follow-up..........................................................71
3.12
Subject Compliance...........................................................................................72
3.13
Protocol Deviations...........................................................................................72
4
Restrictions .........................................................................................72
4.1
Prohibited Medications .....................................................................................72
4.2
Other Restrictions..............................................................................................76
5
Reporting of Adverse Events.............................................................77
5.1
Definitions.........................................................................................................77
5.2
Eliciting and Reporting Adverse Events ...........................................................79
5.3
Immediately Reportable Events ........................................................................79
5.4
Potential Serious Hepatotoxicity.......................................................................79
5.5
Pregnancy..........................................................................................................80
5.6
Procedure for Breaking the Blind......................................................................81
5.7
Follow-up of Adverse Events............................................................................82
5.7.1
Follow-up of Nonserious Adverse Events......................................................82
5.7.2
Follow-up of Serious Adverse Events and Immediately Reportable 
Events .............................................................................................................82
5.7.3
Follow-up and Reporting of Serious Adverse Events and Immediately 
Reportable Events Occurring after Last Scheduled Contact ..........................82
5.7.4
Follow-up Mortality Assessment....................................................................83
6
Pharmacokinetic
 Analysis.................................83
7
Statistical Analysis..............................................................................83
7.1
Sample Size.......................................................................................................83
7.2
Datasets for Analysis.........................................................................................83
7.3
Handling of Missing Data .................................................................................84
7.4
Primary and Secondary Endpoint Analyses......................................................84


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7.4.1
Primary Efficacy Endpoint Analysis ..............................................................84
7.4.2
Key Secondary Efficacy Endpoint Analysis...................................................84
7.4.3
Secondary Efficacy Endpoint Analysis ..........................................................85
7.4.5
Interim Analysis..............................................................................................86
7.5
Analysis of Demographic and Baseline Characteristics....................................86
7.6
Safety Analysis..................................................................................................86
7.6.1
Adverse Events...............................................................................................86
7.6.2
Clinical Laboratory Data ................................................................................87
7.6.3
Physical and Neurological Examination and Vital Signs Data ......................87
7.6.4
Electrocardiogram Data..................................................................................87
7.6.5
Other Safety Data ...........................................................................................87
8
Management of Investigational Medicinal Product........................88
8.1
Packaging and Labeling ....................................................................................88
8.2
Storage...............................................................................................................88
8.3
Accountability ...................................................................................................88
8.4
Returns and Destruction....................................................................................89
8.5
Reporting of Product Quality Complaints.........................................................89
8.5.1
Eliciting and Reporting Product Quality Complaints.....................................89
8.5.2
Information Required for Reporting Purposes ...............................................90
8.5.3
Return Process ................................................................................................90
8.5.4
Assessment/Evaluation...................................................................................90
9
Records Management ........................................................................90
9.1
Source Documents.............................................................................................90
9.2
Data Collection..................................................................................................91
9.3
File Management at the Trial Site.....................................................................92
9.4
Records Retention at the Trial Site....................................................................92
10
Quality Control and Quality Assurance...........................................93
10.1
Monitoring.........................................................................................................93
10.2
Auditing.............................................................................................................93
11
Ethics and Responsibility...................................................................94


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Confidentiality....................................................................................94
13
Amendment Policy .............................................................................94
14
Publication Authorship Requirements.............................................95
15
References ...........................................................................................97


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List of In-text Tables
Table 3.2-1
Dosing Scheme ..............................................................................34
Table 3.4.2-1
Inclusion Criteria ...........................................................................40
Table 3.4.3-1
Exclusion Criteria ..........................................................................41
Table 3.7-1
Schedule of Assessments...............................................................48
Table 3.7.3.4-1
Consensus Provisional Definition of Agitation 
in Cognitive Disorders...................................................................57
Table 3.7.5.2-1
Clinical Laboratory Assessments...................................................59
Table 4.1-1
List of Restricted and Prohibited Medications...............................73
Table 4.1-2
Selected CYP2D6 Inhibitors and CYP3A4 Inhibitors and 
Inducers
................................................................................76
Table 4.1-3
Oral Benzodiazepine (or Equivalent) Therapy 
During the Trial..............................................................................76


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List of In-text Figures
Figure 3.1-1
Trial Design Schematic..................................................................32


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List of In-text Appendices
Appendix 1
Handling and Shipment of Bioanalytical Samples 
Pharmacokinetic Sample Collection............................................100
Appendix 2
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance .......................................................................102
Appendix 3
Criteria for Identifying Vital Signs of Potential 
Clinical Relevance .......................................................................103
Appendix 4
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance .......................................................................104
Appendix 5
Protocol Amendment(s)/Administrative Change(s) ....................106


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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 (SGPT)
Alanine transaminase (serum glutamic-pyruvic transaminase)
Anti-HCV
Hepatitis C antibodies
aPTT
Activated partial thromboplastin time
AST (SGOT)
Aspartate transaminase (serum glutamic-oxaloacetic 
transaminase)
BARS
Barnes Akathisia Rating Scale
bpm
Beats per minute
CGI-I
Clinical Global Impression Improvement of Illness
CGI-S
Clinical Global Impression Severity of Illness
CMAI
Cohen-Mansfield Agitation Inventory
CPK
Creatine phosphokinase
CRO
Clinical Research Organization
CST
Clinical Surveillance & Training
CT
Computed tomography
CYP
Cytochrome P450
D
Dopamine
D2
Dopamine type 2
DBP
Diastolic blood pressure
DMC
Data Monitoring Committee
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition
ECG
Electrocardiogram
eICF
Electronic informed consent form
EPS
Extrapyramidal symptoms
ET
Early termination
EudraCT
European Clinical Trial Data Base
FBR
Future biospecimen research
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HbA1c
Glycosylated hemoglobin
HBsAg
Hepatitis B surface antigen
HDL
High-density lipoprotein
IAP
Independent Adjudication Panel
IB
Investigator’s Brochure


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Abbreviation
Definition
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
INR
International Normalized Ratio
IPA
International Psychogeriatric Association
IRB
Institutional review board
IRE
Immediately reportable event
ITT
Intent-to-treat
LDL
Low-density lipoprotein
LOCF
Last-observation-carried-forward
MDD
Major depressive disorder
MMRM
Mixed-effect model repeated measures
MMSE
Mini-Mental State Examination
MNAR
Missing not at random
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
NINCDS-
ADRDA
National Institute of Neurological and Communicative Disorders 
and Stroke and the Alzheimer’s Disease and Related Disorders 
Association
 
OC
Observed-case
OPC
Otsuka Pharmaceutical Company, Ltd.
OPDC
Otsuka Pharmaceutical Development & Commercialization, Inc.
OTC
Over-the-counter
PK
Pharmacokinetic
PT
Prothrombin time
PTSD
Post-traumatic stress disorder
PQC
Product Quality Complaint
QTc
Corrected QT interval
QTcB
QT interval as corrected for heart rate by Bazett’s formula
QTcF
QT interval as corrected for heart rate by Fridericia’s formula
QTcN
QT interval as corrected for heart rate by the FDA Neuropharm 
Division formula
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Simpson Angus Scale
SBP
Systolic blood pressure


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Abbreviation
Definition
Sheehan-STS
Sheehan Suicidality Tracking Scale
T4
Thyroxine
TEAE
Treatment-emergent adverse event
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
UN
Un-structured
US
United States
WBC
White blood cell
WOCBP
Women of childbearing potential
Term
Definition
Investigational 
medicinal product 
(IMP)
For the purposes of this protocol, IMP refers to all trial 
medication supplied to the sites by the sponsor (or designated 
agent) and includes blister cards containing brexpiprazole or 
matching placebo.


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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 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 (6 weeks).  
Without approved labeling, at best in current clinical practice, clinicians rely on 


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guidelines when 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


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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 
(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.14,15  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 


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Trial 331-12-284) showed that brexpiprazole doses up to 2 mg/day are safe and well-
tolerated in this population.
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
Preliminary 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 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 statistical 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 could 
receive the 2 mg/day dose.  Additionally, post-hoc analyses of subjects who were titrated 
to 2 mg/day brexpiprazole or similar placebo in the flexible-dose trial (Trial 331-12-284) 
supported the efficacy of brexpiprazole 2 mg/day (change in CMAI total score from 
baseline to Week 12, p < 0.05).
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).  During this meeting, the FDA recommended exploring a higher dose 
(3 mg), measures to reduce placebo response, and potential enrichment strategies.
Based on the collective data from the 2 completed phase 3 trials, and the positive 
benefit/risk profile associated with brexpiprazole 2 mg/day, the proposed trial 
(Trial 331-14-213) is designed to confirm the efficacy, safety, and tolerability of 
brexpiprazole 2 mg/day compared with placebo as well as provide information about the 
efficacy, safety, and tolerability of brexpiprazole at 3 mg/day.
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 


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considered the minimum effective dose.  The 3 mg/day dose is included to explore the 
efficacy, safety, and tolerability of a higher dose of brexpiprazole, as recommended by 
the FDA.
2.3
Trial Objectives
Primary:
To confirm the efficacy of brexpiprazole compared with placebo in subjects 
with AAD
Secondary: To evaluate the safety and tolerability of brexpiprazole compared with 
placebo in subjects with AAD
3
Trial Design
3.1
Type/Design of Trial
This is a phase 3, 12-week, multicenter, randomized, double-blind, placebo-controlled, 
fixed-dose trial designed to assess the efficacy, safety, and tolerability of brexpiprazole 
compared with placebo.  Subjects will be randomized in a 2:1 ratio to brexpiprazole or 
placebo.  Within the brexpiprazole arm, subjects will be further randomized in a 1:2 ratio 
to 2 mg/day or 3 mg/day, to explore the efficacy, safety, and tolerability of 2 mg/day and 
3 mg/day brexpiprazole versus placebo.
The trial consists of a 2- to 42-day screening period, a 12-week double-blind treatment 
period, and a 30-day post-treatment safety follow-up period.  In addition, for all subjects 
who terminate early from the trial, attempts will be made to collect data on mortality 
status by telephone contact with the subject’s caregiver at Week 16.  See Figure 3.1-1 for 
a schematic of the trial design and Table 3.7-1 for the Schedule of Assessments.
This trial will be monitored by an independent Data Monitoring Committee (DMC) 
(Section 3.7.8).  The DMC will periodically monitor safety based on a predetermined 
schedule.  In addition, an interim analysis of efficacy data is planned during the course of 
the trial, and will be performed by the independent DMC.  The sponsor will remain 
blinded to the observed results of the interim analysis, and will only receive 
recommendations as per the interim analysis plan and DMC Charter.  The details of the 
DMC structure and its roles and responsibilities will be documented in a DMC Charter.
The trial is organized as follows:
Screening Period
The screening period will range from 2 days up to 42 days, with the goal of completing 
all screening activities within 30 days, if possible, and will begin when the informed 


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consent form (ICF) is signed, prior to the initiation of any procedures.  The screening 
period may be extended after discussion with and approval by the medical monitor.  
Additional requirements for obtaining informed consent from this vulnerable subject 
population are provided in Section 3.4.1.  An eSource method will be used to obtain an 
identification (ID) number for each subject with documented consent.
The purpose of the screening period is to determine the subject’s eligibility and to 
washout prohibited concomitant pharmacotherapy prior to randomization (refer to 
Section 4.1).
External quality oversight methods will be used by Clinical Surveillance & Training 
(CST) and the Independent Adjudication Panel (IAP) to promote appropriate subject 
enrollment.  Such methods will require sites to communicate certain aspects of subject 
data during the screening period to CST and the IAP, as detailed in the Operations 
Manual.  The IAP will provide an independent assessment of the subject’s eligibility at 
time of enrollment and may request exclusion of a subject from entry into the trial.  
Subjects cannot be randomized until approval from CST and the IAP has been received.  
The investigator is responsible for ensuring that subjects are eligible for enrollment into 
the trial and for assessing subject safety throughout the trial.
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.
In addition, starting at screening and continuing throughout the 12-week double-blind 
treatment period, the subject’s behavior will be logged into a diary by the caregiver or 
facility staff.  This diary will be sent to CST on a routine basis in order to corroborate 
information recorded on the CMAI.  Since the diary data is a tool to assist CST in 
monitoring CMAI rater training, the diary data will not be statistically analyzed.
While it is preferred that diary data are collected 7 days a week, it is realized that diary 
use for 7 days a week may not be possible because the minimum amount of time that the 
caregiver is required to observe the subject is 4 days a week.  Every effort should be put 
forth by the sites to encourage the caregivers to collect and submit as much data as 
possible.  Caretakers, facility personnel, or family members may provide information to 
the caregiver to complete the diary, but this is not a requirement.
Details around this procedure can be found in the Operations Manual.


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12-Week, Double-blind Treatment Period
Based on a randomization scheme, eligible subjects will be randomized in a 2:1 ratio to 
one of the following 2 treatment groups:

Brexpiprazole (further randomized 1:2 to 2 mg/day or 3 mg/day)

Placebo
Subjects will follow a titration schedule, depending upon their assigned treatment group, 
to gradually increase their dose of the IMP to their assigned target dose 
 
Subjects unable to tolerate their assigned dose of brexpiprazole (or matching placebo) 
will be withdrawn from the trial.  Down-titration is not allowed at any time during the 
trial.  If a subject is withdrawn or discontinues prematurely before Week 12, every effort 
will be made to complete all of the Week 12 or early termination (ET) evaluations prior 
to administering any additional medications for the treatment of agitation or other 
prohibited medications.
Subjects will be evaluated at baseline and at Weeks 2, 4, 6, 8, 10, and 12 during the 
double-blind treatment period.  Trial-related efficacy and safety assessments will be 
performed as outlined in the Schedule of Assessments (Table 3.7-1).
Subjects who complete the 12-week double-blind treatment period of Trial 331-14-213 
may be eligible to enter a 12-week open-label extension trial. 
If this trial is terminated early due to overwhelming efficacy from the interim analysis, 
subjects in this trial at the time may be offered entry into the open-label extension trial 
(Trial 331-201-00182) if they choose to participate.
Follow-up Period
All subjects, with the exception of those entering the optional open-label extension trial, 
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.


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Figure 3.1-1
Trial Design Schematic
aWithin the brexpiprazole arm, subjects will be further randomized in a 1:2 ratio to 2 mg/day or 3 mg/day.
bThe trial will have a two-stage group-sequential design with the planned maximum sample size of approximately 330 subjects for the final analysis if the trial 
does not stop at the interim analysis (on the first group of 255 subjects).
Brexpiprazolea (n = 220b)
Subjects with 
dementia of the 
Alzheimer’s type 
who exhibit agitation 
per IPA criteria
2 to 42 days
Days –42 to –2
≥ 1 visits as needed
Screening
12-week Double-blind Treatment Period
Safety Follow-up
Duration: 12 weeks
Day 30 (+2)
Clinic visit or 
telephone contact
Telephone contact
Baseline visit
(Day 0)
End of treatment
(Week 12/ET)
Placebo (n = 110b)
Week 16
(early terminators)
Titrationc
2 mg/day (n=73) 
3 mg/day (n=147)
Randomization 2:1 brexpiprazole versus 
placebo


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3.2
Trial Treatments
Treatment assignments will be obtained by accessing eSource.  Based on the fixed-block, 
computer-generated randomization, eligible subjects will be allocated in a 2:1 ratio at 
randomization to 1 of the following 2 treatment groups:

Brexpiprazole (further randomized 1:2 to 2 mg/day or 3 mg/day)

Placebo
Neither the investigator nor the subject will be aware of the treatment assignment.  All 
doses of brexpiprazole and matching placebo will be taken orally once daily, preferably 
in the morning, and will be administered without regard to meals.  Brexpiprazole (or 
matching placebo) should be taken at approximately the same time each day, particularly 
prior to visits with PK sampling.
Subjects will follow a titration schedule, depending upon their assigned treatment group, 
to gradually increase their dose of the IMP to their assigned target dose 
 
The first dose of IMP (brexpiprazole or placebo) will be administered on the day after the 
baseline visit (ie, Day 1), and ending on Week 12 or ET (the last day of the treatment 
period).
For subjects randomly assigned to the brexpiprazole treatment group:

 
 

Subjects will remain on their assigned dose until Week 12 or ET (the last day of the 
treatment period).


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Down-titration will not be allowed at any time during the trial.  Subjects unable to 
tolerate brexpiprazole (or matching placebo) will be discontinued from the trial 
(Section 3.1).
3.3
Trial Population
The trial is expected to randomize a maximum of approximately 330 subjects at 
approximately 80 sites worldwide.  Based on the result of the interim analysis to be 
conducted on the first 255 randomized subjects, the trial may stop per the 
recommendation of the independent DMC.  The trial population will include male and 
female subjects between 55 and 90 years of age (inclusive), 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.  All subjects must have a 
diagnosis of probable Alzheimer’s disease according to the National Institute of 
Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and 
Related Disorders Association (NINCDS-ADRDA) criteria, have a Mini-Mental State 
Examination (MMSE) score between 5 and 22 (inclusive), meet the criteria for the 
provisional IPA16 consensus definition of agitation in patients with cognitive disorders 
(Section 3.7.3.4), and meet additional predetermined blinded eligibility criteria to which 
the site clinical investigators will remain blinded (described in a separate blinded protocol 
addendum that will not be accessible to the site clinical investigators).
All trial visits will take place as a clinic visit at either the investigator’s site or residential 
facility, as applicable.  All attempts should be made to maintain the subject’s normal 
routine with regard to physician appointments and overnight accommodations.  Subjects 
who at any point during the double-blind treatment period transfer from an 
institutionalized setting to a non-institutionalized setting, or vice versa, will be withdrawn 
from the trial.  Individual circumstances that fall outside this general convention (eg, 
short-term hospitalization) should be discussed with the medical monitor in order to 
determine appropriateness to proceed.  In case of a short-term hospitalization, a 
determination of the subject’s eligibility to stay in the trial must be made based on the 
subject’s safety by the investigator and medical monitor.  A subject in an institutionalized 
setting may receive supervised day passes at the discretion of the investigator and may 
also receive supervised overnight passes at the discretion of the investigator as long as 
such overnight stays are part of the subject’s normal routine.


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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, 
including completion of the diary.  A caregiver must be identified during the screening 
period for participation in the interview of the applicable trial assessments.  At the time of 
the subject’s screening visit, the caregiver will be provided a document that will outline 
all caregiver responsibilities.  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 
 are administered unless other 
arrangements are made and approved by the sponsor.  Starting at screening, 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 
subject’s behavior in order to participate in the interview for the CMAI, 
 


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 and other applicable trial assessments.  A caregiver 
must be identified during the screening period for participation in the interview of the 
applicable trial assessments.  At the time of the subject’s screening visit, the caregiver 
will be provided a document that will outline all caregiver responsibilities.  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
Number of Subjects and Description of Population
Sufficient numbers of male and female subjects between 55 and 90 years of age 
(inclusive), who are living in either an institutionalized setting or in a 
non-institutionalized setting where the subject is not living alone, are planned to be 
screened at approximately 80 sites worldwide in order to randomize a maximum of 
approximately 330 subjects.  Based on the result of the interim analysis to be conducted 
on the first 255 randomized subjects, the trial may stop per the recommendation of the 
independent DMC.
3.3.3
Subject Selection and Numbering
See Section 3.6.1 (Randomization).
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 


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law to consent to the subject’s participation in the clinical trial on behalf of that 
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) Guideline17 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.


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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 
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.


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3.4.2
Inclusion Criteria
Subjects are required to meet the inclusion criteria presented in Table 3.4.2-1.
Table 3.4.2-1
Inclusion Criteria
1.
The investigator must assess the capacity of the subject to provide informed consent during the 
screening period and throughout the course of the trial.  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 Section 3.4.1. 
2. 
Male and female subjects between 55 and 90 years of age, inclusive, at the time of informed 
consent.
3.
Subjects with a diagnosis of probable Alzheimer’s disease according to the NINCDS-ADRDA 
criteria.
4.
Subjects with a diagnosis of agitation that meets the IPA provisional definition of agitation 
(Section 3.7.3.4).
5.
Subjects with a MMSE score of 5 to 22, inclusive, at the screening and baseline visits.
6.
Subjects with a previous MRI or CT scan of the brain, that was performed after the onset of the 
symptoms of dementia, with findings consistent with a diagnosis of Alzheimer’s disease.  
7.
Subjects who are residing at their current location for at least 28 days before screening and are 
expected to remain at the same location for the duration of the trial.
8.
Institutionalized subjects with an identified caregiver (Section 3.3.1) 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 (Section 3.3.1) 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.
9.
Subjects with a total score (frequency × severity) of ≥ 4 on the agitation/aggression item of the 
 at 
the screening and baseline visits.
10.
Subjects with onset of symptoms of agitation at least 2 weeks prior to the screening visit.
11.
Subjects must meet additional predetermined blinded eligibility criteria according to the blinded 
addendum.
12.
Subjects who require pharmacotherapy for the treatment of agitation per the investigator’s 
judgment, after:

An evaluation for reversible factors (eg, pain, infection, or polypharmacy), and

A trial of nonpharmacological interventions (eg, redirecting behavior, group activities, 
music therapy)
13.
Subjects who are capable of self-locomotion or locomotion with an assistive device (eg, 4-point 
walker, wheelchair).
14.
Subjects willing and able to discontinue all prohibited concomitant medications to meet protocol 
required washouts prior to and during the trial period.
15.
Subjects able to satisfactorily comply with the protocol requirements.
CT = computed tomography; MRI = magnetic resonance imaging.


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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
Target Disease
1.
Subjects with dementia or other memory impairment not due to Alzheimer’s disease, such as 
mixed or vascular dementia, dementia with Lewy bodies, Parkinson’s disease dementia, 
frontotemporal dementia, substance-induced dementia, HIV-dementia, traumatic brain injury, 
normal pressure hydrocephalus, or any other specific non-Alzheimer’s-type dementia; subjects 
with a diagnosis of Down syndrome.
2.
Subjects with a previous MRI or CT scan of the brain, which was performed after the onset of 
the symptoms of dementia, with findings consistent with a clinically significant central nervous 
system disease other than Alzheimer’s disease, such as vascular changes (eg, cortical stroke, 
multiple infarcts), space-occupying lesion (eg, tumor), or other major structural brain disease.
3.
Subjects with a history of stroke, well-documented transient ischemic attack, or pulmonary or 
cerebral embolism.
4.
Subjects who had an insufficient response, based on the investigator’s judgment, to 2 or more 
previous antipsychotic medications.
5.
Subjects who have received high-dose antipsychotics exceeding the equivalent of ≥ 3 mg of 
risperidone (eg, ≥ 5 mg of haloperidol, ≥ 375 mg quetiapine, ≥ 10 mg olanzapine, or local 
equivalent) within 90 days prior to screening.
6.
Subjects who have received multiple antipsychotic medications simultaneously for a period of 
> 7 days within 90 days prior to screening.
7.
Subjects with delirium or history of delirium within the 30 days prior to the screening visit.
8.
Subjects who have been diagnosed with an Axis I disorder (DSM-5 criteria) including, but not 
limited to:

Schizophrenia, schizoaffective disorder, or other psychotic disorder not related to dementia

Bipolar I or II disorder, bipolar disorder not otherwise specified

Current Major Depressive Episode.  Subjects with a history of MDD, that is not currently 
symptomatic, are eligible.  Subjects currently on a stable dose(s) of antidepressant 
medication(s) for the 30 days prior to randomization are eligible.  For those not currently 
on antidepressant medication(s), no medication(s) should have been taken for 30 days prior 
to randomization.  Please note: antidepressant medications that are CYP2D6 or CYP3A4 
inhibitors are prohibited (Section 4.1).
9.
Subjects with evidence of serious risk of suicide based on the Sheehan-Suicidality Tracking 
Scale, ie, 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 question 1a, 7 through 10, or 12; or who, in the opinion of the investigator, present a 
serious risk of suicide.
10.
Subjects who currently have clinically significant neurological, hepatic, renal, metabolic, 
hematological, immunological, cardiovascular, pulmonary, gastrointestinal, or psychiatric 
disorders.  Clinically significant cardiovascular disorders include uncontrolled atrial fibrillation, 
heart failure, or ischemic heart disease.  Surrogates for uncontrolled cardiovascular disease 
would include recent (within the last 6 months) hospitalizations or procedures, such as 
percutaneous coronary intervention or coronary artery bypass surgery.
Medical conditions that are minor or well-controlled may be considered acceptable if the 
condition does not expose the subject to an undue risk of a significant adverse event or interfere 
with assessments of safety or efficacy during the course of the trial.  The medical monitor 
should be contacted in any instance where the investigator is uncertain regarding the stability of 
a subject’s medical condition(s) and the potential impact of the condition(s) on trial 
participation.


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Table 3.4.3-1
Exclusion Criteria
11.
Subjects with uncontrolled hypertension (DBP > 95 mmHg) or symptomatic hypotension, or 
orthostatic hypotension, which is defined as a decrease of ≥ 30 mmHg in SBP or a decrease of 
≥ 20 mmHg in DBP within 3 minutes of standing compared to the previous supine blood 
pressure, OR development of symptoms.  Abnormal vital signs results should be repeated to 
ensure reproducibility of the abnormality before excluding a subject based on the criteria noted 
above.
12.
Subjects with diabetes mellitus (IDDM and non-IDDM) may be eligible for the trial if their 
condition is stable and well-controlled as determined by satisfying ALL of the following 
criteria at screening and baseline:

Screening HbA1c < 8.0%, AND

Screening glucose must be  125 mg/dL (fasting) or < 200 mg/dL (nonfasting).  If the 
nonfasting screening glucose is  200 mg/dL, subjects must be retested in a fasted state 
and the retest value must be  125 mg/dL, AND

Subject has not had any hospitalizations within the 3 months prior to screening due to 
diabetes or complications related to diabetes.
Subjects with non-IDDM (ie, any subjects not using insulin) must also satisfy the below 
criterion:

Subject has been maintained on a stable regimen of oral antidiabetic medication(s) for at 
least 28 days prior to screening or diabetes has been well-controlled by diet for at least 28 
days prior to screening.
Subjects with newly diagnosed diabetes during screening will be excluded.
13.
Subjects with a history of hypothyroidism or hyperthyroidism (unless condition has been 
stabilized with medications for at least the past 90 days) or an abnormal result for free T4 at 
screening.  Eligibility of subjects excluded based on an abnormal free T4 result can be discussed 
with the medical monitor if, in the investigator’s judgment, the subject is a suitable candidate 
for the trial.
14.
Subjects with epilepsy or a history of seizures, except for a single childhood febrile seizure, 
post-traumatic seizure, alcohol withdrawal seizure.
15.
Subjects with seropositive status for hepatitis B (ie, HBsAg positive) or hepatitis C (ie, anti-
HCV positive).
16.
Subjects considered in poor general health based on the investigator’s judgment.  Examples 
include subjects who have a recent clinically significant weight loss, chronic dehydration or 
hypovolemia, poor fluid or nutritional intake, or a recent clinically significant infection, as per 
the investigator’s judgment.
17.
Subjects with a body mass index < 18.5 kg/m2 at screening and baseline.
18.
Subjects who have met DSM-5 criteria for substance abuse or dependence within the past 
180 days; including alcohol and benzodiazepines, but excluding caffeine and nicotine.
19.
Subjects with a positive drug screen for cocaine, marijuana (whether medically prescribed or 
not), or other illicit drugs are excluded and may not be retested or rescreened.  Subjects with a 
positive blood alcohol test or urine drug screen resulting from use of prescription or over-the-
counter medications or products that in the investigator’s opinion do not signal a clinical 
condition that would impact the safety of the subject or interpretation of the trial results may 
continue evaluation for the trial following consultation and approval by the medical monitor.
20.
Subjects with abnormal laboratory tests results, vital signs results, or ECG findings, unless, 
based on the investigator’s judgment, the findings are not medically significant and would not 
impact the safety of the subject or the interpretation of the trial results and the results have been 
discussed with and approved as acceptable for trial eligibility by the trial medical monitor.  
Criteria will be provided in a protocol appendix to assist investigators in their assessments of 
results that may be potentially medically significant, depending on the subject’s medical history 
and clinical presentation.


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Table 3.4.3-1
Exclusion Criteria
In addition, subjects with the following laboratory test and ECG results at screening must be 
excluded from the trial:

Platelets ≤ 75000/mm3

Hemoglobin ≤ 9 g/dL

Neutrophils, absolute ≤ 1000/mm3

AST > 2 × ULN

ALT > 2 × ULN

CPK > 3 × ULN, unless discussed with and approved by the medical monitor

Albumin < 3 g/dL

HbA1c ≥ 8%

Abnormal T4, unless discussed with and approved by the medical monitor.  (Note:  Free T4 
is measured only if the result for TSH is abnormal.)

QTcF  450 msec in men and  470 msec in women (detailed further in the protocol), 
unless due to ventricular pacing
Tests with exclusionary results should be repeated (if ECG, 3 consecutive recordings) to ensure 
reproducibility of the abnormality before excluding a subject based on the criteria noted above.
21.
Sexually active women of childbearing potential (detailed further in Section 5.5) and male 
subjects who are not practicing 2 different methods of birth control with their partner during the 
trial and for 30 days after the last dose of IMP or who will not remain abstinent during the trial 
and for 30 days after the last dose.  If employing birth control, each couple must use 2 of the 
following precautions:  vasectomy, tubal ligation, vaginal diaphragm, intrauterine device, birth 
control pill, birth control implant, birth control patch, birth control depot injections, condom 
with spermicide, or sponge with spermicide.
22.
Women who are breast-feeding or who have a positive pregnancy test result prior to receiving 
IMP in Trial 331-14-213.
23.
Subjects who have a current medical condition that requires treatment with an anticoagulant, 
although antiplatelet medications are not prohibited.
24.
Subjects who have received immunotherapy, such as vaccines, for the treatment of Alzheimer’s 
disease (through clinical trial or compassionate use program) in the 6 months preceding 
randomization.
25.
Subjects who would be likely to require prohibited concomitant therapy during the trial.
26.
Subjects who received commercially available brexpiprazole (REXULTI) or participated in any 
brexpiprazole clinical trial.
27.
Subjects with a history of neuroleptic malignant syndrome.
28.
Subjects with a history of true allergic response (ie, not intolerance) to more than 1 class of 
medications.
29.
Subjects who participated in a clinical trial within the last 30 days prior to screening.
30.
Subjects who, in the opinion of the investigator, medical monitor, sponsor, IAP, or CST, should 
not participate in the trial.
ALT (SGPT) = alanine transaminase (serum glutamic-pyruvic transaminase); anti-HCV = hepatitis C 
antibodies; AST (SGOT) = aspartate transaminase (serum glutamic-oxaloacetic transaminase); 
CPK = creatine phosphokinase; CYP = cytochrome P450; DBP = diastolic blood pressure; 
DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth edition; 
ECG = electrocardiogram; HbA1c = glycosylated hemoglobin; HBsAg = hepatitis B surface antigen; 
HIV = human immunodeficiency virus; IDDM = insulin-dependent diabetes mellitus; QTcF = QT 
interval as corrected for heart rate by Frederica’s formula; SBP = systolic blood pressure; 
T4 = thyroxine; TSH = thyroid-stimulating hormone; ULN = upper limit of normal.


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Screen failures (Section 3.9) previously excluded for a positive drug screen for cocaine, 
marijuana, or other illicit drugs are not eligible to be retested or rescreened.  Screen 
failures previously excluded for a positive blood alcohol test or a positive urine drug 
screen due to use of prescription or over-the-counter (OTC) medications or products may 
be retested or rescreened once for participation in the trial with consent of the medical 
monitor.  Screen failures excluded for any other reasons may be retested (the evaluation 
may be repeated within the screening period) or rescreened at any time if the exclusion 
characteristic has changed.  A subject may be rescreened more than once after discussion 
with and approval by the medical monitor.  In the event that a screen failure is 
rescreened, a new ICF must be signed, a new screening number assigned, and all 
screening procedures repeated.
Nonchildbearing potential is defined as male and female subjects who are surgically 
sterile (ie, male subjects who have undergone bilateral orchidectomy and female subjects 
who have undergone bilateral oophorectomy or hysterectomy) and female subjects who 
have been postmenopausal for at least 12 consecutive months.
Subjects must agree to restrictions to medications and lifestyle as described in Section 4.
3.5
Endpoints
3.5.1
Primary Endpoint
3.5.1.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the change from baseline to Week 12 in the CMAI total 
score.
3.5.2
Secondary Endpoints
3.5.2.1
Key Secondary Efficacy Endpoint
The key secondary efficacy endpoint is the change from baseline to Week 12 in the 
Clinical Global Impression Severity of Illness (CGI-S) score, as related to agitation.
3.5.2.2
Secondary Efficacy Endpoints
Secondary efficacy endpoints are as follows:

Change from baseline to Week 12 in CMAI subscale scores (aggressive behavior, 
physically nonaggressive behavior, verbally agitated behavior)

Change from baseline in CMAI total score for each trial visit during the double-blind 
treatment period


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
Change from baseline in CGI-S for each trial visit during the double-blind treatment 
period

Clinical Global Impression Improvement of Illness (CGI-I) score at each trial visit 
during the double-blind treatment period

CMAI-based responder analysis as described in the statistical analysis plan (SAP)

CGI-I responder analysis as described in the SAP
3.5.3
Exploratory Endpoints
 
 
3.5.4
Safety Endpoints
Safety and tolerability will be evaluated by reports of adverse events (AEs), clinically 
significant changes in: physical examinations, neurological examinations, vital signs, 
body weight, waist circumference, clinical laboratory tests, and 12-lead 
electrocardiograms (ECGs).  Other safety variables will include body mass index (BMI), 
the MMSE score and assessments of suicidality (Sheehan Suicidality Tracking Scale 
[Sheehan-STS]), EPS (the Simpson Angus Scale [SAS], the Abnormal Involuntary 
Movement Scale [AIMS], and the Barnes Akathisia Rating Scale [BARS]).
Adverse events will be examined by frequency, severity, seriousness, discontinuation, 
and relationship to treatment.  Mean change from baseline and the incidence of 
potentially clinically relevant abnormal values will be calculated for vital signs, body 
weight, routine laboratory tests (including prolactin), and ECG parameters.  Mean change 
from baseline will be calculated for glycosylated hemoglobin (HbA1c), waist 
circumference, and BMI (derived programmatically from body weight and height 
measurements).  A central ECG service will be used to review all ECGs to standardize 
interpretations for the safety analysis.  Extrapyramidal symptoms (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-subject 


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listings of physical and neurological examination findings will be reviewed as a further 
assessment of safety.
3.5.5
Pharmacokinetic/Pharmacodynamic Endpoints
Plasma concentrations will be determined for brexpiprazole and descriptive statistics will 
be calculated.  Concentrations of metabolites of brexpiprazole that are not identified in 
the protocol may also be determined if needed. No formal statistical comparisons are 
planned.  Additional population or PK or pharmacodynamic modeling may be performed 
as a separate analysis by combining data from this trial with data from all other trials.
3.6
Measures to Minimize/Avoid Bias
3.6.1
Randomization
During the trial, administration of the IMP will be double-blind.  In other words, neither 
the investigator nor the subject will have knowledge of the treatment assignment (ie, 
placebo or brexpiprazole).  Treatment assignments will be based on a computer-generated 
randomization code provided by the Otsuka Pharmaceutical Development & 
Commercialization, Inc. (OPDC) Biometrics Department.  Sponsor personnel, including 
those involved in monitoring, data management, and data analysis, will not have access to 
the treatment code during the trial.  Access to the treatment codes will be restricted to 
personnel charged with generating and maintaining randomization files, packaging trial 
medication, operating eSource, and reporting serious adverse events (SAEs) to regulatory 
agencies.  The randomization will be stratified by site.  Subjects will be randomized to 
brexpiprazole or placebo in a 2:1 ratio within each stratum.  Within the brexpiprazole 
arm, subjects will be further randomized in a 1:2 ratio to 2 mg/day or 3 mg/day.
3.7
Trial Procedures
The time from enrollment of the first subject to the last (330th) subject’s last trial visit 
will be approximately 4.0 years, of which approximately 3.75 years are allotted for 
recruitment of subjects.  Enrollment timelines could be shortened, as the trial may stop at 
the interim analysis based on the interim analysis result. Individual participation for 
subjects who complete the trial will range from 16 to 22 weeks, consisting of a 2- to 42-
day screening period, a 12-week double-blind treatment period, and a 30-day follow-up 
period.  All subjects, with the exception of those entering the optional open-label 
extension trial, whether they complete the trial or are withdrawn prematurely for any 
reason, 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 


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attempts will be made to collect mortality data by telephone contact with the subject’s 
caregiver at Week 16.
The Schedule of Assessments is summarized in Table 3.7-1.


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Table 3.7-1
Schedule of Assessments
Visit
Assessment
Screeninga
Baseline
(Day 0)
Week
2
(±2 
days)
Week
4
(±2 
days)
Week
6
(±2 
days)
Week
8
(±2 
days)
Week
10
(±2 
days)
Week
12 or 
ETb
(±2 
days)
Follow-
upc
(+2 
days)
Week
16d
Notes
ENTRANCE and HISTORY
Informed consent
X
Section 3.4.1.1
Inclusion and exclusion criteria
X
X
Section 3.4
Demography
X
Medical history
X
Psychiatric history
X
Neurological history
X
Section 3.7.3.3
Section 3.7.5.3.2
Prior medication washout
X
Section 4.1
HBsAg and anti-HCV
X
Eligibility assessment by CST and IAP
X
Section 3.1
MRI or CT scane
X
Section 3.7.3.3
Randomization
X
EFFICACY
CMAI
X
X
X
X
X
X
X
X
CGI-S
X
X
X
X
X
X
X
X
CGI-I
X
X
X
X
X
X
SAFETY
Physical examination
X
X
Section 3.7.5.3.1
Neurological examination
X
X
Section 3.7.5.3.2
Vital signs
X
X
X
X
X
X
X
X
Section 3.7.5.3.3
Body weight
X
X
X
Section 3.7.5.3.3
Clinical laboratory tests (hematology, 
serum chemistry, urinalysis)
X
Xf
X
X
Section 3.7.5.2


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Table 3.7-1
Schedule of Assessments
Visit
Assessment
Screeninga
Baseline
(Day 0)
Week
2
(±2 
days)
Week
4
(±2 
days)
Week
6
(±2 
days)
Week
8
(±2 
days)
Week
10
(±2 
days)
Week
12 or 
ETb
(±2 
days)
Follow-
upc
(+2 
days)
Week
16d
Notes
Prolactin (blinded)
X
X
Section 3.7.5.2
TSH with reflex to free T4 if abnormal
X
Section 3.7.5.2
HbA1c
X
X
Section 3.7.5.2
PT, aPTT, and INR
X
Section 3.7.5.2
Urine pregnancy test (women of 
childbearing potential) only
X
X
Section 3.7.5.2
ECG
X
X
X
X
Section 3.7.5.4
Urine drug screen and blood alcohol test
X
Section 3.7.5.2
Section 4.2
MMSE
X
X
X
Sheehan-STS
X
X
X
Section 3.7.5.5.4
Extrapyramidal symptoms scales (SAS, 
AIMS, BARS)
X
X
Adverse events
X
X
X
X
X
X
X
X
X
Section 5
Pharmacokinetic sampling
X
X
X
Section 3.7.6.1.1
 
Concomitant medications
X
X
X
X
X
X
X
X
X
Section 3.7.4
Mortality status assessment
X
Section 3.7.1.5
OTHER PROCEDURES
IMP dispensing
X
X
X
X
X
X
Section 8.4
IMP accountability
X
X
X
X
X
X
X
aPTT = activated partial thromboplastin time; INR = International Normalized Ratio; PT = prothrombin time.
aSee Section 3.7.1.1.
bSee Section 3.1.
cSee Section 3.8.3.2.


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dNote that this visit is 16 weeks postbaseline and only for subjects who terminate early from the trial.
eIf a previous MRI or CT scan of the brain performed after the onset of symptoms of dementia is not available, then an MRI/CT scan of the brain should be 
performed during screening. In addition, a repeat MRI/CT scan of the brain may be requested to be performed by CST or the IAP in order to confirm 
eligibility.  
fIf a fasting blood sample was obtained at the screening visit and less than 14 days have elapsed since the screening visit, clinical laboratory tests 
(hematology, serum chemistry, and urinalysis) do not need to be repeated at the baseline visit.


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3.7.1
Schedule of Assessments
3.7.1.1
Screening
The screening period begins after informed consent has been obtained.  All required 
assessments will be performed as described in the Schedule of Assessments 
(Table 3.7-1).  Subjects will participate in screening activities from 2 days up to 42 days, 
with the goal of completing all screening activities within 30 days, if possible.  The 
screening period maximum of 42 days may be extended after discussion with and 
approval by the medical monitor.  After a subject has provided consent, sites will obtain a 
subject ID number for the subject by accessing eSource.  Completion of screening 
activities may require more than one visit.
Sites are required to communicate certain aspects of subject data during the screening 
period to CST and the IAP, as detailed in the Operations Manual.  The CST and IAP 
must approve subject eligibility in order for the subject to be randomized.  The following 
should also be noted:

At the time of the subject’s screening visit, the caregiver will be provided a document 
that will outline all caregiver responsibilities and their role in this 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 investigator must assess the capacity of the subject to provide informed consent 
during the screening period.  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 Section 3.4.1.

An assessment of all inclusion and exclusion criteria will be made to determine the 
subject’s eligibility for the trial.

A general clinical evaluation will be performed, including concurrent medical 
conditions, medical history over the past 2 years, and medical history beyond 2 years 
that is considered to be clinically relevant per the investigator’s judgment.

Washout from prohibited concomitant medications, if applicable, will begin after 
consent has been obtained (see Section 4.1).

The eligibility review for each subject will be completed and submitted to CST and 
the IAP per the Operations Manual.

The subject’s caregiver or facility staff will complete a diary daily (if possible) after 
the ICF is signed, continuing through Week 12 or ET.


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3.7.1.2
Baseline (Day 0)
If the subject is found to be eligible for the trial during the screening period, all required 
baseline assessments will be performed according to the Schedule of Assessments 
(Table 3.7-1).  The following should also be noted:

Approval from CST and the IAP for randomization of subject will be verified.

Inclusion and exclusion criteria will be verified.

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.

Diary recording will continue.

The subject will take the first dose of the IMP from the assigned blister card on Day 1 
(ie, 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.
3.7.1.3
Double-blind Treatment Period
3.7.1.3.1
Weeks 2, 4, 6, 8, and 10
All subjects will be evaluated at Weeks 2, 4, 6, 8, and 10.  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 3.7-1).  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.

Diary recording will continue.

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.
3.7.1.4
End of Treatment (Week 12)
All required evaluations will be performed as described in the Schedule of Assessments 
(Table 3.7-1). The Week 12 visit signifies the end of treatment for all subjects.  
Therefore, all subjects will undergo a complete evaluation at Week 12 (± 2 days).  In 
addition, Week 12 or 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 


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medications for the treatment of agitation or other prohibited medications.  The following 
should be noted:

Diary recording will be stopped.

Final IMP accountability will be performed.
Subjects who complete the 12-week double-blind treatment period of Trial 331-14-213 
may be eligible to enter a 12-week open-label extension trial.
If this trial is terminated early due to overwhelming efficacy from the interim analysis, 
subjects in this trial at the time may be offered entry into the open-label extension trial 
(Trial 331-201-00182) if they choose to participate.
3.7.1.5
Follow-up
All required assessments will be performed as described in the Schedule of Assessments 
(Table 3.7-1). All subjects, with the exception of those entering the optional open-label 
extension trial, 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.
3.7.2
Efficacy Assessments
It is required that adequately trained and experienced clinicians administer the CMAI, 
, CGI-S, and CGI-I.  In addition, the raters must be certified for 
this trial to administer the CMAI.  Notations in the subject’s trial records should 
substantiate the ratings.  Training, certification, and materials for rating will be provided 
by a rater training group.
A caregiver must be identified during the screening period for participation in the 
interview for the CMAI, 
 and other applicable trial assessments.  
In addition to providing responses to trial questionnaires, the identified caregiver will be 
interviewed by the trial personnel regarding the subject’s general medical condition, 
behavioral symptoms, and activities of daily living.  If the subject is in an 
institutionalized setting, the identified caregiver will gather information from several 
informants, including staff from the day, afternoon, and night shifts, as well as from 
reliable family members or friends, in order to provide an accurate and comprehensive 


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overview of the subject’s behavioral symptoms and condition.  If the subject is in a 
non-institutionalized setting, the identified caregiver can gather information from the 
caretaker (if different than the identified caregiver) or from other informants who are in a 
position to observe the subject and provide information regarding behavioral symptoms 
and activities of daily living.  Details on the caregiver requirements can be found in 
Section 3.3.1.
3.7.2.1
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.18  As initially described by Cohen-Mansfield18 and outlined in 
the Instruction Manual for the CMAI19 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.
3.7.2.2
Clinical Global Impression Severity of Illness (CGI-S)
The severity of agitation for each subject will be rated using the CGI-S.20  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.
3.7.2.3
Clinical Global Impression Improvement of Illness (CGI-I)
The efficacy of brexpiprazole in the treatment of agitation will be rated for each subject 
using the CGI-I.20  The investigator (or designee) will rate the subject’s total 
improvement (as related to agitation) compared to baseline whether or not it is due 
entirely to drug treatment.  Response choices are 0 = not assessed, 1 = very much 
improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally 
worse, 6 = much worse, and 7 = very much worse.


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.
3.7.3
Other Assessments
3.7.3.1
National Institute of Neurological and Communicative 
Disorders and Stroke and the Alzheimer’s Disease and 
Related Disorders Association
The NINCDS-ADRDA, which has shown good reliability and validity, provides criteria 
for the possible and probable diagnosis of Alzheimer’s disease.25  These criteria require 
that cognitive impairment and a suspected dementia syndrome be confirmed by 
neuropsychological testing for a clinical diagnosis of Alzheimer’s disease.  The 
NINCDS-ADRDA criteria specify 8 cognitive domains that may be impaired in 
Alzheimer’s disease:  memory, language, perceptual skills, attention, constructive 
abilities, orientation, problem solving, and functional abilities.
3.7.3.2
Hachinski Ischemic Scale (Rosen Modification)
The Rosen-modified Hachinski Ischemic Scale assesses whether a subject’s dementia is 
likely due to vascular causes by the response to 8 questions:  abrupt onset, stepwise 
deterioration, somatic complaints, emotional incontinence, history of hypertension, 
history of stroke, focal neurologic signs, and focal neurologic symptoms.26  The Rosen 
modified Hachinski Ischemic Scale will be completed to assess eligibility for the trial by 
the same physician who performs the neurological examination (see Section 3.7.5.3.2).
3.7.3.3
Magnetic Resonance Imaging/Computed Tomography Scan of 
the Brain
If a previous magnetic resonance imaging (MRI) or computed tomography (CT) scan of 
the brain performed after the onset of the symptoms of dementia is not available, then an 
MRI or CT scan should be performed during screening.  In addition, a repeat MRI or CT 
scan of the brain may be requested to be performed by CST or the IAP in order to 
confirm eligibility.
3.7.3.4
International Psychogeriatric Association
The IPA developed a provisional consensus definition of agitation utilizing Diagnostic 
and Statistical Manual of Mental Disorders, Fifth edition (DSM-5) terminology.  The 
definition is intended to advance further research in agitated patients with cognitive 
impairment.  The IPA provisional consensus definition of agitation16 is described in 
Table 3.7.3.4-1.


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Table 3.7.3.4-1
Consensus Provisional Definition of Agitation 
in Cognitive Disorders
Item
Definition
A.
The patient meets criteria for a cognitive impairment or dementia syndrome (eg, Alzheimer’s 
disease, frontotemporal dementia, dementia with Lewy bodies, vascular dementia, other 
dementias, a pre-dementia cognitive impairment syndrome such as mild cognitive impairment 
or other cognitive disorder).
Note: Only subjects who meet the NINCDS-ADRDA criteria for Alzheimer’s Disease as 
noted in Inclusion Criterion #3 (Section 3.4.2) are eligible for this trial.
B.
The patient exhibits at least one of the following behaviors that are associated with observed 
or inferred evidence of emotional distress (eg, rapid changes in mood, irritability, outbursts).  
The behavior has been persistent or frequently recurrent for a minimum of 2 weeks’ and 
represents a change from the patient’s usual behavior.
(a) Excessive motor activity (examples include: pacing, rocking, gesturing, pointing fingers, 
restlessness, performing repetitious mannerisms).
(b) Verbal aggression (eg, yelling, speaking in an excessively loud voice, using profanity, 
screaming, shouting).
(c) Physical aggression (eg, grabbing, shoving, pushing, resisting, hitting others, kicking 
objects or people, scratching, biting, throwing objects, hitting self, slamming doors, tearing 
things, and destroying property).
C.
Behaviors are severe enough to produce excess disability, which in the clinician’s opinion is 
beyond that due to the cognitive impairment and including at least one of the following:
(a) Significant impairment in interpersonal relationships.
(b) Significant impairment in other aspects of social functioning.
(c) Significant impairment in ability to perform or participate in daily living activities.
D.
While co-morbid conditions may be present, the agitation is not attributable solely to another 
psychiatric disorder, suboptimal care conditions, medical condition, or the physiological 
effects of a substance.
3.7.4
Prior and Concomitant Medications
The investigator will record all medications and therapies taken by the subject from 
30 days prior to signing of informed consent 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.
3.7.5
Safety Assessments
3.7.5.1
Adverse Events
Refer to Section 5, Reporting of Adverse Events.


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3.7.5.2
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.  Urine will be 
collected and blood will be drawn from each subject during screening prior to treatment 
with the IMP.  Subjects should be fasting for a minimum of 8 hours prior to the blood 
draws, if possible.  If fasting blood samples are not feasible at screening, nonfasting 
blood samples may be obtained initially for determining eligibility for the trial.  A fasting 
blood sample is required at baseline prior to dosing.  Clinical laboratory tests at other 
visits should be drawn fasting, if possible, but must be drawn after a minimum 8-hour 
fast at Week 12 or ET.  Vital sign measurements and ECG assessments should be 
completed before any blood samples are collected.  See exclusion criteria (Section 3.4.3) 
based on screening laboratory tests.  If a fasting blood sample was obtained at the 
screening visit and less than 14 days have elapsed since the screening visit, clinical 
laboratory tests (hematology, serum chemistry, and urinalysis) do not need to be repeated 
at the baseline visit.  The results of these tests must be reviewed by the investigator prior 
to initiation of the administration of the IMP.  Urinalysis is not required at Week 8.  
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 3.7.5.2-1.


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Table 3.7.5.2-1
Clinical Laboratory Assessments
Hematology
WBC count with differential
RBC 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)
Urine Drug Screen
Amphetamines
Barbiturates
Benzodiazepines
Cannabinoids
Cocaine
Marijuana
Methadone
Opiates
Phencyclidine
Propoxyphene
Other
Blood alcohol
Additional Tests (Screening Only)
HBsAg
Anti-HCV
Serum Chemistry
ALP
ALT (SGPT)
AST (SGOT)
BUN
CPK
Creatinine
Total bilirubin
Triglycerides
Cholesterol (total, LDL, and HDL)
Calcium
Chloride
Glucose
Insulin
Sodium
Potassium
Total protein
Uric acid
GGT
Prolactin (blinded)
Albumin
Additional Tests
Urine pregnancy (women of childbearing potential)a
TSH, with reflex to free T4 if TSH is abnormal
PT, aPTT, and INR (screening only)
HbA1c
ALP = alkaline phosphatase; BUN = blood urea nitrogen; GGT = gamma-glutamyl transferase; 
HDL = high-density lipoprotein; LDL = low-density lipoprotein; RBC = red blood cell; WBC = white 
blood cell.
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.
A pregnancy test will be conducted in women of childbearing potential (WOCBP; 
Section 5.5) prior to trial intervention; results must be available prior to the 
administration of the IMP.  Pregnancy tests can be performed at any point during the trial 
if pregnancy is suspected.  An additional pregnancy test will be conducted in WOCBP at 
the Week 12 or ET visit.


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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.  
Refer to Appendix 2 for criteria for identifying values of potential clinical relevance.
The following laboratory test results at screening are exclusionary:

Platelets ≤ 75,000/mm3

Hemoglobin ≤ 9 g/dL

Neutrophils, absolute ≤ 1000/mm3

Aspartate transaminase (AST) > 2 × upper limit of normal (ULN)

Alanine transaminase (ALT) > 2 × ULN

Creatine phosphokinase (CPK) > 3 × ULN, unless discussed with and approved by 
the medical monitor

Albumin < 3 g/dL 

HbA1c ≥ 8%

Abnormal free thyroxine (T4), unless discussed with and approved by the medical 
monitor.  (Note:  Free T4 is measured only if the result for thyroid-stimulating 
hormone [TSH] is abnormal.)
3.7.5.3
Physical and Neurological Examination and Vital Signs
3.7.5.3.1
Physical Examinations
A complete physical examination will be performed at screening and will consist of 
measurement of height and waist circumference and a review of the following body 
systems:  head, eyes, ears, nose, and throat; thorax; abdomen; urogenital; extremities; 
neurological (see Section 3.7.5.3.2); and skin and mucosa.  At screening, height will be 
measured with a stadiometer, measuring stick or tape.  Repeat measurement of height is 
not required at the physical examinations scheduled for the Week 12 or ET visit.  Waist 
circumference will be measured at each physical examination (screening and Week 12 or 


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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.27
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.
3.7.5.3.2
Neurological Examinations
A detailed neurological examination will be performed by a physician at screening, 
Week 12 or 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 
satisfactory conclusion.  If new potentially clinically relevant neurological signs or 
symptoms are identified, referral to a neurologist is recommended.
3.7.5.3.3
Vital Signs
Vital sign measurements will include body weight, body temperature, systolic blood 
pressure (SBP), diastolic blood pressure (DBP), and heart rate.  The following guidelines 
will aid in the standardization of body weight measurements:


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
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.
Subjects with uncontrolled hypertension (screening DBP > 95 mmHg in any position) or 
symptomatic hypotension at screening or baseline are excluded from the trial as are 
subjects with orthostatic hypotension, which is defined as a decrease of ≥ 30 mmHg in 
SBP or a decrease of ≥ 20 mmHg in DBP within 3 minutes of standing compared to the 
previous supine blood pressure or development of symptoms (see Table 3.7-1).  In 
addition, subjects should be excluded if they have any other vital sign measurement at 
screening or baseline that, in the investigator’s judgment, is medically significant in that 
it would impact the safety of the subject or the interpretation of the trial results.  
However, any abnormal screening or baseline vital sign result(s) considered to be 
clinically significant should be repeated to confirm the finding(s) before excluding the 
subject from the trial.  Refer to Appendix 3 for a list of potentially clinically significant 
vital signs.
3.7.5.4
Electrocardiogram Assessments
Standard 12-lead ECGs will be recorded at screening and at the visits specified in 
Table 3.7-1.  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 


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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.
If during screening, according to the investigator's judgment, any abnormal ECG finding 
is deemed medically significant (impacting the safety of the subject or the interpretation 
of the trial results) or meets an exclusion criterion (see Table 3.4.3-1), the subject should 
be excluded from the trial.  Abnormal results for ECGs should be repeated once at 
screening with 3 consecutive ECG recordings to ensure reproducibility of the 
abnormality before excluding a subject based on the criteria noted above.  Each ECG 
recording should be taken approximately 5 minutes apart (the ECG result reported will be 
evaluated at each time point).  The central ECG service will provide the corrections for 
the 3 ECGs performed.  Based on the QT interval as corrected for heart rate by 
Fridericia’s formula (QTcF) reported by the central service, a subject will be excluded if 
the corrections are ≥ 450 msec in men and ≥ 470 msec in women for 2 of the 3 time 
points of the ECGs done, unless due to ventricular pacing.  If only 1 ECG time point has 
a QTcF of ≥ 450 msec in men and ≥ 470 msec in women, and this is not reproduced at 
either of the other 2 time points, the subject can be included in the trial.
Refer to Appendix 4 for a list of potentially clinically relevant ECG abnormalities to 
guide investigators for the assessment of potential ECG abnormalities for clinical 
significance postrandomization.  Exclusion criteria for screening do not apply as 
mandatory discontinuation criteria for subjects who are already randomized.  Please 
consult the medical monitor in case of questions.
3.7.5.5
Other Safety Assessments
3.7.5.5.1
Simpson Angus Scale
The SAS28 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 


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administered and the use of the medication documented, including a notation of the drug 
name, dose, and time of administration on the eSource.
3.7.5.5.2
Abnormal Involuntary Movement Scale
The AIMS20 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).
3.7.5.5.3
Barnes Akathisia Rating Scale
The BARS29 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 


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the eSource.  The BARS global score is defined as the global clinical assessment of 
akathisia.
3.7.5.5.4
Sheehan Suicidality Tracking Scale
Suicidality will be monitored during the trial using the Sheehan-STS.30  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” 
versions 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, 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 (see Table 3.4.3-1).  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.
3.7.5.5.5
Mini-Mental State Examination
The MMSE31 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 
(refer to Table 3.4.2-1) and is also to be completed at baseline and Week 12 or ET.
3.7.6
Pharmacokinetic/
 Assessments
3.7.6.1
Pharmacokinetic Assessments
3.7.6.1.1
Pharmacokinetic Blood Samples
The PK samples will be collected at baseline and during Week 8 and Week 12 or ET 
visits.  The samples will be collected at the same time as clinical laboratory sample 
collection for the designated trial visits, as applicable.  Every possible effort should be 
made to collect PK samples at the same time at each visit.  Furthermore, the subject 
should be advised to take the IMP at approximately the same time each day throughout 
the trial, but most importantly, prior to each PK sampling.  The date and time of the last 
2 doses of IMP prior to each sample draw, and the date and time of the actual blood draw 


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will be recorded on the eSource.  Vital sign and ECG assessments should be completed 
before any blood samples are collected.  All blood samples will be shipped to the testing 
facility for analysis.  Detailed handling and shipping instructions are provided in 
Appendix 1.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.7.7
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.
3.7.8
Independent Data Monitoring Committee
This trial will be monitored by an independent DMC.  The DMC will periodically 
monitor safety based on a predetermined schedule.  In addition, an interim analysis of 
efficacy data is planned during the course of the trial, and will be performed by the 
independent DMC.  The sponsor will remain blinded to the observed results of the 
interim analysis, and will only receive recommendations as per the interim analysis plan 
and DMC Charter.  The DMC meetings will occur as outlined in the DMC Charter, but 
can be convened at any time at the discretion of the DMC chair or the trial medical 
officer.  The details of the DMC structure and its roles and responsibilities will be 
documented in a DMC Charter.
3.7.9
Independent Adjudication Panel and Clinical Surveillance Team
The IAP will consist of medical experts from different specialties, independent from the 
sponsor or designee, who in collaboration with the CST at Syneos Health™ will use 
external quality oversight methods to promote appropriate subject enrollment.  Such 
methods will require sites to communicate certain aspects of subject data during the 
screening period to CST and the IAP, as detailed in the Operations Manual.  Eligibility 
review must be completed for each subject and submitted to CST and the IAP per the 
Operations Manual.  Subjects cannot be randomized until approval from CST and the 
IAP has been received.  The investigator is responsible for ensuring that subjects are 
eligible for enrollment into the trial and for assessing subject safety throughout the trial.  
The IAP will provide an independent assessment of the subject’s eligibility at time of 
enrollment and may request exclusion of a subject from entry into the trial.


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3.8
Stopping Rules, Withdrawal Criteria, and Procedures
3.8.1
Entire Trial or Treatment Arm(s)
If the sponsor terminates or suspends the trial for any reason, prompt notification will be 
given to investigators, IRBs or IECs, and regulatory authorities in accordance with 
regulatory requirements.
3.8.2
Individual Site
Individual trial site participation may be discontinued by the sponsor, the investigator, or 
the IRB or 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 or IEC 
at the site.
3.8.3
Individual Subject Discontinuation
3.8.3.1
Treatment Discontinuation
After randomization, 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 3.8.3.4.  Refer to the Schedule of Assessments (Table 3.7-1) for a description of 
follow-up procedures.
3.8.3.2
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.
All subjects have the right to withdraw at any time during treatment without prejudice.  
The investigator can discontinue a subject’s participation in the trial at any time if 
medically necessary.  In addition, 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


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
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 3.12, 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 (or matching placebo)

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

Subject transfers from an institutionalized setting to a non-institutionalized setting, or 
vice versa.  In case of a brief hospitalization, determination of subject eligibility to 
stay in the trial must be made based on subject safety by the investigator and medical 
monitor.
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 
continuation based on subject safety.  The investigator will consult with the medical 
monitor to determine subject continuation in the trial.


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3.8.3.3
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 3.8.3.1).  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 3.8.3.2 to determine if the subject can continue 
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 


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of the above degrees of follow-up are considered to have completely withdrawn their 
consent to participate in the trial.
3.8.3.4
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.
3.9
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, 
whether through randomization or open assignment.  For this trial, treatment begins with 
the first dose of the IMP.  If a subject fails to qualify for the trial during the 42-day 
screening period for a reason other than a positive screen for cocaine, marijuana, or other 
illicit drugs, the subject is permitted to be rescreened at a later date.  A subject may be 
rescreened more than once after discussion with and approval by the medical monitor.  
The medical monitor must be contacted before rescreening any subjects who initially 
failed screening due to a positive drug screens resulting from use of prescription or OTC 
medications or products.  In the event that the subject is rescreened for trial participation, 
a new ICF must be signed, a new screening number assigned, and all screening 
procedures repeated.
3.10
Definition of Completed Subjects
The treatment period is defined as the time period during which subjects are evaluated for 
primary 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 Week 12 visit will be defined as trial completers.
3.11
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted on or before 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 


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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 
the subject via certified mail or an alternative similar method, where appropriate, before 
assigning a “lost to follow-up” status.
3.12
Subject Compliance
Responsible trial personnel will dispense the IMP (ie, brexpiprazole or matching placebo) 
according to the visits outlined in the Schedule of Assessments (Table 3.7-1).  
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.
3.13
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
All subjects must discontinue all prohibited medications after signing the ICF during the 
screening period to meet the protocol-specified washout periods.  The required duration 
of washout for selected prohibited medications is provided in Table 4.1-1.  All other 
psychotropic agents not listed in Table 4.1-1 are prohibited and must be discontinued at 
least 24 hours before the first dose of IMP.  Select CYP2D6 inhibitors and CYP3A4 


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inhibitors and inducers are listed in Table 4.1-2.  The oral benzodiazepine therapy 
permitted during the trial is summarized in Table 4.1-3.
Table 4.1-1
List of Restricted and Prohibited Medications
All other psychotropic agents not listed in the below table are prohibited and must be discontinued 
at least 24 hours before the first dose of IMP.
Medication
Prior to Randomization
During Double-Blind Treatment 
Period
1.
Medications to treat 
Alzheimer’s disease 
(cholinesterase inhibitors, 
memantine, or other 
cognitive enhancers)
Allowed provided that the dose 
has been stable for 90 days 
prior to randomization, and 
there is no decrease or 
discontinuation within 30 days 
prior to randomization.
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
7-day washout
Prohibited
High-dose antipsychotics 
exceeding the equivalent 
of ≥ 3 mg of risperidone 
(eg ≥ 5 mg of haloperidol, 
≥ 375 mg quetiapine, 
≥ 10 mg olanzapine, or 
local equivalent)
Not allowed within 90 days 
prior to screening.
Prohibited
Clozapine
Not allowed within 30 days 
prior to randomization.
Prohibited
2.
Depot or long-acting 
injectable antipsychotic 
drugs
Washout of 1.5 times the 
dosing interval (according to 
the prescribing information) 
prior to randomization.
Prohibited
3.
Antidepressants
Allowed provided that the dose 
has been stable for 30 days 
prior to randomization.
Antidepressant medications that 
are CYP2D6 or CYP3A4 
inhibitors are prohibited and 
require a 7-day washout; 
fluoxetine requires a 28-day 
washout (see Table 4.1-2 for 
prohibited antidepressant 
medications).  If a medication is 
discontinued, the subject must 
be stable off the drug for 30 
days prior to randomization.
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)
7-day washout
Prohibited
5.
Anticonvulsants
7-day washout
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 and must be discontinued 
at least 24 hours before the first dose of IMP.
Medication
Prior to Randomization
During Double-Blind Treatment 
Period
6.
Benzodiazepines 
(short-acting)a
Allowed but limited to 
4 days/week between screening 
and randomization with a 
maximum dose of 2 mg/day of 
lorazepam (or equivalent) or 
less depending on dose-limiting 
side effects.
During the first 4 weeks of the 
randomized period (baseline to 
Week 4 visit): allowed but limited 
to 4 days/week with a maximum 
dose of 2 mg/day of lorazepam (or 
equivalent) depending on dose-
limiting side effects.  Prohibited 
after the Week 4 visit.
7.
Non-benzodiazepine sleep 
agentsb
If a bedtime dose of a sleep 
agent for insomnia was taken 
prior to randomization on a 
regular basis, a stable pretrial 
dose of the sleep agent may be 
continued as needed during the 
trial.  If a sleep agent was not 
previously taken prior to 
randomization and needs to be 
initiated, medication should be 
limited to a maximum dose of 
5 mg/day of zolpidem (or 
equivalent).
If a bedtime dose of a sleep agent 
for insomnia was taken prior to 
randomization on a regular basis, 
a stable pretrial dose of the sleep 
agent may be continued as needed 
during the trial.  If a sleep agent 
was not previously taken prior to 
randomization 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.
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 symptomsc
7-day washout
Prohibited
10.
Propranolold
For treatment of akathisia or 
tremor:  7-day washout
For treatment of heart disease: 
allowed provided that the dose 
has been stable for 30 days 
prior to randomization and total 
dose does not exceed 
60 mg/day
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. 


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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 and must be discontinued 
at least 24 hours before the first dose of IMP.
Medication
Prior to Randomization
During Double-Blind Treatment 
Period
11.
Varenicline
7-day washout
Prohibited
12.
Medications to treat other 
medical conditions, such 
as hypertension, 
hypercholesterolemia, 
etc., and anti-platelet 
agents
Allowed provided that the dose 
has been stable for 30 days 
prior to randomization
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)
7-day washout
Prohibited
14.
CYP2D6 inhibitors or 
CYP3A4 inhibitors and 
inducers (see Table 4.1-2)
7-day washout
Prohibited
CNS = central nervous system; GABA = gamma-aminobutyric acid.
aUse of intramuscular benzodiazepines are prohibited throughout the trial.  However, limited use of 
specific oral benzodiazepines is permitted during screening and during the first 4 weeks of the 
randomization period (baseline to Week 4 visit) to treat agitation or insomnia (see Table 4.1-3).
bNon-benzodiazepine sleep aids (ie, zolpidem, zaleplon, zopiclone, and eszopiclone only) are permitted 
for the treatment of insomnia, but not on the same day as administration of a benzodiazepine, 
regardless of indication.  For the non-benzodiazepine sleep aids, sites 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.
cAnticholinergic treatment of extrapyramidal symptoms (eg, benztropine) is not permitted within the 
7 days prior to randomization and for the duration of the trial. 
dPropranolol 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.


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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
aFluoxetine requires a 28-day washout prior to randomization.
Table 4.1-3
Oral Benzodiazepine (or Equivalent) Therapy 
During the Trial
Maximum Allowable Daily Dose (mg/day)
Oral Benzodiazepine (or 
equivalent)a
Screening
(limited to 4 days/week)
Baseline to Week 4 Visit 
(limited to 4 days/week)
Lorazepam
2
2
Oxazepam
30
30
aIn countries where no short-acting benzodiazepines are commercially available, use of oral diazepam 
(maximum allowable daily dose of 10 mg/day) or oral clonazepam (maximum allowable daily dose of 
1 mg/day) may be acceptable if prior authorization is obtained from the medical monitor.
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.


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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.
An SAE includes any event that results in any of the following outcomes:

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 


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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 
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.


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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 
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 AST or ALT that is  3 times the 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.


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5.5
Pregnancy
Women of childbearing potential 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

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).


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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 (if reasonable, taking into consideration any potential withdrawal 
risks) 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.
5.6
Procedure for Breaking the Blind
The investigator is encouraged to contact the sponsor and Clinical Research Organization 
(CRO) medical advisor to discuss their rationale for unblinding.  However, to prevent 
delays to the investigator or medical personnel responding to a potentially emergent 
situation, unblinding of IMP will not be dependent upon the investigator receiving 
approval from the sponsor or CRO medical advisor (ie, the investigator will be able to 
obtain the code break information independent of the sponsor or CRO medical advisor).  
The investigator must contact the sponsor and CRO medical advisor by telephone or 
e-mail with an explanation of the need for opening the treatment assignment code within 
24 hours of opening the code.  If the blind is broken, the Clinical Safety and 
Pharmacovigilance department must be notified immediately (see the cover page of this 
protocol for contact information).  Documentation of breaking the blind should be 
recorded in the subject’s medical record with the date and time the blind was broken and 
the names of the personnel involved.  Once the blind is broken for a subject, that subject 
may not reinitiate treatment with the IMP.


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5.7
Follow-up of Adverse Events
5.7.1
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).
5.7.2
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.
5.7.3
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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5.7.4
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
The PK samples will be analyzed for brexpiprazole (OPC-34712) and descriptive 
statistics will be calculated.  
 
  No formal statistical 
comparisons are planned.  
 
7
Statistical Analysis
7.1
Sample Size
The planned maximum sample size for this trial is approximately 330 randomized 
subjects.  The sample size will be approximately 255 subjects if the trial stops at the 
interim analysis.   Statistical assumptions and additional details are provided in the 
blinded addendum to the protocol.
7.2
Datasets for Analysis
The following samples are defined for this trial:

Randomized:  consists of all subjects who were randomized into this trial

Safety:  consists of all subjects who were administered at least 1 dose of IMP

Efficacy:  The intent-to-treat (ITT) population consists of all subjects in the 
randomized sample who took at least 1 dose of IMP (brexpiprazole or placebo), have 
a baseline, and at least 1 postbaseline evaluation for the CMAI total score.
In general, baseline of an efficacy endpoint is defined as the last observation of the 
endpoint before the subject is randomized.
The core dataset for all efficacy analyses is based on the ITT population, which is defined 
in the efficacy sample above.  As will be described below, in order to handle missing data 
and restrictions imposed by different types of analyses (eg, change from baseline 
analysis), datasets derived from the ITT population will be used for the efficacy analysis.


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7.3
Handling of Missing Data
In general, missing data will be handled by analysis of mixed-effect model repeated 
measures (MMRM) methodology based on observed-case (OC) data from protocol 
specified visits in the ITT population under the assumption of missing at random.  Details 
of sensitivity analyses under the assumption of missing data being missing not at random 
(MNAR) will be provided in the SAP as well as additional sensitivity analyses, as 
applicable.
The OC dataset consists of actual observations recorded at each visit during the 
double-blind treatment period, and no missing data will be imputed.
7.4
Primary and Secondary Endpoint Analyses
7.4.1
Primary Efficacy Endpoint Analysis
The primary endpoint will be analyzed using an MMRM model.  The primary efficacy 
outcome measure is the mean change from baseline to Week 12 in the CMAI total score.  
The primary statistical comparison of interest is brexpiprazole versus placebo.  The null 
hypothesis of this comparison is that there is no difference between the brexpiprazole 
treatment group and placebo in change from baseline to Week 12 in CMAI total score.
The statistical comparison will be performed by the MMRM analysis with an 
unstructured (UN) variance covariance matrix for the repeated measures in which the 
change from baseline in CMAI total score (at Weeks 2, 4, 6, 8, 10, and 12) will be the 
dependent variable based on the OC dataset.  The model will include fixed class-effect 
terms for treatment, trial site, visit week, and an interaction term of treatment by visit 
week and include the interaction term of baseline values of CMAI total score by visit 
week as a covariate.  The primary comparison between brexpiprazole and the placebo 
arm at Week 12 will be estimated as the difference between least squares (LS) means 
from the interaction term of treatment by visit week utilizing the computing software 
SAS procedure PROC MIXED.
Details of sensitivity analyses for MNAR, as well as additional sensitivity analyses will 
be prespecified in the SAP.
7.4.2
Key Secondary Efficacy Endpoint Analysis
The key secondary efficacy variable is the change from baseline to Week 12 in the CGI-S 
score, as related to agitation.  It will be analyzed by the same statistical methodology 
specified for the analysis of the primary efficacy variable.  In order to control the overall 


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type I error rate for this key secondary efficacy analysis, a hierarchical testing procedure 
will be used so that the overall experiment-wise type I error rate is maintained.  Thus, if 
the primary efficacy analysis for the CMAI total score (as described in Section 7.4.1) 
yields a statistically significant result for the comparison of brexpiprazole versus placebo, 
then the corresponding comparison for this key secondary efficacy variable (CGI-S 
score) will be tested.
7.4.3
Secondary Efficacy Endpoint Analysis
Secondary efficacy variables include the following:

Change from baseline to Week 12 in CMAI subscale scores (aggressive behavior, 
physically nonaggressive behavior, verbally agitated behavior)

Change from baseline in CMAI total score for each trial visit during the double-blind 
treatment period

Change from baseline in CGI-S for each trial visit during the double-blind treatment 
period

CGI-I score at each trial visit during the double-blind treatment period 

CMAI-based responder analysis as described in the SAP

CGI-I responder analysis as described in the SAP
Change from baseline will be evaluated using the same MMRM model described in the 
primary analysis.  The CGI-I score will be evaluated by the Cochran–Mantel–Haenszel 
row mean score differ test (van Eltern) controlling for trial site in 
last-observation-carried-forward (LOCF) analysis.
Further details and analysis methods will be described in the SAP.
 
 
 


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7.4.5
Interim Analysis
Details of the interim analysis will be provided in a blinded addendum to the protocol.
7.5
Analysis of Demographic and Baseline Characteristics
Demographic characteristics and disease severity at baseline will be summarized by 
descriptive statistics, eg, proportion, mean, median, standard deviation, and minimum and 
maximum values.
7.6
Safety Analysis
Standard safety variables to be analyzed include AEs, clinical laboratory tests, vital signs, 
ECGs, and physical examination.  In addition, data from the following safety scales will 
be evaluated:  MMSE score, assessments of suicidality (eg, Sheehan-STS), and EPS (eg, 
the SAS, AIMS, and BARS).  Safety analysis will be conducted based on the Safety 
Sample defined in Section 7.2.  In general, baseline of a safety variable is defined as the 
last observation of the variable before taking the first dose of IMP, unless specified 
otherwise.  Prospectively defined criteria will be used to identify potentially clinically 
relevant abnormal values for clinical laboratory tests, vital signs, ECGs, body weight, and 
BMI.  Details of safety analysis will be provided in the 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 by treatment group:

Treatment-emergent AEs (TEAEs)

TEAEs by severity

TEAEs potentially causally related to the IMP

TEAEs with an outcome of death

Serious TEAEs

TEAEs leading to discontinuation of the IMP


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The above summaries will also be prepared for TEAEs potentially causally related to the 
IMP.
7.6.2
Clinical Laboratory Data
Summary statistics for changes from baseline in the routine clinical laboratory 
measurements, and prolactin concentrations will be provided.  In addition, the incidence 
of potentially clinically relevant values identified using prospectively defined criteria for 
laboratory tests will be summarized.
7.6.3
Physical and Neurological Examination and Vital Signs Data
Physical and neurological examination findings will be listed by subject.  Potentially 
clinically relevant results in vital signs and body weight will also be summarized.  
Summary statistics for change from baseline in vital signs, body weight, and waist 
circumference will be provided.
7.6.4
Electrocardiogram Data
Mean change from baseline will be summarized by treatment group and by visit.  
Incidence of clinically relevant changes will be calculated for ECG parameters and 
summarized by treatment group and 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, and

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.
7.6.5
Other Safety Data
Change from baseline in scores for the MMSE score will be evaluated using ANCOVA 
with baseline value as a covariate and treatment as main factors.  The analyses will be 
based on the OC and LOCF datasets of the Safety Sample.
The suicidality (eg, Sheehan-STS) will be summarized by treatment group based on the 
OC dataset of the Safety Sample.  Details will be described in SAP.


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8
Management of Investigational Medicinal Product
For full details on IMP management, please refer to the OPC-34712 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 or matching placebo 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 or matching placebo 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.
8.3
Accountability
The investigator or designee must maintain an inventory record of IMP (including 
investigational, active control, or placebo) received, dispensed, administered, and 
returned.


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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 
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.


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
Online:  Send information required for reporting purposes (listed below) to 
OAPI-EQCProductComplaints@Otsuka-us.com

Phone:  Rocky Mountain Call Center at 1-800-438-6055.
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 
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 


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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, 
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.


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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:

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


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
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.
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.


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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.
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 


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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.
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 


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trial, investigators or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct.


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15
References
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Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, Ofstedal MB, et al. 
Prevalence of dementia in the United States: the aging, demographics, and memory 
study. Neuroepidemiology. 2007;29(1-2):125–132.
4
Antonsdottir IM, Smith J, Keltz M, Porsteinsson AP. Advancements in the treatment 
of agitation in Alzheimer's disease. Expert Opin Pharmacother. 
2015;16(11):1649-1656.
5
Cummings J, Mintzer J, Brodaty H, Sano M, Banerjee S, Devanand DP, et al. 
Agitation in cognitive disorders: International Psychogeriatric Association 
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Peters ME, Schwartz S, Han D, Rabins PV, Tschanz JT, Lyketsos CG. 
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Zahodne LB, Ornstein K, Cosentino S, Devanand DP, Stern Y. Longitudinal 
relationships between Alzheimer disease progression and psychosis, depressed mood, 
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Gauthier S, Cummings J, Ballard C,  Brodaty H, Grossberg G, Robert P, et al. 
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Gaugler JE, Wall MM, Kane RL, Menk JS, Sarsour K, Johnston JA, et al. Does 
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10 McGrath AM, Jackson GA. Survey of neuroleptic prescribing in residents of nursing 
homes in Glasgow. BMJ. 1996;312(7031):611-612.
11 Margallo-Lana M, Swann A, O’Brien J, Fairbairn A, Reichelt K, Potkins D, et al. 
Prevalence and pharmacological management of behavioural and psychological 
symptoms amongst dementia sufferers living in care environments. Int J Geriatr 
Psychiatry. 2001;16(1):39-44.
12 Bell JS, Taipale HT, Soini H, Pitkala KH. Sedative load among long-term care 
facility residents with and without dementia: a cross-sectional study. Clin Drug 
Investig. 2010;30(1):63-70.


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13 Otsuka Pharmaceutical Co, Ltd., Otsuka Pharmaceutical Development & 
Commercialization, Inc., H. Lundbeck A/S. REXULTI® (brexpiprazole) 
Investigator's Brochure, Edition 13. Otsuka Report, issued 10 Aug 2017.
14 Wu S. A phase 3, 12-week, multicenter, randomized, double-blind, placebo-
controlled trial to evaluate the efficacy, safety, and tolerability of 2 fixed doses of 
brexpiprazole (OPC-34712) in the treatment of subjects with agitation associated with 
dementia of the Alzheimer's type. Otsuka Protocol 331-12-283, issued 18 Feb 2013; 
amended 06 May 2013, 16 Dec 2013, 07 Jul 2014, and 10 Sep 2015.
15 Wu S. A phase 3, 12-week, multicenter, randomized, double-blind, 
placebo-controlled trial to evaluate the efficacy, safety, and tolerability of flexible 
dosing of brexpiprazole (OPC-34712) in the treatment of subjects with agitation 
associated with dementia of the Alzheimer's type. Otsuka Protocol 331-12-284, 
issued 06 May 2013, amended 16 Dec 2013, 07 Jul 2014, and 10 Sep 2015.
16 Agitation in cognitive disorders: International Psychogeriatric Association 
provisional consensus clinical and research definition. Int Psychogeriatr. 2014;1-11.
17 International Conference for Harmonisation (ICH) [homepage on the Internet]. E6:  
Good Clinical Practice:  Consolidated Guideline [finalized 1996 May, corrected 1996 
Jun; cited 2015 May 07]. Available from:  
http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html.
18 Cohen-Mansfield J, Marx MS, Rosenthal AS. A description of agitation in a nursing 
home. J Gerontol. 1989;44(3):M77-84.
19 Instruction Manual for the Cohen Mansfield Agitation Inventory (CMAI). Rockville, 
MD. The Research Institute of the Hebrew Home of Greater Washington; 1991.
20 Guy W. ECDEU Assessment Manual for Psychopharmacology. US Department of 
Health, Education, and Welfare publication (ADM) 76-338. Rockville, MD: National 
Institute of Mental Health; 1976.
21 Iverson GL, Hopp GA, DeWolfe K, Solomons K. Measuring change in psychiatric 
symptoms using the Neuropsychiatric Inventory: Nursing Home version. Int J Geriatr 
Psychiatry. 2002;17(5):438-443.
22 Cummings JL. Neuropsychiatric Inventory Nursing Home Version (NPI-NH): 
Comprehensive assessment of psychopathology in patients with dementia residing in 
nursing homes. 2009.
23 Lange RT, Hopp GA, Kang N. Psychometric properties and factor structure of the 
Neuropsychiatric Inventory Nursing Home version in an elderly neuropsychiatric 
population. Int J Geriatr Psychiatry. 2004;19(5):440-448.
24 Cummings JL. The Neuropsychiatric Inventory: assessing psychopathology in 
dementia patients. Neurology. 1997;48(5 Suppl 6):S10-16.


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25 Knopman DS, DeKosky ST, Cummings JL, Chuit H, Corey-Bloom J, Relkin N, et al. 
Practice parameter: diagnosis of dementia (an evidence-based review). Quality 
Standards Subcommittee of the American Academy of Neurology. Neurology. 
2001;56(9):1143-1153.
26 Rosen WG, Terry RD, Fuld PA, Katzman R, Peck A. Pathological verification of 
ischemic score in differentiation of dementias. Ann Neurol. 1980;7(5):486-488.
27 The Practical Guide: Identification, evaluation, and treatment of overweight and 
obesity in adults. Developed by National Institutes of Health National Heart, Lung 
and Blood Institute. North American Association for the Study of Obesity. NIH 
Publication Number 00-4084, October 2000.
28 Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta 
Psychiatr Scand Suppl. 1970;212(Suppl 44):S11-19.
29 Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672-
676.
30 Coric V, Stock EG, Pultz J, Marcus R, Sheehan DV. Sheehan Suicidality Tracking 
Scale (Sheehan-STS): Preliminary results from a multicenter clinical trial in 
generalized anxiety disorder. Psychiatry. 2009;6(1):26-31.
31 Folstein MF, Folstein SE, McHugh PR. "Mini-mental state": a practical method for 
grading the cognitive state of patients for the clinician. J Psychiatr Res. 
1975;12(3):189-198.


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Appendix 1
Handling and Shipment of Bioanalytical Samples 
Pharmacokinetic Sample Collection
Pharmacokinetic Sample Collection
A 4 mL sample of blood for PK testing will be collected into 4-mL Vacutainer tubes 
containing sodium heparin. Each tube should be gently inverted three to four times and 
then centrifuged at 2500 rpm for at least 10 minutes at 4°C.  The separated plasma from 
the tube should then be divided equally between the 2 bar-code labeled polypropylene 
tubes.  All tubes must be labeled using the central lab’s barcode labels provided with the 
sample collection kits.  The central lab’s requisition form must be completely filled out in 
regards to the PK sample information.  It is important to note the exact date and time of 
the blood collection, the date and time of the last dose of brexpiprazole/placebo prior to 
each blood draw, and the time of the meal closest to the last dose.
The sample must be stored at −70°C, if available, or −20°C or below.  If only a −20°C 
freezer is available, samples must be shipped within 30 days of collection and primary 
and backup samples may be shipped together.  If samples are stored in a −70°C freezer, 
then one tube (primary sample) will be shipped on dry ice to the central lab as soon as 
possible after collection.  Following confirmation that the first tube arrived safely, the 
second tube (backup sample) can also be shipped to the central lab.  If neither a −70°C 
nor −20°C freezer is available, the primary and backup PK samples must be shipped on 
dry ice in the same box to the central laboratory on the day of collection.
 
 
  
 
 
 
 
 
  
 
 


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Pharmacokinetic,
 Sample Shipment
Plasma or whole blood samples must be neatly packed in the kits provided by the central 
lab and restrained in a Styrofoam container. Boxes should be completely filled with dry 
ice to avoid air spaces that allow evaporation of the dry ice.  The Styrofoam container 
should be sealed with tape and placed in a cardboard box.  When possible, samples 
should be shipped together to reduce the number of shipments.
The central laboratory must be alerted of sample shipment.  Packages must not be 
shipped on Thursdays, Fridays, Saturdays, or any day prior to a holiday without the 
expressed consent of OPDC.  Shipments from clinical sites will be via an overnight 
carrier to the central laboratory. 


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Appendix 2
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance
Laboratory Tests
Criteria
Chemistry
     AST (SGOT)
 3 × ULN
     ALT (SGPT)
 3 × ULN
     Alkaline phosphatase
 3 × ULN
     Lactate dehydrogenase
 3 × ULN
     Blood urea nitrogen
 30 mg/dL
     Creatinine
 2.0 mg/dL
     Uric acid
        Men
 10.5 mg/dL
        Women
 8.5 mg/dL
     Bilirubin (total)
 2.0 mg/dL
     Creatine phosphokinase
> 3 × ULN
     Prolactin
> ULN
Hematology
     Hematocrit
        Men
 37 % and decrease of  3 percentage points from baseline
        Women
 32 % and decrease of  3 percentage points from baseline
     Hemoglobin
        Men
 11.5 g/dL
        Women
 9.5 g/dL
     WBC count
 2,800 mm3 or  16,000 mm3
     Eosinophils
 10%
     Neutrophils
 15%
     Absolute neutrophil count
 1,500/mm3
     Platelet count
 75,000/mm3 or  700,000/mm3
Urinalysis
     Protein
Increase of  2 units
     Glucose
Increase of  2 units
     Casts
Increase of  2 units
Additional Criteria
     Chloride
 90 mEq/L or  118 mEq/L
     Potassium
 2.5 mEq/L or  6.5 mEq/L
     Sodium
 126 mEq/L or  156 mEq/L
     Calcium
 8.2 mg/dL or  12 mg/dL
     Glucose
        Fasting
 100 mg/dL
        Nonfasting
 200 mg/dL
     Total cholesterol, fasting
 240 mg/dL
     LDL cholesterol, fasting
 160 mg/dL
     HDL cholesterol, fasting
        Men
< 40 mg/dL
        Women
< 50 mg/dL
     Triglycerides, fasting
150 mg/dL


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Appendix 3
Criteria for Identifying Vital Signs of Potential 
Clinical Relevance
Variable
Criterion Valuea
Change Relative to 
Baselinea
Heart rateb
> 120 bpm
< 50 bpm
 15 bpm increase
 15 bpm decrease
Systolic blood pressureb
> 180 mmHg
< 90 mmHg
 20 mmHg increase
 20 mmHg decrease
Diastolic blood pressureb
> 105 mmHg
< 50 mmHg
 15 mmHg increase
 15 mmHg decrease
Orthostatic hypotension
 20 mmHg decrease in systolic blood 
pressure and a  25 bpm increase in 
heart rate from supine to sitting/standing
Not applicable
(baseline status not 
considered)
Weight
−
 7% increase
 7% decrease
bpm = beats per minute
a In order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column.
b As defined in “Supplementary Suggestions for Preparing an Integrated Summary of Safety 
Information in an Original New Drug Application Submission and for Organizing Information in 
Periodic Safety Updates,” FDA Division of Neuropharmacological Drug Products draft (2/27/87).


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Appendix 4
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance
Variable
Criterion Valuea
Change Relative to 
Baselinea
Rate
     Tachycardia
 120 bpm
increase of  15 bpm
     Bradycardia
 50 bpm
decrease of  15 bpm
Rhythm
     Sinus tachycardiab
 120 bpm
increase of  15 bpm
     Sinus bradycardiac
 50 bpm
decrease of  15 bpm
     Supraventricular premature beat
all
not present  present
     Ventricular premature beat
all
not present  present
     Supraventricular tachycardia
all
not present  present
     Ventricular tachycardia
all
not present  present
     Atrial fibrillation
all
not present  present
     Atrial flutter
all
not present  present
Conduction
     1 atrioventricular block
PR  200 msec
increase of  50 msec
     2 atrioventricular block
all
not present  present
     3 atrioventricular block
all
not present  present
     Left bundle-branch block
all
not present  present
     Right bundle-branch block
all
not present  present
     Pre-excitation syndrome
all
not present  present
     Other intraventricular conduction blockd
QRS  120 msec
increase of  20 msec
Infarction
     Acute or subacute
all
not present  present
     Old
all
not present  present
 12 weeks post trial entry
ST/T Morphological
     Myocardial ischemia
all
not present  present
     Symmetrical T-wave inversion
all
not present  present
     Increase in QTc
QTcF  450 msec
(men)
QTcF  470 msec 
(women)
a In order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column.
b No current diagnosis of supraventricular tachycardia, ventricular tachycardia, atrial fibrillation, 
atrial flutter, or other rhythm abnormality.


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c No current diagnosis of atrial fibrillation, atrial flutter, or other rhythm abnormality.
d No current diagnosis of left bundle branch block or right bundle branch block.


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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, OPC-34712, 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 OPC-34712 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


This page is a manifestation of an electronically captured signature
SIGNATURE PAGE
Document Name: 331-14-213 Protocol Amendment 3
Document Number: 
Document Version: 9.0
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:min) -
UTC timezone
Clinical Approval
15-Sep-2020
14:50:16
Biostatistics Approval
14-Sep-2020
23:24:55
Approved for Clinical
Pharmacology
and Nonclinical
15-Sep-2020
13:37:17

SAP_001.pdf: 


Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigational Medicinal Product
Brexpiprazole (OPC-34712)
STATISTICAL ANALYSIS PLAN
A Phase 3, 12-Week, Multicenter, Randomized, Double-blind, Placebo-controlled, 
2-Arm, Fixed-dose Trial to Evaluate the Efficacy, Safety, and Tolerability of 
Brexpiprazole (OPC-34712) in the Treatment of Subjects With Agitation Associated 
With Dementia of the Alzheimer’s Type
Protocol No. 331-14-213
IND No. 115,960
EudraCT No. 2017-003940-19
Version:  2.0
Date:  25 January 2021
CONFIDENTIAL - PROPRIETARY INFORMATION
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Otsuka Pharmaceutical Development & Commercialization, Inc.
Clinical Study Report 331-14-213
16.1.9 Documentation of Statistical Methods
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Statistical Analysis Plan 331-14-213                                                                                 25 January 2021
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Table of Contents
Table of Contents ..........................................................................................2
List of In-text Tables.....................................................................................5
List of Appendices .........................................................................................6
List of Abbreviations and Definition of Terms...........................................7
1
Introduction..........................................................................................9
2
Trial Objectives ....................................................................................9
3
Trial Design...........................................................................................9
4
Sample Size and Power Justification................................................11
5
Data Sets and Missing Data...............................................................12
5.1
Data Sets for analysis ........................................................................................12
5.2
Handling of Missing Data .................................................................................12
6
Trial Conduct......................................................................................13
6.1
Subject Disposition and Reasons for Discontinuations.....................................13
6.2
Treatment Compliance ......................................................................................13
6.3
Protocol Deviation.............................................................................................13
7
Baseline Characteristics.....................................................................13
7.1
Baseline Definition............................................................................................13
7.2
Demographic Characteristics ............................................................................14
7.3
Disease History .................................................................................................14
7.4
Baseline Disease Characteristics.......................................................................14
8
Efficacy Analysis ................................................................................14
8.1
Primary Efficacy Analysis.................................................................................15
8.1.1
Primary Estimand ...........................................................................................15
8.1.2
Method of the Primary Analysis.....................................................................17
8.1.3
Technical Computation Details for Primary Efficacy Analysis .....................18
8.1.4
Sensitivity Analyses for the Primary Efficacy Endpoint................................19
8.1.5
Subgroup Analyses for Primary Efficacy Endpoint .......................................20
8.1.6
COVID-19 Pandemic related Sensitivity Analyses........................................20
8.1.7
Compliance related Sensitivity Analyses .......................................................21
8.1.8
Sensitivity Analyses based on the OTC Subset..............................................21
Clinical Study Report 331-14-213
16.1.9 Documentation of Statistical Methods
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Statistical Analysis Plan 331-14-213                                                                                 25 January 2021
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8.2
Key Secondary Analysis ...................................................................................21
8.3
Secondary Efficacy Analyses............................................................................22
8.5
Interim Analysis ................................................................................................23
8.6
Multiplicity Adjustment ....................................................................................24
8.7
Bias Estimation .................................................................................................26
9
Safety Analysis....................................................................................27
9.1
Adverse Events..................................................................................................27
9.2
Clinical Laboratory Tests..................................................................................27
9.2.1
Change from Baseline in Lab Tests................................................................27
9.2.2
Potentially Clinically Relevant Values...........................................................27
9.2.3
Potentially Liver Injury Related Laboratory Test...........................................28
9.2.4
Metabolic Change...........................................................................................28
9.3
Physical and Neurological Examination and Vital Signs..................................29
9.4
12-Lead ECG.....................................................................................................29
9.5
Body Weight, Waist Circumference and Body Mass Index .............................30
9.6
Simpson-Angus Scale, Abnormal Involuntary Movement Scale, and 
Barnes Akathisia Rating Scale ..........................................................................30
9.7
Mini-Mental State Examination........................................................................31
9.8
Suicidality Data.................................................................................................31
9.9
Concomitant Medications .................................................................................31
9.10
Extent of Exposure............................................................................................31
10
Conventions.........................................................................................32
10.1
Trial Visit Windows..........................................................................................32
10.2
Pooling of small centers ....................................................................................32
10.3
Scales: Rules for Scoring and Handling of Missing Data.................................33
10.3.1
Cohen-Mansfield Agitation Inventory............................................................33
10.3.2
Clinical Global Impression-Severity of Illness Scale.....................................34
10.3.3
Clinical Global Impression-Improvement Scale ............................................34
10.3.4
Neuropsychiatric Inventory ............................................................................35
10.3.5
Hachinski Ischemic Scale (Rosen Modification) ...........................................35
10.3.6
Simpson-Angus Scale.....................................................................................35
10.3.7
Abnormal Involuntary Movement Scale ........................................................36
Clinical Study Report 331-14-213
16.1.9 Documentation of Statistical Methods
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Statistical Analysis Plan 331-14-213                                                                                 25 January 2021
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10.3.8
Barnes Akathisia Rating Scale........................................................................36
10.3.9
Sheehan Suicidality Tracking Scale ...............................................................36
10.3.10
Mini-Mental State Examination .....................................................................37
11
References ...........................................................................................38
12
Proposed List of Summary Tables....................................................42
13
History of SAP Amendments ............................................................48
Clinical Study Report 331-14-213
16.1.9 Documentation of Statistical Methods
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Statistical Analysis Plan 331-14-213                                                                                 25 January 2021
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List of In-text Tables
Table 9.2.4-1
Criteria for Treatment-Emergent Significant Change in 
Lipids and Glucose ........................................................................28
Table 9.2.4-2
Criteria for Treatment-Emergent Metabolic Syndrome ................29
Table 9.4-1
Categorical Change Criteria in QT/QTc Parameters.....................30
Table 10.1-1
Trial Day and Visit Window..........................................................32
Clinical Study Report 331-14-213
16.1.9 Documentation of Statistical Methods
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Statistical Analysis Plan 331-14-213                                                                                 25 January 2021
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List of Appendices
Appendix 1
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance.........................................................................39
Appendix 2
Criteria for Identifying Vital Signs of Potential Clinical 
Relevance.......................................................................................40
Appendix 3
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance.........................................................................41
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Statistical Analysis Plan 331-14-213                                                                                 25 January 2021
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List of Abbreviations and Definition of Terms
Abbreviation
Definition
AAD
Agitation in Alzheimer’s dementia
AIM
Abnormal involuntary movement
AIMS
Abnormal Involuntary Movement Scale
ALT
Alanine transaminase
ANCOVA
Analysis of covariance
ARH1
Heterogeneous autoregressive of order 1
AST
Aspartate transaminase
BARS
Barnes Akathisia Rating Scale
BMI
Body mass index
bpm
Beats per minute
BUN
Blood urea nitrogen
CGI-I
Clinical Global Impression Improvement Scale
CGI-S
Clinical Global Impression Severity of Illness Scale
CMAI
Cohen-Mansfield Agitation Inventory
CMH
Cochran-Mantel-Haenszel
COVID-19
Coronavirus Disease 2019
CPK
Creatine phosphokinase
CRF
Case report form
CSH
Heterogenous compound symmetry
CST
Clinical Surveillance & Training
DMC
Data Monitoring Committee
ECG
Electrocardiogram
EPS
Extrapyramidal symptoms
ET
Early termination
FDA
Food and Drug Administration
HDL
high-density lipoprotein
IA
Interim Analysis
IAP
Interim Analysis Plan
ICF
Informed consent form
IMP
Investigational medicinal product
ITT
Intent-to-treat
LDL
Low-density lipoprotein
LOCF
Last-observation-carried-forward
LS
Least squares
MAR
Missing at Random
MCAR
Missing Completely at Random
MCMC
Monte Carlo Markov Chain
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple imputation
MMRM
Mixed-effect model repeat measurement
MMSE
Mini Mental State Examination
MNAR
Missing Not at Random
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Statistical Analysis Plan 331-14-213                                                                                 25 January 2021
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1
Introduction
This statistical analysis plan (SAP) expands the statistical section of the protocol 331-14-
213 Amendment 3 and documents the statistical methodology and data analysis 
algorithms and conventions to be applied for statistical analysis and reporting of efficacy, 
safety and tolerability data of the study. All amendments to the protocol and the 
addendums to protocol amendment are taken into consideration in developing this SAP.
2
Trial Objectives
Primary: To confirm the efficacy of brexpiprazole compared with placebo in subjects 
with Agitation in Alzheimer’s dementia (AAD)
Secondary: To evaluate the safety and tolerability of brexpiprazole compared with 
placebo in subjects with AAD
3
Trial Design
This is a phase 3, 12-week, multicenter, randomized, double-blind, placebo-controlled, 
fixed-dose trial designed to assess the efficacy, safety, and tolerability of brexpiprazole 
compared with placebo.  Subjects will be randomized in a 2:1 ratio to brexpiprazole or 
placebo.  Within the brexpiprazole arm, subjects will be further randomized in a 1:2 ratio 
to 2 mg/day or 3 mg/day, to explore the efficacy, safety, and tolerability of 2 mg/day and 
3 mg/day brexpiprazole versus placebo.  The randomization will be stratified by site.
The trial consists of a 2- to 42-day screening period, a 12-week double-blind treatment 
period, and a 30-day post-treatment safety follow-up period.  In addition, for all subjects 
who terminate early from the trial, attempts will be made to collect data on mortality 
status by telephone contact with the subject’s caregiver at Week 16.
This trial will utilize a two-stage group sequential design with one interim analysis (IA) 
and one final analysis. One unblinded interim analysis of efficacy data will be performed 
by an independent Data Monitoring Committee (DMC) on approximately the first 255 
randomized subjects who have either completed the Week 12 visit or discontinued early 
from the trial. The trial may stop for efficacy or futility at the conclusion of the IA or may 
continue to the final analysis when reaching the maximum planned sample size of about 
330 randomized subjects.   The sponsor will remain blinded to the observed results of the 
IA, and will only receive recommendation regarding whether to stop or continue the trial 
as per the interim analysis plan (IAP) and the DMC Charter.
The trial is organized as follows:
Screening Period
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Statistical Analysis Plan 331-14-213                                                                                 25 January 2021
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The screening period will range from 2 days up to 42 days, with the goal of completing 
all screening activities within 30 days, if possible, and will begin when the informed 
consent form (ICF) is signed, prior to the initiation of any procedures.  The screening 
period may be extended after discussion with and approval by the medical monitor.  An 
eSource method will be used to obtain an identification number for each subject with 
documented consent.
The purpose of the screening period is to determine the subject’s eligibility and to 
washout prohibited concomitant pharmacotherapy prior to randomization.
External quality oversight methods will be used by Clinical Surveillance & Training 
(CST) and the Independent Adjudication Panel to promote appropriate subject 
enrollment.
In addition, starting at screening and continuing throughout the 12-week double-blind 
treatment period, the subject’s behavior will be logged into a diary by the caregiver or 
facility staff.  This diary will be sent to CST on a routine basis in order to corroborate 
information recorded on the Cohen-Mansfield Agitation Inventory (CMAI).
12-week, Double-blind Treatment Period
Based on a randomization scheme, eligible subjects will be randomized in a 2:1 ratio to 
one of the following 2 treatment groups:

Brexpiprazole (further randomized in a 1:2 ratio to 2 mg/day or 3 mg/day)

Placebo
Subjects will follow a titration schedule, depending upon their assigned treatment group, 
to gradually increase their dose of the investigational medicinal product (IMP) to their 
assigned target dose as follows:
The first dose of IMP (brexpiprazole or placebo) will be administered on the day after the 
baseline visit (ie, Day 1) and ending on Week 12 or early termination (ET; the last day of 
the treatment period).
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Statistical Analysis Plan 331-14-213                                                                                 25 January 2021
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Subjects unable to tolerate their assigned dose of brexpiprazole (or matching placebo) 
will be withdrawn from the trial.  Down titration is not allowed at any time during the 
trial.  If a subject is withdrawn or discontinues prematurely before Week 12, 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.
Subjects will be evaluated at baseline and at Weeks 2, 4, 6, 8, 10, and 12 during the 
double-blind treatment period.  Trial-related efficacy and safety assessments will be 
performed as outlined in the Schedule of Assessments.
Subjects who complete the 12-week double-blind treatment period of Trial 331-14-213 
may be eligible to enter a 12-week open-label extension trial.  If this trial is terminated 
due to overwhelming efficacy from the IA, subjects in this trial at the time may be 
offered entry into the open-label extension trial if they choose to participate.
Follow-up Period
All subjects with the exception of those entering the optional open-label extension trial, 
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.
4
Sample Size and Power Justification
The initial sample size was calculated based on the treatment effect of 6.5 points with a 
standard deviation of 16.5 in the change from baseline to Week 12 in the CMAI total 
score, to achieve 89% power at a 2-sided alpha level of 0.05.  The initial sample size was 
300 total subjects randomized in a 2:1 ratio to brexpiprazole or placebo. The statistical 
assumption of the treatment effect of 6.5 points separation (for brexpiprazole versus 
placebo) is the same as that used for the two completed phase 3 AAD Trials 331-12-283 
and 331-12-284. 
To account for an empirical dropout rate of 12-13% (based on the two completed phase 3 
AAD Trials 331-12-283 and 331-12-284) and a lack of compliance at one identified 
clinical site, an increment of at least 30 additional subjects will be needed to maintain the 
target power. The resulting sample size is about 330 total subjects randomized in a 2:1 
ratio to brexpiprazole or placebo.  Within the brexpiprazole arm, subjects will be further 
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Statistical Analysis Plan 331-14-213                                                                                 25 January 2021
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randomized in a 1:2 ratio to 2 mg/day or 3 mg/day, to explore the efficacy, safety, and 
tolerability of 2 mg/day and 3 mg/day brexpiprazole versus placebo.
One IA will be conducted when approximately the first 255 subjects had an opportunity 
to complete (OTC) the 12-week trial. The conservative Bonferroni critical boundary will 
be used for the two-stage group sequential analysis. Specifically, the alpha allocated to 
the IA is 0.015 and the alpha left for the final analysis is 0.035, both two-sided. The two-
stage group sequential test will attain a power of 87%. 
5
 Data Sets and Missing Data
5.1
Data Sets for analysis
The following analysis samples are defined for this trial:
Randomized Sample:  Consists of all subjects who were randomized into this trial.  
Subjects are considered randomized when they are assigned a treatment number by the 
eSource method at the end of Screening Period.  A subject receiving trial treatment 
outside of the eSource will not be considered randomized, but safety will be reported.
Safety Sample:  Consists of all subjects who were administered at least one dose of IMP.  
Subjects will be excluded from this population only if there is documented evidence (ie, 
number of tablets dispensed = number of tablets returned or no trial drug dispensed) that 
the subject did not take trial drug.  If a subject is dispensed investigational medicinal 
product (IMP) and is lost to follow-up, he/she will be considered exposed.
Efficacy Sample:  The intent-to-treat (ITT) population consists of all subjects in the 
randomized sample, who took at least 1 dose of IMP and have a baseline and at least one 
post-baseline evaluation for the CMAI total score.
5.2
Handling of Missing Data
The CMAI is utilized as the primary efficacy assessment of a subject’s level of agitated 
behaviors.  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.
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Statistical Analysis Plan 331-14-213                                                                                 25 January 2021
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In addition, CMAI subscale scores for distinct agitation syndromes, also known as CMAI 
factors of agitation, will be calculated.  The three factors include:  aggressive behavior, 
physically nonaggressive behavior, and verbally agitated behavior.  Each CMAI factor 
will be calculated only when all items for the factor are recorded and non-missing.   
CMAI factors will be derived based on a subset of CMAI items8 as described in Section 
10.3.1. 
6
Trial Conduct
6.1
Subject Disposition and Reasons for Discontinuations
Subject disposition is summarized for the randomized sample.  Disposition is 
summarized by treatment group and by subgroup of gender, age (< 65; ≥ 65 and < 75; 
or ≥ 75), race, and region (North America or Other).
Reasons for discontinuation will be summarized for the randomized sample by treatment 
group and by subgroup of gender, age, race, and region.
6.2
Treatment Compliance
Compliance in taking investigational medicinal product is calculated by dividing the 
number of tablets taken by the total number of tablets the subjects were scheduled to take 
during the trial period.  For lost-to-follow-up subjects, last IMP end date record will be 
used as the treatment end date.
Number (%) of subjects meeting compliance cut-offs (< 70%, ≥ 70% and < 80%, ≥ 80% 
and < 90%, ≥ 90%) will be summarized by treatment group. 
6.3
Protocol Deviation
Protocol deviations are summarized by center and type of deviation for randomized 
subjects by treatment group.  A listing of protocol deviations will also be generated.
7
Baseline Characteristics
7.1
Baseline Definition 
For analyses of the double-blind treatment period data, the baseline is the Baseline 
measurement (expected to be at Day 0).  Baseline measurement is defined as the last 
available measurement prior to the start of double-blind IMP.
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Statistical Analysis Plan 331-14-213                                                                                 25 January 2021
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7.2
Demographic Characteristics
Baseline demographic characteristics including age, gender, race, ethnicity, height, 
weight, waist circumference, and body mass index (BMI) will be tabulated by treatment 
group for all randomized subjects.  Additional summaries by the following subgroups 
will be also generated: by gender, by age group (< 65; ≥ 65 and < 75; or ≥ 75), by race, 
and by region (North America or Other).
Mean, range and standard deviation will be used to describe continuous variables such as 
age.  Frequency distributions will be tabulated for categorical variables such as race.
7.3
Disease History
A summary of medical, psychiatric, neurological (excluding Alzheimer’s), and 
Alzheimer’s disease history will be presented for the Randomized Sample (by treatment 
group and overall).
7.4
Baseline Disease Characteristics
For the Randomized Sample, baseline and baseline disease characteristics will be 
summarized by treatment group and overall.  The following baseline characteristics will 
be summarized at baseline: number (%) of institutionalized / non institutionalized 
subjects; CMAI total score; CMAI derived agitation factors of aggressive behavior, 
physically nonaggressive behavior, and verbally agitated behavior; Clinical Global 
Impression-Severity of Illness Scale (CGI-S) score, 
 
 Mini Mental State Examination (MMSE) score; Sheehan 
Suicidality Tracking Scale (Sheehan-STS) score.
Number of subjects with presence of psychotic symptoms will be summarized at baseline 
using 
 
 
8
Efficacy Analysis
All efficacy analyses pertaining to the double-blind treatment period will be performed 
on the Efficacy Sample, and subjects will be included in the treatment group as 
randomized.
 
 
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Statistical Analysis Plan 331-14-213                                                                                 25 January 2021
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8.1
Primary Efficacy Analysis
The primary efficacy endpoint is the change from the baseline (Day 0 visit) to the end of 
the double-blind treatment period (Week 12 visit) in CMAI total score. The null 
hypothesis is that there is no difference in the mean change from baseline to Week 12 in 
CMAI total score between the two treatments brexpiprazole and placebo.  
The primary analysis will be performed on the Efficacy Sample which includes all 
randomized subjects who took at least one dose of IMP in the double-blind treatment 
period and who have both a baseline and at least one post-randomization CMAI total 
score during the double-blind treatment period. 
8.1.1 Primary Estimand 
In order to support the primary objective of the trial, treatment effect will be estimated 
under hypothetical situation had no subjects discontinued early from treatment.  Due to 
this strategy, the last collected efficacy assessment after premature trial discontinuation 
will be done only once at the Early Termination (ET) Visit.  Every effort will be made to 
complete all the ET evaluations prior to administering any additional medications for the 
treatment of agitation or any other prohibited medications.  In the case of terminal or lost 
to follow-up event, no ET evaluations would be expected, and only scheduled 
assessments performed before such an event would be used for the primary efficacy 
analysis.  All collected efficacy assessments will be slotted as per the Visit Window 
Definition, and only one assessment per visit window will be used for the primary 
efficacy analysis. If there are multiple assessments available in the same window, the 
latest one will be used.
This trial seeks to clarify the efficacy of brexpiprazole in improving the CMAI total score 
in the idealistic scenario of full adherence to the assigned treatment in all subjects. In 
clinical trial practice, however, instances of non-adherence such as treatment 
discontinuation are likely to occur before the study endpoint (i.e., the Week 12 Visit for 
this trial).  Given this consideration, the hypothetical estimand is the most appropriate for 
achieving the primary objective of the trial. The primary estimand is described by five 
attributes as follows. 

Target Population: Subjects with agitation associated with dementia of the 
Alzheimer’s type who have met protocol inclusion/exclusion criteria
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
Endpoint: Change from Baseline to Week 12 in the CMAI total score

Intercurrent Events: Intercurrent events refer to premature treatment 
discontinuation (i.e., early dropout) prior to Week 12 attributable to adverse 
events or lack of efficacy or withdrawal of consent/assent or any other causes.

Measure of Intervention effect: Difference in endpoint means between the 
brexpiprazole and placebo treatment arm.

Treatment regimen: 2 or 3 mg daily for 12 weeks.  
During the course of this trial, the COVID-19 pandemic broke out. The pandemic had a 
significant impact on many aspects of clinical trials. There are occasionally virtual visits 
(i.e., remote assessments) and possibly early discontinuation of treatment directly or 
indirectly related to the pandemic.  However, subjects were required to attend the 
screening, Day 1 and the end of trial visits in person (i.e., face-to-face). Note that virtual 
visits in the pandemic environment will not be treated as an intercurrent event for the 
primary analysis. Subjects who drop out with a reason relating to the COVID-19 
pandemic will be handled as they would have dropped out for another reason if the 
pandemic had not happened.  
The hypothetical strategy of handling intercurrent events will be used to clarify the 
efficacy of the brexipiprazole had there be no occurrence of intercurrent events, 
regardless of being COVID-19 related or not.  In other words, the estimand as described 
above will use the hypothetical strategy to address the treatment effect of interest that 
would be envisioned under the hypothetical setting of no occurrence of intercurrent 
events in the planned 12-week treatment period. 
The estimator will be the Mixed Model Repeated Measurements (MMRM) estimate for 
treatment difference at Week 12, based on all observed case (OC) data until 
discontinuation from the trial. This reflects the chosen strategies for the identified 
intercurrent events. Details of the model is provided in the next section. 
The OC data consist of actual observations recorded at each visit during the double-blind 
treatment period. The term “OC data” means that longitudinal data, if missing, will not be 
imputed by applying an imputation rule (e.g., the LOCF rule).  For example, if the subject 
had a missing CMAI total score at Week 12, then his score at Week 12 will not be 
imputed with his score observed at an earlier visit.  Note that in this SAP the OC data will 
be used as input data for all the MMRM analyses, though “OC” is not explicitly 
mentioned. 
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8.1.2 Method of the Primary Analysis 
Mean change from baseline in CMAI total score will be analyzed using a restricted 
maximum likelihood (REML)-based repeated measures approach. The analysis will be 
performed by fitting the MMRM model with an unstructured (UN) variance-covariance 
structure in which the change from the baseline in CMAI total score (Week 2, 4, 6, 8, 10, 
12) will be the dependent variable based on the OC data.  The analysis will include 
treatment (brexpiprazole and placebo), trial center, visit week, and an interaction term of 
treatment by visit week as the fixed, categorical effects and include the interaction term 
of baseline CMAI total score by visit week as covariates. In case there is a convergence 
problem with the MMRM model with the UN variance-covariance matrix, the following 
structures will be used in the order of 1) heterogeneous Toeplitz (TOEPH), 2) 
heterogeneous autoregressive of order 1 (ARH1), and 3) heterogeneous compound 
symmetry (CSH) and the first variance-covariance structure converging to the best fit will 
be used as the primary analysis.  
The Kenward-Roger approximation will be used to estimate denominator degree of 
freedom and adjust standard errors. The contrast (i.e., difference in least-square means 
between brexpiprazole and placebo) at the Week 12 visit will be estimated from the 
interaction term of treatment by visit week and will serve as the primary treatment 
comparison. The point estimate and the 95% confidence interval estimate of the contrast 
at the Week 12 visit will be reported. Significance test will be based on the contrast 
estimate at the Week 12 visit by using a two-sided 0.015 level for the interim analysis 
and a two-sided 0.035 level for the final analysis (when the trial does not stop at the 
interim analysis).  Analysis will be implemented using the software Statistical Analysis 
System® (SAS® version 9.4 or later) procedure PROC MIXED.
If a structured variance-covariance is used, the empirical sandwich estimator of the 
standard error of the fixed effects parameters will be used in order to deal with possible 
model misspecification of the variance-covariance matrix.
Small centers will be defined as centers that do not have at least one evaluable subject 
(evaluability with regard to the primary efficacy variable) in each treatment arm in the 
double-blind treatment period.  All small centers will be pooled within region to form 
“pseudo centers” for the purpose of analysis according to the following algorithm. Small 
centers will be ordered from the largest to the smallest based on the number of evaluable 
subjects.  The process will start by pooling the largest of the small centers with the 
smallest of the small centers until a non-small center is formed.  This process will be 
repeated using the centers left out of the previous pass.  In case of ties in center size, the 
center with the smallest center code will be selected.  If any centers are left out at the end 
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Statistical Analysis Plan 331-14-213                                                                                 25 January 2021
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of this process, they will be pooled with the smallest pseudo centers, or if no pseudo 
centers exist, they will be pooled with the smallest non-small center.  The pooling of the 
small centers will be performed within each region (North America and Other).
The chosen MMRM analysis assumes missing data to be “missing at random” (MAR), 
which is a reasonable assumption in longitudinal clinical trials.2  However, the possibility 
of “missing not at random” (MNAR) data can never be ruled out.  In order to further 
evaluate robustness of the primary results to the deviations from MAR assumptions, 
additional sensitivity analysis will be conducted.  Sensitivity analyses based on selection 
model3, pattern-mixture model4,5,6, and/or shared parameter model7 will be performed in 
order to explore data missing mechanisms of MNAR and investigate the response profile 
of dropout reason.  
In case of gross violations of the MMRM model assumptions, additional supportive 
analyses will be provided using the generalized version of the Cochran-Mantel-Haenszel 
(CMH) procedure (van Elteren test), controlling for trial site.
8.1.3 Technical Computation Details for Primary Efficacy Analysis
1) For primary analyses at Week 12 during the double-blind treatment period, the 
following algorithm will be used for including subjects in the 12-week analysis.
a) All scheduled visits during the 12 weeks after randomization, regardless of 
compliance to trial assessment schedule, will be included in the 12-week 
analysis.
b) All early terminated (ET) visits before week 12 will be included according to 
visit window in the 12-week analysis.
c) All ET visits > 12 weeks after randomization and outside of visit window will 
not be included in 12-week analysis.
d) The week number for an ET visit will be calculated by (date of ET visit 
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Statistical Analysis Plan 331-14-213                                                                                 25 January 2021
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Baseline is the CMAI total score at baseline (Day 0 visit).
8.1.4 Sensitivity Analyses for the Primary Efficacy Endpoint
Traditionally the dropout mechanisms are divided into three types4:  (1) Missing 
Completely at Random (MCAR), in which the probability of dropout doesn’t depend on 
the observed data and the missing data; (2) MAR, in which the probability of dropout 
depends on the observed data; and (3) MNAR, where the probability of dropout depends 
on the missing data and possibly the observed data.
Most of MNAR methods have treated all observations with dropout as if they fall within 
the same dropout type3.  In practice, we would find that different dropout reasons may be 
related to the outcomes in different ways, for example, detailed dropout reasons for this 
trial are:  adverse events (AE), lost to follow-up, protocol deviation, sponsor discontinued 
trial, subject met (protocol-specified) withdrawal criteria, subject was withdrawn from 
participation by the investigator, and subject withdrew consent to participate.  Dropout 
due to an AE may lead to MNAR dropout.  Subject withdrew consent may also lead to 
MNAR dropout.  However, it is debatable whether a dropout caused by subjects 
withdrew consent is MAR or MNAR.  Except AE, and subject withdrew consent, all 
other dropout reasons may be assumed as either MCAR or MAR dropout.
As sensitivity analyses for MAR assumption, analyses for MNAR will be carried out.  
Pattern Mixture Models (PMM) based on Multiple Imputation (MI) with mixed missing 
data mechanisms will be used to investigate the response profile of dropout subjects by 
last dropout reason under MNAR mechanism for the following three scenarios:

Dropout reasons due to AE as MNAR

Dropout reasons due to either AE or subject withdrew consent as MNAR

All dropouts as MNAR
Delta Adjustment Imputation Methods
This MNAR sensitivity analysis is to departure from MAR assumption by progressively 
increasing the delta until conclusion from the primary analysis is overturned.  The delta is 
0%, 10%, 20%, 30%, ..., 100% of the expected treatment difference of 6.5 points and/or 
the observed treatment difference between brexpiprazole and placebo from the primary 
analysis of MMRM model until conclusion of the primary analysis is overturned.  When 
delta = 0 the missing data are assumed to be MAR.  When delta > 0, the missing data are 
assumed to be MNAR.
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Statistical Analysis Plan 331-14-213                                                                                 25 January 2021
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1) Using Monte Carlo Markov Chain (MCMC) methodology from PROC MI to 
impute the intermittent missing data to a monotone missing pattern
2) Using a standard MAR-based multiple imputation approach from PROC MI to 
impute the monotone missingness data
3) For subjects in the treated group and with a dropout reason of AE or subject 
withdrew consent, a delta will be added for all the values after the dropout time
4) Using MMRM model in the primary analysis to analyze the completed data using 
PROC MIXED on the multiple imputed data
5) Obtaining the overall results using PROC MIANALYZE.
Placebo Based Imputation Methods
Similar to the “Standard” multiple imputations, except parameters for imputation model 
obtained from only the placebo (control) group.  Missing data for both placebo and drug 
group are imputed based on the imputation model derived from placebo data.  If drug 
improved outcomes prior to dropout, this benefit is carried into subsequent imputed 
values, but will diminish over time in accordance with the correlation structure.
8.1.5 Subgroup Analyses for Primary Efficacy Endpoint
Subgroup analyses of change from baseline in CMAI total score to every trial week in the 
double-blind treatment period will be performed for the following factors:

Gender

Race (White and All Other Races)

Age group (< 65; ≥ 65 and < 75; or ≥ 75)

Region (North America and Other)
Interaction effects of treatment-by-subgroup will be assessed at Week 12 for the 
subgroups identified in the previous paragraph.  The same MMRM model will be used as 
for the primary efficacy analysis with the addition of terms for subgroup-by-week and 
treatment-by-subgroup-by-week.  These treatment-by-subgroup interaction analyses will 
be presented in statistical documentation.
All subgroup analyses will be conducted using the same MMRM analysis as for the 
primary efficacy analysis except that the fixed class effect terms trial center will not be 
included in the model.
8.1.6 COVID-19 Pandemic related Sensitivity Analyses
On March 13, 2020, the national emergence concerning the COVID-19 pandemic was 
announced in the US. The following analyses will be performed on the Efficacy Sample 
to evaluate the sensitivity of the primary analysis results to the impact of pandemic. The 
same model (e.g., with the same set of explanatory variables and the response variable) as 
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Statistical Analysis Plan 331-14-213                                                                                 25 January 2021
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that for the primary efficacy analysis will be used for these analyses specified below. Of 
note, the definition of intercurrent events and the strategy for handling intercurrent events 
are identical to that for the primary efficacy analysis.
1) An MMRM analysis based on the pre-COVID Efficacy Sample. The pre-COVID 
Efficacy Sample comprises those subjects in Efficacy Sample who had completed 
or discontinued the trial before March 13, 2020.
2) An MMRM analysis based on the Efficacy Sample by using the subset of pre-
COVID data. The pre-COVID data consist of the data collected before March 13, 
2020.
3) An MMRM analysis based on the non-COVID Efficacy Sample. The non-COVID 
Efficacy Sample comprises those subjects in Efficacy Sample who had no remote 
assessment of the primary endpoint.
4) An MMRM analysis based on the Efficacy Sample by using the subset of non-
COVID data.  At the subject level, the non-COVID data refer to the data that 
exclude his/her first remote assessment of the primary endpoint and all the 
assessments thereafter.  
5) An MMRM analysis based on the Efficacy Sample by using the subset of data 
that exclude all remote assessments.
If the trial stops early for efficacy at the conclusion of IA, the above COVID-19 related 
sensitivity analyses will be performed on all available data including the data accrual post 
IA database lock. The point estimate along with the 95% confidence interval estimate of 
the treatment contrast will be presented for each of the above sensitivity analyses.
8.1.7 Compliance related Sensitivity Analyses
Two clinical sites were identified by audit as having had non-compliance issues. The 
primary analysis as described in Section 8.1.2 and the key secondary analysis as 
described in Section 8.2 will be repeated on all available data but with the exclusion of 
the data from the two identified sites. 
8.1.8 Sensitivity Analyses based on the OTC Subset
The primary analysis as described in Section 8.1.2 and the key secondary analysis as 
described in Section 8.2 will be repeated on the data of the OTC subset of the Efficacy 
Sample.
8.2
Key Secondary Analysis 
The key secondary efficacy variable is the change from baseline to Week 12 in the CGI-S 
score, as related to agitation.  It will be analyzed by the same statistical methodology 
specified for the analysis of the primary efficacy variable.  In order to control the overall 
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Statistical Analysis Plan 331-14-213                                                                                 25 January 2021
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type I error rate for this key secondary efficacy analysis, a hierarchical testing procedure 
will be used so that the overall experiment-wise type I error rate is maintained.  Thus, if 
the primary efficacy analysis for the CMAI total score yields a statistically significant 
result for the comparison of brexpiprazole versus placebo, then the corresponding 
comparison for this key secondary efficacy variable (CGI-S score) will be tested.
8.3
Secondary Efficacy Analyses
Secondary efficacy variables include the following:

Change from baseline to Week 12 in CMAI subscale scores (aggressive behavior, 
physically nonaggressive behavior, verbally agitated behavior)

Change from baseline in CMAI total score for each trial visit during the double-
blind treatment period

Change from baseline in CGI-S for each trial visit during the double-blind 
treatment period

CGI-Improvement (CGI-I) score at each trial visit during the double-blind 
treatment period 

CMAI response rate at every scheduled trial visit in the double-blind treatment 
period, where response is defined as ≥ 40%, ≥ 30%, and ≥ 20% reduction in 
CMAI total score from baseline;

CMAI Response Rate based on improvement from baseline in agitation status at 
every scheduled trial visit in the double blind treatment period;

CGI-I response rate at every scheduled trial visit in the double-blind treatment 
period, where response is defined as a CGI-I score of 1 or 2 (very much improved 
or much improved);
Change from baseline will be evaluated using the same MMRM model described in the 
primary analysis.  The CGI-I score will be evaluated by the Cochran–Mantel–Haenszel 
row mean score differ test (van Elteren) controlling for trial site in 
last-observation-carried-forward (LOCF) analysis.  Response endpoints will be evaluated 
by the CMH General Association Test controlling for trial site in LOCF analysis.
CMAI subscale scores or factors and agitated status for the first 3 factors will be derived 
based on a subset of CMAI items8 as described in Section 10.3.1.
Improvement in agitation status is defined as subject meeting agitation status criteria at 
baseline on at least one of the 3 subscale scores (aggressive, physically nonaggressive, 
verbally agitated) and changing the status to non-agitated for the same subscale, while not 
becoming agitated on another at each visit.
Each factor will be analyzed by the same statistical methodology specified for the 
analysis of the primary efficacy variable, based on the Efficacy Sample.
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Statistical Analysis Plan 331-14-213                                                                                 25 January 2021
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level of 0.05 (two-sided) will be used for this additional analysis. All on-going subjects 
will be given a chance to rollover to the active treatment extension trial Trial 331-201-
00182.
8.6
Multiplicity Adjustment
In this SAP, the term endpoint and hypothesis are interchangeably used. The hierarchical 
testing procedure11 will be applied to this trial to strongly control the experimental-wise 
error rate at 5% (two-tailed), wherein the experimental-wise error rate is the probability 
of making at least one false rejection of the true nulls arising from repeated testing of 
multiple hypotheses in a group sequential trial. The testing will be conducted on 5 
hypotheses of interest in the sequence specified below, respectively at the IA and at the 
final analysis (if the trial does not stop at the IA), by using pre-specified significance 
levels. The alpha-spending for the primary endpoint will be applied to the key secondary 
endpoint and other efficacy endpoints included in the hierarchical testing procedure.
1)  The primary efficacy endpoint via the MMRM analysis with an unstructured variance 
covariance, based on the OC data.
2)  The key secondary efficacy endpoint (i.e., Change from baseline to Week 12 in the 
CGI-S score) via the MMRM analysis with an unstructured variance-covariance, based 
on the OC data.
3)  Change from baseline to Week 12 in the CMAI subscale score (aggressive behavior) 
via the MMRM analysis with an unstructured variance-covariance, based on the OC data.
4)  Change from baseline to Week 12 in the CMAI subscale score (physically 
nonaggressive behavior) via the MMRM analysis with an unstructured variance-
covariance, based on the OC data.
5)  Change from baseline to Week 12 in the CMAI subscale score (verbally agitated 
behavior) via the MMRM analysis with an unstructured variance-covariance, based on 
the OC data.
The hierarchical testing procedure is described as follows. 
If the trial stops at the IA, the primary efficacy endpoint will be re-tested on all available 
data (including the recent data accrual post IA database lock) at a two-sided 0.05 level, as 
mentioned in Section 8.5. Meanwhile, the key secondary endpoint will be tested on the 
IA data at a two-sided 0.015 level and will also be tested on all available data (including 
the recent data accrual) at a two-sided 0.035 level. If either of these two tests is nominally 
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Statistical Analysis Plan 331-14-213                                                                                 25 January 2021
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significant at the pre-specified level, then statistical significance on the key secondary 
endpoint will be claimed and the testing will proceed down to test the CMAI subscale 
score (aggressive behavior). If neither of these two tests is nominally significant, then 
statistical significance on the key secondary endpoint cannot be claimed and testing will 
stop. Testing for each of the other secondary endpoints in the above sequence from 3) to 
5) will be conducted similarly to that of key secondary endpoint. Specifically, one test 
will be conducted on the IA data at a two-sided 0.015 level and the other will be on all 
available data at a two-sided 0.035 level. Decision rules regarding whether to claim 
statistical significance and whether to stop the testing will be similar as in the case of 
testing the key secondary endpoint.
If the trial does not stop at the IA, the above sequence of testing from 1) to 5) will be 
repeated for the final analysis with the use of a two-sided 0.035 level. In this scenario, the 
final analysis will be conducted using the data of approximately 330 subjects. There will 
be no data accrual after the database lock for the final analysis.
Below is the flowchart illustrating the above multiple testing procedure:
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Statistical Analysis Plan 331-14-213                                                                                 25 January 2021
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For completeness of the presentation, all unadjusted (unadjusted for multiplicity) p-
values will be reported regardless of whether the endpoints are nominally significant or 
not.
8.7
Bias Estimation
The naïve point estimate of the parameter mean difference is usually biased upward in a 
group sequential trial with early efficacy stopping. In this trial, the bias of the estimate of 
mean difference in change from baseline CMAI total score at Week 12 between 
brexpiprazole and placebo is fairly small due to (1) the sample size is not small; (2) 
information fraction for the IA is large, which is 255/330 = 0.77.  Regardless of the true 
mean difference θ, the bias of the mean difference estimate will not exceed 3.02% unit of 
standard deviation, per the analytic expression for bias (see the penultimate expression on 
Page 177 of Jennison & Turnbull (2000; Section 8.3)). As a result, the upper bound of the 
bias will be less than 0.5 point (in terms of the CMAI total score) assuming one unit of 
within-group standard deviation of 16.5 points. 
If the trial stops for efficacy at the IA, a rough bias estimate will be calculated by simply 
plugging the naïve estimate of mean difference θ into the following expression, which is 
a simplification from the bias expression mentioned above.
The small overestimation bias inherent in the analysis of a group sequential trial is 
practically negligible given the attenuating circumstance as follows.  Due to the 
enrollment challenges in the US and Western Europe, this study is expected to 
supplement enrollment with at least 25% of subjects from Eastern Europe and rest of the 
world (ROW). Based on the results observed in two completed pivotal studies, it is 
expected that, due to the different healthcare system and different standard of care in 
Eastern Europe, the effect size in that region would be reduced when compared to that of 
observed in US, Western Europe and potentially ROW. The oversampling of subjects 
from Eastern Europe is expected to result in underestimation of the true effect to such a 
degree that would negate any potential overestimation bias.  
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9
Safety Analysis
Standard safety variables to be analyzed include AEs, clinical laboratory tests, vital signs, 
electrocardiograms (ECGs), and physical examination.  In addition, data from the 
following safety scales will be evaluated:  MMSE score, assessments of suicidality (e.g, 
Sheehan-STS), and extrapyramidal symptoms (EPS; e.g, the Simpson-Angus Scale, 
abnormal involuntary movement scale [AIMS], and Barnes Akathisia Rating Scale 
[BARS]).  Safety analysis will be conducted based on the Safety Sample.  In general, 
baseline of a safety variable is defined as the last observation of the variable before 
taking the first dose of IMP, unless specified otherwise.  Prospectively defined criteria 
will be used to identify potentially clinically relevant (PCR) abnormal values for clinical 
laboratory tests, vital signs, ECGs, body weight, and BMI.
9.1
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 by treatment group:

Treatment-emergent AEs (TEAEs)

TEAEs by severity

TEAEs with an outcome of death

Serious TEAEs

TEAEs leading to discontinuation of the IMP
The above summaries will also be prepared for TEAEs potentially causally related to the 
IMP.
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 treatment and by visit.
9.2.2 Potentially Clinically Relevant Values
In addition, the incidence of treatment-emergent PCR values identified using 
prospectively defined criteria in Appendix 1 for laboratory tests will be summarized by 
treatment group.  A listing of PCRs by subject and by test will be provided.
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Statistical Analysis Plan 331-14-213                                                                                 25 January 2021
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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 be will summarized for subjects who met 
following criteria in the Short-term Controlled Trials and Long-term Open-label Trials 
groups.  The corresponding listing will be provided as well.

AST or ALT ≥ 3 × upper limit of normal (ULN) and 

T_Bili ≥ 2 × ULN 
9.2.4 Metabolic Change
In addition to mean change from baseline, the incidence of treatment emergent significant 
changes in fasting lipids, fasting glucose, and metabolic syndrome will be summarized by 
treatment group using the following criteria.
Table 9.2.4-1
Criteria for Treatment-Emergent Significant Change in 
Lipids and Glucose
Lab Parameter
Baselinea
Anytime Post Baseline
LDL Direct, Fasting  (mg/dL)
Borderline 100 < 160
Normal/Borderline < 160
Normal < 100
Any Value
High ≥ 160
High ≥ 160
Borderline/High ≥ 100
Increased ≥ 30
HDL Cholesterol, Fasting 
(mg/dL)
Normal ≥ 40
Any Value
Low <40
Decreased ≥ 20
Triglycerides, Fasting  (mg/dL)   
Normal < 150
Borderline 150 < 200 
Normal/Borderline < 200
Normal < 150
Any Value
High 200 < 500
High 200 < 500
High 200 < 500
Borderline/High/Very
High ≥ 150
Increased ≥ 50
Glucose Fasting, 
Serum(mg/dL)
Normal < 100
Impaired 100 < 126
Normal/Impaired < 126
Any Value
High ≥ 126
High ≥ 126
High ≥ 126
Increased ≥ 10
a Baseline is calculated from Day 0; if Day 0 is unavailable screen visit will be used
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Table 9.2.4-2
Criteria for Treatment-Emergent Metabolic Syndrome
Description
Lab Parameter
Anytime Post Baselinea
Central Obesity
Waist Circumference
Males: ≥ 102 cm
Females: ≥ 88 cm
Dyslipidemia
Triglycerides
≥ 150 mg/dL
HDL
Males: < 40 mg/dL
Females: < 50 mg/dL
Supine Blood Pressure
Systolic
≥ 130 mmHg
Diastolic
≥ 85 mmHg
Fasting Glucose
Glucose Fasting, Serum
≥ 100 mg/dL
a Baseline is calculated from Day 0; if Day 0 is unavailable screen visit will be used
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, and waist 
circumference will be provided by treatment group.
In addition, the incidence of treatment-emergent PCR values identified using 
prospectively defined criteria in Appendix 2 for vital signs and body weight will be 
summarized by 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 
treatment and by visit.
In addition, the incidence of treatment-emergent PCR values identified using 
prospectively defined criteria for ECG will be summarized by 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 double-blind 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
Body Weight, Waist Circumference and Body Mass Index
Analyses of body weight, waist circumference and BMI will be performed for the Safety 
Sample.  Body mass index is defined as weight in kilograms divided by the square of 
height in meters.  The mean change from baseline to Week 12 and the last visit in the 
double-blind treatment period in body weight will be tabulated and analyzed using 
analysis of covariance (ANCOVA).  The ANCOVA models will include the baseline as a 
covariate and the treatment group as fixed effect.
Percentages of subjects showing significant weight gain (≥ 7% increase in weight), as 
well as percentages of subjects showing significant weight loss (≥ 7% decrease in weight) 
from baseline to Week 12 (OC and LOCF) will be analyzed using CMH General 
Association Test.
9.6
Simpson-Angus Scale, Abnormal Involuntary Movement Scale, and 
Barnes Akathisia Rating Scale
The mean change from baseline to Week 12/ET in the double-blind treatment period 
obtained from the Simpson-Angus Scale total score, AIMS total score (total of the first 
7 item scores), and BARS Global Clinical Assessment will be performed for the Safety 
Sample and tabulated and analyzed using ANCOVA.
The ANCOVA model will include the baseline measure and the treatment group.
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The same analyses will be performed on the AIMS individual item scores 8, 9, and 10.  In 
addition, incidence of BARS Global Clinical Assessment of Akathisia during the 
double-blind treatment period by severity category will be provided.  Analyses of these 
EPS rating scales will be performed for the Safety Sample.
9.7
Mini-Mental State Examination
The mean changes from baseline to Week 12/ET visit in the double-blind treatment 
period in MMSE will be tabulated and analyzed by treatment group using ANCOVA.  
The ANCOVA model will include the baseline item score as covariate and treatment 
group as main effect.  The analyses will be performed for Safety Sample.
9.8
Suicidality Data
The mean changes from baseline to Week 12/ET visit in the double-blind treatment 
period in Sheehan-STS individual item scores, suicidal ideation subscale score, suicidal 
behavior subscale score, or total score will be tabulated and analyzed by treatment group 
using ANCOVA.  The ANCOVA model will include the baseline item score as covariate 
and treatment group as main effects.
Incidence of treatment emergent suicidal ideation, suicidal behavior will be summarized 
by treatment, and overall.
9.9
Concomitant Medications
Number and proportion of subjects taking concomitant medications prior to IMP, during 
the double-blind treatment period, and after IMP are tabulated by drug classification 
using the World Health Organization drug dictionary.
9.10 Extent of Exposure
The start date of double-blind IMP with brexpiprazole or placebo will be the first day of 
double-blind dosing.  The number and percentage of subjects who receive double-blind 
IMP will be presented by week and by 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 treatment 
group.
The mean daily dosage will be summarized by week and 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 
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treatment group the number of subjects receiving double-blind IMP, and the mean and 
range of the mean daily dose for each week.
10
Conventions
10.1 Trial 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.  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.
 
 
 
 
 
 
10.2 Pooling of small centers
Primary efficacy analysis will be performed on the ITT Efficacy Sample which comprises 
those subjects in the randomized sample who have a baseline value and at least one 
post-randomization value for CMAI total score in the double-blind treatment period.  
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Small centers will be defined as centers that do not have at least one evaluable subject 
(evaluable with regard to the primary efficacy variable) in each treatment arm in the 
double-blind treatment period.  All small centers will be pooled to form “pseudo centers” 
for the purpose of analysis according to the following algorithm.  Small centers will be 
ordered from the largest to the smallest based on the number of evaluable subjects (ie, 
subjects who have a baseline value and at least one post-randomization value for CMAI 
total score in the double-blind treatment period).  The process will start by pooling the 
largest of the small centers with the smallest of the small centers until a non-small center 
is formed.  This process will be repeated using the centers left out of the previous pass.  
In case of ties in center size, the center with the smallest center code will be selected.  If 
any centers are left out at the end of this process, they will be pooled with the smallest 
pseudo centers, or if no pseudo centers exist, they will be pooled with the smallest non-
small center.  The pooling of the small centers will be performed within each region 
(North America and Other).
10.3 Scales: Rules for Scoring and Handling of Missing Data
10.3.1
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 behavior occurring at a frequency of at least 3; or

at least three aggressive behavior occurring at a frequency of at least 2;
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
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
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 derivation8: Intentional Falling; Making 
Verbal Sexual Advances; Making Physical Sexual Advances; Strange Noises (weird 
laughter or crying); Eating or Drinking Inappropriate Substances.
10.3.2
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.
10.3.3
Clinical Global Impression-Improvement Scale
The efficacy of brexpiprazole in the treatment of agitation will be rated for each subject 
using the CGI-I.  The investigator (or designee) will rate the subject’s total improvement 
(as related to agitation) whether or not it is due entirely to IMP.  Response choices are 
0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 
4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse.
This is also a 7-point scale (1 to 7), with 1 being very much improved and 7 being very 
much worse.  The scale also includes 0: not assessed, which will be set to missing for 
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purposes of analysis.  At each visit other than randomization, the global improvement 
will be judged with respect to subject’s condition at randomization.
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
10.3.5
Hachinski Ischemic Scale (Rosen Modification)
The Rosen-modified Hachinski Ischemic Scale assesses whether a subject’s dementia is 
likely due to vascular causes by the response to 8 questions:  abrupt onset, stepwise 
deterioration, somatic complaints, emotional incontinence, history of hypertension, 
history of stroke, focal neurologic signs, and focal neurologic symptoms.  The Rosen 
modified Hachinski Ischemic Scale will be completed to assess eligibility for the trial by 
the same neurologist who performs the neurological examination.
10.3.6
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 
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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.
10.3.7
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.
10.3.8
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).
10.3.9
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, 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.
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10.3.10 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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Appendix 1
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance
Laboratory Tests
Criteria
Chemistry
AST (SGOT)
 3 ×  ULN
ALT (SGPT)
 3 × ULN
Alkaline phosphatase
 3 × ULN
LDH
 3 × ULN
BUN
 30 mg/dL
Creatinine
 2.0 mg/dL
Uric Acid
Men
 10.5 mg/dL
Women
 8.5 mg/dL
Bilirubin (total)
 2.0 mg/dL
CPK
 3 × ULN
Prolactin
> ULN
Hematology
Hematocrit
Men
 37% and decrease of  3 percentage points from Baseline
Women
 32% and decrease of  3 percentage points from Baseline
Hemoglobin
Men
 11.5 g/dL
Women
 9.5 g/dL
White blood count
 2,800/ mm3 or  16,000/ mm3
Eosinophils
 10%
Neutrophils
 15%
Absolute neutrophil count
 1,000/mm3
Platelet count
 75,000/mm3 or  700,000/ mm3
Urinalysis
Protein
Increase of  2 units
Glucose
Increase of  2 units
Casts
Increase of  2 units
Additional Criteria
Chloride
 90 mEq/L or  118 mEq/L
Potassium
 2.5 mEq/L or  6.5 mEq/L
Sodium
 126 mEq/L or  156 mEq/L
Calcium
 8.2 mg/dL or  12 mg/dL
Glucose
Fasting
 100 mg/dL 
Non-Fasting
 200 mg/dL
Total Cholesterol, Fasting
 240 mg/dL 
LDL Cholesterol, Fasting
 160 mg/dL 
HDL Cholesterol, Fasting
Men
< 40 mg/dL
Women
< 50 mg/dL
Triglycerides, Fasting
 150 mg/dL
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Appendix 2
Criteria for Identifying Vital Signs of Potential Clinical 
Relevance
Variable
Criterion Valuea
Change Relative to Baselinea
> 120 bpm
 15 bpm increase
Heart Rateb
< 50 bpm
 15 bpm decrease
> 180 mmHg
 20 mmHg increase
Systolic Blood Pressureb
< 90 mmHg
 20 mmHg decrease
> 105 mmHg
 15 mmHg increase
Diastolic Blood Pressureb
< 50 mmHg
 15 mmHg decrease
Orthostatic Hypotension
 20 mmHg decrease in systolic 
blood pressure and a  25 bpm 
increase in heart rate from supine 
to sitting/standing
Not Applicable
(baseline status not considered)
Weight

 7% increase
 7% decrease
a In order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column.
b As defined in “Supplementary Suggestions for Preparing an Integrated Summary of Safety 
Information in an Original NDA Submission and for Organizing Information in Periodic Safety 
Updates,” FDA Division of Neuropharmacological Drug Products draft (2/27/87).
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Appendix 3
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance
Variable
Criterion Valuea
Change Relative to Baselinea
Rate
Tachycardia
 120 bpm
increase of   15 bpm
Bradycardia
 50 bpm
decrease of  15 bpm
Rhythm
Sinus tachycardiab
 120 bpm
increase of  15 bpm
Sinus bradycardiac
 50 bpm
decrease of  15 bpm
Supraventricular premature beat
all
not present  present
Ventricular premature beat
all
not present  present
Supraventricular tachycardia
all
not present  present
Ventricular tachycardia
all
not present  present
Atrial fibrillation
all
not present  present
Atrial flutter
all
not present  present
Conduction
1 atrioventricular block
PR  200 msec
increase of   50 msec
2 atrioventricular block
all
not present  present
3 atrioventricular block
all
not present  present
Left bundle-branch block
all
not present  present
Right bundle-branch block
all
not present  present
Pre-excitation syndrome
all
not present  present
Other intraventricular conduction 
blockd
QRS  120 msec
increase of  20 msec
Infarction
Acute or subacute
all
not present  present
Old
all
not present  present
 12 weeks post trial entry
ST/T Morphological
Myocardial Ischemia
all
not present  present
Symmetrical T-wave inversion
all
not present  present
Increase in QTc
QTcF  450 msec 
(men)
QTcF  470 msec 
(women)
a In order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column.
b No current diagnosis of supraventricular tachycardia, ventricular tachycardia, atrial fibrillation, atrial 
flutter, or other rhythm abnormality.
c No current diagnosis of atrial fibrillation, atrial flutter, or other rhythm abnormality.
d No current diagnosis of left bundle branch block or right bundle branch block.
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Statistical Analysis Plan 331-14-213                                                                                 25 January 2021
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Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigational Medicinal Product
Brexpiprazole (OPC-34712)
Addendum to Statistical Analysis Plan Version 2.0
A Phase 3, 12-Week, Multicenter, Randomized, Double-blind, Placebo-controlled, 
2-Arm, Fixed-dose Trial to Evaluate the Efficacy, Safety, and Tolerability of 
Brexpiprazole (OPC-34712) in the Treatment of Subjects With Agitation Associated 
With Dementia of the Alzheimer’s Type
Protocol No. 331-14-213
IND No. 115,960
EudraCT No. 2017-003940-19
Version:  1.0 
Date:  08 September 2021
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Statistical Analysis Plan 331-14-213                                                                                 08 September 2021
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Table of Contents
Table of Contents ..........................................................................................2
1
Introduction..........................................................................................3
2
Modification to the Multiplicity Adjustment.....................................3
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Statistical Analysis Plan 331-14-213                                                                                 08 September 2021
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1
Introduction
This addendum to the statistical analysis plan (SAP) version 2.0 is to document a 
modification to the multiplicity adjustment after the approval of the original SAP (version 
2.0, issued on 29 January 29, 2021) and the interim analysis plan (version 4.0, issued on 
September 10, 2020), and to address FDA’s feedbacks on the SAP.  The modification 
will have no impact on the familywise Type-I error rate, which is strongly controlled at a 
two-sided 5% level. The statistical methodology, data analysis algorithms and 
conventions remain the same as those in the original SAP. 
2
Modification to the Multiplicity Adjustment
The hypotheses of interest for the planned labeling will be comprised of only the primary 
endpoint CMAI total score and the key secondary endpoint CGI-S score. The hypotheses 
pertaining to all other secondary endpoints will be excluded from the hierarchical testing 
procedure. 
The testing will be conducted on two hypotheses of interest in the order specified below:
1)  The primary efficacy endpoint, change from baseline to Week 12 in the CMAI total 
score
2)  The key secondary efficacy endpoint, change from baseline to Week 12 in the CGI-S 
score
After reviewing the unblinded interim analysis results, DMC recommended that the trial 
be continued to the planned end.  As a result, at the final analysis, the primary efficacy 
endpoint will be tested at a two-sided 3.5% significance level, and upon achieving 
significance on the primary endpoint, the key secondary endpoint will be tested at the 
same level. The hierarchical testing procedure controls the Type-I error rate for both the 
primary efficacy endpoint and the key secondary efficacy endpoint. 
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Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigational Medicinal Product
Brexpiprazole (OPC-34712)
Addendum 2 to Statistical Analysis Plan Version 2.0
A Phase 3, 12-Week, Multicenter, Randomized, Double-blind, Placebo-controlled, 
2-Arm, Fixed-dose Trial to Evaluate the Efficacy, Safety, and Tolerability of 
Brexpiprazole (OPC-34712) in the Treatment of Subjects With Agitation Associated 
With Dementia of the Alzheimer’s Type
Protocol No. 331-14-213
IND No. 115,960
EudraCT No. 2017-003940-19
Version:  Final 
Date:  31 May 2022
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Statistical Analysis Plan 331-14-213                                                                                31 May 2022
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Table of Contents
Table of Contents ..........................................................................................2
1
Introduction..........................................................................................3
2
Addition of List of EPS-related AEs...................................................3
3
Updated Proposed List of Summary Tables......................................4
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Statistical Analysis Plan 331-14-213                                                                                31 May 2022
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1
Introduction
This addendum to the statistical analysis plan (SAP) version 2.0 is to add the list of 
Extrapyramidal symptoms (EPS)-related adverse events (AEs) and document the changes 
in the Proposed List of Summary Tables after the approval of the original SAP (version 
2.0, issued on 29 January 29, 2021). The addition and changes will have no impact on the 
familywise Type-I error rate, which is strongly controlled at a two-sided 5% level. The 
statistical methodology, data analysis algorithms and conventions remain the same as 
those in the original SAP version 2.0. 
2
Addition of List of EPS-related AEs
EPS-related AEs are listed below and 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 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, 
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Statistical Analysis Plan 331-14-213                                                                                31 May 2022
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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.
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Statistical Analysis Plan 331-14-213                                                                                31 May 2022
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Statistical Analysis Plan 331-14-213                                                                                31 May 2022
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Statistical Analysis Plan 331-14-213                                                                                31 May 2022
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Statistical Analysis Plan 331-14-213                                                                                31 May 2022
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Statistical Analysis Plan 331-14-213                                                                                31 May 2022
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Statistical Analysis Plan 331-14-213                                                                                31 May 2022
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Statistical Analysis Plan 331-14-213                                                                                31 May 2022
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Statistical Analysis Plan 331-14-213                                                                                31 May 2022
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Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigational Medicinal Product
Brexpiprazole (OPC-34712)
INTERIM ANALYSIS PLAN
for
Protocol No. 331-14-213
IND No. 115,960
EudraCT No. 2017-003940-19
A Phase 3, 12-Week, Multicenter, Randomized, Double-blind, Placebo-controlled, 
2-Arm, Fixed-dose Trial to Evaluate the Efficacy, Safety, and Tolerability of 
Brexpiprazole (OPC-34712) in the Treatment of Subjects With Agitation Associated 
With Dementia of the Alzheimer’s Type
Version 4.0 
Date: 10 September 2020
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Otsuka Pharmaceutical Development & Commercialization, Inc.


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Protocol 331-14-213 Interim Analysis Plan                                                                       
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Table of Contents
Table of Contents ..........................................................................................2
List of Abbreviations and Definitions of Terms .........................................3
1
Introduction..........................................................................................4
2
Statistical Methods...............................................................................4
2.1
Sample Size and Power Justification...................................................................4
2.2
Interim Analysis ..................................................................................................5
3
Data Analysis ........................................................................................6
3.1
Planned Interim Analyses of Unblinded Efficacy data .......................................7
4
Confidentiality of Results ....................................................................7
5
Appendix ...............................................................................................8
5.1
Statistical Table Outputs .....................................................................................8
5.2
Summary of IAP Amendments ...........................................................................8


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Protocol 331-14-213 Interim Analysis Plan                                                                       
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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
AAD
CGI-S
Agitation in Alzheimer’s dementia
Clinical Global Impression - Severity of Illness
CMAI
Cohen-Mansfield Agitation Inventory
CP
Conditional power
DMC
Data Monitoring Committee
IA
Interim analysis
IAP
Interim analysis plan
IMP
Investigational medicinal product(s)
IWRS
Interactive web response system
LS
Least square
MMRM
Mixed-effect model repeated measure
OC
Observed case
OPDC
OTC
Otsuka Pharmaceutical Development & Commercialization, Inc.
Opportunity to complete
SAP
Statistical analysis plan
UN
Unstructured


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Protocol 331-14-213 Interim Analysis Plan                                                                       
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1
Introduction
This interim analysis plan (IAP) documents the statistical methodology, data analysis 
algorithms, and conventions to be applied in the interim analysis (IA) and reporting of 
efficacy data of Trial 331-14-213.
Protocol 331-14-213 is a phase 3, 12-week, multicenter, randomized, double-blind, 
placebo-controlled, fixed-dose trial designed to assess the efficacy, safety, and 
tolerability of brexpiprazole compared with placebo.  Subjects will be randomized in a 
2:1 ratio to brexpiprazole or placebo.  Within the brexpiprazole arm, subjects will be 
further randomized in a 1:2 ratio to 2 mg/day or 3 mg/day, to explore the efficacy, safety, 
and tolerability of 2 mg/day and 3 mg/day brexpiprazole versus placebo.  The 
randomization will be stratified by site.
The primary objective is to compare the efficacy of brexpiprazole with placebo in 
subjects with agitation associated with dementia of the Alzheimer’s type, as assessed by 
the change from baseline to week 12 in the Cohen-Mansfield Agitation Inventory 
(CMAI) total score.
The trial consists of a 2- to 42-day screening period, a 12-week double-blind treatment 
period, and a 30-day post-treatment safety follow-up period.  In addition, for all subjects 
who terminate early from the trial, attempts will be made to collect data on mortality 
status by telephone contact with the subject’s caregiver at Week 16.
2
Statistical Methods
2.1
Sample Size and Power Justification
A sample of 300 subjects was calculated based on the treatment effect of 6.5 points with 
a standard deviation of 16.5 in the change from baseline to Week 12 CMAI total score, to 
achieve 89% power at a 2-sided alpha level of 0.05.  Taking into account an empirical 
dropout rate of 12-13% (based on two completed phase 3 AAD trials) and a lack of 
compliance at one identified clinical site, an increment of at least 30 additional subjects is 
needed to maintain the target power. The resulting sample size is about 330 total subjects 
to be randomized in a 2:1 ratio to brexpiprazole and placebo.  Within the brexpiprazole 
arm, subjects will be further randomized in a 1:2 ratio to 2 mg/day and 3 mg/day, to 
explore the efficacy, safety, and tolerability of 2 mg/day and 3 mg/day brexpiprazole 
versus placebo.


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Protocol 331-14-213 Interim Analysis Plan                                                                       
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One interim look will be conducted when approximately the first 255 subjects have had 
an opportunity to complete (OTC) the 12-week trial. A Bonferroni boundary will be used 
for the two-stage group sequential analysis. The alpha allocated to the IA is 0.015 and the 
alpha left for the final analysis is 0.035, both two-sided.  The power of the group-
sequential test is about 87%.
The statistical assumption of the treatment effect of 6.5 points separation (for 
brexpiprazole versus placebo) is the same as that used for the two completed phase 3 
AAD Trials 331-12-283 and 331-12-284.  
2.2
Interim Analysis 
A DMC will provide oversight for safety monitoring and reviewing the IA data.
An unblinded interim analysis of efficacy data is planned during the course of the trial 
and will be performed by an independent Data Monitoring Committee (DMC) when 
approximately the first 255 subjects have had an opportunity to complete the 12-week 
trial (i.e., either completed or discontinued from the trial before Week 12).  Using a 
Bonferroni critical boundary for the rejection of the null hypothesis, a significance level 
of 0.015 (2-tailed) will be allocated to the interim analysis, and the significance level for 
the final analysis will be conservatively set at 0.035 (2-tailed).
Should the interim analysis be performed for a different number of subjects, the alpha 
allocation will remain unchanged for the interim and the final analysis. 
For ethical concerns as well as to avoid wasting resources, a non-binding futility 
boundary for the IA will be implemented as follows. If a standardized effect size of ≤ 
0.10 is observed at the IA, the DMC should recommend terminating the trial for futility. 
The DMC will make a recommendation about stopping the trial at the IA or continuing 
the trial as planned based on the efficacy review.  The results of the IA and individual 
subject data will remain blinded to the sponsor during the course of the trial and only 
DMC’s recommendation to stop the trial for efficacy or to stop the trial for futility or to 
continue the trial to the planned maximum sample size will be communicated to the 
sponsors.  The details of the DMC structure and its roles and responsibilities will be 
documented in the DMC charter.
The primary efficacy endpoint is the change from the baseline (Day 0 visit) to the end of 
the double-blind treatment period (the Week 12 visit) in the CMAI total score. The 
primary analysis will be performed on the portion of efficacy sample consisting of all 


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Protocol 331-14-213 Interim Analysis Plan                                                                       
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randomized subjects included in the IA who took at least one dose of IMP in the 
double-blind treatment period and had both a baseline and at least one post-
randomization CMAI total score during the double-blind treatment period.  The primary 
efficacy analysis will be performed by fitting a mixed-effect model repeated measure 
(MMRM) analysis with an unstructured (UN) variance covariance structure in which the 
change from the baseline in CMAI total score (Weeks 2, 4, 6, 8, 10, 12) will be the 
dependent variable based on the observed data.  The model will include fixed class-effect 
terms for IMP (brexpiprazole and placebo), trial center, visit week, and an interaction 
term of IMP by visit week and include the interaction term of baseline values of CMAI 
Total Score by visit week as covariates.  The primary comparison between the 
brexpiprazole (2-3 mg/day) and the placebo arm at Week 12 will be estimated as the 
difference between Least Squares (LS) means from the interaction term of IMP by visit 
week utilizing the computing software SAS procedure PROC MIXED.
Based on the IA result, the DMC will make one recommendation out of the three as 
follows: 
1) Early stop for efficacy 
2) Early stop for futility
3) Continue to the final analysis 
IA result 
DMC Recommendation
Outcome
Two-sided p-value ≤ 0.015 
Stop the trial for superiority 
in efficacy
The trial will be terminated at IA
Observed effect size ≤ 0.10 
Stop the trial for futility
The trial may be terminated at IA 
subject to Sponsors’ final decision
Otherwise (None of the 
above)
Continue the trial to the final 
analysis
The trial will proceed to the planned 
maximum sample size of approximately 
N=330
The sponsors will remain blinded to any modification of the primary model due to non-
convergence and should not be informed of any additional analysis or modification 
requested by the DMC and performed by the unblinded statistician.
3
Data Analysis
All interim efficacy and monitoring will be performed by the DMC.  Reference is made 
to the DMC Charter for details of constituents and roles and responsibilities of DMC.  


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Protocol 331-14-213 Interim Analysis Plan                                                                       
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The DMC (Unblinded) Statistician will work closely with the DMC and will assist in the 
retrieval and analysis of efficacy data.  The DMC will follow rules delineated in the IAP 
and the DMC Charter in disposing its responsibilities.
3.1
Planned Interim Analyses of Unblinded Efficacy data
A set of pre-specified efficacy tables (in Appendix) will be produced at the planned IA 
following statistical methods described in the Trial 331-14-213 Statistical Analysis Plan 
(SAP).  The OPDC Biometrics Group will provide blinded SAS datasets and SAS 
programming codes to the DMC Statistician.  The unblinded randomization codes will be 
provided to DMC Statistician directly by interactive web response system (IWRS) 
vendor.  The DMC Statistician will produce all prespecified summary tables using the 
SAS codes and analysis datasets provided by the OPDC Biometrics Group.
4
Confidentiality of Results
Except for the situation when the DMC recommends stopping the trial because of 
compelling efficacy or safety reasons, all deliberations, results and findings of the DMC 
will remain confidential within their jurisdictions, and the sponsor and investigators will 
remain blinded of any or all findings of unblinded analysis of efficacy and safety data.


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     Protocol 331-14-213 Interim Analysis Plan                                                                       
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FILE: cp_cal6a.lis, RUN: 31MAR2021 14:53
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      Otsuka    
 
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   otsBREXd                                                   CONFIDENTIAL                                                                   CLOSED Session 
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