Conditions: Agitation Associated With Alzheimer's Disease Alzheimer's Type Mental Disorder Nervous System Diseases
Keywords: OPC-34712 brexpiprazole Dementia Alzheimer's Disease Cognitive Disorders Agitation
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 270
Healthy volunteers: no

Brief summary:
To compare the efficacy of flexible dosing of brexpiprazole with placebo in subjects with agitation associated with dementia of the Alzheimer's type

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

This is a trial designed to assess the safety and efficacy of flexible dosing of brexpiprazole in the treatment of subjects with agitation associated with dementia of the Alzheimer's type. 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 subjects 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 subject is not living alone.

Arms:
arm 1: Matching Placebo Once-Daily arm 2: Titrate up from 0.25 mg/day brexpiprazole to 1 mg/day brexpiprazole. After achieving 1 mg/day target dose may be increased or decreased based on efficacy and tolerability. Allowable flexible doses will be 0.5 mg/day, 1 mg/day, or 2 mg/day.

Interventions: intervention 1: Brexpiprazole, OPC-34712
Intervention descriptions: intervention 1: Flexible dose of 0.5 to 2 mg/day or placebo tablets for up to 12 weeks

Protocol document:
Prot_000.pdf: 
Protocol 331-12-284
• Protocol number: 331-12-284
• Document title: 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
• Version number: 4.0
• Date of the document:10September2015
• NCT number: NCT01922258
Confidential -Proprieta1y Info1mation 


Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigational Medicinal Product
OPC-34712
REVISED CLINICAL PROTOCOL
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
Protocol No. 331-12-284
IND No. 115,960
EudraCT No. 2013-000503-17
CONFIDENTIAL – PROPRIETARY INFORMATION
Clinical Development Phase:
3
Sponsor:
Otsuka Pharmaceutical
Development & Commercialization, Inc
2440 Research Boulevard
Rockville, Maryland 20850, United States
Sponsor Representatives:
Director, Global Clinical Development
Phone:  
Fax:  
E-mail:  
Phone:  
Fax:  
E-mail:  
Director, Clinical Management
Phone:
Fax:
E-mail:
Associate Director, Clinical Management
Phone:
Fax:
E-mail:
Immediately Reportable Event:
INC Research (see Appendix 2)
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Issue Dates:
Original Protocol:  
Date of Amendment 1:
Date of Amendment 2:
Date of Amendment 3:
06 May 2013
16 Dec 2013
07 Jul 2014
10 Sep 2015
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Protocol 331-12-284
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Protocol Synopsis
Name of Company:  Otsuka Pharmaceutical
Development & Commercialization, Inc.
Name of Product:  Brexpiprazole (OPC-34712)
Protocol #331-12-284
IND #115,960
EudraCT #2013-000503-17
Protocol Title:
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
Clinical Phase:
3
Treatment Indication: 
Agitation associated with dementia of the Alzheimer’s type
Objective(s):
Primary:  To compare the efficacy of flexible dosing of 
brexpiprazole (dose range of 0.5 to 2 mg/day) with placebo in 
subjects with agitation associated with dementia of the 
Alzheimer’s type, as assessed by the Cohen-Mansfield 
Agitation Inventory (CMAI) after 12 weeks of treatment.
Secondary:  To evaluate the safety and tolerability of flexible 
dosing of brexpiprazole (dose range of 0.5 to 2 mg/day) 
compared with placebo in subjects with agitation associated 
with dementia of the Alzheimer’s type after 12 weeks of 
treatment.
Trial Design:
This is a phase 3, 12-week, multicenter, randomized, 
double-blind, placebo-controlled, 2-arm, flexible-dose trial 
designed to assess the efficacy, safety, and tolerability of 
brexpiprazole (dose range of 0.5 to 2 mg/day) in the treatment 
of subjects with agitation associated with dementia of the 
Alzheimer’s type.  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 the subject is 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 the 
subject in order to assess changes in the subject’s condition.
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.
The trial comprises a 2- to 42-day screening period, a 12-week 
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double-blind treatment period, and a 30-day post-treatment 
follow-up period.  
 
 
 
This trial will be monitored under the supervision of an 
independent Data Monitoring Committee (DMC).  The DMC 
will monitor safety periodically, based on a predetermined 
schedule.  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 to 42 days 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.  
The investigator must assess the capacity of the subject to 
provide informed consent during the screening period and 
throughout the course of the trial.  Determinations by the 
investigator of the capacity of the subject to provide informed 
consent and the options for obtaining informed consent from 
and/or on behalf of the subject under each potential 
circumstance will be made and implemented according to strict 
criteria.
 
An interactive voice response system (IVRS) or interactive web 
response system (IWRS) will be used to obtain the subject trial
identification number for each subject with a signed ICF.
The purpose of the screening period is to determine the 
subject’s eligibility and to washout prohibited concomitant 
pharmacotherapy prior to randomization.  The subject should 
be randomized into the double-blind treatment period as soon 
as all the screening assessments are completed, the screening 
and baseline eligibility criteria have been met, and the required 
washout period has occurred.
 
 
 
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12-week, Double-blind Treatment Period:
Based on a randomization scheme, eligible subjects will be 
allocated in a 1:1 ratio at randomization to 1 of the following 
2 treatment groups:

Brexpiprazole

Placebo
Subjects will be titrated to a target dose of 1 mg/day of 
brexpiprazole over a 2-week period, using the recommended 
titration schedule, as follows:
Dosing Scheme
Treatment 
Group
Recommended Daily Dose Administered
Day after
the
Baseline
visit
(Day 1)
Day after
the
Day 3 visit
(Day 4
[ +2 days])
Day after
the
Week 2 visit
(Day 15
[± 2 days])
Day after 
the
Week 4 visit 
(Day 29
[±2 days])
Brexpiprazole 
0.5-2 mg/day
0.25 mg/day
0.5 mg/day
1 mg/daya
2 mg/dayb
Placebo
<----------------------------------------------------------------------------->
aAfter achieving the target dose of 1 mg/day, the dose may be decreased 
to a 0.5 mg/day and re-increased to 1 mg/day based on the 
investigator’s clinical judgment.  Dose decreases and increases can 
occur at any time (scheduled or unscheduled visits).   
bThe earliest time point that the dose can be increased to 2 mg/day is 
starting on the day after the Week 4 visit (ie, Day 29 [±2 days]); 
however, it is not mandatory for the dose to be increased to 2 mg/day.  
The decision to increase the dose should be based on the investigator’s 
clinical evaluation of the subject’s response and tolerability.  
Allowable IMP doses that may be given starting the day after the 
Week 4 visit (ie, Day 29 [±2 days]) will be 0.5 mg/day, 1 mg/day, or 
2 mg/day.
The first dose of investigational medicinal product (IMP) will 
be administered on the day after the Baseline visit (ie, Day 1).  
All subjects randomly assigned to receive brexpiprazole will 
receive 0.25 mg/day as a starting dose.
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The dose of IMP will be increased from 0.25 mg/day to 
0.5 mg/day starting on the day after the Day 3 visit (ie, Day 4 
[+2 days]). 
The dose will then be increased to 1 mg/day starting on the day 
after the Week 2 visit (ie, Day 15 [±2 days]).  After achieving 
the target dose of 1 mg/day, the dose may be decreased to a 
0.5 mg/day and re-increased to 1 mg/day based on the 
investigator’s clinical judgment. Dose decreases and increases 
can occur at any time (scheduled or unscheduled visits).   
The dose of IMP can be further increased from 1 mg/day to 
2 mg/day starting on the day after the Week 4 visit (ie, Day 29 
[±2 days]).  Note: The earliest time point that the dose can be 
increased to 2 mg/day is starting on the day after the Week 4 
visit (ie, Day 29 [±2 days]); however, it is not mandatory for 
the dose to be increased to 2 mg/day. The decision to increase 
the dose should be based on the investigator’s clinical 
evaluation of the subject’s response and tolerability.  
Allowable IMP doses that may be given starting the day after 
the Week 4 visit (ie, Day 29 [±2 days]) will be 0.5 mg/day, 
1 mg/day, or 2 mg/day. Dose decreases and increases must 
occur in a stepwise manner and can occur at any time 
(scheduled or unscheduled visits). 
For subjects randomly assigned to receive placebo, their dose 
of IMP will be administered daily starting on the day after the 
Baseline visit (ie, Day 1) and ending on Week 12/ Early 
Termination (ET) (the last day of the Treatment Period).
Subjects unable to tolerate 0.5 mg/day of the IMP (or matching 
placebo) will be discontinued from the trial.  
If a subject is discontinued from the trial, every effort will be 
made to complete all of the Week 12/ET evaluations prior to 
administering any additional medications for the treatment of 
agitation or other prohibited medications.
Subjects will be evaluated at Baseline, Day 3, and at Weeks 2, 
4, 6, 8, 10, and 12 during the double-blind treatment period.  
All trial visits will take place as a clinic visit at either the 
investigator’s site or residential facility, if applicable.  All 
attempts should be made to maintain the subjects’ normal 
routine with regard to physician appointments.  Individual 
circumstances that fall outside this general convention should 
be discussed with the medical monitor in order to determine 
appropriateness to proceed.  In addition, the subject’s 
identified caregiver will be contacted by telephone at Weeks 3, 
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5, and 7 to assess compliance with IMP, confirm any changes 
to concomitant medications, and assure the subject’s 
well-being.  Trial-related efficacy and safety assessments will 
be performed as outlined in the Schedule of Assessments.
Follow-up Period:
All subjects, whether they complete the trial or are withdrawn 
prematurely for any reason, will be followed up for a safety 
evaluation 30 (+ 2) days after the last dose of IMP during a 
clinic visit at either the investigator’s site or residential facility, 
if applicable.  If a clinic visit is not possible, the subject should 
be assessed by telephone contact with the subject and a 
caregiver.  
 
Subjects who complete both the 12-week double-blind 
treatment period and the 30-day safety follow-up visit are 
eligible to enroll into Trial 331-13-211, which is a 2-month, 
observational, rollover trial to evaluate the safety of subjects 
with agitation associated with Alzheimer's disease who 
previously participated in Trial 331-12-284.  For those subjects
who plan to enroll into Trial 331-13-211, the 30-day safety 
follow-up visit for Trial 331-12-284 will occur as a clinic visit 
at either the investigator’s site or residential facility, if 
applicable.  
Subject Population:
The subject 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 the subject is 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 the subject in order to assess 
changes in the subject’s condition. All subjects must have a 
diagnosis of probable Alzheimer’s disease according to the 
NINCDS-ADRDA criteria.  Subjects must have a previous 
magnetic resonance imaging (MRI) or computed tomography 
(CT) scan of the brain, which was performed after the onset of 
symptoms of dementia, with findings consistent with a 
diagnosis of Alzheimer’s disease.  If a previous MRI or 
CT scan of the brain performed after the onset of the symptoms 
of dementia is not available, then an MRI/CT scan should be 
performed during screening.  Additionally, at both the 
screening and baseline visits, subjects must have a Mini-Mental 
State Examination (MMSE) score of 5 to 22, inclusive, and a 
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total score (frequency x severity) of ≥4 on the 
agitation/aggression item of the Neuropsychiatric Inventory—
Nursing Home (NPI-NH) or the Neuropsychiatric Assessment 
for Non-institutionalized Patients based on the NPI/NPI-NH 
(hereafter referred to as “NPI/NPI-NH”).  The NPI-NH will be 
used for institutionalized subjects and the NPI/NPI-NH will be 
used for non-institutionalized subjects.  The onset of the 
subject’s symptoms of agitation must be at least 2 weeks prior 
to the screening visit. Subjects must require pharmacotherapy 
for the treatment of agitation per the investigator’s judgment, 
after an evaluation for reversible factors (eg, pain, infection, 
polypharmacy) and a trial of nonpharmacological interventions.
Subjects must have been residing at their current location for at 
least 14 days before screening and be expected to remain at the 
same location for the duration of the trial. Subjects who at any 
point during the double-blind treatment phase transfer from an 
institutionalized setting to a non-institutionalized setting, or 
vice versa, will be withdrawn from the trial.  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.  All attempts should be made to 
maintain the subjects’ normal routine with regard to
appointments with physicians and overnight 
accommodations.  Subjects 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 subjects’ normal routine.  
Subjects in a non-institutionalized setting may have a caretaker 
as well as a caregiver. The subject’s caretaker is the person 
who lives with and cares for the subject on a regular basis. 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 the person 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, NPI/NPI-NH, and 
other applicable trial assessments.  
For subjects in an institutionalized setting, there is only one role 
defined and that is the role of caregiver.  The identified 
caregiver can be a staff member of the institutionalized setting 
or another individual (eg, family member, family friend, hired 
professional caregiver) who has sufficient contact to describe 
the subject’s symptoms and who has direct observation of the 
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subject’s behavior in order to participate in the interview for the 
CMAI, NPI-NH, and other applicable trial assessments.  
The recommended minimum level of contact between the 
caregiver and the subject is 2 hours per day for 4 days per week
in both the institutionalized and non-institutionalized settings.    
 
 
 
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, HIV-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 MRI/CT scan of the brain, which 
was performed after the onset of 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 
30 days prior to the screening visit.

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.
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
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 Sites:
It is planned that approximately 520 subjects will be screened 
at approximately 65 trial sites worldwide so that 260 subjects 
will be randomized to treatment.
Investigational 
Medicinal Product, 
Dose, Formulation, 
Mode of 
Administration:
The IMP will consist of brexpiprazole tablets (identical 
0.25-mg, 0.5-mg, 1-mg, and 2-mg tablets) and matching 
placebo tablets.  The 0.25 mg/day dose will be supplied as a 
blister card containing sufficient tablets for 3 (+2) days; the 
0.5 mg/day, 1 mg/day, and 2 mg/day doses will be supplied as a 
weekly blister card containing sufficient tablets for 
7 (+ 2) days.  An IVRS or IWRS will be used at each trial site 
to assign the specific blister-card number to be dispensed to 
each subject at each visit.
After a 2- to 42-day screening period, eligible subjects will be 
randomly assigned to 1 of 2 treatment groups (brexpiprazole 
group or placebo group).  Subjects will be titrated to a target 
dose of 1 mg/day of brexpiprazole over a 2-week period, using 
the recommended titration schedule.  
The total duration of double-blind treatment will be 12 weeks 
for all randomized subjects.
All doses of brexpiprazole and matching placebo will be taken 
orally once daily, preferably in the morning, and can be 
administered without regard to meals.  Brexpiprazole should be 
taken at approximately the same time each day, particularly 
prior to visits with pharmacokinetic sampling.
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Criteria for 
Evaluation:
Primary Efficacy Variable:
The primary efficacy variable is the change from baseline to 
Week 12/ET in the CMAI total score.
Key Secondary Efficacy Variable:
The key secondary efficacy variable is the change from 
baseline to Week 12/ET in the Clinical Global 
Impression-Severity of Illness (CGI-S) score, as related to 
agitation.
 
 
 
 
 
 
 
 
 
 
 
 
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
Safety Variables:
Standard safety variables to be examined will include adverse 
events, physical examinations, neurological examinations, vital 
signs, body weight, waist circumference, clinical laboratory 
tests (hematology, serum chemistry, and urinalysis), and 
electrocardiograms (ECGs).  In general, summarized statistics 
of changes from baseline will be provided for safety variables 
based on all available data.  Prospectively defined criteria will 
be used to identify potentially clinically relevant abnormal 
values for clinical laboratory tests, vital signs, ECGs, and body 
weight.  Change from baseline in body mass index (BMI) 
(derived programmatically from body weight and height 
measurements) will be summarized.  Other safety variables will 
include the MMSE score 
 
 
 
Pharmacokinetic samples for determination of brexpiprazole 
and its metabolite(s) will be collected at the baseline visit and at 
the Week 8 and Week 12/ET trial visits, at the same time as the 
sample collection for the clinical laboratory tests. 
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 
(SD).  Tabulations of frequency distributions will be provided 
for categorical variables.  The primary endpoint will be 
analyzed using a mixed-effect model repeated measure 
(MMRM) methodology.  The model will include fixed 
class-effect terms for treatment, trial center, visit week, and an 
interaction term of treatment by visit week and include the 
interaction term of baseline by visit week as a covariate.  The 
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primary efficacy outcome measure is the mean change from 
baseline (Day 0 Visit) to the end of the double-blind treatment 
period (Week 12 visit) in the CMAI total score.  
 
 
The alpha used in the analysis of the key secondary endpoint is 
0.05 (2-sided), if the comparison of the brexpiprazole group 
versus placebo in the primary efficacy endpoint is statistically 
significant.
The 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 the endpoint in the CMAI total score, to achieve 
85% power at a 2-sided alpha level of 0.05.  The resulting 
sample size is 117 subjects/arm.  After allowance of 10% 
non-evaluable subjects, it results in a sample size of 
130 subjects/arm, which means the total sample size is 
260 subjects.  The sample size was estimated based on a 
1:1 randomization ratio (brexpiprazole:placebo).  The 
randomization will be stratified by center.
 
 
 
Trial Duration:
The time from enrollment of the first subject to the last 
subject’s last trial visit will be approximately 4.5 years, of 
which approximately 4 years are allotted for recruitment of 
subjects.  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 will be 
followed up at a clinic visit or via telephone contact 30 (+ 2) 
days after the last dose of the IMP. 
 
 
 
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Table of Contents
Protocol Synopsis...........................................................................................3
Table of Contents.........................................................................................14
List of In-text Tables ...................................................................................20
List of In-text Figures..................................................................................21
List of Appendices........................................................................................22
List of Abbreviations and Definitions of Terms .......................................23
1.
Introduction ........................................................................................27
1.1.
Nonclinical Data................................................................................................29
1.1.1.
Efficacy Pharmacology...................................................................................29
1.1.2.
Safety Pharmacology......................................................................................29
1.2.
Clinical Data......................................................................................................30
1.2.1.
Pharmacokinetics and Pharmacodynamics.....................................................30
1.2.2.
Phase 2 and Phase 3 Studies Conducted Under a US IND.............................32
1.2.2.1.
Major Depressive Disorder (MDD) ............................................................32
1.2.2.2.
Schizophrenia..............................................................................................34
1.2.2.3.
Attention-Deficit/Hyperactivity Disorder (ADHD)....................................35
1.3.
Known and Potential Risks and Benefits ..........................................................36
2.
Trial Rationale and Objectives..........................................................38
2.1.
Trial Rationale...................................................................................................38
2.2.
Dosing Rationale...............................................................................................38
2.3.
Trial Objectives.................................................................................................40
3.
Trial Design.........................................................................................41
3.1.
Type/Design of Trial .........................................................................................41
3.2.
Treatments.........................................................................................................45
3.3.
Trial Population.................................................................................................46
3.3.1.
Caregiver/Caretaker Requirements.................................................................47
3.3.1.1.
Non-institutionalized Subjects ....................................................................47
3.3.1.2.
Institutionalized Subjects ............................................................................48
3.4.
Eligibility Criteria..............................................................................................49
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3.4.1.
Informed Consent ...........................................................................................49
3.4.1.1.
Determinations of Capacity ........................................................................49
3.4.1.2.
Documentation of Informed Consent..........................................................50
3.4.2.
Inclusion Criteria ............................................................................................52
3.4.3.
Exclusion Criteria...........................................................................................53
3.5.
Outcome Variables............................................................................................56
3.5.1.
Primary Efficacy Variable..............................................................................56
3.5.2.
Key Secondary Efficacy Variable ..................................................................56
3.5.3.
57
3.5.6.
Safety Variables..............................................................................................58
3.5.7.
Pharmacokinetic/Pharmacodynamic Variables ..............................................58
3.6.
Measures to Minimize/Avoid Bias....................................................................58
3.6.1.
Randomization................................................................................................58
3.7.
Trial Procedures ................................................................................................59
3.7.1.
Schedule of Assessments................................................................................66
3.7.1.1.
Screening.....................................................................................................66
3.7.1.2.
Baseline (Day 0)..........................................................................................68
3.7.1.3.
Double-blind Treatment Period...................................................................70
3.7.1.3.1.
Day 3 .......................................................................................................70
3.7.1.3.2.
Weeks 2, 4, 6, 8, and 10 ..........................................................................71
3.7.1.4.
End of Treatment (Week 12/ET).................................................................72
3.7.1.5.
Follow-up....................................................................................................74
3.7.2.
Efficacy Assessments .....................................................................................74
3.7.2.1.
Cohen-Mansfield Agitation Inventory (CMAI)..........................................75
3.7.2.2.
Clinical Global Impression-Severity of Illness Scale (CGI-S) ...................75
3.7.2.3.
.75
3.7.2.5.
Neuropsychiatric Inventory-Nursing Home (NPI-NH) ..............................76
3.7.2.6.
Neuropsychiatric Assessment for Non-institutionalized Patients 
Based on the NPI/NPI-NH (NPI/NPI-NH) .................................................76
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3.7.3.
Other Assessments..........................................................................................77
3.7.3.1.
.77
3.7.3.2.
.78
3.7.3.3.
78
3.7.3.4.
.78
3.7.3.5.
National Institute of Neurological and Communicative Disorders and 
Stroke and the Alzheimer’s Disease and Related Disorders 
Association (NINCDS-ADRDA)................................................................79
3.7.3.6.
Hachinski Ischemic Scale (Rosen Modification)........................................79
3.7.3.7.
Magnetic Resonance Imaging/Computed Tomography Scan of the 
Brain............................................................................................................80
3.7.4.
80
3.7.4.1.
Adverse Events............................................................................................80
3.7.4.2.
Clinical Laboratory Assessments................................................................80
3.7.4.3.
Physical and Neurological Examination and Vital Signs ...........................82
3.7.4.3.1.
Physical Examination..............................................................................82
3.7.4.3.2.
Neurological Examination.......................................................................83
3.7.4.3.3.
Vital Signs ...............................................................................................84
3.7.4.4.
ECG Assessments .......................................................................................85
3.7.4.5.
86
3.7.4.5.1.
86
3.7.4.5.2.
.86
3.7.4.5.3.
87
3.7.4.5.4.
87
3.7.4.5.5.
Mini-Mental State Examination (MMSE)...............................................88
3.7.5.
Pharmacokinetic Assessments........................................................................88
3.7.5.1.
Blood Collection Times ..............................................................................88
3.7.5.2.
Sample Handling and Processing................................................................88
3.7.6.
.88
3.7.6.1.
.89
3.7.6.2.
90
3.7.7.
End of Trial.....................................................................................................90
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3.7.8.
Independent Data Monitoring Committee......................................................90
3.7.9.
90
3.8.
Stopping Rules, Withdrawal Criteria, and Procedures......................................91
3.8.1.
Entire Trial or Treatment Arm(s) ...................................................................91
3.8.2.
Individual Site.................................................................................................91
3.8.3.
Individual Subject...........................................................................................91
3.9.
Screen Failures ..................................................................................................93
3.10.
Definition of Completed Subjects.....................................................................93
3.11.
Definition of Subjects Lost to Follow-up..........................................................93
3.12.
Subject Compliance...........................................................................................94
3.13.
Protocol Deviations...........................................................................................94
4.
Restrictions..........................................................................................94
4.1.
Prohibited Medications......................................................................................94
4.2.
Other Restrictions..............................................................................................98
5.
Reporting of Adverse Events.............................................................99
5.1.
Definitions.........................................................................................................99
5.2.
Eliciting and Reporting Adverse Events .........................................................101
5.3.
Immediately Reportable Events (IRE) ............................................................101
5.4.
Potential Hy’s Law Cases................................................................................102
5.5.
Pregnancy........................................................................................................102
5.6.
Procedure for Breaking the Blind....................................................................104
5.7.
Follow-up of Adverse Events..........................................................................104
5.7.1.
Follow-up of Nonserious Adverse Events....................................................104
5.7.2.
Follow-up of Post-Trial Serious Adverse Events .........................................104
5.7.3.
Follow-up and Reporting of Serious Adverse Events Occurring after 
Last Scheduled Contact ................................................................................105
5.7.4.
105
6.
Pharmacokinetic Analysis................................................................105
7.
Statistical Analysis............................................................................105
7.1.
Sample Size.....................................................................................................105
7.2.
Datasets for Analysis.......................................................................................106
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7.3.
Handling of Missing Data ...............................................................................106
7.4.
Efficacy Analyses............................................................................................107
7.4.1.
Primary Efficacy Analysis............................................................................107
7.4.2.
Key Secondary Efficacy Analysis ................................................................107
7.4.3.
.108
7.4.4.
108
7.4.5.
Interim Analysis............................................................................................108
7.5.
Analysis of Demographic and Baseline Characteristics..................................108
7.6.
Safety Analysis................................................................................................109
7.6.1.
Adverse Events .............................................................................................109
7.6.2.
Clinical Laboratory Data ..............................................................................109
7.6.3.
Physical and Neurological Examination and Vital Signs Data ....................109
7.6.4.
ECG Data......................................................................................................110
7.6.5.
110
7.7.
110
8.
Management of Investigational Medicinal Product......................111
8.1.
Packaging and Labeling ..................................................................................111
8.2.
Storage.............................................................................................................111
8.3.
Accountability .................................................................................................111
8.4.
Returns and Destruction..................................................................................111
8.5.
Reporting of Product Quality Complaints (PQC) ...........................................112
8.5.1.
Eliciting and Reporting Product Quality Complaints...................................112
8.5.2.
Information Required for Reporting Purposes .............................................113
8.5.3.
Return Process ..............................................................................................113
8.5.4.
Assessment and Evaluation ..........................................................................113
9.
Records Management.......................................................................113
9.1.
Source Documents...........................................................................................113
9.2.
Data Collection................................................................................................114
9.3.
File Management at the Trial Site...................................................................114
9.4.
Records Retention at the Trial Site..................................................................115
10.
Quality Control and Quality Assurance.........................................115
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10.1.
Monitoring.......................................................................................................115
10.2.
Auditing...........................................................................................................115
11.
Ethics and Responsibility.................................................................116
12.
Confidentiality ..................................................................................116
13.
Amendment Policy............................................................................116
14.
References..........................................................................................118
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List of In-text Tables
Table 3.2-1
Dosing Scheme ..............................................................................45
Table 3.4.2-1
Inclusion Criteria ...........................................................................52
Table 3.4.3-1
Exclusion Criteria ..........................................................................53
Table 3.7-1
Schedule of Assessments...............................................................60
Table 3.7.4.2-1
Clinical Laboratory Assessments...................................................81
Table 4.1-1
List of Restricted and Prohibited Medications...............................95
Table 4.1-2
Selected CYP2D6 Inhibitors and CYP3A4 Inhibitors and 
Inducers..........................................................................................98
Table 4.1-3
Oral Benzodiazepine Therapy During the Trial.............................98
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List of In-text Figures
Figure 3.1-1
Trial Design Schematic..................................................................44
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List of Appendices
Appendix 1
Names of Sponsor Personnel .......................................................122
Appendix 2
Institutions Concerned With the Trial..........................................123
Appendix 3
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance .......................................................................126
Appendix 4
Criteria for Identifying Vital Signs of Potential Clinical 
Relevance.....................................................................................127
Appendix 5
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance .......................................................................128
Appendix 6
Cohen-Mansfield Agitation Inventory (CMAI)...........................129
Appendix 7
Clinical Global Impression (CGI)................................................131
Appendix 8
Neuropsychiatric Inventory-Nursing Home Rating Scale 
(NPI-NH) .....................................................................................134
Appendix 9
Neuropsychiatric Assessment for Non-Institutionalized 
Patients Based on the NPI/NPI-NH.............................................146
Appendix 14
National Institute of Neurological and Communicative 
Disorders and Stroke and the Alzheimer’s Disease and 
Related Disorders Association (NINCDS-ADRDA)...................192
Appendix 15
Hachinski Ischemic Scale (Rosen Modification).........................194
Appendix 16
.195
Appendix 17
198
Appendix 18
.199
Appendix 19
201
Appendix 20
Mini-Mental State Examination (MMSE) ...................................204
Appendix 21
Handling and Shipment of Bioanalytical Samples ......................210
Appendix 22
Protocol Amendment(s)/Administrative Change(s) ....................212
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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
5-HT1A
Serotonin type 1A receptor
5-HT2A
Serotonin type 2A receptor
ACR
Albumin-to-creatinine ratio
ACTH
Adrenocorticotropic hormone
ADHD
Attention-deficit/hyperactivity disorder
ADL
Activities of daily living
ADT
Antidepressant therapy
AE
Adverse event
ALP
Alkaline phosphatase
ALT (SGPT)
Alanine transaminase (serum glutamic-pyruvic transaminase)
AMP
Adenosine monophosphate
ANCOVA
Analysis of covariance
APO
Apomorphine
Anti-HCV
Antibodies to hepatitis C
aPTT
Activated partial thromboplastin time
AST (SGOT)
Aspartate transaminase (serum glutamic-oxaloacetic transaminase)
AUCt
Area under the concentration-time curve calculated to the last 
observable concentration at time t
BMI
Body mass index
BUN
Blood urea nitrogen
Ca2+
Calcium
CAARS-O:SV
Conners’ Adult ADHD Rating Scale-Observer: Screening Version
CGI-S
Clinical Global Impression-Severity of Illness scale
CHO-K1
Chinese hamster ovary cells
CMAI
Cohen-Mansfield Agitation Inventory
CMH
Cochran-Mantel-Haenszel
Cmax
Maximum (peak) plasma concentration
CNS
Central nervous system
CPK
Creatine phosphokinase
CRO
Clinical Research Organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CST
Clinical Surveillance Team
CT
Computed tomography
CVAE
Cardiovascular Adverse Events
CYP2D6
Cytochrome P450 2D6 isozyme
CYP3A4
Cytochrome P450 3A4 isozyme
D2
Dopamine type 2 receptor
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Abbreviation
Definition
D2L
Dopamine type 2 long receptor 
D3
Dopamine type 3 receptor
DBP
Diastolic blood pressure
DMC
Data Monitoring Committee
DSM-IV-TR
Diagnostic and Statistical Manual of Mental Disorders, Fourth 
Edition, Text Revision
ECG
Electrocardiogram
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
EPS
Extrapyramidal symptoms
ET
Early termination
EU
European Union
EudraCT
European Clinical Trial Data Base
FDA
Food and Drug Administration
GABA
Gamma-aminobutyric acid
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
HbA1c
Glycosylated hemoglobin
HBsAg
Hepatitis B surface antigen
HDL
High density lipoprotein
HEENT
Head, eyes, ears, nose, and throat
hERG
Human ether-a-go-go related gene
HIV
Human immunodeficiency virus
IADL
Instrumental activities of daily living
IAP
Independent Adjudication Panel
ICF
Informed consent form
ICH
International Conference on Harmonization
ID
Identification/identifier
IDDM
Insulin-dependent diabetes mellitus
IEC
Independent ethics committee
IMP
Investigational medicinal product
IND
Investigational New Drug
INR
International Normalized Ratio
IRB
Institutional review board
IRE
Immediately reportable event
ISI
Insomnia Severity Index
ITT
Intent-to-treat
IUD
Intrauterine device
IVRS
Interactive voice response system
IWRS
Interactive web response system
K2EDTA
Potassium ethylenediaminetetraacetic acid
LDH
Lactic dehydrogenase
LDL
Low density lipoprotein
LOCF
Last-observation-carried-forward
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Abbreviation
Definition
LS
Least squares
MADRS
Montgomery-Asberg Depression Rating Scale
MDD
Major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
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
NMS
Neuroleptic malignant syndrome
NPI
Neuropsychiatric Inventory 
NPI-NH
Neuropsychiatric Inventory—Nursing Home
NPI/NPI-NH
Neuropsychiatric Assessment for Non-Institutionalized Patients 
based on the NPI/NPI-NH
OAPI-EQC
Otsuka America Pharmaceutical, Inc. Ethics, Quality and 
Compliance
OC
Observed case
OPC
Otsuka Pharmaceutical Co.
OPDC
Otsuka Pharmaceutical Development & Commercialization, Inc
OTC
Over-the-counter
PANSS
Positive and Negative Syndrome Scale
PET
Positron emission tomography
PT
Prothrombin time
PQC
Product quality complaint
QoL
Quality of life
QTc
Corrected QT interval
QTcB
QT interval as corrected by Bazett’s formula
QTcF
QT interval as corrected by Fridericia’s formula
QTcN
QT interval as corrected by the FDA Neuropharm Division 
formula
RBC
Red blood cell
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SAS
Simpson Angus Scale
SBP
Systolic blood pressure
SD
Standard deviation
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Abbreviation
Definition
T4
Thyroxine
TEAE
Treatment-emergent adverse event
tmax
Time to maximum (peak) plasma concentration
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
US
United States
WRAADDS
Wender-Reimherr Adult Attention Deficit Disorder Scale
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
Dementia is a term that describes disorders that cause cognitive decline. The most 
common type of dementia is Alzheimer’s disease.1  It is currently estimated that 
5.3 million Americans have Alzheimer’s disease, and future projections estimate that, due 
to an increase in the aging population, there will be between 11 million and 16 million 
Americans with Alzheimer’s disease by 2050.1  In the United States, among adults older 
than age 65, prevalence estimates of dementia range from 5% to 15%, with Alzheimer’s 
disease being the most common type of dementia.2,3,4  Dementia is the most frequent 
contributing factor to the transition from home-based care to a long-term care facility, 
such as a nursing home, assisted living facility, or group home.  Across numerous studies, 
it has been consistently demonstrated that cognitive decline, behavioral disturbances, and 
depression associated with Alzheimer’s disease are strong predictors of nursing home 
admission.5
Neuropsychiatric symptoms, including agitation and aggression, are core features of 
Alzheimer’s disease and related dementias.  Alzheimer’s disease-associated behavioral 
disturbances cause frequent emergency room visits and can lead to mismanagement of 
other medical conditions.  These behavioral disturbances also are associated with major 
adverse effects on quality of life (QoL) and reduced time to institutionalization.  
Neuropsychiatric symptoms also have a major adverse effect on caregivers.5  These 
neuropsychiatric symptoms contribute to subject and caregiver distress6 and increased 
healthcare costs7 and even may lead to institutionalization.8
Currently, there is no cure for Alzheimer’s disease and no treatment approved in the 
United States for the management of behavioral disturbances, including agitation, in 
patients with Alzheimer’s disease.  In some countries of the European Union (EU), 
risperidone is indicated for the short-term treatment (up to 6 weeks) of persistent 
aggression in subjects with moderate to severe Alzheimer's dementia unresponsive to 
nonpharmacological approaches and when there is a risk of harm to self or others.9  
Adequate treatment of behavioral disturbances is essential to increasing the comfort and 
safety of subjects and easing the burden of provision of care placed on families and other 
caregivers; it remains an ongoing and serious unmet medical need in this subject 
population.
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In the literature, agitation has been defined as “inappropriate verbal, vocal, or motor 
activity that is not judged by an outside observer to result directly from the needs or 
confusion of the agitated individual.”  Agitation is a term used by clinicians for a group 
of symptoms that may reflect an underlying disorder.10,11 Agitated behavior is considered 
to be socially inappropriate and may be:

Abusive or aggressive toward self or others, such as hitting or kicking

An appropriate behavior that is performed with an inappropriate frequency, such as 
constantly asking questions

Considered inappropriate according to social standards, such as putting on too many 
layers of clothes11
Brexpiprazole (also referred to as OPC-34712 or Lu AF41156) is an organic compound 
synthesized by Otsuka Pharmaceutical Co, Ltd, that is a partial agonist at dopamine 
type 2 (D2), dopamine type 3 (D3), and serotonin type 1A (5-HT1A) receptors and an 
antagonist at serotonin type 2A (5-HT2A) receptors; and has a low binding affinity for 
histamine and muscarinic receptors.  Details of the receptor affinity profile of 
brexpiprazole are summarized in Section 1.1.1.  Activity at dopamine and serotonin 
receptors has been shown to be useful in the treatment of psychiatric disorders, eg, 
schizophrenia and bipolar mania.  Hence, brexpiprazole is expected to be a promising 
antipsychotic agent.  As the relative activity at these and other receptors appears to be 
related to the side-effect profiles of antipsychotic drugs,12 ,13,14,15 brexpiprazole may have 
the potential to exhibit improved safety compared with other agents.  The more potent 
antagonism at 5-HT2A receptors for brexpiprazole relative to aripiprazole, another D2 
partial agonist, may afford a more favorable profile with respect to sleep quality; whereas 
the low binding affinities for histamine and muscarinic receptors suggest that 
brexpiprazole may have less potential to cause H1-receptor-related weight gain than 
olanzapine.  Preclinical data also suggest that brexpiprazole will have lower potential for 
hyperprolactinemia than risperidone.  Results from initial phase 2 trials showed 
brexpiprazole to be well tolerated by subjects with major depressive disorder (MDD), 
attention-deficit/hyperactivity disorder (ADHD), and schizophrenia (see Section 1.2 and 
Section 1.3).
Refer to the Investigator’s Brochure for more detailed information about the 
investigational medicinal product (IMP).16
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1.1.
Nonclinical Data
Efficacy and safety pharmacology are summarized in Section 1.1.1 and Section 1.1.2, 
respectively.  A complete description of the available data from nonclinical studies, 
including pharmacokinetic and toxicology studies in different animal species, can be 
found in the Investigator’s Brochure.16
1.1.1.
Efficacy Pharmacology
Brexpiprazole functions as a partial agonist at the D2 receptor.  In in vitro assay systems, 
based on forskolin-induced cyclic adenosine monophosphate (AMP) accumulation and 
calcium (Ca2+) mobilization in human dopamine D2L receptor-expressing cells, its 
intrinsic activity at the D2 receptor was slightly lower than that of aripiprazole.  
Brexpiprazole inhibited apomorphine (APO)-induced hyperlocomotion, APO-induced 
stereotyped behavior, and conditioned avoidance response in rats, which are predictive 
animal models for antipsychotic-like efficacy.  The inhibitory effects of brexpiprazole 
were more potent than those of aripiprazole.  Moreover, in contrast to the D2 receptor 
antagonist risperidone, brexpiprazole did not increase plasma prolactin levels in 
reserpine-treated rats, thus demonstrating a D2 receptor partial agonistic profile in vivo.  
Despite its lower intrinsic activity at the D2 receptor, the in vivo catalepsy liability of 
brexpiprazole, an index of extrapyramidal symptoms (EPS), was similar to that of 
aripiprazole, but still lower than that of the typical antipsychotic haloperidol.  
Furthermore, brexpiprazole showed high binding affinity for the 5-HT2A receptor and 
dose-dependently inhibited ()-2,5-dimethoxy-4-iodoamphetamine-induced head twitch 
response in rats, indicating that the compound has 5-HT2A receptor antagonistic activity; 
and the effect of brexpiprazole was more potent than that of aripiprazole.  In addition, 
brexpiprazole acted as a partial agonist, exhibiting high binding affinities for the D3 and 
5-HT1A receptors.
1.1.2.
Safety Pharmacology
In safety pharmacology studies in rats at an oral dose of 30 mg/kg or higher, 
brexpiprazole induced pharmacologically mediated clinical signs considered to be due to 
depression of the central nervous system (CNS) and dose-dependent decreases in body 
temperature.  When orally administered at up to 30 mg/kg in conscious male beagle dogs, 
brexpiprazole showed no effect on respiratory parameters or heart rate at any dose tested.  
Brexpiprazole decreased blood pressure at doses of 3 mg/kg or higher and prolonged both 
the QT interval and the corrected QT interval (QTc) by Van de Water’s formula at 
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30 mg/kg.  Brexpiprazole inhibited human ether-a-go-go related gene (hERG) current in 
Chinese hamster ovary cells (CHO-K1) at concentrations of 10−8 mol/L or higher, with a 
50% inhibitory concentration of 1.17 10−7 mol/L.  The mechanism for the blood 
pressure decreasing effect of brexpiprazole was suggested to result from a blockade of 
the 1-adrenoceptor in peripheral blood vessels, which is a part of the compound’s 
pharmacological profile.  Proarrhythmic risk was also evaluated by examining the effects 
of brexpiprazole on monophasic action potential parameters in halothane-anesthetized 
dogs.  Brexpiprazole did not affect the terminal repolarization period even at an 
intravenous dose of 3 mg/kg, suggesting a low potential for proarrhythmic effects.  In 
general, the changes in the CNS and respiratory and cardiovascular systems observed 
with brexpiprazole occurred at doses or exposure levels higher than those at which 
efficacy was confirmed in rats (3 mg/kg), and similar changes were shown to occur after 
administration of risperidone at similar or lower doses.
1.2.
Clinical Data
1.2.1.
Pharmacokinetics and Pharmacodynamics
The pharmacokinetics of single and multiple doses of brexpiprazole were studied in 
healthy subjects and in subjects with MDD, ADHD, and schizophrenia or schizoaffective 
disorder.  Based on preclinical data and human clinical trials, brexpiprazole and the 
metabolite DM-3411 were identified as the major analytes that are present in human 
plasma.  In vitro, the activity of DM-3411 is 17 times lower than that of brexpiprazole; 
thus, it is considered an inactive metabolite.  The pharmacokinetics of both brexpiprazole 
and its major metabolite, DM-3411, were linear following administration of single doses 
(0.2 to 8 mg) and multiple daily doses (0.5 to 2 mg in healthy subjects and 1 to 12 mg in 
schizophrenic subjects).  At steady state, the brexpiprazole and DM-3411 mean terminal 
elimination half-life was 95.4 and 89.3 hours, respectively.  The median time to 
maximum (peak) plasma concentration (tmax) occurred at approximately 2 to 6 hours 
postdose for brexpiprazole and at approximately 10 to 24 hours postdose for DM-3411.  
In healthy subjects, administration of single-dose brexpiprazole with a high-fat meal did 
not affect its rate and extent of absorption.
Steady-state pharmacokinetics also appeared to be linear following multiple daily doses 
of brexpiprazole in the range of 0.5 to 2 mg when administered to healthy subjects.  The 
accumulation ratio, based on the maximum (peak) plasma concentration (Cmax) and area 
under the concentration-time curve calculated to the last observable concentration at time 
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t (AUCt), was approximately 4 times.  After multiple-dose administration of 
brexpiprazole (1-12 mg/day) to subjects with schizophrenia or schizoaffective disorder, 
the mean terminal elimination half-life of brexpiprazole and DM-3411 at steady state was 
95.4 and 89.3 hours, respectively; and the median tmax was 3.0 and 8.0 hours, 
respectively.
In drug interaction trials in healthy subjects, brexpiprazole was shown to be metabolized 
by the cytochrome P450 3A4 (CYP3A4) and 2D6 (CYP2D6) isozymes and was not an 
inhibitor of CYP3A4, CYP2B6, CYP2D6, or P-glycoprotein.  Coadministration of potent 
CYP3A4 or CYP2D6 inhibitors with brexpiprazole resulted in about a 2-fold higher 
exposure and about a 1.5-fold increase in the terminal elimination half-life of 
brexpiprazole.
In a single-dose trial in healthy subjects, approximately 46.0% and 24.6% of 
administered radioactivity following an oral dose of 14C-brexpiprazole was excreted in 
feces and urine, respectively.  In this same trial, brexpiprazole did not preferentially bind 
to red blood cells (RBCs).  Brexpiprazole showed high protein binding in human serum 
(99.8%) in vitro.
The binding of brexpiprazole to dopamine receptors was assessed using positron 
emission tomography (PET).  The mean D2/D3 receptor occupancies at 4 and 24 hours 
postdose after single-dose administration of 0.25, 0.5, 1, 2, 4, 5, and 6 mg of 
brexpiprazole to healthy subjects were 11.4% to 17.4%, 36.5% to 46.3%, 45.6% to 
60.2%, 52.7% to 68.6%, 67.9% to 79.5%, 71.9% to 88.2%, and 69.5% to 92.6%, 
respectively (Trial 331-07-202).  Based on the single-dose D2/D3 receptor occupancy 
data and steady-state pharmacokinetic and pharmacodynamic modeling, it was predicted 
that the D2/D3 receptor occupancy after multiple daily dose administration of 1 to 2 mg 
and higher doses of brexpiprazole will result in at least 80% to 90% D2/D3 receptor 
occupancy.
Trials have investigated the pharmacokinetics of brexpiprazole in special populations 
(subjects with hepatic impairment and renal impairment); one studying the effects of age 
and sex on brexpiprazole pharmacokinetics has been completed.  Based on the results of 
the special population trials, no dose adjustment is needed when brexpiprazole is 
administered to elderly subjects or subjects with renal or hepatic insufficiency.
Additional information on the pharmacokinetics and pharmacodynamics of brexpiprazole 
and its metabolites in humans can be found in the Investigator’s Brochure.16
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1.2.2.
Phase 2 and Phase 3 Studies Conducted Under a US IND
1.2.2.1.
Major Depressive Disorder (MDD)
The use of brexpiprazole as adjunctive therapy for the treatment of MDD has been 
studied in 2 completed, phase 2, double-blind, placebo-controlled trials (Trials 
331-08-211 and 331-09-222).  Additionally, 6 studies are ongoing: 2 United States (US)
trials (1 phase 1, randomized, double-blind, placebo-controlled trial in elderly adults 
[aged 70-80 years] with MDD [Trial 331-12-291]; 1 long-term, open-label safety trial 
[Trial 331-08-212]); and 4 multinational trials (2 randomized, double-blind, 
placebo-controlled trials [Trials 331-10-227 and 331-10-228]; 1 randomized, 
double-blind, placebo- and active comparator-controlled trial of flexible-dose 
brexpiprazole as adjunctive therapy in the treatment of adults with MDD 
[Trial 331-12-282]; and 1 open-label, 52-week safety trial [Trial 331-10-238]).
Trial 331-08-211 was a multicenter, randomized, double-blind, placebo-controlled trial 
designed to assess the safety and efficacy of brexpiprazole (0.15 to 2 mg daily) as 
adjunctive treatment to an assigned open-label antidepressant therapy (ADT) in subjects 
with MDD.  Subjects received brexpiprazole 0.15 mg/day, 0.50 0.25 mg/day, 
1.5 0.50 mg/day, or matching placebo.  In this trial, adjunctive brexpiprazole dosed at 
1.5 0.50 mg/day was superior to adjunctive placebo with respect to the primary 
endpoint (change in Montgomery Asberg Depression Rating Scale [MADRS] Total 
Score) and several secondary efficacy endpoints.  The 1.5 0.50 mg/day brexpiprazole 
dose group also demonstrated a favorable safety profile.  Few subjects experienced 
serious treatment-emergent adverse events (TEAEs) or discontinued due to TEAEs.  The 
analysis of laboratory data, electrocardiogram (ECG) parameters, and EPS scales did not 
indicate any concerns of clinical significance.
In Trial 331-09-222, randomized subjects received a flexible dose of brexpiprazole 1 to 
3 mg/day (average dose 2.2 mg/day) or placebo as adjunctive treatment to an assigned 
open-label ADT.  In this trial, the MADRS Total Score decreased at each visit for both 
brexpiprazole and placebo groups; however, the decrease observed in the brexpiprazole 
group was statistically significant from baseline at all visits except the primary endpoint 
visit.  The MADRS response rate (≥ 50% decrease MADRS Total Score) and remission 
rate (MADRS Total Score ≤ 10) were statistically significant at endpoint.  Brexpiprazole 
at doses up to 3 mg/day was well tolerated when administered as adjunctive therapy to a 
marketed ADT in subjects with MDD.  During the double-blind treatment phase, TEAEs 
were reported in 76.2% of subjects in the brexpiprazole group and 63.6% of subjects in 
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the placebo group.   The most frequently reported TEAEs were akathisia (11.9%), 
increased weight (11.4%), and insomnia (9.2%).  The Columbia-Suicide Severity Rating 
Scale (C-SSRS) and adverse event (AE) data showed no suicidal behavior during 
double-blind treatment.  No serious adverse events (SAEs) were reported for subjects in 
the brexpiprazole group, and 3 subjects (1.6%) in the placebo group experienced an SAE; 
4.9% of subjects who received adjunctive brexpiprazole and 1.1% of subjects who 
received adjunctive placebo discontinued treatment due to TEAEs.  There were no 
clinically relevant changes in laboratory values, ECG parameters, or vital sign 
measurements, except body weight (mean increase of 1.92 kg in the brexpiprazole group 
versus 0.13 kg in the placebo group), in brexpiprazole-treated subjects.  The minimal 
changes in scores for EPS scales during double-blind treatment were not clinically 
relevant.  An EPS-related AE was observed in 21.6% of subjects in the brexpiprazole 
group compared with 9.6% of subjects in the placebo group.
Trial 331-08-212 is an ongoing, 52-week, open-label trial examining the long-term safety 
and tolerability of brexpiprazole in adults with MDD.  Subjects who complete trials 
331-08-211 or 331-09-222 are eligible to enter this trial.
Ongoing Trials 331-10-227 and 331-10-228 are phase 3, multicenter, randomized, 
double-blind, placebo-controlled, fixed-dose trials designed to assess the safety and 
efficacy of brexpiprazole as adjunctive therapy to an assigned open-label marketed ADT 
in depressed subjects who have demonstrated an incomplete response to prospective 
treatment with the same ADT.  Brexpiprazole doses evaluated in these trials include 
1 and 3 mg/day in Trial 331-10-227 and 2 mg/day in Trial 331-10-228.  Subjects who 
complete Trial 331-10-227 or Trial 331-10-228 are eligible to be enrolled into a 
multicenter, 52-week, open-label trial (Trial 331-10-238).  The ongoing trial 331-12-282 
is a phase 3, multicenter, randomized, double-blind, placebo- and active comparator 
(Seroquel XR)-controlled trial designed to assess the safety and efficacy of 
flexible-dose brexpiprazole as adjunctive therapy to an assigned open-label ADT in 
depressed adults, aged 18 to 65 years.  The ongoing trial 331-12-291 is a phase 1, 
multicenter, randomized, double-blind, placebo-controlled trial designed to assess the 
safety and tolerability of multiple ascending oral doses of brexpiprazole as adjunctive 
therapy in the treatment of elderly subjects (70 to 85 years) with MDD.
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1.2.2.2.
Schizophrenia
The use of brexpiprazole monotherapy for the treatment of schizophrenia has been 
studied in 2 completed, multinational, phase 2, double-blind, placebo-controlled trials 
(Trials 331- 07-203 and 331-08-210).  In addition, 4 multinational, phase 3 trials are 
ongoing:  3 randomized, double-blind, placebo-controlled trials (Trials 331-10-230, 
331-10-231, and 331-10-232) and 1 open-label, 52-week safety trial (Trial 331-10-237).
Trial 331-07-203 was a dose-ranging, placebo-controlled trial (with aripiprazole as a 
positive control to confirm the assay sensitivity of the trial) in subjects experiencing an 
acute exacerbation of schizophrenia.  Although the results showed that neither 
brexpiprazole (dose range, 0.25-6 mg/day) nor aripiprazole was significantly different 
from placebo for the primary and secondary efficacy endpoints at Week 6 
(last-observation-carried-forward [LOCF]), numeric improvements in efficacy scale 
scores were similar between the low, mid, and high flexible-dose groups of brexpiprazole 
and aripiprazole for several endpoints, including the primary endpoint (the Positive and 
Negative Syndrome Scale [PANSS] total score, which measures the severity of 
symptoms of schizophrenia).  Factors such as sex, age, and race did not appear to have a 
consistent influence on efficacy outcomes; however, the small sample size in many of the 
subgroup categories precluded definitive conclusions.  The collective efficacy data from 
this trial suggest an active dose range of 1 to 6 mg/day of brexpiprazole for the treatment 
of schizophrenia.  The frequency of TEAEs was similar in the brexpiprazole (69.7%), 
placebo (70.5%), and aripiprazole (70.0%) groups.  The frequency of SAEs was similar 
between the brexpiprazole (3.8%) and placebo (3.2%) groups.  The C-SSRS and AE data 
showed no suicidal behavior during double-blind or open-label treatment.  Brexpiprazole 
did not result in any consistent, clinically relevant changes in laboratory values, vital 
signs, or ECG parameters.  Statistically significant increases in weight, body mass index 
(BMI), and waist circumference were observed in the 2.5 ± 0.5 mg/day and 
5.0 ± 1.0 mg/day brexpiprazole groups compared with the placebo group.
Eligible subjects from Trial 331-07-203 could have continued into the multicenter, 
52-week, open-label trial (Trial 331-08-210) designed to assess the safety and tolerability 
of 1 to 6 mg of oral brexpiprazole in adult subjects with schizophrenia. Twenty-eight 
subjects were included in the 52-week trial: 20 subjects who had received prior 
brexpiprazole, 6 who had received prior placebo, and 2 who had received prior 
aripiprazole.  Assessment of efficacy as a secondary objective showed improvement from 
baseline for each of the efficacy endpoints.  The response rate (reduction of ≥ 30% from 
baseline in PANSS total score or CGI-I score of 1 [very much improved] or 2 [much 
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improved] at the last visit) was 35.2% (86 of 244 subjects).  Further, discontinuation for 
lack of efficacy was infrequent (2.0% [5 of 244 subjects]).  Brexpiprazole (1-6 mg/day) 
was well tolerated when administered for up to 52 weeks.  During the trial, 75.0% (21 of 
28) of subjects enrolled for 52 weeks reported at least 1 TEAE.  Most TEAEs were mild 
or moderate in intensity.  The most frequently reported TEAEs (ie, those reported in 
> 10% of subjects) were viral respiratory tract infection and increased weight (14.3% 
each) and nasopharyngitis and somnolence (10.7% each).  Although there were isolated, 
potentially clinically relevant results for individual subjects in clinical laboratory, vital 
signs, and/or ECG assessments, there were no clinically relevant mean changes overall 
for these assessments.  Brexpiprazole was associated with slight mean increases from 
baseline in body weight, BMI, and waist circumference.  Overall, the long-term safety 
and tolerability of brexpiprazole appeared to be similar to that observed after short-term 
exposure (up to 6 weeks); however, this could not be fully characterized in this trial due 
to the small number of subjects exposed for 52 weeks.
Currently, ongoing Trials 331-10-230 and 331-10-231 are designed to assess the safety 
and efficacy of fixed doses of 1, 2, or 4 mg/day of brexpiprazole and 0.2, 2, and 4 mg/day 
of brexpiprazole, respectively, in adults with acute schizophrenia; and Trial 331-10-232 
will evaluate the use of brexpiprazole (1-4 mg/day) as maintenance treatment in subjects 
with schizophrenia.  Subjects who complete Trial 331-10-230, Trial 331-10-231, or 
Trial 331-10-232 are eligible to be enrolled into a multicenter, 52-week, open-label trial 
(Trial 331-10-237), along with de novo subjects from select sites.
1.2.2.3.
Attention-Deficit/Hyperactivity Disorder (ADHD)
For ADHD, 1 phase 2 trial (Trial 331-08-213) has been completed.  Trial 331-08-213 was 
a proof-of-concept, multicenter, randomized, double-blind, placebo-controlled, 
flexible-dose trial in which adults with ADHD who had an incomplete/partial response to 
stimulant therapy in a prospective treatment phase were randomized to double-blind 
treatment with either brexpiprazole-plus-stimulant or placebo-plus-stimulant.  Results 
showed no statistically significant improvement in the brexpiprazole group compared 
with the placebo group with regard to the primary efficacy endpoint (ie, the Conners’ 
Adult ADHD Rating Scale-Observer:  Screening Version [CAARS-O:SV]), the key 
secondary efficacy endpoints (ie, Wender-Reimherr Adult Attention Deficit Disorder 
Scale [WRAADDS] total score and sleep improvement as measured by the Insomnia 
Severity Index [ISI] total score and the ISI Item 2) or other efficacy endpoints.  During 
the double-blind treatment phase (Phase B), a similar percentage of subjects in the 
brexpiprazole group (95 of 155 [61.3%]) and the placebo group (48 of 80 [60.0%]) 
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reported at least 1 TEAE.  Only insomnia (in 13 of 155 [8.4%] subjects) and headache (in 
11 of 155 [7.1%] subjects) were reported in greater than 5% of subjects in the 
brexpiprazole group.  Most TEAEs were mild or moderate in intensity.  During the 
double-blind treatment phase, 2 subjects reported SAEs (pneumonia and urinary tract 
infection), both of whom were in the placebo group.  There were no unexpected or 
clinically relevant findings related to assessments of movement disorders, metabolic 
syndrome, EPS rating scales, or suicidality (based on the C-SSRS) during the double-
blind phase.
1.3.
Known and Potential Risks and Benefits
Based on the Investigator’s Brochure,16 combined data from the completed phase 1 
clinical trials indicate that brexpiprazole is safe and well tolerated in healthy subjects at 
single oral doses of 0.2 to 6 mg and at multiple oral doses up to 2 mg/day.  Data from the 
completed multiple-dose clinical trials indicate brexpiprazole is well tolerated at multiple 
oral doses up to 12 mg/day in subjects with schizophrenia or schizoaffective disorder; up 
to 4 mg/day when coadministered with marketed ADT in subjects with MDD; and up to 
4 mg/day when coadministered with marketed stimulant therapy in subjects with ADHD. 
Based on data from the 18 completed phase 1 clinical trials in healthy subjects or special 
populations (including healthy subjects from 2 phase 1 trials conducted in special 
populations) (15 in the US, 2 in Japan, and 1 in Korea), the most frequently reported 
TEAEs (incidence ≥ 5% or more of all healthy subjects who received brexpiprazole and 
more than placebo, administered either alone or with another marketed drug) were:

Healthy subjects (N = 15 trials conducted in the US):  dizziness, headache, postural 
dizziness, nausea, somnolence, constipation, and diarrhoea

Healthy subjects (N = 3 trials conducted in Japan and Korea):  nausea, orthostatic 
hypotension, somnolence, and dizziness
By indication, the most frequently reported TEAEs (incidence ≥ 5% or more of all 
subjects who received brexpiprazole and more than placebo, administered either alone or 
with another marketed therapy or drug (ie, ADT, stimulant therapy, or antibiotic) in 
completed phase 1, phase 1b, and/or phase 2 double-blind patient trials (excluding 
subjects enrolled in phase 2 open-label extension trials) conducted under US 
Investigation New Drug Applications (INDs) were:

Schizophrenia or schizoaffective disorder (N = 4 trials):  headache, anxiety, akathisia, 
nausea, increased weight, and dizziness
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
MDD (N = 3 trials):  akathisia, increased weight, insomnia, upper respiratory tract 
infection, and nasopharyngitis

ADHD (N = 2 trials):  insomnia
In the single completed phase 1 trial in subjects with schizophrenia conducted in Japan, 
TEAEs reported in 3 or more subjects who received brexpiprazole (of 21 total subjects) 
were:

Schizophrenia (N = 1 trial): increased serum prolactin and increased serum creatine 
phosphokinase
Brexpiprazole did not result in any consistent, clinically relevant changes in laboratory 
values, vital signs (blood pressure or heart rate), or ECG parameters in the completed 
phase 1 and 2 clinical trials in subjects with MDD or schizophrenia.  Statistically 
significant increases in weight were observed with brexpiprazole relative to placebo in 
both sample populations.  Brexpiprazole exhibited a favorable profile with respect to 
movement disorders in subjects with MDD at doses up to 3 mg/day (Trial 331-09-221) 
and in subjects with schizophrenia at doses up to 12 mg/day (Trial 331-08-205).  In the 
dose-ranging trial that enrolled subjects who were experiencing an acute exacerbation of 
schizophrenia (Trial 331-07-203), an increase in the incidence of EPS was observed at 
the highest dose (ie, brexpiprazole 5 1 mg/day).
Two deaths have been reported in the 30 completed clinical trials.  One death was 
reported in the completed phase 2 double-blind trial in adult subjects with acute 
schizophrenia (Trial 331-07-203).  The second death was reported in the completed 
phase 2 open-label MDD trial (Trial 331-08-212).  None of these subjects were taking 
IMP at the time of death and none of these fatal events were considered by the 
investigator to be related to IMP.  Additionally, 4 deaths have been reported in 2 ongoing 
phase 3 open-label trials of brexpiprazole.  One death was reported in an ongoing 
schizophrenia trial (331-10-237) and 3 deaths were reported in an ongoing MDD trial 
(331-10-238).  One of the deaths (completed suicide in Trial 331-10-238) was considered 
by the investigator to be possibly related to IMP.
Serious TEAEs have been reported for 64 subjects who received brexpiprazole in the 
30 completed trials.  In ongoing trials of brexpiprazole, 120 subjects receiving 
brexpiprazole had reported serious TEAEs. 
Refer to the current Investigator’s Brochure for a summary of available nonclinical and 
clinical safety data.16
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2. Trial Rationale and Objectives
2.1.
Trial Rationale
Behavioral symptoms, such as agitation, are core features in subjects with Alzheimer’s 
disease and related dementias and develop in the majority of dementia subjects.  The 
presence of agitation in subjects with Alzheimer’s disease places a significant burden not 
only on subjects and their caregivers but also on the healthcare system.
Based on the data available from atypical antipsychotics in the treatment of agitation or 
aggression in Alzheimer’s disease, brexpiprazole is an appropriate candidate to evaluate 
the benefit-risk ratio of this class of drugs in this subject population in today’s clinical 
setting.  In addition to potential treatment effects, the receptor binding profile of 
brexpiprazole may confer additional benefits in terms of the safety profile, particularly 
with respect to hyperprolactinemia, sleep quality, and weight gain.
In light of the Food and Drug Administration (FDA) boxed warning of increased 
mortality with the use of antipsychotics in elderly subjects with dementia-related 
psychosis and similar caution advised by other regulatory authorities, the clinical trial 
will be conducted in an environment that allows for close safety monitoring, in subjects 
who are living in either an institutionalized setting or in a non-institutionalized setting 
where the subject is not living alone and has a caregiver who can spend a minimum of 
2 hours per day for 4 days per week with the subject in order to assess changes in the 
subject’s condition.  Furthermore, a slow titration schedule will be implemented with 
brexpiprazole being titrated to the highest assigned dose (2 mg/day) over a 4-week 
period.  
 
 
 
2.2.
Dosing Rationale
Brexpiprazole in a dose range of 0.5 mg/day to 2 mg/day will be studied in this 
flexible-dose trial.  Doses will be increased slowly so that the highest dose will be 
reached at end of the fourth week of treatment (ie, at the Week 4 visit).
The doses to be used in this indication have been determined based on results from 
completed phase 1 safety and tolerability trials; from a PET trial of dopamine receptor 
occupancy; from phase 2 and phase 3 trials in subjects with schizophrenia, MDD, or 
ADHD; and from review of data from trials of similar medications in subjects with 
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dementia.  The following doses of brexpiprazole have been well tolerated in completed 
phase 1 single- and multiple-ascending-dose clinical trials:

Up to 6 mg from single-dose trials and up to 2 mg/day from multiple-dose trials in 
healthy subjects

Up to 12 mg/day from multiple-dose trials in subjects with schizophrenia or 
schizoaffective disorder (the maximum tolerated dose [MTD] was not reached)

Up to 4 mg/day from a multiple-dose trial in subjects with MDD when 
coadministered with marketed ADT (the MTD was not reached)

Up to 4 mg/day from a multiple-dose trial in subjects with ADHD when 
coadministered with marketed stimulant therapy (the MTD was not reached)
In the multiple-ascending-dose studies of subjects with schizophrenia, MDD, and ADHD, 
the studies ended when a prospectively chosen daily dose was reached.  In all 3 studies, 
the MTD was not reached.  The MTD of brexpiprazole in subjects with schizophrenia is 
greater than 12 mg/day.  The MTD in subjects with MDD and ADHD, when 
coadministered with ADT and stimulant therapy, respectively, is greater than 4 mg/day.  
These data indicate that doses of at least 4 mg/day are well tolerated in nonpsychotic 
adult psychiatric subjects.
Efficacy in treating schizophrenia by dopamine D2 antagonists has been associated with 
occupancy of greater than 65% of the dopamine receptors.17,18,19  However, the 
occupancy associated with effective doses of another partial dopamine agonist, 
aripiprazole, are greater than 80%20,21 and the occupancy associated with therapeutic 
benefit of the brexpiprazole would be expected to be in the same range.  To further define 
the proper dose range for brexpiprazole, the binding of brexpiprazole to dopamine D2/D3 
receptors was investigated in a PET trial in healthy subjects (Trial 331-07-202).  Single 
doses of up to 6 mg of brexpiprazole were administered to 15 subjects.  Results from the 
trial predicted steady-state receptor occupancies of 80% to 90% at brexpiprazole doses of 
1 to 2 mg (79.3% predicted occupancy at 1 mg brexpiprazole, 88.8% at 2 mg 
brexpiprazole, and 95.1% at 4 mg brexpiprazole).  Based on the single-dose D2/D3 
receptor occupancy data and steady-state pharmacokinetic/pharmacodynamic modeling, 
it was predicted that the D2/D3 receptor occupancy after multiple daily dose 
administration of 1 mg to 2 mg doses would result in 80% to 90% D2/D3 receptor 
occupancy.
 
 
 
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  Since 4 mg/day has been well tolerated and to ensure 
that D2 occupancy levels at and above 80% are achieved, doses up to 4 mg/day are being 
studied in the phase 3 trials in schizophrenia and up to 3 mg/day in adjunctive treatment 
of MDD.  In the phase 2 trial of adults with ADHD, the highest dose was 3 mg/day.
Three studies of another compound discovered by Otsuka, aripiprazole (Abilify), have 
been conducted to investigate its benefit in the treatment of psychosis in subjects with 
Alzheimer’s dementia.21,22,23  In the 2 of the 3 aripiprazole trials that were conducted in 
subjects in institutional settings such as nursing homes, benefit in the treatment of 
agitation in that subject population was suggested by the finding of statistically 
significant differences between the aripiprazole treatment groups and the placebo 
treatment groups on 2 secondary endpoints, the Cohen-Mansfield Agitation Inventory 
(CMAI) and the agitation item of the Neuropsychiatric Inventory-Nursing Home 
(NPI-NH).  In the fixed dose trial, which included 2 mg/day, 5 mg/day, and 10 mg/day 
dose arms, there were significant differences found on both measures for the 5 mg/day 
and 10 mg/day groups.  Significant differences compared with placebo on both measures 
were also observed in the second flexible-dose trial of the 2 mg/day to 15 mg/day dose 
range.
Because of concerns about tolerability and safety in subjects, the doses of antipsychotics 
used in clinical trials in subjects with dementia have generally been lower than the doses 
recommended for subjects with schizophrenia.21,22,24  While the dose range for 
brexpiprazole in schizophrenia studies is 1 mg/day to 4 mg/day, the selected dose range 
in the Alzheimer’s population is 0.5 mg/day to 2 mg/day, to maximize tolerability while 
investigating doses that should achieve the occupancy of the D2 receptor associated with 
benefit in the alleviation of target symptoms by a D2 partial agonist.  Slow titration of the 
dosing also will be employed to maximize tolerability.
2.3.
Trial Objectives
Primary:
To compare the efficacy of flexible dosing of brexpiprazole (dose range of 
0.5 to 2 mg/day) with placebo in subjects with agitation associated with 
dementia of the Alzheimer’s type, as assessed by the CMAI after 12 weeks of 
treatment.
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Secondary: To evaluate the safety and tolerability of flexible dosing of brexpiprazole 
(dose range of 0.5 to 2 mg/day) compared with placebo in subjects with 
agitation associated with dementia of the Alzheimer’s type after 12 weeks of 
treatment.
3. Trial Design
3.1.
Type/Design of Trial
This is a phase 3, 12-week, multicenter, randomized, double-blind, placebo-controlled, 
2-arm, flexible-dose trial designed to assess the efficacy, safety, and tolerability of 
brexpiprazole (dose range of 0.5 mg/day to 2 mg/day) in the treatment of subjects with 
agitation associated with dementia of the Alzheimer’s type.  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 the 
subject is 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 the subject in order to assess changes in the subject’s condition. 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.
The trial comprises a 2- to 42-day screening period, a 12-week double-blind treatment 
period, and a 30-day post-treatment follow-up period.  
 
 
  
This trial will be monitored under the supervision of an independent Data Monitoring 
Committee (DMC).  The DMC will monitor safety periodically, based on a 
predetermined schedule.  The details of the DMC structure and its roles and 
responsibilities will be documented in a DMC charter (refer to Section 3.7.8).
The trial is organized as follows (refer to Figure 3.1-1 for a schematic of the trial design):
Screening Period
The screening period will range from 2 days to 42 days 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.  
Additional requirements for obtaining informed consent from this vulnerable subject 
population are provided in Section 3.4.1.  An interactive voice response system (IVRS) or 
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interactive web response system (IWRS) will be used to obtain the subject trial
identification number for each subject with a signed ICF.
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).  The subject should be randomized into the double-blind treatment period as 
soon as all the screening assessments are completed, the screening and baseline eligibility 
criteria have been met, and the required washout period has occurred.
 
 
 
  The investigator is responsible for ensuring that subjects are 
eligible for enrollment into the trial and for assessing subject safety throughout the trial.  
 
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 
and/or facility staff.  This diary data along with the collection of progress notes will be 
sent to the 
 on a routine basis in order to corroborate information recorded on 
the CMAI.  Since the diary data is a tool to assist 
 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, and/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.
12-week, Double-blind Treatment Period
Based on a randomization scheme, eligible subjects will be allocated in a 1:1 ratio at 
randomization to 1 of the following 2 treatment groups:

Brexpiprazole

Placebo
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Subjects will follow a titration schedule to gradually increase their dose of the IMP to the 
target dose (refer to Table 3.2-1).  
Subjects will be evaluated at Baseline, Day 3, and at Weeks 2, 4, 6, 8, 10, and 12 during 
the double-blind treatment period.  All trial visits will take place as a clinic visit at either 
the investigator’s site or residential facility, if applicable.  All attempts should be made 
to maintain the subjects’ normal routine with regard to physician appointments.  
Individual circumstances that fall outside this general convention should be discussed 
with the medical monitor in order to determine appropriateness to proceed.  In 
addition, the subject’s identified caregiver will be contacted by telephone at Weeks 3, 5,
and 7 to assess compliance with IMP, confirm any changes to concomitant medications, 
and assure the subject’s well-being.  Trial-related efficacy and safety assessments will 
be performed as outlined in the Schedule of Assessments (Table 3.7-1).
If a subject discontinues the trial prematurely, every effort will be made to complete the 
Week 12/Early Termination (ET) evaluations prior to administering additional 
medications for the treatment of agitation or other prohibited medications.
Follow-up Period
All subjects, whether they complete the trial or are withdrawn prematurely for any 
reason, will be followed up for a safety evaluation 30 (+ 2) days after the last dose of 
IMP during a clinic visit at either the investigator’s site or residential facility, if 
applicable.  If a clinic visit is not possible, the subject should be assessed by telephone 
contact with the subject and a caregiver.  
 
 
Subjects who complete both the 12-week double-blind treatment period and the 30-day 
safety follow-up visit are eligible to enroll into Trial 331-13-211, which is a 2-month, 
observational, rollover trial to evaluate the safety of subjects with agitation associated 
with Alzheimer's disease who previously participated in Trial 331-12-284. For those 
subjects who plan to enroll into Trial 331-13-211, the 30-day safety follow-up visit for 
Trial 331-12-284 will occur as a clinic visit either at the investigator’s site or the 
residential facility, if applicable. 
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Figure 3.1-1
Trial Design Schematic
 
Safety
Follow-Up
R
Screening
Brexpiprazole flexible dose
Dose range 0.5 mg/day to 2 mg/day (target dose is 1 mg/day)
(N = 130)
Subjects with agitation 
associated with dementia 
of the Alzheimer’s type 
(N = 520 screened)
Placebo (N = 130)
30 (+ 2) 
Days
Duration:  12 weeks
2 to 42 days
Days –42 to –2
(with an option to extend 
with approval of the 
medical monitor)
Baseline Visit
(Day 0)
End of Treatment 
(Week 12/ET)
12-week Double-blind Treatment Period
= Randomized (1:1)
(N = 260)
1 or more visits
as needed
Clinic visit or
telephone 
contact
 
 
 
 
 
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3.2.
Treatments
Treatment assignments will be obtained by accessing the IVRS or IWRS.  Based on the 
fixed-block, computer-generated randomization, eligible subjects will be allocated in a 
1:1 ratio at randomization to 1 of the following 2 treatment groups:

Brexpiprazole

Placebo
Neither the investigator nor the subject will be aware of the treatment assignment.  All 
doses of brexpiprazole and matching placebo should be taken orally once daily, 
preferably in the morning, and can be administered without regard to meals.  
Brexpiprazole should be taken at approximately the same time each day, particularly 
prior to visits with pharmacokinetic sampling.
Subjects will be titrated to a target dose of 1 mg/day of brexpiprazole over a 2-week 
period using the recommended titration schedule as follows:
Table 3.2-1
Dosing Scheme
Treatment Group
Recommended Daily Dose Administered
Day after the
Baseline visit
(Day 1)
Day after the
Day 3 visit
(Day 4[+2 days])
Day after the
Week 2 visit
(Day 15[±2 days])
Day after the
Week 4 visit 
(Day 29[±2 days])
Brexpiprazole 
0.5-2 mg/day
0.25 mg/day
0.5 mg/day
1 mg/daya
2 mg/dayb
Placebo
<-------------------------------------------------------------------------------------------------->
aAfter achieving the target dose of 1 mg/day, the dose may be decreased to a 0.5 mg/day and re-increased 
to 1 mg/day based on the investigator’s clinical judgment. Dose decreases and increases can occur at any 
time (scheduled or unscheduled visits).   
bThe earliest time point that the dose can be increased to 2 mg/day is starting on the day after the Week 4 
visit (ie, Day 29 [±2 days]); however, it is not mandatory for the dose to be increased to 2 mg/day. The 
decision to increase the dose should be based on the investigator’s clinical evaluation of the subject’s 
response and tolerability.  Allowable IMP doses that may be given starting the day after the Week 4 visit 
(ie, Day 29 [±2 days]) will be 0.5 mg/day, 1 mg/day, or 2 mg/day.
The first dose of IMP will be administered on the day after the Baseline visit (ie, Day 1).  
All subjects randomly assigned to receive brexpiprazole will receive 0.25 mg/day as a 
starting dose.
The dose of IMP will be increased from 0.25 mg/day to 0.5 mg/day starting on the day 
after the Day 3 visit (ie, Day 4 [+2 days]). 
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The dose will then be increased to 1 mg/day starting on the day after the Week 2 visit (ie, 
Day 15 [±2 days]).  After achieving the target dose of 1 mg/day, the dose may be 
decreased to a 0.5 mg/day and re-increased to 1 mg/day based on the investigator’s 
clinical judgment. Dose decreases and increases can occur at any time (scheduled or 
unscheduled visits).   
The dose of IMP can be further increased from 1 mg/day to 2 mg/day starting on the day 
after the Week 4 visit (ie, Day 29 [±2 days]).  Note: the earliest time point that the dose 
can be increased to 2 mg/day is starting on the day after the Week 4 visit (ie, Day 29 
[±2 days]); however, it is not mandatory for the dose to be increased to 2 mg/day. The 
decision to increase the dose should be based on the investigator’s clinical evaluation of 
the subject’s response and tolerability.  
Allowable IMP doses that may be given starting the day after the Week 4 visit (ie, 
Day 29 [±2 days]) will be 0.5 mg/day, 1 mg/day, or 2 mg/day. Dose decreases and 
increases must occur in a stepwise manner and can occur at any time (scheduled or 
unscheduled visits). 
For subjects randomly assigned to receive placebo, their dose of IMP will be 
administered daily starting on the day after the Baseline visit (ie, Day 1) and ending on 
Week 12/ET (the last day of the Treatment Period).
Subjects unable to tolerate 0.5 mg/day of the IMP (or matching placebo) will be 
discontinued from the trial.  
3.3.
Trial Population
The subject 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 the subject is 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 the subject in order to assess 
changes in the subject’s condition. All subjects must have a diagnosis of probable 
Alzheimer’s disease according to the NINCDS-ADRDA criteria.  Subjects must have a 
previous magnetic resonance imaging (MRI) or computed tomography (CT) scan of the 
brain, which was performed after the onset of symptoms of dementia, with findings 
consistent with a diagnosis of Alzheimer’s disease.  If a previous MRI or CT scan of the 
brain performed after the onset of the symptoms of dementia is not available, then an 
MRI/CT scan should be performed during screening.  Additionally, at both the screening 
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and baseline visits, subjects must have a Mini-Mental State Examination (MMSE) score 
of 5 to 22, inclusive, and a total score (frequency x severity) of ≥4 on the 
agitation/aggression item of the NPI-NH or the Neuropsychiatric Assessment for 
Non-institutionalized Patients based on the NPI/NPI-NH (hereafter referred to as 
“NPI/NPI-NH”). The NPI-NH will be used for institutionalized subjects and the 
NPI/NPI-NH will be used for non-institutionalized subjects.  The onset of the subject’s 
symptoms of agitation must be at least 2 weeks prior to the screening visit.  Subjects must 
require pharmacotherapy for the treatment of agitation per the investigator’s judgment, 
after an evaluation for reversible factors (eg, pain, infection, polypharmacy) and a trial of 
nonpharmacological interventions.
Subjects must have been residing at their current location for at least 14 days before 
screening and be expected to remain at the same location for the duration of the trial.  
Subjects who at any point during the double-blind treatment phase transfer from an 
institutionalized setting to a non-institutionalized setting, or vice versa, will be withdrawn 
from the trial.  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.  All attempts should be made to maintain the subjects’ normal routine with 
regard to appointments with physicians and overnight accommodations.  Subjects 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 subjects’ normal routine.
 
 
 
It is planned that approximately 520 subjects will be screened at approximately 65 trial 
sites worldwide in order to randomize 260 subjects.
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 
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by contacting appropriate emergency services, the subject’s primary physician, or the 
principal investigator, whatever is warranted.  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, NPI/NPI-NH, 
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 the same individual who fulfills the role of caretaker 
depending on the circumstances of the subject.  The recommended 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 
and NPI/NPI-NH are administered unless other arrangements are made and approved by 
the sponsor.
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, NPI-NH, 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.
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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 and/or on behalf of the subject must be followed:

If the subject is deemed capable by the investigator, written informed consent will be 
obtained from the subject prior to the initiation of any trial protocol-required 
procedures.  In such cases, acknowledgement from the subject’s legally acceptable 
representative (an individual, or judicial or other body, authorized under applicable 
law to consent to the subject’s participation in the clinical trial on behalf of that 
prospective subject) will also be obtained, if required, in accordance with state and/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), written 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 and/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 and/or applicable state and/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 and/or local regulations prior to the initiation or continuation 
of any trial protocol-required procedures.  
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3.4.1.2.
Documentation of Informed Consent
Consent will be documented on a written ICF.  The ICF will be approved by the same 
institutional review board (IRB)/independent ethics committee (IEC) that approves this 
protocol.  Each ICF will comply with the International Conference on Harmonization 
(ICH) Good Clinical Practice (GCP) Guideline25 and local regulatory requirements.  The 
investigator agrees to obtain sponsor approval of any written ICF used in the trial prior to 
submission to the IRB/IEC.
Investigators may discuss trial availability and the possibility for entry with a potential 
subject and subject’s legally acceptable representative without first obtaining consent.  
However, informed consent must be obtained and documented prior to initiation of any 
procedures that are performed solely for the purpose of determining eligibility for this 
trial, including withdrawal from current medication(s).
The subject must be informed about the trial to the extent compatible with the subject’s 
understanding and, if capable, personally sign and date the consent or assent form, 
depending on local regulations. 
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 and/or assent form attesting that the information is accurate and that the 
subject’s legally acceptable representative and subject understand and freely have 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/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.
Once appropriate essential information has been provided and fully explained in 
layman’s language to the subject and the subject’s legally acceptable representative by 
the investigator (or a qualified designee), the IRB/IEC-approved written ICF will be 
signed and dated by the subject, if capable, or the subject’s legally acceptable 
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representative, and the person obtaining consent (investigator or designee), as well as by 
any other parties required by the IRB/IEC.  The subject and the subject’s legally 
acceptable representative will receive a copy of the signed ICF; the original shall be kept 
on file by the investigator.
During a subject’s participation in the trial, any updates to the consent form and any 
updates to the written information will be provided to the subject and the subject’s legally 
acceptable representative.
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3.4.2.
Inclusion Criteria
Subjects are required to meet the following inclusion criteria:
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 and/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 MMSE score of 5 to 22, inclusive, at the screening and baseline visits.
5.
Subjects must have a previous MRI or CT scan of the brain, which was performed after the onset of 
symptoms of dementia, with findings consistent with a diagnosis of Alzheimer’s disease.
6.
Subjects who are residing at their current location for at least 14 days before screening and are 
expected to remain at the same location for the duration of the trial.  
7. 
Institutionalized subjects with an identified caregiver who has sufficient contact 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 (see Section 3.3.1.1 for caretaker definition) 
and must have an identified caregiver who has sufficient contact to describe the subject’s 
symptoms and has direct observation of the subject’s behavior.
8.
Subjects with a total score (frequency x severity) of ≥4 on the agitation/aggression item of the 
NPI-NH (for institutionalized subjects) or the NPI/NPI-NH (for non-institutionalized subjects) at 
the screening and baseline visits.
9.
Subjects with onset of symptoms of agitation at least 2 weeks prior to the screening visit. 
10.
Subjects who require pharmacotherapy for the treatment of agitation per the investigator’s 
judgment, after an evaluation for reversible factors (eg, pain, infection, polypharmacy) and a trial 
of nonpharmacological interventions.
11.
Subjects who are capable of self-locomotion or locomotion with an assistive device (eg, 4-point 
walker, wheelchair).
12.
Subjects willing and able to discontinue all prohibited concomitant medications to meet 
protocol-required washouts prior to and during the trial period.
13.
Subjects able to satisfactorily comply with the protocol requirements.
CT = computed tomography; MRI = magnetic resonance imaging; MMSE = Mini-Mental State 
Examination; NINCDS-ADRDA = National Institute of Neurological and Communicative Disorders and 
Stroke and the Alzheimer’s Disease and Related Disorders Association; NPI-NH = Neuropsychiatric 
Inventory-Nursing Home; NPI/NPI-NH = Neuropsychiatric Assessment for Non-Institutionalized Patients 
based on the NPI/NPI-NH.
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3.4.3.
Exclusion Criteria
Subjects will be excluded if they meet any of the following exclusion criteria prior to 
randomization:
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 
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 have an insufficient response, based on the investigator’s judgment, to 2 or more 
previous antipsychotic medications for the treatment of agitation associated with Alzheimer’s 
disease.
5.
Subjects with delirium or history of delirium within the 30 days prior to the screening visit.
6.
Subjects who have been diagnosed with an Axis I disorder (DSM-IV-TR 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 major depressive disorder are eligible 
provided that they have been on a stable dose(s) of antidepressant medication(s) for the 30 days 
prior to randomization. Please note: antidepressant medications that are CYP2D6 or CYP3A4 
inhibitors are prohibited (see Table 4.1-2 for prohibited antidepressant medications).
7.
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.
Medical History and Concurrent Diseases
8.
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, coronary 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
9.
Subjects with uncontrolled hypertension (DBP > 95 mmHg) or symptomatic hypotension, or 
orthostatic hypotension, which is defined as a decrease of ≥30 mmHg in SBP and/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.
10.
Subjects with diabetes mellitus may be eligible for the trial if their condition is stable and 
well-controlled as determined by satisfying ALL of the following criteria:

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 IDDM (ie, any subjects using insulin) must also satisfy the below criterion:

No current microalbuminuria; ie, urine ACR must be < 30 mg/g (calculated).
Subjects with newly diagnosed diabetes during screening are excluded.
11.
Subjects with hypothyroidism or hyperthyroidism (unless condition has been stabilized with 
medications for at least the past 90 days) and/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.
12.
Subjects with epilepsy or a history of seizures, except for a single childhood febrile seizure, post 
traumatic, alcohol withdrawal, etc.
13.
Subjects with seropositive status for hepatitis B (ie, HBsAg positive) or hepatitis C (ie, anti-HCV 
positive).  
14.
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.
15.
Subjects with a BMI < 18.5 kg/m2.
16.
Subjects who have met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, 
Text Revision (DSM-IV-TR) criteria for substance abuse or dependence within the past 180 days; 
including alcohol and benzodiazepines, but excluding caffeine and nicotine.
Physical and Laboratory Results
17.
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 urine 
drug screen resulting from use of prescription or over-the-counter (OTC) medications or products 
that in the investigator’s documented 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. 
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Table 3.4.3-1
Exclusion Criteria
18.
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.  The medical monitor should be 
contacted to discuss individual cases, as needed.  Criteria are provided in Appendix 3, Appendix 4, 
and Appendix 5 to assist investigators in their assessments of results that may be potentially 
medically significant, depending on the subject’s medical history and clinical presentation.  
In addition, subjects with the following laboratory test and ECG results at screening must be 
excluded from the trial:

Platelets ≤ 75,000/mm3

Hemoglobin ≤ 9 g/dL 

Neutrophils, absolute ≤ 1000/mm3

Aspartate transaminase (AST) > 2 x ULN

Alanine transaminase (ALT) > 2 x ULN

Creatine phosphokinase (CPK) > 3 x 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 thyroid-stimulating hormone [TSH] is abnormal.)

QTcF 450 msec in men and 470 msec in women (see Section 3.7.4.4 for further details), 
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.
Sex and Reproductive Status
19.
Sexually active females of childbearing potential (see 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 trial medication 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 (IUD), birth control pill, birth 
control implant, birth control depot injections, condom with spermicide, or sponge with spermicide.
20.
Females who are breast-feeding and/or who have a positive pregnancy test result prior to receiving 
trial drug in Trial 331-12-284.
Prohibited Therapies or Medications
21.
Subjects who have a current medical condition that requires treatment with an anticoagulant. 
22.
Subjects who have received bapineuzumab, solanezumab, or other immunotherapy, such as 
vaccines, for the treatment of Alzheimer’s disease (through clinical trial or compassionate use 
program) in the 6 months preceding randomization.
23.
Subjects who would be likely to require prohibited concomitant therapy during the trial (see 
Table 4.1-1).
24.
Subjects who received brexpiprazole in any prior clinical trial or commercially available
brexpiprazole (Rexulti®).
Allergies and Adverse Drug Reactions
25.
Subjects with a history of neuroleptic malignant syndrome (NMS).
26.
Subjects with a history of true allergic response (ie, not intolerance) to more than 1 class of 
medications.
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Table 3.4.3-1
Exclusion Criteria
Other
27.
Subjects who participated in a clinical trial within the last 30 days.
28.
Any subject who, in the opinion of the investigator, medical monitor, or sponsor should not 
participate in the trial.
ACR = albumin-to-creatinine ratio; anti-HCV = hepatitis C antibodies; BMI = body mass index; 
CT = computed tomography; CYP2D6 = cytochrome P450 2D6 isozyme; DBP = diastolic blood pressure; 
DSM-IV-TR = Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision; 
ECG = electrocardiogram; HbA1c = glycosylated hemoglobin; HBsAg = hepatitis B surface antigen; 
HIV = human immunodeficiency virus; IDDM = insulin-dependent diabetes mellitus; MRI = magnetic 
resonance imaging; QTcF = QT interval as corrected for heart rate by Frederica’s formula; SBP = systolic 
blood pressure; T4 = thyroxine; ULN = upper limit of normal.
Screen failures 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 once 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.
3.5.
Outcome Variables
3.5.1.
Primary Efficacy Variable
The primary efficacy variable is the change from baseline to Week 12/ET in the CMAI 
total score.  The primary analysis will use a mixed-effect model repeated measure 
(MMRM) approach.
3.5.2.
Key Secondary Efficacy Variable
The key secondary efficacy variable is the change from baseline to Week 12/ET in the 
Clinical Global Impression-Severity of Illness (CGI-S) score, as related to agitation.
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3.5.3.
 
 
3.5.4.
 
 
 
3.5.5.
 
 
 
 
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3.5.6.
Safety Variables
Safety variables to be examined in this trial will include AEs, physical and neurological 
examinations, vital signs, body weight, waist circumference, clinical laboratory tests 
(hematology, serum chemistry, and urinalysis), ECGs, 
 
 
 
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 coagulation parameters (prothrombin time [PT], 
activated partial thromboplastin time [aPTT], and International Normalized Ratio [INR]), 
glycosylated hemoglobin (HbA1c), cortisol, adrenocorticotropic hormone (ACTH), 
thyroid-stimulating hormone (TSH), 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.  
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 listings of physical and neurological examination findings will be reviewed as 
a further assessment of safety.
3.5.7.
Pharmacokinetic/Pharmacodynamic Variables
Plasma concentrations will be determined for brexpiprazole and its metabolite(s) and 
descriptive statistics will be calculated.  No formal statistical comparisons are planned.  
Additional population or pharmacokinetic 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 
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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 the IVRS/IWRS, and reporting SAEs to 
regulatory agencies.  The randomization will be stratified by center.  Subjects will be 
randomized to brexpiprazole or placebo in a 1:1 ratio within each stratum.
3.7.
Trial Procedures
The time from enrollment of the first subject to the last subject’s last trial visit will be 
approximately 4.5 years, of which approximately 4 years are allotted for recruitment of 
subjects.  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 will be followed up at a 
clinic visit or via telephone contact 30 (+ 2) days after the last dose of the IMP.  
 
 
 
 
 
 
 
 
 
 
 
All trial visits will take place as a clinic visit at either the investigator’s site or residential 
facility, if applicable.  All attempts should be made to maintain the subjects’ normal 
routine with regard to physician appointments.  Individual circumstances that fall 
outside this general convention should be discussed with the medical monitor in order 
to determine appropriateness to proceed.  Trial assessment time points are summarized 
in Table 3.7-1.
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Table 3.7-1
Schedule of Assessments
Assessment
Visit
Screeninga
Baseline 
(Day 0)
Day 3
Wk 2
Wk 4
Wk 6
Wk 8
Wk 10
Wk 12/ ETb
FUc
ENTRANCE/HISTORY
Informed consente
X
Inclusion/exclusion criteriaf
X
X
Demography
X
Medical history
X
Psychiatric history
X
Neurological historyg
X
Prior medication washouth
X
NINCDS-ADRDA
X
Hachinski Ischemic Scale (Rosen 
Modification)g
X
HBsAg and anti-HCV
X
EFFICACY
CMAI
X
X
X
X
X
X
X
X
CGI-Sj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
NPI-NH (for institutionalized subjects) or 
NPI/NPI-NH (for non-institutionalized 
subjects)
X
X
X
X
X
X
X
X
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Table 3.7-1
Schedule of Assessments
Assessment
Visit
Screeninga
Baseline 
(Day 0)
Day 3
Wk 2
Wk 4
Wk 6
Wk 8
Wk 10
Wk 12/ ETb
FUc
OTHER
SAFETY
Physical examinationk
X
X
Neurological examinationl
X
X
Vital signsm
X
X
X
X
X
X
X
X
X
Clinical laboratory tests (hematology, serum 
chemistry, urinalysis)n
X
Xo
Xp
Xp
X
Prolactin (blinded)n
X
X
TSH with reflex to free T4 if abnormaln
X
X
HbA1c
n
X
X
PT, aPTT, and INRn
X
X
ACTH and cortisoln
X
X
Urine pregnancy test (women of childbearing 
potential) onlyq
X
X
ECGr
X
X
X
X
X
Blood alcohols,t
X
Urine drug screens,t
X
MMSE
X
X
X
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Table 3.7-1
Schedule of Assessments
Assessment
Visit
Screeninga
Baseline 
(Day 0)
Day 3
Wk 2
Wk 4
Wk 6
Wk 8
Wk 10
Wk 12/ ETb
FUc
Adverse eventsv
X
X
X
X
X
X
X
X
X
X
Pharmacokinetic samplingw
X
X
X
Concomitant medicationsy
X
X
X
X
X
X
X
X
X
X
OTHER PROCEDURES
Register trial visit in IVRS/IWRS
X
X
X
X
X
X
X
X
X
Randomize eligible subjects via IVRS/IWRS
X
IMP dispensingaa
X
X
X
X
X
X
X
IMP accountability
X
X
X
X
X
X
X
Telephone contactbb
ADDITIONAL ENTRANCE/HISTORY
MRI/CT scancc
Xcc
ACTH = adrenocorticotropic hormone; AIMS = Abnormal Involuntary Movement Scale; anti-HCV = hepatitis C antibodies; aPTT = activated partial 
thromboplastin time 
; 
 
 
 CGI-S = Clinical Global Impression-Severity of Illness; CMAI = Cohen-Mansfield Agitation Inventory; 
 
 CT = computed tomography; ECG = electrocardiogram; ET = early termination; FU = follow up; HbA1c = glycosylated hemoglobin; 
HBsAg = hepatitis B surface antigen; IAP = Independent Adjudication Panel; ICF = informed consent form; IMP = investigational medicinal product; 
INR = International Normalized Ratio; IVRS = interactive voice response system; IWRS = interactive web response system; MMSE = Mini-Mental State 
Examination; 
; MRI = magnetic resonance imaging; NINCDS-ADRDA = National Institute of 
Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association; 
 
; NPI-NH = Neuropsychiatric Inventory-Nursing Home rating scale; NPI/NPI-NH = Neuropsychiatric Assessment for 
Non-Institutionalized Patients based on the NPI/NPI-NH; PT = prothrombin time; 
; 
 
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; 
; T4 = thyroxine; TSH = thyroid-stimulating 
hormone.
aScreening begins when the ICF is signed.  Screening procedures must be initiated between Day −42 and Day −2. The screening period may be extended after 
discussion with and approval by the medical monitor.  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.
bIf a subject discontinues prematurely before Week 12, every effort should be made to complete the Week 12/ET evaluations prior to administering additional 
medications for the treatment of agitation or other prohibited medications.
cAll subjects, whether they complete the trial or are withdrawn prematurely for any reason, will be followed up for a safety evaluation 30 (+ 2) days after the 
last dose of IMP during a clinic visit at either the investigator’s site or residential facility, if applicable.  If a clinic visit is not possible, the subject should be 
assessed by telephone contact with the subject and a caregiver. Subjects who complete both the 12-week double-blind treatment period and the 30-day 
safety follow-up visit are eligible to enroll into Trial 331-13-211, which is a 2-month, observational, rollover trial to evaluate the safety of subjects with 
agitation associated with Alzheimer's disease who previously participated in Trial 331-12-284. For those subjects who plan to enroll into Trial 331-13-211, 
the 30-day safety follow-up visit for Trial 331-12-284 will occur as a clinic visit at either the investigator’s site or residential facility, if applicable.
d
eThe 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 and/or on behalf of the subject must be followed as 
provided in Section 3.4.1.
fThe investigator is responsible for ensuring that subjects are eligible for enrollment into the trial and for assessing subject safety throughout the trial.  
 
gThe neurological history and Hachinski Ischemic Scale (Rosen Modification) will be completed to assess eligibility for the trial by the same physician who
performs the neurological examinations (refer to Section 3.7.4.3.2).  The neurological history will include an MRI/CT scan as described in Section 3.7.3.7
and as scheduled in the ADDITIONAL ENTRANCE/HISTORY.
hWashout of prohibited medications begins after signing the ICF and must comply with the required washout periods (refer to Section 4.1).
i
 
j
 CGI-S, 
 are based on agitation.
kPhysical examination includes measurement of height and waist circumference at screening and waist circumference at Week 12/ET.
lA detailed neurological examination will be performed by a physician at screening, Week 12/ET, and as needed during the trial for new onset neurological 
symptoms. The neurological examination will consist of an evaluation of the subject’s mental status, cranial nerves, motor system (eg, motor strength, 
muscle tone, reflexes), cerebellar system (eg, coordination), gait and station, and sensory system.
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mVital signs include body weight, body temperature, systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate.  Blood pressure and heart 
rate will be measured in the supine (performed first), sitting, and standing positions.  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 sign measurements scheduled for the same visit as blood samples are to be completed before blood is drawn.
nSubjects should be fasting for a minimum of 8 hours prior to blood draws for screening laboratory assessments, if at all 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/ET.  Vital sign measurements and ECG assessments should be completed before any blood samples are collected.  See Table 3.4.3-1 for exclusion
criteria based on screening laboratory tests.
oIf 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.
pUrinalysis is not required at Week 4 or Week 8.
qAll 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.  Pregnancy 
tests can be performed at any point during the trial if pregnancy is suspected.
rStandard 12-lead ECGs will be performed after the subject has been supine and at rest for 5 minutes prior to the ECG.  The ECGs will be evaluated at the 
investigational site to determine the subject’s eligibility and to monitor safety.  Any screening ECG with abnormal result(s) considered to be clinically 
significant should be repeated (with 3 consecutive ECG recordings) to confirm the finding(s) before excluding the subject from the trial.  A central ECG 
service will review all ECGs to standardize interpretations for the safety analysis.  Any ECGs scheduled for the same visit as blood samples are to be 
completed before blood is drawn.
sA urine drug screen and a blood alcohol test are required at screening, but either or both can be conducted at any time during the trial at the discretion of the 
investigator.
tEligibility for randomization is based on the screening urine drug screen results.  Subjects whose urine drug screen is positive for cocaine, marijuana, or other 
illicit drugs at screening are not eligible for participation in the trial.  Subjects with a positive blood alcohol test or a positive urine drug screen due to use of 
prescription or OTC medications or products may be retested (the evaluation may be repeated within the screening period) or rescreened once for 
participation in the trial with consent of the medical monitor.
u
 
 
 
vAdverse events will be recorded, starting after the ICF has been signed.
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wPharmacokinetic samples will be obtained at baseline and at any time during the Week 8 and Week 12/ET visits.  If blood samples for clinical laboratory 
tests are not collected at the baseline visit, pharmacokinetic samples do not need to be obtained at baseline.  Every possible effort should be made to collect 
samples at the same time at each visit.  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 pharmacokinetic sampling.  The date and time of the last 2 doses prior to each pharmacokinetic blood draw will be recorded 
on the electronic case report form (eCRF).  Vital sign and ECG assessments should be completed before any blood samples are collected.
x
 
yAll medications taken within 30 days of screening (signing of ICF/assent) will be recorded.  In addition, all prescription and nonprescription medications 
taken during the trial will be recorded as concomitant medications.  Details of prohibited and restricted medications are provided in the protocol (refer to 
Section 4.1).  During the first 4 weeks of the randomized phase (baseline to Week 4 visit), benzodiazepines are allowed but limited to 4 days/week with a 
maximum dose of 2 mg/day of lorazepam (or equivalent) or less depending on dose-limiting side effects.  Benzodiazepines must not be administered within 
12 hours prior to the efficacy and safety scales. After the Week 4 visit, benzodiazepines are prohibited.
z
 
 
aaSubjects will start taking IMP from the new blister card the day after the clinic visit.
bbThe subject’s identified caregiver will be contacted by telephone at Weeks 3, 5, and 7 to assess compliance with IMP, confirm any changes to concomitant 
medications, and assure the subject’s well-being.
ccIf 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 
 in order to confirm 
eligibility.
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3.7.1.
Schedule of Assessments
3.7.1.1.
Screening
The screening period begins after written informed consent has been obtained.  Subjects 
will participate in screening activities for 2 days to 42 days.  The screening period may be 
extended after discussion with and approval by the medical monitor.  After the ICF has 
been signed, the site will obtain a Subject identification/identifier (ID) by accessing the 
IVRS or IWRS.  Completion of screening activities may require more than 1 visit; 
however, only the initial visit will be registered in the IVRS or IWRS.
Screening evaluations will include the following:

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.

Trial personnel will call the IVRS or access the IWRS to register the visit (initial 
screening visit only).

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 and/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.

Demographic data will be recorded.

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.

Psychiatric and neurological history will be recorded.

If 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 
 in order to confirm eligibility.  

Medications taken within 30 days of screening (signing of ICF/assent) will be 
recorded.

Washout from prohibited concomitant medications will begin, if applicable (see 
Section 4.1).

A complete physical examination (including height and waist circumference) will be 
performed.
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
A detailed neurological examination, which 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, 
will be performed by a physician.

Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded.  Blood pressure and heart rate are to be measured in the 
following order:  supine, sitting, and 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.  See Section 3.4.3 for exclusions based on 
outcome of screening vital sign measurements.  Vital signs are to be completed before 
any blood is drawn.

A standard 12-lead ECG will be performed after the subject has been supine and at 
rest for at least 5 minutes.  Subjects with screening QTcF 450 msec (males) or 
470 msec (females) will be excluded from the trial, unless due to ventricular pacing
(see Section 3.7.4.4).  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.  The ECG is to be completed before any 
blood is drawn.

Blood samples will be drawn for the presence of hepatitis B surface antigen (HBsAg) 
and antibodies to hepatitis C (anti-HCV). Subjects with a positive result for any of 
these tests will be excluded from the trial. Vital sign and ECG assessments should be 
completed before any blood samples are collected.

Blood samples will be collected for clinical laboratory tests (hematology, including 
PT, aPTT, and INR, and serum chemistry, including prolactin [blinded], HbA1c, 
ACTH, cortisol, and TSH with reflex to free T4 if the result for TSH is abnormal) and 
should be obtained after a minimum 8-hour fast, if possible.  See Section 3.7.4.2 for 
exclusions based on outcome of screening clinical laboratory tests.  Vital signs and 
ECG assessments should be completed before any blood samples are collected.

Samples will be obtained for blood alcohol testing.  Subjects with a positive blood 
alcohol test at screening may be retested or rescreened once for participation in the 
trial with consent of the medical monitor.

Urine will be collected from all potential subjects for urinalysis and urine screen(s) 
for drugs of abuse.  Subjects positive for cocaine, marijuana, or other illicit drugs are 
not eligible to be retested or rescreened.  Subjects with a positive drug screen 
resulting from use of prescription or OTC medications or products may be retested 
(the evaluation may be repeated within the screening period) or rescreened once for 
participation in the trial after consent of the medical monitor.

Urine albumin-to-creatinine ratio (ACR) will be determined only for subjects with 
insulin-dependent diabetes mellitus (IDDM) (must be < 30 mg/g; calculated as urine 
albumin [mg/dL]/urine creatinine [g/dL]).
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
A urine pregnancy test will be performed for all women of childbearing potential.  All 
positive results must be confirmed by a serum pregnancy test.  Subjects with positive 
urine and serum test results will be excluded from the trial.

An adequately trained and experienced clinician will confirm the diagnosis of 
probable Alzheimer’s disease using the NINCDS-ADRDA criteria.

An adequately trained and experienced physician who performs the neurological 
examination will complete the Hachinski Ischemic Scale (Rosen Modification).

A qualified and certified rater will administer the CMAI and NPI-NH (for 
institutionalized subjects) or NPI/NPI-NH (for non-institutionalized subjects) to the 
identified caregiver.

An adequately trained and experienced clinician will administer the CGI-S.

An adequately trained and experienced clinician will administer the MMSE.

 

AEs will be recorded, beginning with the signing of the ICF.

Concomitant medications will be recorded.

 

The subject’s caregiver and/or facility staff will complete a paper diary daily (if 
possible) after the ICF is signed, continuing through Week 12/ET.
3.7.1.2.
Baseline (Day 0)
If the subject is found to be eligible for the trial during the screening period, the 
following procedures will be performed at the baseline visit:


Inclusion and exclusion criteria will be verified.

The investigator must assess the capacity of the subject to provide informed consent 
throughout the course of the trial.  Once this determination is made by the 
investigator, the options for obtaining informed consent from and/or on behalf of the 
subject must be followed as provided in Section 3.4.1.

A qualified and certified rater will administer the CMAI and NPI-NH (for 
institutionalized subjects) or NPI/NPI-NH (for non-institutionalized subjects) to the 
identified caregiver.

An adequately trained and experienced clinician will administer the CGI-S.

 
 
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
 
 

An adequately trained and experienced clinician will administer the MMSE.

 
 
 
 

Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded.  Blood pressure and heart rate are to be measured in the 
following order:  supine, sitting, and 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 are to be completed before any 
blood is drawn.

Blood samples will be collected for clinical laboratory tests (hematology and serum 
chemistry) and should be obtained after a minimum 8-hour fast, if possible. Urine 
will be collected for urinalysis. 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.  Vital signs and ECG assessments should be completed 
before any blood samples are collected.

A standard 12-lead ECG will be performed after the subject has been supine and at 
rest for at least 5 minutes.  The ECG is to be completed before any blood is drawn.

Blood samples will be obtained for pharmacokinetic analysis.  If blood samples for 
clinical laboratory tests are not collected at the baseline visit, pharmacokinetic 
samples do not need to be obtained at baseline.  Vital sign and ECG assessments 
should be completed before any blood samples are collected.

 

AEs and concomitant medications will be recorded. 
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
Trial personnel will call the IVRS or access the IWRS to randomize the subject and 
obtain a blister card assignment.

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.
Day 3
This visit is to occur within + 2 days of the target visit date.  At the Day 3 visit the 
following evaluations will be performed:

The investigator must assess the capacity of the subject to provide informed consent 
throughout the course of the trial.  Once this determination is made by the 
investigator, the options for obtaining informed consent from and/or on behalf of the 
subject must be followed as provided in Section 3.4.1.  

Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded.  Blood pressure and heart rate are to be measured in the 
following order:  supine, sitting, and 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 sign measurements are to be completed 
before any blood is drawn.

AEs and concomitant medications will be recorded.

IMP accountability will be performed.

Trial personnel will call the IVRS or access the IWRS to register the visit and obtain 
the blister card assignments for the IMP.

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.

Diary recording will continue.
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3.7.1.3.2.
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.  The following evaluations will be performed at the 
Weeks 2, 4, 6, 8, and 10 visits.

The investigator must assess the capacity of the subject to provide informed consent 
throughout the course of the trial.  Once this determination is made by the 
investigator, the options for obtaining informed consent from and/or on behalf of the 
subject must be followed as provided in Section 3.4.1.  

A qualified and certified rater will administer the CMAI and NPI-NH (for 
institutionalized subjects) or NPI/NPI-NH (for non-institutionalized subjects) to the 
identified caregiver.

An adequately trained and experienced clinician will administer the CGI-S, 
 

Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded.  Blood pressure and heart rate are to be measured in the 
following order:  supine, sitting, and 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 sign measurements are to be completed 
before any blood is drawn.

 
 
 

AEs and concomitant medications will be recorded.

Diary recording will continue.

IMP accountability will be performed.

Trial personnel will call the IVRS or access the IWRS to register the visit and to 
obtain their blister card assignments for the IMP.

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.
The following additional evaluations will be performed at the designated visits:

 

A fasting blood draw for clinical laboratory tests (hematology and serum chemistry) 
will be obtained at Weeks 4 and 8 only.  Vital sign and ECG assessments should be 
completed before any blood samples are collected.
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
Blood samples will be obtained for pharmacokinetic analysis at Week 8 only.  The 
date and time of the blood draw and the date and time of the last 2 doses of IMP prior 
to the blood draw will be recorded on the electronic case report form (eCRF).  Vital 
sign and ECG assessments should be completed before any blood samples are 
collected.


A standard 12-lead ECG will be performed after the subject has been supine and at 
rest for at least 5 minutes at Weeks 4 and 8 only.  The ECG is to be completed before 
any blood is drawn.
In addition, the subject’s identified caregiver will be contacted by telephone at Weeks 3, 
5, and 7 to assess compliance with IMP, confirm any changes to concomitant 
medications, and assure the subject’s well-being.
3.7.1.4.
End of Treatment (Week 12/ET)
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/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/ET evaluations prior to administering any additional medications for the 
treatment of agitation or other prohibited medications.
The following activities and assessments will occur at Week 12 (or at the ET visit, if 
applicable):

A qualified and certified rater will administer the CMAI and NPI-NH (for 
institutionalized subjects) or NPI/NPI-NH (for non-institutionalized subjects) to the 
identified caregiver.

An adequately trained and experienced clinician will administer the CGI-S, 
 

 
 

 
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
 

An adequately trained and experienced clinician will administer the MMSE.

 

 

A complete physical examination (including waist circumference) will be performed.

A detailed neurological examination, which 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, 
will be performed by a physician.

Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded.  Blood pressure and heart rate are to be measured in the 
following order:  supine, sitting, and 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 are to be completed before any 
blood is drawn.

A standard 12-lead ECG will be performed after the subject has been supine and at 
rest for at least 5 minutes.  The ECG is to be completed before any blood is drawn.

A fasting blood draw will be collected for clinical laboratory tests (hematology, 
including PT, aPTT, and INR; and serum chemistry, including prolactin [blinded] 
HbA1c, ACTH, cortisol, and TSH with reflex to free T4 if the result for TSH is 
abnormal) and urine will be collected for urinalysis.  Vital sign and ECG assessments 
should be completed before any blood samples are collected.

A blood sample will be obtained for pharmacokinetic analysis.  The date and time of 
the blood draw and the date and time of the last 2 doses of IMP prior to the blood 
draw will be recorded on the eCRF. Vital sign and ECG assessments should be 
completed before any blood samples are collected.

 
 

Women of childbearing potential will be given a urine pregnancy test.  Any positive 
result must be confirmed by a serum pregnancy test.

AEs and concomitant medications will be recorded.

Diary recording will be stopped.

Final IMP accountability will be performed.
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
Trial personnel will call the IVRS or access the IWRS to register completion or 
discontinuation from the trial.
3.7.1.5.
Follow-up
All subjects, whether they complete the trial or are withdrawn prematurely for any 
reason, will be followed up for a safety evaluation 30 (+ 2) days after the last dose of 
IMP during a clinic visit at either the investigator’s site or residential facility, if 
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.  
 
Subjects who complete both the 12-week double-blind treatment period and the 30-day 
safety follow-up visit are eligible to enroll into Trial 331-13-211, which is a 2-month, 
observational, rollover trial to evaluate the safety of subjects with agitation associated 
with Alzheimer's disease who previously participated in Trial 331-12-284. For those 
subjects who plan to enroll into Trial 331-13-211, the 30-day safety follow-up visit for 
Trial 331-12-284 will occur as a clinic visit at either the investigator’s site or residential 
facility, if applicable. 
3.7.2.
Efficacy Assessments
It is required that adequately trained and experienced clinicians administer the CMAI, 
NPI-NH, NPI/NPI-NH, CGI-S, 
 
  In addition, the raters must be 
certified for this trial to administer the CMAI, NPI-NH, and NPI/NPI-NH.  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, NPI-NH, NPI/NPI-NH, 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 
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 
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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 (CMAI)
The primary efficacy variable is the change from baseline to Week 12/ET in the CMAI 
total score. 
 
  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.11  As initially described by Cohen-Mansfield11 and outlined in the Instruction 
Manual for the CMAI,26 these distinct agitation syndromes include:  aggressive behavior, 
physically nonaggressive behavior, and verbally agitated behavior.  A sample of the 
CMAI is provided in Appendix 6.
3.7.2.2.
Clinical Global Impression-Severity of Illness Scale (CGI-S)
The severity of agitation for each subject will be rated using the CGI-S.27  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.  A sample of the CGI-S is provided in Appendix 7.
3.7.2.3.
 
  
 
  
 
 
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3.7.2.4.
 
 
  
 
 
 
 
 
 
 
3.7.2.5.
Neuropsychiatric Inventory-Nursing Home (NPI-NH)
The NPI-NH questionnaire is used to interview the identified caregiver about the 
institutionalized subject’s possible neuropsychiatric symptoms (ie, delusions, 
hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, 
apathy/indifference, disinhibition, irritability, aberrant motor behavior, nighttime 
behaviors, and appetite/eating behaviors).  The NPI-NH gives an insight into the 
frequency (on a scale of 1 to 4), severity (on a scale of 1 to 3), and occupational 
disruption (on a scale of 0 to 5) of each of the 12 separate behavioral domains.28,29  
Therefore, for each behavioral domain, there are 4 scores:  frequency, severity, total 
(frequency x severity), and occupational disruptiveness.  A total NPI-NH score can be 
calculated by adding the first 10 domain total scores (frequency x severity scores) 
together.  All 12 domain total scores can be summed in special circumstances where the 
neurovegetative symptoms are of particular importance.29  Administering the 
questionnaire generally takes about 15 minutes.  The psychometric properties and factor 
structure of the NPI-NH have been shown to have internal consistency, reliability, 
convergent validity, and discriminant validity.30
A sample of the NPI-NH is provided in Appendix 8.
3.7.2.6.
Neuropsychiatric Assessment for Non-institutionalized Patients
Based on the NPI/NPI-NH (NPI/NPI-NH)
The NPI/NPI-NH is a structured caregiver interview designed to obtain information on 
the presence of psychopathology in non-institutionalized subjects with brain disorders, 
including Alzheimer’s disease and other dementias.31  The NPI/NPI-NH differs from the 
NPI-NH in that questions referring to “Occupational Disruptiveness” from the NPI-NH 
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have been replaced with questions referring to “Distress” from the Neuropsychiatric 
Inventory (NPI).  Item domains are identical between the NPI/NPI-NH and NPI-NH.  
Ten behavioral and two neurovegetative symptom domains comprise the NPI/NPI-NH
(ie, delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, 
elation/euphoria, apathy/indifference, disinhibition, irritability, aberrant motor behavior, 
nighttime behavior disorders, and appetite/eating disorders).  The identified caregivers 
are instructed to indicate the frequency (on a scale of 1 to 4), severity (on a scale of 1 to 
3), and distress (on a scale of 0 to 5) of each of the 12 separate behavioral domains.  
Therefore, for each behavioral domain, there are 4 scores:  frequency, severity, total 
(frequency x severity), and distress.  A total NPI/NPI-NH score is calculated by adding 
the first 10 domain total scores (frequency x severity scores) together.  All 12 domain 
total scores can be summed in special circumstances where the neurovegetative 
symptoms are of particular importance.  Administering the NPI/NPI-NH generally takes 
about 15 minutes.  
A sample of the NPI/NPI-NH is provided in Appendix 9.
3.7.3.
Other Assessments
3.7.3.1.
 
 
  
 
 
 
 
 
 
 
 
 
 
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3.7.3.2.
 
 
 
 
 
 
 
  
 
 
 
 
 
 
3.7.3.3.
  
 
 
 
 
  
 
 
3.7.3.4.
  
 
 
 
 
  
 
 
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3.7.3.5.
National Institute of Neurological and Communicative 
Disorders and Stroke and the Alzheimer’s Disease and Related 
Disorders Association (NINCDS-ADRDA)
The NINCDS-ADRDA, which has shown good reliability and validity, provides criteria 
for the possible and probable diagnosis of Alzheimer’s disease.37  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.
A sample of the NINCDS-ADRDA is provided in Appendix 14.
3.7.3.6.
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.38  The 
Rosen-modified Hachinski Ischemic Scale will be completed to assess eligibility for the 
trial by the same physician who performs the neurological examinations (see 
Section 3.7.4.3.2).
A sample of the Hachinski Ischemic Scale (Rosen Modification) is provided in
Appendix 15.
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3.7.3.7.
Magnetic Resonance Imaging/Computed Tomography Scan of 
the Brain
If 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 
 in order to confirm eligibility.  
3.7.4.
Safety Assessments
3.7.4.1.
Adverse Events
Refer to Section 5, Reporting of Adverse Events.
3.7.4.2.
Clinical Laboratory Assessments
A central laboratory designated by the sponsor will be used for all laboratory testing 
required during the trial.  The central laboratory should be used for all laboratory testing 
whenever possible (including unscheduled and follow-up, if needed).  In cases where an 
immediate result is required for a particular laboratory test, the sample should be divided 
and sent to both a local laboratory and the designated central laboratory.  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.  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.  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 should be filed with the 
source documents for each subject.  The central laboratory will provide laboratory results 
to the sponsor electronically.
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Table 3.7.4.2-1
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
Urine albumin (only for subjects with IDDM)
Urine creatinine (only for subjects with IDDM)
Serum Chemistry
ALP
ALT (SGPT)
AST (SGOT)
BUN
CPK
Creatinine
LDH
Total bilirubin
Triglycerides
Cholesterol (total, LDL, and HDL)
Calcium
Chloride
Glucose
Insulin
Magnesium
Bicarbonate
Inorganic phosphorous
Sodium
Potassium
Total protein
Uric acid
GGT
Prolactin (blinded)
Albumin
eGFR
Additional Tests
Urine pregnancy (women of childbearing potential)a
TSH, with reflex to free T4 if TSH is abnormal
PT, aPTT, and INR
ACTH
Cortisol
HbA1c
ACTH = adrenocorticotropic hormone; ALP = alkaline phosphatase; 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); 
BUN = blood urea nitrogen; CPK = creatine phosphokinase; eGFR = estimated glomerular filtration rate; 
GGT = gamma glutamyl transferase; HbA1c = glycosylated hemoglobin; HBsAg = hepatitis B surface 
antigen; HDL = high density lipoprotein; IDDM = insulin-dependent diabetes mellitus; INR = International 
Normalized Ratio; LDH = lactic dehydrogenase; LDL = low density lipoprotein; PT = prothrombin time; 
RBC = red blood cell; T4 = thyroxine; TSH = thyroid-stimulating hormone; 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.
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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, follow-up 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 3 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 x upper limit of normal (ULN)

Alanine transaminase (ALT) > 2 x ULN

Creatine phosphokinase (CPK) > 3 x 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 TSH is abnormal.)

Subjects with IDDM (ie, any subjects using insulin) must also satisfy the following 
criterion:  no current microalbuminuria; ie, urine ACR must be < 30 mg/g 
(calculated).
3.7.4.3.
Physical and Neurological Examination and Vital Signs
3.7.4.3.1.
Physical Examination
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 (HEENT); thorax; abdomen; urogenital; 
extremities; neurological (see Section 3.7.4.3.2); 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/ET visits.  Waist circumference will be measured at each physical examination 
(screening and Week 12/ET), using the provided measuring tape.  
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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.39
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/her name must be included on the Form FDA1572.  
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.
3.7.4.3.2.
Neurological Examination
A detailed neurological examination will be performed by a physician at screening, 
Week 12/ET, and as needed during the trial for new onset neurological symptoms.  The 
neurological examination will consist of an evaluation of the subject’s mental status, 
cranial nerves, motor system (eg, motor strength, muscle tone, reflexes), cerebellar 
system (eg, coordination), gait and station, and sensory system.
The physician is responsible for performing the neurological examination and must be 
included on the Form FDA 1572.  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.
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3.7.4.3.3.
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:

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.
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 are excluded from the trial as are subjects with orthostatic 
hypotension, which is defined as a decrease of 30 mmHg in SBP and/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 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 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 4 for a list of 
potentially clinically significant vital signs.
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3.7.4.4.
ECG 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.  ECG recordings will be obtained after the subject has 
been supine and at rest for at least 5 minutes.  Additional 12-lead ECGs may be obtained 
at the investigator’s discretion and should always be obtained if the subject is terminated 
early.  The ECG results will be evaluated at the investigational site to determine the 
subject’s eligibility and to monitor safety during the trial.  The principal investigator (or 
qualified designee) will review, sign, and date each ECG reading, noting whether or not 
any abnormal results are of clinical significance.  The ECG will be repeated if any results 
are considered to be clinically significant.  A central ECG service will be used for reading 
all ECGs in order to standardize interpretations for the safety analysis.
If, according to the investigator's judgment, any abnormal ECG finding is deemed 
medically significant (impacting the safety of the subject and/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 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 5 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.
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3.7.4.5.
 
 
 
3.7.4.5.1.
 
 
 
 
 
 
 
 
 
 
 
 
3.7.4.5.2.
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
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3.7.4.5.3.
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
3.7.4.5.4.
  
 
 
 
 
 
 
 
 
 
 
 
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3.7.4.5.5.
Mini-Mental State Examination (MMSE)
The MMSE43 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 3.4.3-1) and is also to be completed at Week 12/ET.  A sample of the MMSE is 
provided in Appendix 20.
3.7.5.
Pharmacokinetic Assessments
3.7.5.1.
Blood Collection Times
Pharmacokinetic samples will be collected at baseline and at any time during Week 8 and 
Week 12/ET.  If blood samples for clinical laboratory tests are not collected at the 
baseline visit, pharmacokinetic samples do not need to be obtained at baseline.  The 
samples will be collected at the same time as clinical laboratory sample collection for the 
designated trial visits, if applicable.  Every possible effort should be made to collect 
pharmacokinetic 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 pharmacokinetic 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 will be recorded on the eCRF.
3.7.5.2.
Sample Handling and Processing
Details for drawing and processing pharmacokinetic samples are provided in 
Appendix 21.
3.7.6.
 
 
 
 
 
 
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3.7.6.1.
 
 
 
 
 
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3.7.6.2.
 
 
 
 
 
 
 
  
 
 
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 eCRF page for the last subject completing or 
withdrawing from the trial.
3.7.8.
Independent Data Monitoring Committee
The DMC will monitor safety in subjects who participate in the trial.  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 chair will be notified by the 
trial medical officer of all SAEs and will receive summaries of other safety data as 
available.
The responsibilities of the DMC include:

Evaluating the progress of the trial, subjects’ risk versus benefit, and other factors that 
could affect the trial outcome

Considering relevant information that may have an impact on the safety of the 
participants or the ethics of the trial
3.7.9.
 
 
  
 
  
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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 safety or unanticipated other reasons, 
prompt notification will be given to investigators, IRBs/IECs, and regulatory authorities 
in accordance with regulatory requirements.
3.8.2.
Individual Site
A particular center may be terminated from the trial at the discretion of the investigator, 
sponsor, or IRB/IEC, eg, for non-enrollment of subjects or noncompliance with the 
protocol.  The investigator will notify the sponsor promptly if the trial is terminated by 
the investigator or the IRB/IEC at the site.
3.8.3.
Individual Subject
If a subject discontinues the trial prematurely, the reason must be fully evaluated and 
recorded appropriately in source documents and the eCRF.  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:
1) 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
2) Treatment with a prohibited concomitant medication other than the use of appropriate 
medications for the treatment of AEs under direction of the investigator
3) Subject noncompliance, defined as refusal or inability to adhere to the trial schedule 
or procedures (see Section 3.12, Subject Compliance)
4) At the request of the subject, caregiver, legally acceptable representative, investigator, 
sponsor, or regulatory authority
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5) Subject becomes pregnant
6) Subject cannot tolerate a dose of 0.5 mg/day of brexpiprazole (or matching placebo)
7) Subject cannot be titrated to the target dose of 1 mg/day of brexpiprazole (or 
matching placebo)
8) 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 and/or others 
9) Subject is lost to follow-up
10) 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 investigator will notify the sponsor promptly when a subject is withdrawn.  Subjects 
withdrawn prior to Week 12 must complete the Week 12/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, if applicable.  If a clinic visit is not possible, the subject should be 
assessed by telephone contact with the subject and a caregiver.
 
 
  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.
Any subject who withdraws prematurely from the trial will not be eligible to roll-over 
into Trial 331-13-211.
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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 could consult with the medical 
monitor to determine subject continuation in the trial.
3.9.
Screen Failures
A screen failure is a subject from whom a signed ICF is obtained, but who has not started 
on treatment.  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 blood 
alcohol test or 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 was 
administered all doses of the IMP.  Subjects who are evaluated at the last scheduled visit 
during the treatment period will be defined as trial completers.  For purposes of this trial, 
subjects who complete the Week 12 visit will be defined as trial completers.
3.11.
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted on or before the Week 12 visit during the treatment 
period and who do not have a known reason for discontinuation (eg, withdrew consent or 
AE) will be classified as “lost to follow-up.”  If an institutionalized subject leaves the 
residential facility in which he/she was residing before completion of the trial, the site 
will make 3 attempts to contact the subject by telephone; 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.  A similar procedure will be 
followed for non-institutionalized subjects who are lost to follow-up.
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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.
For non-institutionalized subjects, the caretaker or caregiver may administer IMP to the 
subject, as long as the subject is compliant with IMP dosing requirements.
For institutionalized subjects, the caregiver will be responsible for administering IMP to 
the subject.  It may be possible that there is more than one caregiver for a subject.  The 
caregiver(s) should be appropriately instructed to ensure that the subject is compliant 
with IMP dosing requirements.
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 by telephone.  The investigator 
and sponsor’s designee (medical monitor) 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 and reviewed by the site monitor.
4. Restrictions
4.1.
Prohibited Medications
All subjects must discontinue all prohibited medications 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. The oral benzodiazepine therapy permitted during the trial 
is summarized in Table 4.1-3.
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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
1.
Medications to treat 
Alzheimer’s disease 
(cholinesterase inhibitors, 
memantine, and/or other 
cognitive enhancers)  
Allowed provided that the dose 
has been stable for 90 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.
2.
Antipsychotics
7-day washout
Prohibited
Clozapine
Not allowed within 30 days prior 
to randomization.
Prohibited
Depot or long-acting 
injectable antipsychotic 
drugs
Washout of 1.5 times the dosing 
interval (according to the 
prescribing information)
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).
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
6.
Benzodiazepines 
(short-acting)a,b
Allowed but limited to 
4 days/week 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 phase (baseline to 
Week 4 visit): allowed but limited 
to 4 days/week with a maximum 
dose of 2 mg/day of lorazepam (or 
equivalent) or less depending on 
dose-limiting side effects.  
Benzodiazepines must not be 
administered within 12 hours prior 
to the efficacy and safety scales.
After Week 4 visit:  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
7.
Nonbenzodiazepine sleep 
agentsc
If a bedtime dose of a sleep 
agent for insomnia was taken 
prior to screening 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 screening and needs to 
be initiated, medication should 
be limited to a maximum dose of 
5 mg/day of zolpidem (or 
equivalent).
Sleep agents must not be 
administered within 8 hours prior 
to the efficacy and safety scales.  
Combined use of benzodiazepines 
and nonbenzodiazepine sleep 
agents for insomnia is not allowed.
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 symptomsd
7-day washout
Prohibited
10.
Propranolole
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.
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.
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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
13.
Nutritional supplements 
and nonprescription herbal 
preparations with CNS 
effects (eg, St. John’s wort, 
omega-3 fatty acids, kava 
extracts, gamma-
aminobutyric acid (GABA) 
supplements, etc.)
7-day washout
Prohibited
14.
Cytochrome P450 2D6 
isozyme (CYP2D6) 
inhibitors or CYP3A4 
inhibitors and inducers (see 
Table 4.1-2)
7-day washout
Prohibited
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 phase (baseline to Week 4 visit) to treat agitation and/or insomnia (see Table 4.1-3).
bBenzodiazepines 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 benzodiazepine documented, including a 
notation of the drug name, dose, and time of administration on the eCRF.
cNonbenzodiazepine 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 nonbenzodiazepine 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.  
Nonbenzodiazepine sleep aids must not be administered within 8 hours prior to scheduled efficacy and 
safety scales, including EPS scales.  Investigators are encouraged to delay scale administration until 
8 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 the sleep aid documented, including 
a notation of the drug name, dose, and time of administration on the eCRF.
dAnticholinergic treatment of extrapyramidal symptoms (eg, benztropine) is not permitted within the 
7 days prior to randomization and for the duration of the trial. 
ePropranolol 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 eCRF.
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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 Therapy During the Trial
Oral Benzodiazepinea,b
Maximum Allowable Daily Dose (mg/day)
Screening
(limited to 4 days/week)
Baseline to Week 4 Visit 
(limited to 4 days/week)
Lorazepam
2
2
Oxazepam
30
30
aBenzodiazepines 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 benzodiazepine documented, including a 
notation of the drug name, dose, and time of administration on the eCRF.
bIn 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.
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
The investigator may request a blood or urine drug screen at any time during the trial 
if there is a suspicion of illicit drug use.

Treatment with other investigational agents is not permitted during the trial.
New onset nonpharmacological interventions for the treatment of agitation are not 
permitted during the double-blind treatment period. Subjects who have been treated with 
nonpharmacological interventions prior to trial entry may continue these therapies during 
the double-blind treatment period. 
5. Reporting of Adverse Events
5.1.
Definitions
An AE is defined as any untoward medical occurrence associated with the use of a drug 
in humans, whether or not considered drug related.
A suspected adverse reaction means any AE for which there is a reasonable possibility 
that the drug caused the AE.  For the purpose of IND safety reporting, “reasonable 
possibility” means there is evidence to suggest a causal relationship between the drug 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:
1) Death
2) 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.
3) Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.
4) Requires in-patient hospitalization or prolongs hospitalization (NOTE:  A 
prescheduled hospitalization is not considered an SAE.)
5) Congenital anomaly/birth defect
6) Other medically significant events that, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above, eg, allergic bronchospasm requiring 
intensive treatment in an emergency room or home, blood dyscrasias or convulsions 
that do not result in hospitalization, or the development of drug dependency or drug 
abuse.
Nonserious adverse events are AEs that do not meet the criteria for an SAE.
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If a subject is experiencing an extrapyramidal symptom, the specific extrapyramidal 
symptom must be indicated on the AE page of the eCRF.  Examples of AEs that are 
considered extrapyramidal symptoms include, but are not limited to: generalized rigidity, 
dyskinesia, hyperkinesia, bradykinesia, akinesia, dystonia, hypertonia, akathisia, tremor, 
flexed posture, involuntary muscle contractions, athetosis, and chorea. If a subject is 
experiencing two or more of these symptoms, whether or not treatment with an 
anticholinergic is required, this is considered as extrapyramidal syndrome and must be 
entered as “extrapyramidal syndrome” on the AE page of the eCRF instead of the 
individual symptoms.
Immediately Reportable Event (IRE)

Any SAE

Any AE that necessitates discontinuation of the IMP

Potential Hy’s law cases (any increase of AST or ALT ≥ 3 times the ULN with an 
increase in total bilirubin ≥ 2 times the ULN)
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 INC Research.  
Pregnancy will only be documented on the AE eCRF if there is an abnormality or 
complication.
Clinical Laboratory 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 determined by the investigator to be an abnormal change from 
baseline for that subject, this is considered an AE. 
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Severity
All AEs will be graded on a 3-point scale and reported as indicated on the eCRF.  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
The causal relationship of an AE to the use of the IMP will be assessed as follows:
Related: 
There is a reasonable possibility of a causal relationship
Possibly related: There is a reasonable causal relationship between the IMP and the 
AE.  Dechallenge is lacking or unclear
Unlikely related: There is a temporal relationship to the IMP administration, but 
there is not a reasonable causal relationship between the IMP and 
the AE
Not related: 
There is no temporal or reasonable relationship to the IMP 
administration
5.2.
Eliciting and Reporting Adverse Events
The investigator will periodically assess subjects for the occurrence of AEs.  To avoid 
bias in eliciting AEs, subjects should be asked the following nonleading 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 eCRFs provided by the sponsor or 
designee.
In addition, INC Research (refer to Appendix 2) must be notified immediately by 
telephone or fax of any immediately reportable events 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 (IRE)
The investigator must immediately report within 24 hours after either the investigator or 
site personnel become aware of any SAE or potential Hy’s law cases (refer to 
Section 5.4) by telephone or by fax to the sponsor or designee as outlined in Appendix 2.  
An IRE form must be completed and sent by fax or overnight courier to the sponsor.  
(Note:  The IRE form is NOT the AE eCRF.)
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Nonserious events that require discontinuation of the IMP (including laboratory 
abnormalities) should be reported to the sponsor within 3 working days.  The IRE form 
must be completed and sent by fax or overnight courier to the sponsor.
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.
5.4.
Potential Hy’s Law Cases
For subjects that experience 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, 
confirmatory repeat laboratory samples should be drawn within 48 to 72 hours of the 
initial draw.  If these values are confirmed, trial personnel will complete an IRE form 
with all values listed and also report the event as an AE on the eCRF.  Please note: if the 
subject was enrolled into the trial with non-exclusionary elevated transaminase levels at 
baseline, please discuss any potential drug-induced liver injury events with the medical 
monitor.
5.5.
Pregnancy
Women of childbearing potential and men who are sexually active must use an effective 
method of birth control during the course of the trial and for at least 30 days after the last 
dose in a manner such that risk of failure is minimized.  Unless the subject is sterile (ie, 
women who have had an oophorectomy and/or hysterectomy or have been 
postmenopausal for at least 12 consecutive months; or men who have had orchiectomy) 
or remains abstinent, two 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 or sponge with spermicide, or any other method 
approved by the medical monitor.  Any single method of birth control, including 
vasectomy and tubal ligation, may fail, leading to pregnancy.
Before enrolling women of childbearing potential in this clinical trial, investigators must 
review guidelines about their participation in this trial.  The topics should generally 
include:

General information

Informed consent

Pregnancy prevention information
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
Drug interactions with hormonal contraceptives

Contraceptives in current use

Guidelines for the follow-up of a reported pregnancy
Prior to trial enrollment, women of childbearing potential 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.
During the trial, all women of childbearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (eg, missed or late 
menstrual cycle).
If a subject or investigator suspects that the subject may be pregnant prior to IMP 
administration, 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 the IMP, the IMP must be withheld immediately (if reasonable, taking into 
consideration any potential withdrawal risks) until the result of the pregnancy is known.  
If pregnancy is confirmed, the IMP will be permanently discontinued in an appropriate 
manner (eg, dose tapering if necessary for subject safety) and the subject withdrawn from 
the trial.  Exceptions to trial discontinuation may be considered for life-threatening 
conditions only after consultation as indicated in Appendix 2.
The investigator must immediately notify the sponsor (or sponsor’s designee) of any 
pregnancy associated with IMP exposure, including at least 30 days after the last dose for 
female subjects and the female partner of a male subject and record the event on the IRE 
form and forward it to the sponsor (or sponsor’s designee).
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 (or sponsor’s designee), 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.
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5.6.
Procedure for Breaking the Blind
The investigator is encouraged to contact the sponsor/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 the IMP will not be dependent upon the investigator receiving 
approval from the sponsor/CRO medical monitor (ie, the investigator will be able to 
obtain the code break information independent of the sponsor/CRO medical advisor).  
The investigator must contact the sponsor/CRO medical advisor by telephone 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 listed in Appendix 2 will be notified immediately.  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 given subject, that subject may not reinitiate treatment with the IMP.
5.7.
Follow-up of Adverse Events
5.7.1.
Follow-up of Nonserious Adverse Events
Nonserious AEs that are identified on the last scheduled contact must be recorded on the 
AE eCRF with the current status noted.  All nonserious events that are ongoing at this 
time will be recorded as ongoing on the eCRF.
5.7.2.
Follow-up of Post-Trial Serious Adverse Events
All SAEs that are identified on the last scheduled contact must be recorded on the AE 
eCRF page and reported to the sponsor according to the reporting procedures outlined in 
Section 5.3.  This may include unresolved previously reported SAEs or new SAEs.  The 
investigator will follow SAEs until the events are resolved or the subject is lost to 
follow-up.  Resolution means the subject has returned to the baseline state of health, or 
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 OPDC up to the point the event has been resolved.
This trial requires that subjects be actively monitored for SAEs up to 30 days after 
discharge from the trial.
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5.7.3.
Follow-up and Reporting of Serious Adverse Events Occurring 
after Last Scheduled Contact
Any new SAEs reported by the subject to the investigator that 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 OPDC.  This may include SAEs that are 
captured on follow-up or at any other time point after the defined trial period (ie, up to 
last scheduled contact).  The investigator should follow related SAEs identified after the 
last scheduled contact until the events are resolved or the subject is lost to follow-up.  
The investigator should continue to report any significant follow-up information to 
OPDC up to the point the event has been resolved.
5.7.4.
 
 
 
 
subject's caregiver via certified mail or an alternative similar method where appropriate.
6. Pharmacokinetic Analysis
Pharmacokinetic samples will be analyzed for brexpiprazole (OPC-34712) and its 
metabolite(s) and descriptive statistics will be calculated.  No formal statistical 
comparisons are planned.  A separate population or pharmacokinetic/pharmacodynamic 
modeling may be performed using the data from this trial and other trials.
7. Statistical Analysis
7.1.
Sample Size
The 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 the endpoint in the CMAI total score, to 
achieve 85% power at a 2-sided alpha level of 0.05.  The resulting sample size is 
117 subjects/arm.  After allowance of 10% non-evaluable subjects, it results in a sample 
size of 130 subjects/arm, which means the total sample size is 260 subjects.  The sample 
size was estimated based on 1:1 randomization ratio (brexpiprazole:placebo).  
 
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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 one 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 the IMP and have a baseline and at 
least one 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.
7.3.
Handling of Missing Data
 
 
 
 
 
 
 
 
 
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7.4.
Efficacy Analyses
7.4.1.
Primary Efficacy Analysis
The primary endpoint will be analyzed using an MMRM model.  The primary efficacy 
outcome measure is the mean change from baseline (Day 0 Visit) to the end of the 
double-blind treatment period (Week 12 visit) in the CMAI total score.  Details of 
sensitivity analyses under the assumption of MNAR will be provided in the statistical 
analysis plan (SAP).  The null hypothesis for the comparison of brexpiprazole flexible 
dose versus placebo is that there is no difference between the brexpiprazole treatment 
group and placebo in change from baseline to endpoint in CMAI total score.  The 
comparison will be made at the significance level of alpha = 0.05.
The statistical comparison will be performed by fitting a MMRM analysis with an 
unstructured variance covariance matrix in which the change from baseline (Day 0 Visit) 
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 
center, visit week, and an interaction term of treatment by visit week.  The model will 
also include a random effect for subject and the interaction term of baseline (Day 0 visit) 
by visit week as covariates.  The primary comparison between the brexpiprazole and the 
placebo groups at Week 12 will be estimated as the difference between the least squares 
(LS) means utilizing the computing software SAS procedure PROC MIXED.
The primary analysis 
will be performed on the Efficacy 
Sample.
7.4.2.
Key Secondary Efficacy Analysis
The key secondary efficacy variable is the change from baseline to endpoint 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, based on the ITT population.  
The alpha used in the analysis of this key secondary endpoint is 0.05 (2-sided), if the 
comparison of the brexpiprazole group versus placebo in the primary efficacy endpoint is 
statistically significant.
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7.4.3.
 
 
 
 
 
7.4.4.
 
 
 
 
 
7.4.5.
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, SD, and minimum and maximum 
values.
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7.6.
Safety Analysis
Standard safety variables to be analyzed include AEs, clinical laboratory tests, vital signs, 
ECGs, body weight, waist circumference and physical examination.  In addition, data 
from the following safety scales will be evaluated:  MMSE score, 
 
 
  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, and body weight.  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:
1) TEAEs by severity
2) TEAEs potentially causally related to the IMP
3) TEAEs with an outcome of death
4) Serious TEAEs
5) Discontinuations due to TEAEs
7.6.2.
Clinical Laboratory Data
Summary statistics for changes from baseline in the routine clinical laboratory 
measurements, prolactin concentrations, coagulation parameters (PT, aPTT, and INR), 
HbA1c, cortisol, ACTH, and TSH 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 also will be summarized.  
Summary statistics for change from baseline in vital signs, body weight, and waist 
circumference will be provided.
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7.6.4.
ECG 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.
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:
1) QTcB is the length of the QT interval corrected for heart rate by the Bazett formula: 
QTcB=QT/(RR)0.5, and
2) QTcF is the length of the QT interval corrected for heart rate by the Fridericia 
formula: QTcF=QT/(RR)0.33
3) 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.
 
 
 
 
7.7.
 
 
 
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8. Management of Investigational Medicinal Product
8.1.
Packaging and Labeling
Trial medication will be provided to the investigator(s) by the sponsor or designated 
agent.  The IMP will be supplied as active brexpiprazole tablets or matching placebo 
tablets.  The 0.25 mg/day dose will be supplied as a blister card containing sufficient 
tablets for 3 (+2) days; the 0.5 mg/day, 1 mg/day, and 2 mg/day doses will be supplied as 
weekly blister cards, each containing sufficient tablets for 7 (+ 2) days.  When accessed 
by the site, the IVRS or IWRS 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/investigator), Subject ID (to be filled in by the site 
staff/investigator), subject’s initials or other unique identifier as appropriate (to be filled 
in by the site staff/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 via the IVRS or IWRS, 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.
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.
8.4.
Returns and Destruction
Upon completion or termination of the trial, all unused and/or partially used IMP must be 
returned to the sponsor or a designated agent.
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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 of unused and/or partially used IMP.
8.5.
Reporting of Product Quality Complaints (PQC)
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/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)

Bottle defects (eg, under fill or overfill, no safety seal)

Vial defects

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 sponsor through and including reconciliation and up to 
destruction, including subject dosing.  The investigator or designee must notify the 
sponsor (or sponsor’s designee) within 24 hours of becoming aware of the PQC by e-mail 
or telephone and according to the procedure outlined below.
Online:  Send information required for reporting purposes (listed below) to 
Phone:  Rocky Mountain Call Center at 
Identification of a PQC by the subject should be reported to the site investigator, who 
should then follow one of the reporting mechanisms above.
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8.5.2.
Information Required for Reporting Purposes

Description of compliant

Reporter identification (eg, subject, investigator, site, etc.)

Reporter contact information (eg, address, phone number, e-mail address)

ID of material (product/compound name, coding)

Clinical protocol reference (number and/or trial name)

Dosage form/strength (if known)

Pictures (if available)

Availability for return
8.5.3.
Return Process
It should be indicated during the report of the PQC if the IMP sample is available for 
return.  If the complaint sample is available for return, return it in the product retrieval 
package, which will be provided by Otsuka America Pharmaceutical, Inc. Ethics, Quality 
and Compliance (OAPI-EQC).  It should be documented in the site accountability record 
that a complaint sample for a dispensed kit has been forwarded to OAPI-EQC for 
complaint investigation.
8.5.4.
Assessment and Evaluation
Assessment and evaluation of PQC will be handled by the OAPI EQC-QM group.
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.  
Investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, 
and regulatory inspection(s) by providing direct access to source data/documents by 
authorized persons as defined in the ICF.
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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 revisions

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 the IMP must also be recorded.

Any changes in concomitant medications or dosages

A general reference to the procedures completed

The signature (or initials or other unique identifier) and date of each clinician (or 
designee) who made an entry in the progress notes
In addition, any contact with the subject or caregiver via telephone or other means that 
provides significant clinical information also will be documented in the progress notes as 
described above.  Any changes to information in the trial progress notes and other source 
documents will be initialed and dated on the day the change is made by a 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.
Information from the trial progress notes and other source documents will be data entered 
by investigative site personnel directly onto eCRFs in the sponsor’s electronic data 
capture system.
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 and as required by applicable local regulations.  The 
investigator/institution will take measures to prevent accidental or premature destruction 
of these documents.
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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 following 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).

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 the eCRF data on the CD-ROM and any data clarification 
forms received from the sponsor or sponsor’s designee.  Such documentation is subject to 
inspection by the sponsor, sponsor’s designee, and relevant regulatory agencies.  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 time frame.  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 carefully in a 
detailed and orderly manner in accordance with established research principles, the ICH 
GCP guideline, 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 and written communications.
10.2.
Auditing
The sponsor’s Quality Management Unit (or representative) may conduct trial site audits.  
Audits will include, but are not limited to, drug supply, presence of required documents, 
the informed consent process, and comparison of eCRFs with source documents.  The 
investigator agrees to participate with audits.
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Regulatory authorities may inspect the investigator site during or after the trial.  The 
investigator will cooperate with such inspections and will contact the sponsor 
immediately if such an inspection occurs.
11.
Ethics and Responsibility
This trial must be conducted in compliance with the protocol, the ICH GCP guideline, 
and applicable local laws and regulatory requirements.  Each trial site will seek approval 
by an IRB or IEC according to regional requirements.  The IRB/IEC will evaluate the 
ethical, scientific, and medical appropriateness of the trial.  Further, in preparing and 
handling eCRFs, the investigator, subinvestigator, and their staff will take measures to 
ensure adequate care in protecting subject privacy.  To this end, a subject number and 
subject identification 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) will be allowed full access to inspect and copy the records.  All 
IMPs, subject bodily fluids, and/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 initials and unique subject numbers in eCRFs.  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 by the IRB/IEC.  Any permanent change to the 
protocol, whether an overall change or a change for specific trial site(s), must be handled 
as a protocol amendment.  Any amendment will be written by the sponsor.  Each 
amendment will be submitted to the IRB/IEC.  Except for “administrative” or 
“nonsubstantial” amendments, investigators will wait for IRB/IEC approval of the 
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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, followed by IRB/IEC notification within 5 working days.  The sponsor will 
submit protocol amendments to the applicable regulatory agencies.
When the IRB/IEC, investigators, and/or the sponsor conclude that the protocol 
amendment substantially alters the trial design and/or increases the potential risk to the 
subject, the currently approved written ICF will require similar modification.  In such 
cases, repeat informed consent will be obtained before expecting continued participation.
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14.
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Brexpiprazole (OPC-34712) Investigator's Brochure, Otsuka Pharmaceutical 
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Good Clinical Practice: Consolidated Guideline [finalized 1996 May, corrected 1996 
Jun 1996; cited 2005 Dec 6]. Available from:  
http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html.
26
Instruction Manual for the Cohen Mansfield Agitation Inventory (CMAI). Rockville, 
MD. The Research Institute of the Hebrew Home of Greater Washington; 1991.
27
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.
28
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;17:438-43.
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Cummings JL. Neuropsychiatric Inventory Nursing Home Version (NPI-NH): 
Comprehensive assessment of psychopathology in patients with dementia residing in 
nursing homes. 2009.
30
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;19:440-8.
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Cummings JL. The Neuropsychiatric Inventory: assessing psychopathology in 
dementia patients. Neurology. 1997;48:S10-6.
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Gustavsson A, Cattelin F, Jönsson L. Costs of care in a mild-to-moderate Alzheimer 
clinical trial sample: key resources and their determinants. Alzheimers Demen. 
2011;7(4):466-73.
37
Knopman DS, DeKosky ST, Cummings JL, Chuit H, Corey-Bloom J, Relkin N, et al. 
Practice parameter: diagnosis of dementia (an evidence-based review). Neurology. 
2001;56:1143-53.
38
Rosen WG, Terry RD, Fuld PA, Katzman R, Peck A. Pathological verification of 
ischemic score in differentiation of dementias. Ann Neurol. 1980;7:486-8.
39
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.
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Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
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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):189-98.
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Appendix 1
Names of Sponsor Personnel
Primary Medical Contacts
Otsuka Pharmaceutical Development & Commercialization, Inc.
508 Carnegie Center
Princeton, NJ 08540
Phone: 
Fax: 
Otsuka Pharmaceutical Development & Commercialization, Inc.
508 Carnegie Center
Princeton, NJ 08540
Phone:  
Fax:  
Compound Director
Otsuka Pharmaceutical Development & Commercialization, Inc.
508 Carnegie Center
Princeton, NJ 08540
Phone: 
Fax: 
Clinical Contact
Otsuka Pharmaceutical Development & Commercialization, Inc.
2440 Research Blvd
Rockville, MD 20850
Phone: 
Fax: 
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Appendix 2
Institutions Concerned With the Trial
Safety Reporting
Immediately Reportable Events (serious adverse events, potential Hy’s law cases, 
pregnancies, and adverse events requiring discontinuation of trial drug) should be 
reported to INC Research Pharmacovigilance & Drug Safety as follows:
Country
Safety Fax Line
United States
Canada
United Kingdom
France
Ukraine
Slovenia
Finland
Bulgaria
Russia
* Please note that this is a partner CRO number, not INC.
Clinical Research Organization
INC Research, LLC
3201 Beechleaf Court, Suite 600
Raleigh, NC 27604
USA
Medical Monitors
North America:
INC Research, LLC
3201 Beechleaf Court, Suite 600
Raleigh, NC 27604 USA
Office: 
Mobile: 
Fax:  
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Europe:
INC Research, LLC
UI. Emaus 5
30-201 Kraków, Poland
Office:  
Mobile:  
Fax:  
Clinical Lab - ECG Central Reader
eResearch Technology
1818 Market Street, Suite 1000
Philadelphia, PA 19103
USA
Central Laboratory
Covance Central Laboratory Services
8211 SciCor Drive
Indianapolis, IN 46214
USA
Bioanalytical Laboratory
Covance Laboratories
3301 Kinsman Boulevard
Madison, WI 53704
USA
Electronic Data Capture
Medidata Solutions, Inc.
350 Hudson Street, 9th Floor
New York, NY 10014
USA
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IVRS/IWRS
S-Clinica Inc.
41 University Drive
Suite 400
Newtown, PA 18940
USA
Translation Agency
Global Language Solutions, Inc.
19800 MacArthur Boulevard, Suite 750
Irvine, CA 92612
USA
Central IRB
Rater Training and Scale Management
ProPhase, LLC
3 Park Avenue, 37th Floor
New York, NY 10016
USA
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Appendix 3
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance
Laboratory Tests
Criteria
Chemistry
AST (SGOT)
3 x ULN
ALT (SGPT)
3 x ULN
Alkaline phosphatase
3 x ULN
Lactate dehydrogenase
3 x 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 x 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
ULN = upper limit of normal
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Appendix 4
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
aIn 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.
bAs 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 5
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)
aIn 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.
bNo current diagnosis of supraventricular tachycardia, ventricular tachycardia, atrial fibrillation, atrial 
flutter, or other rhythm abnormality.
cNo current diagnosis of atrial fibrillation, atrial flutter, or other rhythm abnormality.
dNo current diagnosis of left bundle branch block or right bundle branch block.
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Appendix 6
Cohen-Mansfield Agitation Inventory (CMAI)
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Clinical Global Impression-Severity of Illness (CGI-S), as related to agitation
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Appendix 8
Neuropsychiatric Inventory-Nursing Home Rating Scale 
(NPI-NH)
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Appendix 9
Neuropsychiatric Assessment for Non-Institutionalized 
Patients Based on the NPI/NPI-NH
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Appendix 14
National Institute of Neurological and Communicative 
Disorders and Stroke and the Alzheimer’s Disease and Related 
Disorders Association (NINCDS-ADRDA)
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Please complete the following scale using information obtained from the subject’s 
history and neurological examination. Indicate if a clinical feature is present or 
absent by selecting the appropriate score.
Clinical Feature
Present
Absent
Abrupt onset
2
0
Stepwise deterioration
1
0
Somatic complaints
1
0
Emotional incontinence
1
0
History of hypertension
1
0
History of strokes
2
0
Focal neurological symptoms
2
0
Focal neurological signs
2
0
Total Score: __________
Rosen WG, Terry RD, Fuld PA, Katzman R, Peck A. Pathological verification of
ischemic score in differentiation of dementias. Ann Neurol. 1980;7:486-8.
Copyright VC Hachinski, 1975. 
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Appendix 20
Mini-Mental State Examination (MMSE)
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Appendix 21
Handling and Shipment of Bioanalytical Samples
Pharmacokinetic Sample Collection
Four mL of blood for pharmacokinetic 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 bar code labels provided with the sample 
collection kits.  The central lab’s requisition form must be completely filled out in 
regards to the pharmacokinetic 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.  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 
pharmacokinetic 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 
samples must be neatly packed in the kits provided by the central 
lab and restrained in a Styrofoam container (place Styrofoam container supplied within a 
cardboard box).  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.  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 22
Protocol Amendment(s)/Administrative Change(s)
Amendment Number:
1
Issue Date:
16 December 2013
PURPOSE:
The sponsor has determined the need for a first formal amendment to the original 
protocol.  This amendment serves to reflect clarifications and additions to study 
procedures intended to enhance subject safety and accuracy of data.  In addition, 
administrative clarifications were made, including changes to text to enhance readability 
and consistency and to correct typographical, punctuation, and formatting errors. These 
changes were minor and do not change the design or content of the protocol, and 
therefore, are not summarized in this appendix.
The purpose of amending the Protocol 331-12-284, issued 06 May 2013, was to:

update changes to study staff.

increase numbers of participating centers from 20 to 30; trial recruitment period from 
3 to 4 years; and trial duration from 3.5 to 4.5 years.

clarify the role and responsibility of the investigator to assess the capacity of the 
subject to provide informed consent at screening and throughout the study.

add a requirement to screening assessments of an MRI/CT scan of the brain.

clarify the process for achieving the target dose.

clarify the definition of other efficacy variables.

remove the requirement that subjects who cannot provide consent must provide 
assent, and add that if a subject cannot provide assent, but does not dissent, then 
consent from a legally acceptable representative is sufficient.

modify inclusion criteria #1, #5, and #10.

modify exclusion criteria #2, #3, #6, #8, #11, #14, #20, #22, #30, and #34.

clarify the definition for retesting during the screening period.

clarify that the detailed neurological examination can be performed by a physician 
who is not necessarily a neurologist.

clarify the visit window of time and the dosing scheme.

add that subjects who complete this study are eligible to enter study 331-13-211.
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
update Table 4.1-1 List of Restricted and Prohibited Medications, row 3 
Antidepressants, to indicate that antidepressants that are CYP3A4 inhibitors, in 
addition to antidepressants that are CYP2D6 inhibitors, are prohibited from use 
during the study and require a 7-day washout prior to randomization. Add that 
fluoxetine requires a 28-day washout prior to randomization.

add footnote a to fluoxetine in Table 4.1-2 to indicate that fluoxetine requires a 
28-day washout prior to randomization.

clarified restrictions on psychotropic agent use.

add that eDiary information can be entered by facility staff.

clarify the frequency of DMC meetings.

add eGFR to the list of clinical laboratory assessments.

added definition of EPS.

revise the definition of Hy’s law cases.

allow for unique identifiers other than the subject’s initials.

update references to the Investigator’s Brochure to include the most recent version.

update country list and fax numbers for safety reporting.

add agitation as a criterion for the 
 and CGI-S tools.

update the list of abbreviations and definitions of terms.
BACKGROUND:
These changes to Protocol 331-12-284 were made on the basis of adjustments considered 
important to ensure the safety of the subjects enrolled and to facilitate appropriate study 
implementation and communication.
MODIFICATIONS TO PROTOCOL:

Bold and underlined text:
Changed text

Bold and strikethrough text:
Deleted text

Bold and italicized text:
Added text
General Revisions:
No global changes were made to Protocol 331-12-284 in this first amendment.  Changes 
by section are provided below.
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Sectional Revisions:
Location
Current Text
Revised Text
Title Page
Director of Clinical 
Management
Phone: 
Fax: 
E-mail: 
Phone: 
Fax: 
Phone: 
Fax: 
Synopsis
Trial Design
Screening Period
The screening period will range from a 
minimum of 2 days to a maximum of 
42 days and will begin when the 
informed consent form (ICF) is 
signed, prior to the initiation of any 
procedures.  Written informed consent 
will be obtained from the subject, if 
the subject is deemed capable by the 
investigator, and acknowledgement 
will be obtained from the subject’s 
legally acceptable representative, in 
accordance with country, state, and/or 
local regulations, prior to initiation of 
any study-required procedures.  
Alternatively, if the subject is deemed 
incapable of providing consent by the 
investigator, written informed consent 
from the subject’s legally acceptable 
representative and assent from the 
subject will be obtained prior to the 
initiation of any protocol-required 
procedures.  Further, the investigator 
must assess capacity during the 
screening period and throughout the 
course of the study; if the subject no 
longer is deemed capable of providing 
informed consent, informed consent 
must be obtained from the legally 
acceptable representative, and assent 
must be obtained from the subject.
The screening period will range from a 
minimum of 2 days to a maximum of 
42 days and will begin when the 
informed consent form (ICF) is 
signed, prior to the initiation of any 
procedures.  Written informed 
consent will be obtained from the 
subject, if the subject is deemed 
capable by the investigator, and 
acknowledgement will be obtained 
from the subject’s legally acceptable 
representative, in accordance with 
country, state, and/or local 
regulations, prior to initiation of any 
study-required procedures.  
Alternatively, if the subject is 
deemed incapable of providing 
consent by the investigator, written 
informed consent from the subject’s 
legally acceptable representative 
and assent from the subject will be 
obtained prior to the initiation of 
any protocol-required procedures.  
Further, the investigator must 
assess capacity during the screening 
period and throughout the course of 
the study; if the subject no longer is 
deemed capable of providing 
informed consent, informed consent 
must be obtained from the legally 
acceptable representative, and 
assent must be obtained from the 
subject.
The investigator must assess the 
capacity of the subject to provide 
informed consent during the 
screening period and throughout the 
course of the study.  Determinations 
by the investigator of the capacity of 
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PPD
PPD
PPD
PPD
PPD
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Location
Current Text
Revised Text
the subject to provide informed 
consent and the options for obtaining 
informed consent from and/or on 
behalf of the subject under each 
potential circumstance will be made 
and implemented according to strict 
criteria.
Synopsis
Trial Design
12-week, Double-blind 
Treatment Period
Starting with 0.25 mg of brexpiprazole 
(or matching placebo) on Day 1 (the 
day after the Baseline visit), subjects 
will be titrated to a target dose of 
1 mg/day of brexpiprazole over a 
2-week period, using the 
recommended titration schedule (see 
below).  The dose will be increased to 
0.5 mg/day on Day 4 (the day after the 
Day 3 visit).  On Day 15 (the day after 
the Week 2 visit), the dose will be 
increased to 1 mg/day.  In the absence 
of clinical response and dose-limiting 
side effects, the dose may be further 
increased to 2 mg/day on Day 29 the 
day after the Week 4 visit), based on 
the investigator’s clinical evaluation of 
the subject’s efficacy and tolerability.
Starting with 0.25 mg of 
brexpiprazole (or matching placebo) 
on Day 1 (the day after the Baseline 
visit), subjects will be titrated to a 
target dose of 1 mg/day of 
brexpiprazole over a 2-week period, 
using the recommended titration 
schedule (see below).  The dose will 
be increased to 0.5 mg/day on Day 4 
(the day after the Day 3 visit).  On 
Day 15 (the day after the Week 2 
visit), the dose will be increased to 1 
mg/day.  In the absence of clinical 
response and dose-limiting side 
effects, the dose may be further 
increased to 2 mg/day on Day 29 the 
day after the Week 4 visit), based on 
the investigator’s clinical evaluation 
of the subject’s efficacy and 
tolerability.
Subjects will be titrated to a target 
dose of 1 mg/day of brexpiprazole 
over a 2-week period, using the 
recommended titration schedule, as 
follows:
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Synopsis
Trial Design
12-week, Double-blind Treatment Period
Dosing Scheme Titration Schedule for Brexpiprazole
Treatment 
Group
Recommended Daily Dose Administered
Day 1(day after
the Baseline visit
(Day 1)
Day 4 (day after
the Day 3 visit
(Day 4
[+2 days])
Day 15(day after
the Week 2 visit
(Day 15
[±2 days])
Day 29(day after
the Week 4 visit
(Day 29
[±2 days])
Brexpiprazole 
0.5-2 mg/day
0.25 mg/day
0.5 mg/day
1 mg/daya
2 mg/day b
Placebo
<--------------------------------------------------------------------------------------------------------->
a After achieving the target dose of 1 mg/day, the dose may be decreased to a 0.5 mg/day and re-
increased to 1 mg/day based on the investigator’s clinical judgment. Dose decreases and increases 
can occur at any time (scheduled or unscheduled visits).
b The earliest time point that the dose can be increased to 2 mg/day is starting on the day after the 
Week 4 visit (i.e., Day 29 [±2 days]); however, it is not mandatory for the dose to be increased to 2 
mg/day. The decision to increase the dose should be based on the investigator’s clinical evaluation 
of the subject’s response and tolerability.  Allowable IMP doses that may be given starting the day 
after the Week 4 visit (i.e., Day 29 [±2 days]) will be 0.5 mg/day, 1 mg/day, or 2 mg/day.
Location
Current Text
Revised Text
Synopsis
Trial Design
12-week, Double-blind 
Treatment Period
After achieving the target dose of 1 
mg/day, dose decreases can occur at 
any time (scheduled or unscheduled 
visits) based on tolerability.  The dose 
may be reduced to the previously 
highest tolerated dose (to a minimum 
dose of 0.5 mg/day) in a stepwise 
manner.  
Allowable IMP doses after the Week 4 
visit will be 0.5 mg/day, 1 mg/day, or 
2 mg/day.  Subjects unable to tolerate 
0.5 mg/day of the IMP will be 
discontinued from the trial.  If a 
subject is withdrawn, every effort will 
be made to complete all of the Week 
12/ET evaluations prior to 
administering any additional 
medications for the treatment of 
agitation or other prohibited 
medications.
The first dose of IMP will be 
administered on the day after the 
Baseline visit (i.e., Day 1).  All 
subjects randomly assigned to receive 
brexpiprazole will receive 0.25 
mg/day as a starting dose.
The dose of IMP will be increased 
from 0.25 mg/day to 0.5 mg/day 
starting on the day after the Day 3 
visit (i.e., Day 4 [+2 days]). 
The dose will then be increased to 
1 mg/day starting on the day after the 
Week 2 visit (i.e., Day 15 [±2 days]).  
After achieving the target dose of 1 
mg/day, the dose may be decreased to 
a 0.5 mg/day and re-increased to 1 
mg/day based on the investigator’s 
clinical judgment. Dose decreases 
and increases can occur at any time 
(scheduled or unscheduled visits). The 
dose may be reduced to the 
previously highest tolerated dose (to 
a minimum dose of 0.5 md/day) in a 
stepwise manner.  
The dose of IMP can be further 
increased from 1 mg/day to 2 mg/day 
starting on the day after the Week 4 
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visit (i.e., Day 29 [±2 days]).  Note: 
The earliest time point that the dose 
can be increased to 2 mg/day is 
starting on the day after the Week 4 
visit (i.e., Day 29 [±2 days]); however, 
it is not mandatory for the dose to be 
increased to 2 mg/day. The decision 
to increase the dose should be based 
on the investigator’s clinical 
evaluation of the subject’s response 
and tolerability.  
Allowable IMP doses that may be 
given starting the day after the Week 
4 visit (i.e., Day 29 [±2 days]) will be 
0.5 mg/day, 1 mg/day, or 2 mg/day.
Dose decreases and increases must 
occur in a stepwise manner and can 
occur at any time (scheduled or 
unscheduled visits). 
For subjects randomly assigned to 
receive placebo, their dose of IMP 
will be administered daily starting on 
the day after the Baseline visit (i.e., 
Day 1) and ending on Week 12/ET 
(the last day of the Treatment 
Period).
Subjects unable to tolerate 0.5 mg/day 
of the IMP (or matching placebo) will 
be discontinued from the trial.  
If a subject is discontinued from the 
trialwithdrawn, every effort will be 
made to complete all of the Week 
12/Early termination (ET) evaluations 
prior to administering any additional 
medications for the treatment of 
agitation or other prohibited 
medications.
Synopsis
Follow-up Period
All subjects, whether they complete 
the trial or are withdrawn prematurely 
for any reason, will be followed up for 
a safety evaluation at a clinic visit at 
the residential facility 30 (+ 2) days 
after the last dose of the IMP.  If the 
subject has left the residential facility 
where he or she participated in the 
trial, the subject may be seen in the 
investigator’s clinic or (if a clinic visit 
is not possible) assessed by telephone 
contact with the subject and a 
All subjects, whether they complete 
the trial or are withdrawn prematurely 
for any reason, will be followed up for 
a safety evaluation at a clinic visit at 
the residential facility 30 (+ 2) days 
after the last dose of the IMP.  If the 
subject has left the residential facility 
where he or she participated in the 
trial, the subject shouldmay be seen in 
the investigator’s clinic or (if a clinic 
visit is not possible) assessed by 
telephone contact with the subject and 
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caregiver.
If a subject discontinues the trial
prematurely, every effort will be made 
to complete the Week 12/ET 
evaluations prior to administering 
additional medications for the 
treatment of agitation or other 
prohibited medications.
a caregiver.
Subjects who complete both the 12-
week double-blind treatment period 
and the 30-day safety follow-up visit 
are eligible to enroll into Trial 331-
13-211, which is a 2-month, 
observational, rollover trial to 
evaluate the safety of subjects with 
agitation associated with Alzheimer's 
disease who previously participated in 
Trial 331-12-284. For those subjects 
who plan to enroll into Trial 331-12-
211, the 30-day safety follow-up visit 
for Trial 331-12-284 will occur as a 
clinic visit at the residential facility. 
If the subject has left the residential 
facility where he or she participated 
in the trial, the 30-day safety follow-
up visit will occur as a clinic visit at 
the investigator's site.
If a subject discontinues the trial 
prematurely, every effort will be 
made to complete the Week 12/ET 
evaluations prior to administering 
additional medications for the 
treatment of agitation or other 
prohibited medications.
Synopsis
Subject Population
The subject population will include 
male and female subjects between 
55 and 90 years of age (inclusive), 
who are residing in a dementia unit, 
nursing home, assisted living facility, 
or any other residential care facility 
providing long-term care, with a 
diagnosis of probable Alzheimer’s 
disease according to the 
NINCDS-ADRDA criteria.  Subjects 
must have a previous magnetic 
resonance imaging (MRI) or computed 
tomography (CT) scan, which was 
performed after the onset of symptoms 
of dementia, consistent with a 
diagnosis of Alzheimer’s disease.  
Additionally, at both the screening and 
baseline visits, subjects must have a 
Mini-Mental State Examination 
(MMSE) score of 5 to 22, inclusive, 
and a total score (frequency x severity) 
of ≥4 on the agitation/aggression item 
of the NPI-NH.  
Subjects must require 
The subject population will include 
male and female subjects between 
55 and 90 years of age (inclusive), 
who are residing in a dementia unit, 
nursing home, assisted living facility, 
or any other residential care facility 
providing long-term care, with a 
diagnosis of probable Alzheimer’s 
disease according to the 
NINCDS-ADRDA criteria.  Subjects 
must have a previous magnetic 
resonance imaging (MRI) or computed 
tomography (CT) scan of the brain,
which was performed after the onset 
of symptoms of dementia, with 
findings consistent with a diagnosis of 
Alzheimer’s disease.  Additionally, at 
both the screening and baseline visits, 
subjects must have a Mini-Mental 
State Examination (MMSE) score of 
5 to 22, inclusive, and a total score 
(frequency x severity) of ≥4 on the 
agitation/aggression item of the 
Neuropsychiatric Inventory-Nursing 
Home (NPI-NH).  
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pharmacotherapy for the treatment of 
agitation per the investigator’s 
judgment, after an evaluation for 
reversible factors (e.g., pain, infection) 
and trial of nonpharmacological 
interventions.
Subjects must require 
pharmacotherapy for the treatment of 
agitation per the investigator’s
judgment, after an evaluation for 
reversible factors (e.g., pain, infection, 
polypharmacy) and trial of 
nonpharmacological interventions.
Synopsis
Exclusion Criteria

Subjects with a previous magnetic 
resonance imaging (MRI) or computed 
tomography (CT) scan performed after 
the onset of symptoms of dementia 
with findings consistent with a 
clinically significant central nervous 
system disease other than Alzheimer’s 
disease, such as vascular changes 
(e.g., cortical stroke, multiple 
infarcts), space-occupying lesion (e.g., 
tumor), or other major structural brain 
disease.
Subjects with a previous magnetic 
resonance imaging (MRI/) or 
computed tomography (CT) scan of 
the brain, which was performed after 
the onset of symptoms of dementia, 
with findings consistent with a 
clinically significant central nervous 
system disease other than Alzheimer’s 
disease, such as vascular changes 
(e.g., cortical stroke, multiple 
infarcts), space-occupying lesion (e.g., 
tumor), or other major structural brain 
disease.

Subjects with a history of stroke, 
transient ischemic attack, or 
embolism.
Subjects with a history of stroke, 
transient ischemic attack, or 
pulmonary or cerebral embolism.
Synopsis
Trial Sites
It is planned that approximately 330 
subjects will be screened at 
approximately 20 trial centers 
worldwide so that 230 subjects will be 
randomized to treatment.
It is planned that approximately 330 
subjects will be screened at 
approximately 30 trial centers 
worldwide so that 230 subjects will be 
randomized to treatment.
Synopsis
Investigational 
Medicinal Product, 
Dose, Formulation, 
Mode of Administration
The first dose of the IMP will be 
administered on Day 1, i.e., the day 
after the Baseline visit.  On Day 1, all 
subjects will be administered 
0.25 mg/day of brexpiprazole (or 
matching placebo).  The dose will be 
increased to 0.5 mg/day on Day 4 (the 
day after the Day 3 visit).  On Day 15 
(the day after the Week 2 visit), the 
dose will be increased to 1 mg/day.  In 
the absence of clinical response and 
dose-limiting side effects, the dose 
may be further increased to 2 mg/day 
on Day 29 (the day after the Week 4 
visit), based on the investigator’s 
clinical evaluation of the subject’s 
efficacy and tolerability.
After achieving the target dose of 1 
mg/day, dose decreases can occur at 
any time (scheduled or unscheduled 
visits) based on tolerability.  The dose 
may be reduced to the previously 
highest tolerated dose (to a minimum 
The first dose of the IMP will be 
administered on Day 1, i.e., the day 
after the Baseline visit.  On Day 1, 
all subjects will be administered 
0.25 mg/day of brexpiprazole (or 
matching placebo).  The dose will be 
increased to 0.5 mg/day on Day 4 
(the day after the Day 3 visit).  On 
Day 15 (the day after the Week 2 
visit), the dose will be increased to 1 
mg/day.  In the absence of clinical 
response and dose-limiting side 
effects, the dose may be further 
increased to 2 mg/day on Day 29 
(the day after the Week 4 visit), 
based on the investigator’s clinical 
evaluation of the subject’s efficacy 
and tolerability.
After achieving the target dose of 1 
mg/day, dose decreases can occur at 
any time (scheduled or unscheduled 
visits) based on tolerability.  The 
dose may be reduced to the 
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dose of 0.5 mg/day) in a stepwise 
manner.  Allowable IMP doses after 
the Week 4 visit will be 0.5 mg/day, 
1 mg/day, or 2 mg/day.  Subjects 
unable to tolerate 0.5 mg/day of the 
IMP will be discontinued from the 
trial.
previously highest tolerated dose (to 
a minimum dose of 0.5 mg/day) in a 
stepwise manner.  Allowable IMP 
doses after the Week 4 visit will be 
0.5 mg/day, 1 mg/day, or 2 mg/day.  
Subjects unable to tolerate 0.5 
mg/day of the IMP will be 
discontinued from the trial.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Synopsis
Trial Duration
The time from enrollment of the first 
subject to the last subject’s last trial 
visit will be approximately 3.5 years, 
of which approximately 3 years are 
allotted for recruitment of subjects.  
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 
will be followed up at a clinic visit or 
via telephone contact 30 (+ 2) days 
after the last dose of the IMP.
The time from enrollment of the first 
subject to the last subject’s last trial 
visit will be approximately 4.5 years, 
of which approximately 4 years are 
allotted for recruitment of subjects.  
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 
will be followed up at a clinic visit or
via telephone contact 30 (+ 2) days 
after the last dose of the IMP.
Subjects who complete both the 12-
week double-blind treatment period 
and the 30-day safety follow-up visit 
are eligible to enroll into Trial 331-
13-211, which is a 2-month, 
observational, rollover trial to 
evaluate the safety of subjects with 
agitation associated with 
Alzheimer's disease who previously 
participated in Trial 331-12-284. 
For those subjects who plan to 
enroll into Trial 331-12-211, the 30-
day safety follow-up visit for Trial 
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331-12-284 will occur as a clinic visit 
at the residential facility. If the 
subject has left the residential 
facility where he or she participated 
in the trial, the 30-day safety follow-
up visit will occur as a clinic visit at 
the investigator's site.
Section 1.2.1
Pharmacokinetics and 
Pharmacodynamics
Trials have investigated the 
pharmacokinetics of brexpiprazole in 
special populations (subjects with 
hepatic impairment and renal 
impairment); one studying the effects 
of age and sex on brexpiprazole 
pharmacokinetics recently was 
completed.  Based on the results of the 
special population trials, no dose 
adjustment is needed when 
brexpiprazole is administered to 
elderly subjects or subjects with renal 
or hepatic insufficiency.
Trials have investigated the 
pharmacokinetics of brexpiprazole in 
special populations (subjects with 
hepatic impairment and renal 
impairment); one studying the effects 
of age and sex on brexpiprazole 
pharmacokinetics recentlywashas
been completed.  Based on the results 
of the special population trials, no 
dose adjustment is needed when 
brexpiprazole is administered to 
elderly subjects or subjects with renal 
or hepatic insufficiency.
Section 3.1
Type/Design of Trial
Screening Period
The screening period will range from a 
minimum of 2 days to a maximum of 
42 days and will begin when the 
informed consent form (ICF) is 
signed, prior to the initiation of any 
procedures.  Written informed consent 
will be obtained from the subject, if 
the subject is deemed capable by the 
investigator, and acknowledgement 
will be obtained from the subject’s 
legally acceptable representative, in 
accordance with country, state and/or 
local regulations, prior to initiation of 
any study-required procedures.  
Alternatively, if the subject is deemed 
incapable of providing consent by the 
investigator, written informed consent 
from the subject’s legally acceptable 
representative and assent from the 
subject will be obtained prior to the 
initiation of any protocol-required 
procedures.  Further, the investigator 
must assess the subject’s capacity to 
provide informed consent during the 
screening period and throughout the 
course of the study; if the subject is no 
longer deemed capable of providing 
informed consent, informed consent 
must be obtained from the legally 
acceptable representative and assent 
must be obtained from the subject.  An 
interactive voice response system 
(IVRS) or interactive web response 
The screening period will range from a 
minimum of 2 days to a maximum of 
42 days and will begin when the 
informed consent form (ICF) is 
signed, prior to the initiation of any 
procedures.  Additional requirements 
for obtaining informed consent from 
this vulnerable subject population are 
provided in Section 3.4.1.  Written 
informed consent will be obtained 
from the subject, if the subject is 
deemed capable by the investigator, 
and acknowledgement will be 
obtained from the subject’s legally 
acceptable representative, in 
accordance with country, state 
and/or local regulations, prior to 
initiation of any study-required 
procedures.  Alternatively, if the 
subject is deemed incapable of 
providing consent by the 
investigator, written informed 
consent from the subject’s legally 
acceptable representative and assent 
from the subject will be obtained 
prior to the initiation of any 
protocol-required procedures.  
Further, the investigator must 
assess the subject’s capacity to 
provide informed consent during 
the screening period and throughout 
the course of the study; if the 
subject is no longer deemed capable 
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system (IWRS) will be used to obtain 
the subject study identification number 
for each subject with a signed ICF.
of providing informed consent, 
informed consent must be obtained 
from the legally acceptable 
representative and assent must be 
obtained from the subject.  An 
interactive voice response system 
(IVRS) or interactive web response 
system (IWRS) will be used to obtain 
the subject study identification number 
for each subject with a signed ICF.
Section 3.1
Type/Design of Trial
Screening Period
If the subject decides not to wear the 
actigraph at any time after the consent 
is obtained, the assessment may be 
discontinued and study participation 
will not be affected.  The patient’s 
daily behavior will be logged into an 
eDiary by the caregiver.
If the subject decides not to wear the 
actigraph at any time after the consent 
is obtained, the assessment may be 
discontinued and study participation 
will not be affected.  The patient’s 
daily behavior will be logged into an 
eDiary by the caregiver and/or facility 
staff.
Section 3.1
Type/Design of Trial
12-week, Double-blind 
Treatment Period
Starting with 0.25 mg of brexpiprazole 
(or matching placebo) on Day 1 (the 
day after the Baseline visit), subjects 
will be titrated to a target dose of 
1 mg/day of brexpiprazole over a 
2-week period, using the 
recommended titration schedule (refer 
to Table 3.2-1).  The dose will be 
increased to 0.5 mg/day on Day 4 (the 
day after the Day 3 visit).  On Day 15 
(the day after the Week 2 visit), the 
dose will be increased to 1 mg/day. In 
the absence of clinical response and 
dose-limiting side effects, the dose 
may be further increased to 2 mg/day 
on Day 29 (the day after the Week 4 
visit), based on the in
vestigator’s clinical evaluation of the 
subject’s efficacy and tolerability.
Subjects will follow a titration 
schedule to gradually increase their 
dose of the IMP to the target dose 
(refer to Table 3.2-1).  
Starting with 0.25 mg of 
brexpiprazole (or matching placebo) 
on Day 1 (the day after the Baseline 
visit), subjects will be titrated to a 
target dose of 1 mg/day of 
brexpiprazole over a 2-week period, 
using the recommended titration 
schedule (refer to Table 3.2-1).  The 
dose will be increased to 0.5 mg/day 
on Day 4 (the day after the Day 3 
visit).  On Day 15 (the day after the 
Week 2 visit), the dose will be 
increased to 1 mg/day.  In the 
absence of clinical response and 
dose-limiting side effects, the dose 
may be further increased to 
2 mg/day on Day 29 (the day after 
the Week 4 visit), based on the 
investigator’s clinical evaluation of 
the subject’s efficacy and 
tolerability.
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Section 3.1
Type/Design of Trial
12-week, Double-blind 
Treatment Period
After achieving the target dose of 1 
mg/day, dose decreases can occur at 
any time (scheduled or unscheduled 
visits) based on tolerability.  The dose 
may be reduced to the previously 
highest tolerated dose (to a minimum 
dose of 0.5 mg/day) in a stepwise 
manner.  Allowable IMP doses after 
the Week 4 visit will be 0.5 mg/day, 
1 mg/day, or 2 mg/day.  Subjects 
unable to tolerate 0.5 mg/day of the
IMP will be discontinued from the 
trial.  If a subject is withdrawn, every 
effort will be made to complete all of 
the Week 12/ET evaluations prior to 
administering any additional 
medications for the treatment of 
agitation or other prohibited 
medications.
After achieving the target dose of 1 
mg/day, dose decreases can occur at 
any time (scheduled or unscheduled 
visits) based on tolerability.  The 
dose may be reduced to the 
previously highest tolerated dose (to 
a minimum dose of 0.5 mg/day) in a 
stepwise manner.  Allowable IMP 
doses after the Week 4 visit will be 
0.5 mg/day, 1 mg/day, or 2 mg/day.  
Subjects unable to tolerate 0.5 
mg/day of the IMP will be 
discontinued from the trial.  If a 
subject is withdrawn, every effort 
will be made to complete all of the
Week 12/ET evaluations prior to 
administering any additional 
medications for the treatment of 
agitation or other prohibited 
medications.
If a subject discontinues the trial 
prematurely, every effort will be made 
to complete the Week 12/ET 
evaluations prior to administering 
additional medications for the 
treatment of agitation or other 
prohibited medications.
Section 3.1
Type/Design of Trial
Follow-up Period
All subjects, whether they complete 
the trial or are withdrawn prematurely 
for any reason, will be followed up for 
a safety evaluation at a clinic visit at 
the residential facility 30 (+ 2) days 
after the last dose of the IMP.  If the 
subject has left the residential facility 
where he or she participated in the 
trial, the subject may be seen in the 
investigator’s clinic or (if a clinic visit 
is not possible) assessed by telephone 
contact with the subject and a 
caregiver.  If a subject discontinues 
the trial prematurely, every effort will 
be made to complete the Week 12/ET 
evaluations prior to administering 
additional medications for the 
treatment of agitation or other 
prohibited medications.
All subjects, whether they complete 
the trial or are withdrawn prematurely 
for any reason, will be followed up for 
a safety evaluation at a clinic visit at 
the residential facility 30 (+ 2) days 
after the last dose of the IMP.  If the 
subject has left the residential facility 
where he or she participated in the 
trial, the subject shouldmay be seen in 
the investigator’s clinic or (if a clinic 
visit is not possible) assessed by 
telephone contact with the subject and 
a caregiver. If a subject discontinues 
the trial prematurely, every effort 
will be made to complete the Week 
12/ET evaluations prior to 
administering additional 
medications for the treatment of 
agitation or other prohibited 
medications.
Subjects who complete both the 12-
week double-blind treatment period 
and the 30-day safety follow-up visit 
are eligible to enroll into Trial 331-
13-211, which is a 2-month, 
observational, rollover trial to 
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evaluate the safety of subjects with 
agitation associated with Alzheimer's 
disease who previously participated in 
Trial 331-12-284. For those subjects 
who plan to enroll into Trial 331-12-
211, the 30-day safety follow-up visit 
for Trial 331-12-284 will occur as a 
clinic visit at the residential facility. 
If the subject has left the residential 
facility where he or she participated 
in the trial, the 30-day safety follow-
up visit will occur as a clinic visit at 
the investigator's site.
Section 3.2
Treatments
Table 3.2-1
Dosing Scheme
Table 3.2-1
Dosing Scheme  Titration Schedule for Brexpiprazole
Treatment Group
Recommended Daily Dose Administered
Day 1(day after
the Baseline visit
(Day 1)
Day 4 (day after
the Day 3 visit
(Day 4
[+2 days])
Day 15(day after
the Week 2 visit
(Day 15
[±2 days])
Day 29(day after
the Week 4 visit
(Day 29
[±2 days])
Brexpiprazole 0.5-
2 mg/day
0.25 mg/day
0.5 mg/day
1 mg/daya
2 mg/day b
Placebo
<------------------------------------------------------------------------------------------------->
a Subject must achieve the target dose of 1 mg/day before the dose can be decreased. After 
achieving the target dose of 1 mg/day, the dose may be decreased to a 0.5 mg/day and re-increased 
to 1 mg/day based on the investigator’s clinical judgment. Dose decreases and increases can occur 
at any time (scheduled or unscheduled visits).   
b The earliest time point that the dose can be increased to 2 mg/day is starting on the day after the 
Week 4 visit (i.e., Day 29 [±2 days]); however, it is not mandatory for the dose to be increased to 2 
mg/day. The decision to increase the dose should be based on the investigator’s clinical evaluation 
of the subject’s response and tolerability.  Allowable IMP doses that may be given starting the day 
after the Week 4 visit (i.e., Day 29 [±2 days]) will be 0.5 mg/day, 1 mg/day, or 2 mg/day.
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Section 3.2
Treatments
The first dose of the IMP will be 
administered on Day 1, i.e., the day 
after the Baseline visit.  On Day 4, i.e., 
the day after the Day 3 visit, the dose 
will be increased to 0.5 mg/day of 
brexpiprazole (or matching placebo) 
for all subjects; and on Day 15 i.e., the 
day after the Week 2 visit, the dose 
will be increased to 1 mg/day of 
brexpiprazole (or matching placebo) 
for all subjects.  In the absence of 
clinical response and dose-limiting 
side effects, the dose may be further 
increased to 2 mg/day on Day 29 (the 
day after the Week 4 visit), based on 
the investigator’s clinical evaluation of 
the subject’s efficacy and tolerability.
After achieving the target dose of 1 
mg/day, dose decreases can occur at 
any time (scheduled or unscheduled 
visits) based on tolerability.  The dose 
may be reduced to the previously 
highest tolerated dose (to a minimum 
dose of 0.5 mg/day) in a stepwise 
manner.  Allowable IMP doses after 
the Week 4 visit will be 0.5 mg/day, 1 
mg/day, or 2 mg/day.
Subjects unable to tolerate 0.5 mg/day 
of the IMP will be discontinued from 
the trial.  
If a subject is withdrawn, every effort 
will be made to complete all of the 
Week 12/ET evaluations prior to 
administering any additional 
medications for the treatment of 
agitation or other prohibited 
medications.
The first dose of IMP will be 
administered on the day after the 
Baseline visit (i.e., Day 1).  All 
subjects randomly assigned to receive 
brexpiprazole will receive 0.25 
mg/day as a starting dose.
The dose of IMP will be increased 
from 0.25 mg/day to 0.5 mg/day 
starting on the day after the Day 3 
visit (i.e., Day 4 [+2 days]). 
The dose will then be increased to 
1 mg/day starting on the day after the 
Week 2 visit (i.e., Day 15 [±2 days]).  
After achieving the target dose of 1 
mg/day, the dose may be decreased to 
a 0.5 mg/day and re-increased to 1 
mg/day based on the investigator’s 
clinical judgment. Dose decreases 
and increases can occur at any time 
(scheduled or unscheduled visits).   
The dose of IMP can be further 
increased from 1 mg/day to 2 mg/day 
starting on the day after the Week 4 
visit (i.e., Day 29 [±2 days]).  Note: 
The earliest time point that the dose 
can be increased to 2 mg/day is 
starting on the day after the Week 4 
visit (i.e., Day 29 [±2 days]); however, 
it is not mandatory for the dose to be 
increased to 2 mg/day. The decision 
to increase the dose should be based 
on the investigator’s clinical 
evaluation of the subject’s response 
and tolerability.  
Allowable IMP doses that may be 
given starting the day after the Week 
4 visit (i.e., Day 29 [±2 days]) will be 
0.5 mg/day, 1 mg/day, or 2 mg/day. 
Dose decreases and increases must 
occur in a stepwise manner and can 
occur at any time (scheduled or 
unscheduled visits). 
For subjects randomly assigned to 
receive placebo, their dose of IMP 
will be administered daily starting on 
the day after the Baseline visit (i.e., 
Day 1) and ending on Week 12/ET 
(the last day of the Treatment 
Period).
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Subjects unable to tolerate 0.5 mg/day
of the IMP (or matching placebo)will 
be discontinued from the trial.  
If a subject is discontinued from the 
trialwithdrawn, every effort will be 
made to complete all of the 
Week 12/ET evaluations prior to 
administering any additional 
medications for the treatment of 
agitation or other prohibited 
medications.
Section 3.3
Trial Population
The subject population will include 
male and female subjects between 
55 and 90 years of age (inclusive), 
who are residing in a dementia unit, 
nursing home, assisted living facility, 
or any other residential care facility 
providing long-term care, with a 
diagnosis of probable Alzheimer’s 
disease according to the 
NINCDS-ADRDA criteria.  Subjects 
must have a previous magnetic 
resonance imaging (MRI) or computed 
tomography (CT) scan, which was 
performed after the onset of symptoms 
of dementia, consistent with a 
diagnosis of Alzheimer’s disease.  
Additionally, at both the screening and 
baseline visits, subjects must have a 
Mini-Mental State Examination 
(MMSE) score of 5 to 22, inclusive, 
and a total score (frequency x severity) 
of ≥4 on the agitation/aggression item 
of the NPI-NH. 
Subjects must require 
pharmacotherapy for the treatment of 
agitation per the investigator’s 
judgment, after an evaluation for 
reversible factors (e.g., pain, infection) 
and trial of nonpharmacological 
interventions.
The subject population will include 
male and female subjects between 
55 and 90 years of age (inclusive), 
who are residing in a dementia unit, 
nursing home, assisted living facility, 
or any other residential care facility 
providing long-term care, with a 
diagnosis of probable Alzheimer’s 
disease according to the 
NINCDS-ADRDA criteria.  Subjects 
must have a previous magnetic 
resonance imaging (MRI) or computed 
tomography (CT) scan of the brain,
which was performed after the onset 
of symptoms of dementia, with 
findings consistent with a diagnosis of 
Alzheimer’s disease.  Additionally, at 
both the screening and baseline visits, 
subjects must have a Mini-Mental 
State Examination (MMSE) score of 
5 to 22, inclusive, and a total score 
(frequency x severity) of ≥4 on the 
agitation/aggression item of the 
NPI-NH. 
Subjects must require 
pharmacotherapy for the treatment of 
agitation per the investigator’s 
judgment, after an evaluation for 
reversible factors (e.g., pain, infection, 
polypharmacy) and trial of 
nonpharmacological interventions.
Section 3.4.1
Informed Consent
Written informed consent will be 
obtained from the subject, if deemed 
capable by the investigator, and 
acknowledgement from the subject’s 
legally acceptable representative, in 
accordance with state and/or local 
regulations, prior to initiation of any 
study protocol-required procedures.  
Alternatively, if the subject is deemed 
incapable of providing consent by the 
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 study.  Once these 
determinations are made by the 
investigator, the following options for 
obtaining informed consent from 
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investigator, written informed consent 
from the subject’s legally acceptable 
representative and assent from the 
subject will be obtained prior to the 
initiation of any study protocol-
required procedures.  Further, the 
investigator must assess capacity 
during the screening period and 
throughout the course of the study; if 
the subject is no longer deemed 
capable of providing informed 
consent, informed consent must be 
obtained from the legally acceptable 
representative and assent must be 
obtained from the subject.  
and/or on behalf of the subject must 
be followed:
Written informed consent will be 
obtained from the subject, if If the 
subject is deemed capable by the 
investigator, written informed consent 
will be obtained from the subject 
prior to the initiation of any study 
protocol-required procedures.  In 
such cases, and acknowledgement 
from the subject’s legally acceptable 
representative (an individual, or 
judicial or other body, authorized 
under applicable law to consent to the 
subject’s participation in the clinical 
trial on behalf of that prospective 
subject) will also be obtained, in 
accordance with state and/or local 
regulations prior to initiation of any 
study protocol-required procedures.  
Alternatively,
Further, the investigator must 
assess capacity during the screening 
period and throughout the course of 
the study;Iif the subject was initially 
deemed capable of providing 
informed consent but is no longer 
deemed so, informed consent must be 
obtained from the legally acceptable 
representative, and assent from the 
subject, if possible, willmust be 
confirmedobtained from the subject
in accordance with state and/or local 
regulations prior to the initiation of 
any study protocol-required 
procedures.
Iif the subject is deemed incapable by 
the investigator of providing consent 
(e.g., minors, subjects with severe 
dementia)by the investigator, written 
informed consent will be obtained
from the subject’s legally acceptable 
representative prior to initiation of 
any study protocol-required 
procedures.  In such cases, assent 
from the subject, if possible, will be 
confirmedobtained in accordance 
with state and/or local regulations 
prior to the initiation of any study 
protocol-required procedures.  
If the subject cannot provide assent, 
and does not dissent, then the consent 
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of the legally acceptable 
representative is sufficient unless 
otherwise required by the governing 
ethics body and/or applicable state 
and/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 study entry, but subsequent 
dissents to participate in the trial, the 
subject will be early terminated from 
the trial.
Section 3.4.1
Informed Consent
Consent will be documented on a 
written ICF.  The ICF will be 
approved by the same IRB/IEC that 
approves this protocol.  Each ICF will 
comply with the International 
Conference on Harmonization (ICH) 
Good Clinical Practice (GCP) 
Guideline and local regulatory 
requirements.  The investigator agrees 
to obtain sponsor approval of any 
written ICF used in the trial prior to 
submission to the IRB/IEC.
Investigators may discuss trial 
availability and the possibility for 
entry with a potential subject and 
subject’s legally acceptable 
representative without first obtaining 
consent.  However, informed consent 
must be obtained and documented 
prior to initiation of any procedures 
that are performed solely for the 
purpose of determining eligibility for 
this trial, including withdrawal from 
current medication(s).
When a study includes subjects who 
may not have the capacity to provide 
informed consent, the investigator will 
be required to assess capacity.  If the 
subject is deemed capable of 
providing informed consent, then the 
subject can be enrolled with the 
consent of the subject.  If the subject is 
deemed to not have the capacity to 
provide informed consent (e.g., 
minors, subjects with severe 
dementia), then the subject can only 
be enrolled with the consent of the 
subject’s legally acceptable 
Section 3.4.1.2
Documentation of 
Informed Consent 
Consent will be documented on a 
written ICF.  The ICF will be 
approved by the same IRB/IEC that 
approves this protocol.  Each ICF will 
comply with the International 
Conference on Harmonization (ICH) 
Good Clinical Practice (GCP) 
Guideline and local regulatory 
requirements.  The investigator agrees 
to obtain sponsor approval of any 
written ICF used in the trial prior to 
submission to the IRB/IEC.
Investigators may discuss trial 
availability and the possibility for 
entry with a potential subject and 
subject’s legally acceptable 
representative without first obtaining 
consent.  However, informed consent 
must be obtained and documented 
prior to initiation of any procedures 
that are performed solely for the 
purpose of determining eligibility for 
this trial, including withdrawal from 
current medication(s).
When a study includes subjects who 
may not have the capacity to 
provide informed consent, the 
investigator will be required to 
assess capacity.  If the subject is 
deemed capable of providing 
informed consent, then the subject 
can be enrolled with the consent of 
the subject.  If the subject is deemed 
to not have the capacity to provide 
informed consent (e.g., minors, 
subjects with severe dementia), then 
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representative and the subject must be 
informed about the study to the extent 
compatible with the subject’s 
understanding and, if capable, 
personally sign and date the consent or 
assent form, depending on local 
regulations.
the subject can only be enrolled with 
the consent of the subject’s legally 
acceptable representative andTthe 
subject must be informed about the 
study to the extent compatible with the 
subject’s understanding and, if 
capable, personally sign and date the 
consent or assent form, depending on 
local regulations. 
Table 3.4-1
Inclusion Criteria
#1  Written informed consent will be 
obtained from the subject, if deemed 
capable by the investigator, and 
acknowledgement will be obtained 
from the subject’s legally acceptable 
representative, in accordance with 
country, state, and/or local regulations, 
prior to initiation of any study-
required procedures.  Alternatively, if 
the subject is deemed incapable of 
providing consent by the investigator, 
written informed consent from the 
subject’s legally acceptable 
representative and assent from the 
subject will be obtained prior to the 
initiation of any protocol-required 
procedures.  
#1  Written informed consent will be 
obtained from the subject, if deemed 
capable by the investigator, and 
acknowledgement will be obtained 
from the subject’s legally acceptable 
representative, in accordance with 
country, state, and/or local 
regulations, prior to initiation of any 
study-required procedures.  
Alternatively, if the subject is 
deemed incapable of providing 
consent by the investigator, written 
informed consent from the subject’s 
legally acceptable representative 
and assent from the subject will be 
obtained prior to the initiation of 
any protocol-required procedures.
The investigator must assess the 
capacity of the subject to provide 
informed consent during the 
screening period and throughout the 
course of the study.  Once this 
determination is made by the 
investigator, the options for obtaining 
informed consent from and/or on 
behalf of the subject must be followed 
as provided in Section 3.4.1.
Table 3.4-1
Inclusion Criteria
#5 Subjects must have a previous 
MRI or CT scan, which was 
performed after the onset of symptoms 
of dementia, consistent with a 
diagnosis of Alzheimer’s disease.
#5
Subjects must have a previous 
MRI or CT scan of the brain, which 
was performed after the onset of 
symptoms of dementia, with findings 
consistent with a diagnosis of 
Alzheimer’s disease.
Table 3.4-1
Inclusion Criteria
#10  Subjects who require 
pharmacotherapy for the treatment of 
agitation per the investigator’s 
judgment, after an evaluation for 
reversible factors (e.g., pain, infection) 
and trial of nonpharmacological 
interventions.
# 10  Subjects who require 
pharmacotherapy for the treatment of 
agitation per the investigator’s 
judgment, after an evaluation for 
reversible factors (e.g., pain, infection, 
polypharmacy) and trial of 
nonpharmacological interventions.
Table 3.4-2
Exclusion Criteria
#2  Subjects with a previous MRI or 
CT scan performed after the onset of 
symptoms of dementia with findings 
consistent with a clinically significant 
#2  Subjects with a previous MRI or 
CT scan of the brain, which was
performed after the onset of symptoms 
of dementia, with findings consistent 
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central nervous system disease other 
than Alzheimer’s disease, such as 
vascular changes (e.g., cortical stroke, 
multiple infarcts), space-occupying 
lesion (e.g., tumor), or other major 
structural brain disease. 
with a clinically significant central 
nervous system disease other than 
Alzheimer’s disease, such as vascular 
changes (e.g., cortical stroke, multiple 
infarcts), space-occupying lesion (e.g., 
tumor), or other major structural brain 
disease. 
Table 3.4-2
Exclusion Criteria
#3  Subjects with a history of stroke, 
transient ischemic attack, or 
embolism.
#3  Subjects with a history of stroke, 
transient ischemic attack, or 
pulmonary or cerebral embolism.
Table 3.4-2
Exclusion Criteria
#6  Subjects who have an insufficient 
response, based on the investigator’s 
judgment, to previous antipsychotic 
medications for the treatment of 
agitation associated with Alzheimer’s 
disease.
#6  Subjects who have an insufficient 
response, based on the investigator’s 
judgment, to two2 or more previous 
antipsychotic medications for the 
treatment of agitation associated with 
Alzheimer’s disease.
Table 3.4-2
Exclusion Criteria
#8  

Bipolar I or II disorder, bipolar 
disorder not otherwise specified

Current major depressive episode--
unless on a stable dose(s) of 
antidepressant medication(s) for the 30 
days prior to randomization. Please 
note: antidepressant medications that 
are CYP2D6 inhibitors are prohibited 
(see Table 4.1-2 for prohibited 
antidepressant medications).

Eating disorder (including anorexia 
nervosa or bulimia)--unless resolved 
with no symptoms for at least 1 year 
prior to screening
#8  
Bipolar I or II disorder, bipolar 
disorder not otherwise specified
Current major depressive episode--
unless on a stable dose(s) of 
antidepressant medication(s) for the 30 
days prior to randomization. Please 
note: antidepressant medications that 
are CYP2D6 or CYP3A4 inhibitors 
are prohibited (see Table 4.1-2 for 
prohibited antidepressant 
medications).
Eating disorder (including anorexia 
nervosa or bulimia)--unless resolved 
with no symptoms for at least 1 year 
prior to screening
Table 3.4-2
Exclusion Criteria
#11  Subjects who currently have 
clinically significant neurological, 
hepatic, renal, metabolic, 
hematological, immunological, 
cardiovascular, pulmonary, or 
gastrointestinal disorders, such as 
atrial fibrillation, myocardial 
infarction, congestive heart failure, 
procedure for cardiovascular disease 
(i.e., angioplasty, stenting, 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 
#11  Subjects who currently have 
clinically significant neurological, 
hepatic, renal, metabolic, 
hematological, immunological, 
cardiovascular pulmonary, or 
gastrointestinal 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, coronary 
bypass surgery.  
Medical conditions that are minor or 
well-controlled may be considered 
acceptable if the condition does not 
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is uncertain regarding the stability of a 
subject’s medical condition(s) and the 
potential impact of the condition(s) on 
trial participation.
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.
Table 3.4-2
Exclusion Criteria
#14  Subjects with stage 3 or higher 
renal disease.
#14  Subjects with stage 3 or higher 
chronic renalkidney disease 
(glomerular filtration rate < 60 
mL/min/1.73 m2).
Table 3.4-2
Exclusion Criteria
#20  Subjects with significant 
swallowing difficulties that would 
preclude taking oral medications in 
tablet form.
#20  Subjects with significant 
swallowing difficulties that would 
preclude taking oral medications in 
tablet form; subjects with clinically 
relevant dysphagia.
Table 3.4-2
Exclusion Criteria
#22  Subjects with weight loss of more 
than 5% in the last 7 days or more 
than 10% in the last 30 days.
#22  Subjects with weight loss of more 
than 5% in the last the 7 days prior to 
the baseline or more than 10% 
between screening and baseline 
visitsin the last 30 days.
Table 3.4-2
Exclusion Criteria
#30  Subjects with a positive drug 
screen for cocaine, marijuana, or other 
illicit drugs are excluded and may not 
be retested or rescreened.  Subjects 
with a positive urine drug screen 
resulting from use of prescription or 
over-the-counter (OTC) medications 
or products that in the investigator’s 
documented 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. 
#30  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 urine drug 
screen resulting from use of 
prescription or over-the-counter 
(OTC) medications or products that in 
the investigator’s documented 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. 
Table 3.4-2
Exclusion Criteria
#33  Females who are breast-feeding 
and/or who have a positive pregnancy 
test result prior to receiving trial drug 
in Trial 331-12-283.
#33  Females who are breast-feeding 
and/or who have a positive pregnancy 
test result prior to receiving trial drug 
in Trial 331-12-283284.
Table 3.4-2
Exclusion Criteria
#34  Subjects who are being treated 
with anticoagulants. 
#34  Subjects who have a medical 
condition that requires treatment with 
anare being treated with 
anticoagulants.
Table 3.4-2
Exclusion Criteria
Screen failures 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 drug screen for cocaine, 
marijuana, or other illicit drugs are not 
eligible to be retested or rescreened.  
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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 rescreened (or the evaluation 
may be repeated within the screening 
period) once at any time if the 
exclusion characteristic has changed.  
In the event that a screen failure is 
rescreened after the 42-day screening 
period expires, a new ICF must be 
signed, a new screening number 
assigned, and all screening procedures 
repeated.
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 retestedrescreened (or the 
evaluation may be repeated within 
the screening period) or rescreened 
once at any time if the exclusion 
characteristic has changed.  In the 
event that a screen failure is 
rescreened after the 42-day screening 
period expires, a new ICF must be 
signed, a new screening number 
assigned, and all screening procedures 
repeated.
Section 3.7
Trial Procedures
The time from enrollment of the first 
subject to the last subject’s last trial 
visit will be approximately 3.5 years, 
of which approximately 3 years are 
allotted for recruitment of subjects.  
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 
will be followed up at a clinic visit or 
via telephone contact 30 (+ 2) days 
after the last dose of the IMP.
The time from enrollment of the first 
subject to the last subject’s last trial 
visit will be approximately 4.5 years, 
of which approximately 4 years are 
allotted for recruitment of subjects.  
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 
will be followed up at a clinic visit or 
via telephone contact 30 (+ 2) days 
after the last dose of the IMP.
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Section 3.7
Schedule of Assessments
Revised Text (truncated)
Table 3.7-1
Schedule of Assessments
Assessment
Visit
OTHER PROCEDURES
Register trial visit in IVRS/IWRS
X
X
X
X
X
X
X
X
X
Randomize eligible subjects via 
IVRS/IWRS
X
IMP dispensingaa
X
X
X
X
X
X
X
IMP accountability
X
X
X
X
X
X
X
ADDITIONAL ENTRANCE/HISTORY
MRI/CT scanbb
Xbb
Abbreviations:  ACTH = adrenocorticotropic hormone; 
 anti-HCV = hepatitis C antibodies; aPTT = activated 
partial thromboplastin time 
 
 
 CGI-S = Clinical Global Impression-Severity of Illness; CMAI = Cohen-Mansfield Agitation Inventory; 
 
 CT = computed tomography; ECG = electrocardiogram; ET = early termination; FU = follow up; HbA1c = glycosylated hemoglobin; 
HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; IAP = Independent Adjudication Panel; ICF = informed consent form; IMP 
= investigational medicinal product; INR = International Normalized Ratio IVRS = interactive voice response system; IWRS = interactive web response 
system; MMSE = Mini-Mental State Examination; 
 MRI = magnetic resonance imaging;
NINCDS-ADRDA = National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders 
Association; 
; NPI-NH = Neuropsychiatric Inventory-Nursing Home rating scale; 
PT = prothrombin time; 
; 
 
 
 T4 = thyroxine; TSH = thyroid-stimulating hormone.
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d Follow-up at a clinic visit or via telephone contact for evaluation of safety will occur 30 (+ 2 days) after the last dose of IMP and applies to all 
subjects.All subjects, whether they complete the trial or are withdrawn prematurely for any reason, will be followed up for a safety evaluation at a 
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clinic visit at the residential facility 30 (+ 2) days after the last dose of the IMP.  If the subject has left the residential facility where he or she 
participated in the trial, the subject should be seen in the investigator’s clinic.  Eligible subjects who complete the 30-day safety follow-up after 
completing the 12-week treatment period will have the option to enroll into a safety study (protocol number 331-13-211) for an additional 2 months of 
follow-up.
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e Written informed consent will be obtained from the subject, if deemed capable by the investigator, and acknowledgement will be obtained from 
the subject’s legally acceptable representative, in accordance with country, state, and/or local regulations, prior to initiation of any study-required 
procedures.  Alternatively, if the subject is deemed incapable of providing consent by the investigator, written informed consent from the subject’s 
legally acceptable representative and assent from the subject will be obtained prior to the initiation of any protocol-required procedures.  Further, 
the investigator must assess capacity during the screening period and throughout the course of the study; if the subject is no longer deemed 
capable of providing informed consent, informed consent must be obtained from the legally acceptable representative and assent must be obtained 
from the subject.  The investigator must assess the capacity of the subject to provide informed consent during the screening period and throughout the 
course of the study.  Once this determination is made by the investigator, the options for obtaining informed consent from and/or on behalf of the 
subject must be followed as provided in Section 3.4.1.
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g The neurological history and Hachinski Ischemic Scale (Rosen Modification) will be completed to assess eligibility for the trial by the same 
neurologistphysician who performs the neurological examinations (refer to Section 3.7.4.3.2).  The neurologic history will include an MRI/CT scan as 
described in Section 3.7.3.8 and as scheduled in the ADDITIONAL ENTRANCE/HISTORY.
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l
Electronic diary (eDiary) information will be entered by the caregiver and/or facility staff after the ICF is signed.
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n A detailed neurological examination will be performed by a physician at screening, Week 6, Week 12/ET, and as needed during the trial for new onset 
neurological symptomsby a neurologist. 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.
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bb If 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 
 in order to 
confirm eligibility.
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Section 3.7.1.1
Screening
Trial personnel will call the IVRS or 
access the IWRS to register the visit 
(initial screening visit only).
Subject’s capacity will be evaluated 
by the investigator during the 
screening period.  If the subject is no 
longer deemed capable of providing 
informed consent, informed consent 
must be obtained from the legally 
acceptable representative and assent 
must be obtained from the subject.
An assessment of all inclusion and 
exclusion criteria will be made to 
determine the subject’s eligibility for 
the trial.
Trial personnel will call the IVRS or 
access the IWRS to register the visit 
(initial screening visit only).
Subject’s capacity will be evaluated 
by the investigator during the 
screening period.  If the subject is 
no longer deemed capable of 
providing informed consent, 
informed consent must be obtained 
from the legally acceptable 
representative and assent must be 
obtained from the subject. 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 
and/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.
Section 3.7.1.1
Screening
Psychiatric and neurological 
history will be recorded.
Medications taken within 30 days 
of screening (signing of ICF/assent)
will be recorded.

Psychiatric and neurological 
history will be recorded.
If 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 
 
 in order to confirm eligibility.

Medications taken within 30 days 
of screening (signing of ICF/assent)
will be recorded.
Section 3.7.1.1
Screening
A complete physical examination 
(including height and waist 
circumference) will be performed.
A detailed neurological examination, 
which 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, 
will be performed by a neurologist.
Vital sign measurements (body 
weight, body temperature, blood 
A complete physical examination 
(including height and waist 
circumference) will be performed.
A detailed neurological examination, 
which 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, 
will be performed by 
aneurologistphysician.
Vital sign measurements (body 
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pressure, and heart rate) will be 
recorded...
weight, body temperature, blood 
pressure, and heart rate) will be 
recorded...
Section 3.7.1.1
Screening
An adequately trained and experienced 
clinician will confirm the diagnosis of 
probable Alzheimer’s disease using 
the NINCDS-ADRDA criteria.
An adequately trained and experienced 
neurologist who performs the 
neurological examination will 
complete the Hachinski Ischemic 
Scale (Rosen Modification).
A qualified and certified rater will 
administer the CMAI and NPI-NH to 
the caregiver.
An adequately trained and experienced 
clinician will confirm the diagnosis of 
probable Alzheimer’s disease using 
the NINCDS-ADRDA criteria.
An adequately trained and experienced 
neurologistphysician who performs 
the neurological examination will 
complete the Hachinski Ischemic 
Scale (Rosen Modification).
A qualified and certified rater will 
administer the CMAI and NPI-NH to 
the caregiver.
Section 3.7.1.1
Screening
...Once the download is complete, the 
device will be placed back on the 
subject. If the screening period 
extends beyond 4 weeks, the battery 
will need to be replaced once.  Once 
the download is complete, the device 
will be placed back on the subject.
After the ICF has been signed, the 
caregiver will enter daily into the 
electronic diary (eDiary) information 
regarding the subject's behavior.
...Once the download is complete, the 
device will be placed back on the 
subject. If the screening period 
extends beyond 4 weeks, the battery 
will need to be replaced once.  Once 
the download is complete, the device 
will be placed back on the subject.
After the ICF has been signed, the 
caregiver and/or facility staff will 
enter daily into the electronic diary 
(eDiary) information regarding the 
subject's behavior.
Section 3.7.1.2
Baseline (Day 0)
Inclusion and exclusion criteria will be 
verified.
The subject’s capacity to provide 
informed consent will be evaluated by 
the investigator.  If the subject no 
longer is deemed capable of providing 
informed consent, then informed 
consent must be obtained from the 
legally acceptable representative and 
assent must be obtained from the 
subject.
A qualified and certified rater will 
administer the CMAI and NPI-NH to 
the caregiver.
Inclusion and exclusion criteria will be 
verified.
The subject’s capacity to provide 
informed consent will be evaluated 
by the investigator.  If the subject no 
longer is deemed capable of 
providing informed consent, then 
informed consent must be obtained 
from the legally acceptable 
representative and assent must be 
obtained from the subject.  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 
and/or on behalf of the subject must 
be followed as provided in 
Section 3.4.1.
A qualified and certified rater will 
administer the CMAI and NPI-NH to 
the caregiver.
Section 3.7.1.3.1
Day 3
Visits are to occur within + 2 days of 
the target visit date.  At the Day 3 visit 
the following evaluations will be 
Visits are to occur within + 2 days of 
the target visit date.  At the Day 3 visit 
the following evaluations will be 
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performed:
The subject’s capacity to provide 
informed consent will be evaluated by 
the investigator.  If the subject no 
longer is deemed capable of providing 
informed consent, then informed 
consent must be obtained from the 
legally acceptable representative and 
assent must be obtained from the 
subject.
performed:
The subject’s capacity to provide 
informed consent will be evaluated 
by the investigator.  If the subject no 
longer is deemed capable of 
providing informed consent, then 
informed consent must be obtained 
from the legally acceptable 
representative and assent must be 
obtained from the subject  The 
investigator must assess the capacity 
of the subject to provide informed 
consent throughout the study.  Once 
this determination is made by the 
investigator, the options for obtaining 
informed consent from and/or on 
behalf of the subject must be followed 
as provided in Section 3.4.1.
Section 3.7.1.3.2
Weeks 2, 4, 6, 8, and 10
The following evaluations will be 
performed at the Weeks 2, 4, 6, 8, and 
10 visits.
The subject’s capacity to provide 
informed consent will be evaluated by 
the investigator.  If the subject no 
longer is deemed capable of providing 
informed consent, then informed 
consent must be obtained from the 
legally acceptable representative and 
assent must be obtained from the 
subject.
A qualified and certified rater will 
administer the CMAI and NPI-NH to 
the caregiver.
The following evaluations will be 
performed at the Weeks 2, 4, 6, 8, and 
10 visits.
The subject’s capacity to provide 
informed consent will be evaluated 
by the investigator.  If the subject no 
longer is deemed capable of 
providing informed consent, then 
informed consent must be obtained 
from the legally acceptable 
representative and assent must be 
obtained from the subject  The 
investigator must assess the capacity 
of the subject to provide informed 
consent throughout the study.  Once 
this determination is made by the 
investigator, the options for obtaining 
informed consent from and/or on 
behalf of the subject must be followed 
as provided in Section 3.4.1.
A qualified and certified rater will 
administer the CMAI and NPI-NH to 
the caregiver.
Section 3.7.1.3.2
Weeks 2,4,6,8, and 10
The following additional evaluations 
will be performed at the designated 
visits:
A complete physical examination 
(including waist circumference) will 
be performed at Week 6 only.
A detailed neurological examination, 
which will consist of an evaluation of 
the subject’s mental status, cranial 
The following additional evaluations 
will be performed at the designated 
visits:
A complete physical examination 
(including waist circumference) will 
be performed at Week 6 only.
A detailed neurological examination, 
which will consist of an evaluation of 
the subject’s mental status, cranial 
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nerves, motor system (eg, motor 
strength, muscle tone, reflexes), 
cerebellar system (eg, coordination), 
gait and station, and sensory system, 
will be performed by a neurologist at 
Week 6 only.
nerves, motor system (eg, motor 
strength, muscle tone, reflexes), 
cerebellar system (eg, coordination), 
gait and station, and sensory system, 
will be performed by a 
neurologistphysician at Week 6 only.
Section 3.7.1.4
End of Treatment
A complete physical examination 
(including waist circumference) will 
be performed.
A detailed neurological examination, 
which 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, 
will be performed by a neurologist.
A complete physical examination 
(including waist circumference) will 
be performed.
A detailed neurological examination, 
which 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, 
will be performed by a 
neurologistphysician.
Section 3.7.1.5
Follow-up
Follow-up safety information will be 
collected at a clinic visit or via 
telephone contact 30 (+ 2) days after 
the last dose of IMP.  AEs and 
concomitant medications will be 
recorded.
Follow-up safety information will be 
collected at a clinic visit or via 
telephone contact 30 (+ 2) days after 
the last dose of IMP.  AEs and 
concomitant medications will be 
recorded.All subjects, whether they 
complete the trial or are withdrawn 
prematurely for any reason, will be 
followed up for a safety evaluation at 
a clinic visit at the residential facility 
30 (+ 2) days after the last dose of the 
IMP.  If the subject has left the 
residential facility where he or she 
participated in the trial, the subject 
should be seen in the investigator’s 
clinic or (if a clinic visit is not 
possible) assessed by telephone with 
the subject and a caregiver. All AEs 
and concomitant medications will be 
recorded.
Subjects who complete both the 12-
week double-blind treatment period 
and the 30-day safety follow-up visit 
are eligible to enroll into Trial 331-
13-211, which is a 2-month, 
observational, rollover trial to 
evaluate the safety of subjects with 
agitation associated with Alzheimer's 
disease who previously participated in 
Trial 331-12-284. For those subjects 
who plan to enroll into Trial 331-12-
211, the 30-day safety follow-up visit
for Trial 331-12-284 will occur as a 
clinic visit at the residential facility. 
If the subject has left the residential 
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facility where he or she participated 
in the trial, the 30-day safety follow-
up visit will occur as a clinic visit at 
the investigator's site.
Section 3.7.3.5
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 
examinations (see Section 3.7.4.3.2).
A sample of the Hachinski Ischemic 
Scale (Rosen Modification) is 
provided in Appendix 13.
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 neurologistphysician
who performs the neurological 
examinations (see Section 3.7.4.3.2).
A sample of the Hachinski Ischemic 
Scale (Rosen Modification) is 
provided in Appendix 13.
Section 3.7.3.7
Electronic Diary
The CST will perform ongoing 
reviews of CMAI raters by reviewing 
CMAI data relative to other sources of 
behavioral information, including 
daily behavior logs collected by 
caregivers through eDiaries (refer to 
Appendix 15).  Caregivers will record 
occurrence of the 29 behaviors listed 
in the CMAI as they occur using an 
eDiary.  All 29 behaviors will be 
listed, and the caregiver will check the 
box next to the behavior when it 
occurs; there is no free text in the 
eDiary.  Observations recorded using 
the eDiary will be transmitted 
wirelessly to the eDiary vendor.
The CST will perform ongoing 
reviews of CMAI raters by reviewing 
CMAI data relative to other sources of 
behavioral information, including 
daily behavior logs collected by 
caregivers and/or facility staff through 
eDiaries (refer to Appendix 15).  
Caregivers will record occurrence of 
the 29 behaviors listed in the CMAI as 
they occur using an eDiary.  All 29 
behaviors will be listed, and the 
caregiver will check the box next to 
the behavior when it occurs; there is 
no free text in the eDiary.  
Observations recorded using the 
eDiary will be transmitted wirelessly 
to the eDiary vendor.
Section 3.7.3.8
Magnetic Resonance 
Imaging/Computed 
Tomography Scan of 
the Brain
New section.
If 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 
 
 in order to confirm eligibility.  
Section 3.7.4.3.1
Physical Examination
The investigator (or designee) is 
responsible for performing the 
physical examination.  If the appointed 
designee is to perform the physical 
The investigator (or designee) is 
responsible for performing the 
physical examination.  If the appointed 
designee is to perform the physical 
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examination, he or she must be 
permitted by local regulations and 
his/her name must be included on the 
FDA Form 1572.  Whenever possible, 
the same individual should perform all 
physical examinations.  
examination, he or she must be 
permitted by local regulations and 
his/her name must be included on the 
Form FDA Form1572.  Whenever 
possible, the same individual should 
perform all physical examinations.  
Section 3.7.4.3.2
Neurological 
Examination
A detailed neurological examination 
will be performed at screening, Week 
6, Week 12/ET, and as needed during 
the trial for new onset neurological 
symptoms by a neurologist.  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 neurologist is responsible for 
performing the neurological 
examination and must be included on 
the FDA Form 1572.  Whenever 
possible, the same neurologist should 
perform all neurological examinations.  
Any condition present at the post-
treatment neurological examination 
that was not present at the baseline 
examination should be documented as 
an AE and followed to a satisfactory 
conclusion.
A detailed neurological examination 
will be performed by a physician at 
screening, Week 6, Week 12/ET, and 
as needed during the trial for new 
onset neurological symptoms by a 
neurologist.  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 neurologistphysician is 
responsible for performing the 
neurological examination and must be 
included on the Form FDA 
Form1572.  Whenever possible, the 
same neurologistphysician 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 newly identified, 
referral to a neurologist is 
recommended.
Section 3.7.8
Independent Data 
Monitoring Committee
The data monitoring committee 
(DMC) will monitor safety in subjects 
who participate in the trial.  The DMC 
meetings will occur every 6 months, 
but can be convened at any time at the 
discretion of the DMC chair or the 
trial medical officer.  The chair will be 
notified by the trial medical officer of 
all SAEs and will receive summaries 
of other safety data as available.
The data monitoring committee 
(DMC) will monitor safety in subjects 
who participate in the trial.  The DMC 
meetings will occur as outlined in the 
DMC Charterevery 6 months, but 
can be convened at any time at the 
discretion of the DMC chair or the 
trial medical officer.  The chair will be 
notified by the trial medical officer of 
all SAEs and will receive summaries 
of other safety data as available.
Section 3.8.3
Individual Subject
The investigator will notify the 
sponsor promptly when a subject is 
withdrawn.  Subjects withdrawn prior 
to Week 12 must complete the Week 
The investigator will notify the 
sponsor promptly when a subject is 
withdrawn.  Subjects withdrawn prior 
to Week 12 must complete the Week 
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12/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 
the residential facility.  If the subject 
has left the residential facility where 
he or she participated in the trial, the 
subject may be seen in the 
investigator’s clinic or (if a clinic visit 
is not possible) assessed by telephone 
contact with the subject and a 
caregiver.
12/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 
the residential facility.  If the subject 
has left the residential facility where 
he or she participated in the trial, the 
subject shouldmay be seen in the 
investigator’s clinic or (if a clinic visit 
is not possible) assessed by telephone 
contact with the subject and a 
caregiver.
4.1. Prohibited 
Medications
All subjects must discontinue all 
prohibited medications during the 
screening period to meet the protocol-
specified washout periods.  All 
psychotropic agents, including but not 
limited to those listed in Table 4.1-1, 
are prohibited. The required duration 
of washout for selected prohibited 
medications is provided in Table 4.1-
1. The oral benzodiazepine therapy 
permitted during trial is summarized 
in Table 4.1-3. All prohibited 
medications must be discontinued at 
least 24 hours before the first dose of 
IMP. 
All subjects must discontinue all 
prohibited medications 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, including but 
not limited to those not listed in 
Table 4.1-1, are prohibited.  The 
required duration of washout for 
selected prohibited medications is 
provided in Table 4.1-1. The oral 
benzodiazepine therapy permitted 
during trial is summarized in Table 
4.1-3. All Prohibited medications 
and must be discontinued at least 24 
hours before the first dose of IMP. 
The oral benzodiazepine therapy 
permitted during the trial is 
summarized in Table 4.1-3.
Top of Table 4.1-1
Prohibited Medications
Added text
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.
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Table 4.1-1
Prohibited Medications
#3 Prior to Randomization
Allowed provided that the dose has 
been stable for 30 days prior to 
randomization.  Antidepressant 
medications that are CYP2D6 
inhibitors are prohibited (see 
Table 4.1-2 for prohibited 
antidepressant medications).
#3 Prior to Randomization
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 
During Double-Blind Treatment 
Period
Antidepressant medications that are 
CYP2D6 or CYP3A4 inhibitors are 
prohibited. (see Table 4.1-2 for 
prohibited antidepressant 
medications).
Table 4.1-1
Prohibited Medications
Added text
#5 Anticonvulsants, 7-day washout, 
prohibited
Table 4.1-1
Prohibited Medications
#11 Medication
Medications to treat other medical 
conditions, such as hypertension
#11 Medication
Medications to treat other medical
conditions, such as hypertension, 
hypercholesterolemia, etc., and anti-
platelet agents.
Section 5.1
Definitions
Nonserious adverse events are AEs 
that do not meet the criteria for an 
SAE.
Nonserious adverse events are AEs 
that do not meet the criteria for an 
SAE.
If a subject is experiencing an 
extrapyramidal symptom, the specific 
extrapyramidal symptom must be 
indicated on the AE page of the 
eCRF.  Examples of AEs that are 
considered extrapyramidal symptoms 
include, but are not limited to: 
dyskinesia, generalized rigidity, 
hyperkinesia, bradykinesia, akinesia, 
dystonia, hypertonia, akathisia, 
tremor, flexed posture, involuntary 
muscle contractions, athetosis, and 
chorea. If a subject is experiencing 
two or more of these symptoms, 
whether or not treatment with an 
anticholinergic is required, this is 
considered as extrapyramidal 
syndrome and must be entered as 
“extrapyramidal syndrome” on the 
AE page of the eCRF instead of the 
individual symptoms.
Section 5.1
Definitions
Immediately Reportable Event 
(IRE)
Immediately Reportable Event 
(IRE)
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Any SAE
Any AE that necessitates 
discontinuation of the IMP
Potential Hy’s law cases (any increase 
of AST or ALT ≥ 3 times the ULN or 
screening value with an increase in 
total bilirubin ≥ 2 times the ULN or 
screening value)
Any SAE
Any AE that necessitates 
discontinuation of the IMP
Potential Hy’s law cases (any increase 
of AST or ALT ≥ 3 times the ULN or 
screening valuewith an increase in 
total bilirubin ≥ 2 times the ULNor 
screening value)
Section 5.4
Potential Hy’s Law 
Cases
For subjects that experience 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, 
confirmatory repeat laboratory 
samples should be drawn within 48 to 
72 hours of the initial draw.  If these 
values are confirmed, trial personnel 
will complete an IRE form with all 
values listed and also report the event 
as an AE on the eCRF.  Please note: If 
the subject was enrolled into the trial 
with non-exclusionary elevated 
transaminase levels at baseline, please 
discuss any potential drug-induced 
liver injury events with the medical 
monitor.
For subjects that experience an 
elevation in AST or ALT that is ≥ 3 
times the upper normal limit, a total 
bilirubin level should also be 
evaluated.  If the total bilirubin is 
> 2 times the upper normal limit, 
confirmatory repeat labs should be 
drawn within 48 to 72 hours of the 
initial draw. If these values are 
confirmed, study personnel will 
complete an IRE form with all 
values listed and also report the 
event as an AE on the eCRF. Please 
note: If the subject was enrolled into 
the study with nonexclusionary 
elevated transaminase levels at 
baseline, please discuss any 
potential drug-induced liver injury 
events with the medical monitor.  
For subjects that experience 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, 
confirmatory repeat laboratory 
samples should be drawn within 48 to 
72 hours of the initial draw.  If these 
values are confirmed, trial personnel 
will complete an IRE form with all 
values listed and also report the event 
as an AE on the eCRF.  Please note: 
If the subject was enrolled into the 
trial with non-exclusionary elevated 
transaminase levels at baseline, 
please discuss any potential drug-
induced liver injury events with the 
medical monitor.
Section 5.7.3
Follow-up and 
Reporting of Serious 
Adverse Events 
Occurring after Last 
Scheduled Contact
Any new SAEs reported by the subject 
to the investigator that 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 OPDC.  
This may include SAEs that are 
Any new SAEs reported by the subject 
to the investigator that 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 OPDC.  
This may include SAEs that are 
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captured on follow-up telephone 
contact or at any other time point after 
the defined trial period (ie, up to last 
scheduled contact).  The investigator 
should follow related SAEs identified 
after the last scheduled contact until 
the events are resolved or the subject 
is lost to follow-up.  The investigator 
should continue to report any 
significant follow-up information to 
OPDC up to the point the event has 
been resolved.
captured on follow-up telephone 
contact or at any other time point after 
the defined trial period (ie, up to last 
scheduled contact).  The investigator 
should follow related SAEs identified 
after the last scheduled contact until 
the events are resolved or the subject 
is lost to follow-up.  The investigator 
should continue to report any 
significant follow-up information to 
OPDC up to the point the event has 
been resolved.
Section 8.1
Packaging and Labeling
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/investigator), Subject ID (to be 
filled in by the site staff/investigator), 
subject’s initials (to be filled in by the 
site staff/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 via the IVRS or IWRS, it 
cannot be dispensed to another 
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/investigator), Subject ID (to be 
filled in by the site staff/investigator), 
subject’s initials or other unique 
identifier as appropriate (to be filled 
in by the site staff/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 via the IVRS or IWRS, it 
cannot be dispensed to another 
subject.
Section 9.2
Data Collection
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
A general reference to the procedures 
completed
The signature (or initials or other 
unique identifier as appropriate) and 
date of each clinician (or designee) 
who made an entry in the progress 
notes
Section 12
Confidentiality
Subjects will be identified only by 
initials and unique subject numbers in 
eCRFs.  Their full names may, 
however, be made known to a 
regulatory agency or other authorized 
officials if necessary.
Subjects will be identified only by 
initials and unique subject numbers in 
eCRFs.  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.
Section 14
References
16
Brexpiprazole (OPC-34712) 
Investigator's Brochure, Otsuka 
Pharmaceutical Development & 
Commercialization, Inc. Version 
16
Brexpiprazole (OPC-34712) 
Investigator's Brochure, Otsuka 
Pharmaceutical Development & 
Commercialization, Inc.Version No. 
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No. 7, 21 Mar 2012.
7, 21 Mar 2012Version No. 9, 09 Sep 
2013.
Appendix 1
Names of 
Sponsor Personnel
Compound Director
Otsuka Pharmaceutical Development 
& Commercialization, Inc.
2440 Research Boulevard
Rockville, MD 20850
Phone: 
Fax: 
Primary Clinical Contact
Otsuka Pharmaceutical Development 
& Commercialization, Inc.
2440 Research Boulevard
Rockville MD 20850
Phone: 
Mobile: 
Fax: 
E-mail: 
Compound Director
Otsuka Pharmaceutical Development 
& Commercialization, Inc.
2440 Research Boulevard
Rockville, MD 20850
Phone: 
Fax: 
Otsuka Pharmaceutical 
Development & Commercialization, 
Inc.
2440 Research Boulevard
Rockville, MD 20850
Phone: 
Fax: 
Primary Clinical Contact
Otsuka Pharmaceutical 
Development & Commercialization, 
Inc.
2440 Research Boulevard
Rockville MD 20850
Phone: 
Mobile: 
Fax: 
E-mail: 
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PPD
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Appendix 2
Institutions Concerned With the Trial
Safety Reporting
Revised Text
Country
Safety Fax Line
United States
Canada
United Kingdom
France
Germany
Spain
Ukraine
Russia
Slovakia
Czech Republic
Netherlands
Additional countries being considered for participation
Slovenia
Lithuania
Sweden
Austria
Finland
Ireland
* Please note that this is a partner CRO number, not INC.
.
.
.
Medical Monitors
North America:
INC Research, LLC
3201 Beechleaf Court, Suite 600
Raleigh, NC 27604
USA
Phone:
Cell:
Mobile:  
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Appendix 9
Clinical Global Impression (CGI)
Revised Text
Clinical Global Impression Improvement (CGI-S), as related to agitation
ADDITIONAL RISK TO THE SUBJECT:
The addition of the requirement for performing an MRI/CT scan of the brain during 
screening to confirm eligibility for enrollment in the study does pose some additional 
risk to these subjects; however, the sponsor has determined that the benefit derived 
from confirming the diagnosis of Alzheimer’s disease and from ruling out other causes 
for dementia in the subjects enrolled in this study outweighs the risks to the subjects. 
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Amendment Number:
2
Issue Date:
07 Jul 2014 
PURPOSE:
The sponsor has determined the need for a second formal amendment to the first 
amendment of the original protocol.  This amendment serves to reflect clarifications and 
additions to study procedures intended to enhance subject safety and accuracy of data.  In 
addition, administrative clarifications were made, including changes to text to enhance 
readability and consistency, and changes to correct typographical, punctuation, and 
formatting errors. These changes were minor and do not change the design or content of 
the protocol, and therefore, are not summarized in this appendix.
The purpose of amending Protocol 331-12-284, issued 16 Dec 2013, was to:

 

Allow the inclusion of non-institutionalized subjects.

Clarify the caregiver/caretaker requirements.

Modify the Neuropsychiatric Inventory-Nursing Home scale (NPI-NH) by replacing 
the Occupational Disruptiveness NPI-NH questions with the Distress questions from 
the Neuropsychiatric Inventory (NPI) for subjects in a non-institutionalized setting.

 

Increase the number of planned trial centers from 30 to 46.

Modify inclusion criteria #6 and #7.

Modify exclusion criteria #8, #13, #14, #31, #32, and #40.

Remove exclusion criterion #27 (this resulted in renumbering of exclusion criteria 
#28 through #41). 

Add another primary medical contact.

Change the medical monitor for Europe.
BACKGROUND:
These changes to Protocol 331-12-284 Amendment 1 were made to address the potential 
issue of missing data due to subjects terminating early, as well as on the basis of 
adjustments considered important to ensure the safety of the subjects enrolled and to 
facilitate appropriate study implementation and communication.
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MODIFICATIONS TO PROTOCOL:

Bold and underlined text:
Changed text

Bold and strikethrough text:
Deleted text

Bold and italicized text:
Added text
General Revisions:
All changes by section are provided below.
Sectional Revisions:
Location
Current Text
Revised Text
Title Page
Director, Global Clinical Development
Phone: 
Fax: 
E-mail: 
...
Original Protocol:  06 May 2013
Date of Amendment 1:  16 December
2013
Director, Global Clinical Development
Phone: 
Fax: 
E-mail: 
Phone:  
Fax:  
...
Original Protocol:  06 May 2013
Date of Amendment 1:  16 December
2013
Date of Amendment 2:  07 Jul 2014
Synopsis
Trial Design
... The trial population will include 
male and female subjects between 55 
and 90 years of age (inclusive), who 
are residing in a dementia unit, 
nursing home, assisted living facility, 
or any other residential care facility 
providing long-term care, with 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.  
The trial comprises a 2- to 42-day 
screening period, a 12-week 
double-blind treatment period, and a 
30-day post-treatment follow-up 
period.  Subjects may receive 
supervised day passes at the discretion 
of the investigator.  Overnight passes 
will not be allowed for this trial.
... 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 (e.g., 
nursing home, dementia unit, 
assisted living facility, or any other 
residential care facility providing 
long term care) or in a non-
institutionalized setting where the 
subject is 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 the 
subject in order to assess changes in 
the subject’s condition in a 
dementia unit, nursing home, 
assisted living facility, or any other 
residential care facility providing 
long-term care, All subjects must 
havewith a diagnosis of probable
Alzheimer’s disease according to the 
National Institute of Neurological and 
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Communicative Disorders and Stroke 
and the Alzheimer’s Disease and 
Related Disorders Association 
(NINCDS-ADRDA) criteria.  
The trial comprises a 2- to 42-day 
screening period, a 12-week 
double-blind treatment period, and a 
30-day post-treatment follow-up 
period.  In addition, for all subjects 
who terminate early from the study, 
all attempts will be made to collect 
mortality data by telephone contact 
with the subject’s caregiver at Week 
16.  Subjects may receive supervised 
day passes at the discretion of the 
investigator.  Overnight passes will 
not be allowed for this trial.
Synopsis
Trial Design
12-week, Double-blind 
Treatment Period
The subjects’ condition will be 
evaluated routinely, including vital 
signs assessments, as per the local 
guidelines of the facility.  Subjects 
will be evaluated at Baseline, Day 3, 
and at Weeks 2, 4, 6, 8, 10, and 12 
during the double-blind treatment 
period.  Beginning at Week 3, the 
subject’s identified caregiver will be 
contacted by telephone between the 
scheduled visits.  Trial-related efficacy 
and safety assessments will be 
performed as outlined in the Schedule 
of Assessments.
The subjects’ condition will be 
evaluated routinely, including vital 
signs assessments, as required per the 
local guidelines of the 
institutionalized setting or 
according to the discretion of the 
principal investigator the facility.  
Subjects will be evaluated at Baseline, 
Day 3, and at Weeks 2, 4, 6, 8, 10, and 
12 during the double-blind treatment 
period.  All study visits will take place 
as a clinic visit at either the 
investigator’s site (for non-
institutionalized subjects) or 
residential facility (for 
institutionalized subjects).  Beginning 
at Week 3, the subject’s identified 
caregiver will be contacted by 
telephone between the scheduled 
visits.  In addition, the subject’s 
identified caregiver will be contacted 
by telephone every odd numbered 
week after Week 2 (i.e., Weeks 3, 5, 7, 
9, 11) to assess compliance with IMP, 
confirm any changes to concomitant 
medications, and assure the subject’s 
well-being.  Trial-related efficacy and 
safety assessments will be performed 
as outlined in the Schedule of 
Assessments.  
Synopsis
Trial Design
Follow-up Period
All subjects, whether they complete 
the trial or are withdrawn prematurely 
for any reason, will be followed up for 
a safety evaluation at a clinic visit at 
the residential facility 30 (+ 2) days 
All subjects, whether they complete 
the trial or are withdrawn prematurely 
for any reason, will be followed up for 
a safety evaluation 30 (+ 2) days after 
the last dose of IMP during at a clinic 
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after the last dose of the IMP.  If the 
subject has left the residential facility 
where he or she participated in the 
trial, the subject should be seen in the 
investigator’s clinic or (if a clinic visit 
is not possible) assessed by telephone 
contact with the subject and a 
caregiver.  
Subjects who complete both the 12-
week double-blind treatment period 
and the 30-day safety follow-up visit 
are eligible to enroll into Trial 331-13-
211, which is a 2-month, 
observational, rollover trial to evaluate 
the safety of subjects with agitation 
associated with Alzheimer's disease 
who previously participated in Trial 
331-12-284.  For those subjects who 
plan to enroll into Trial 331-12-211, 
the 30-day safety follow-up visit for 
Trial 331-12-284 will occur as a clinic 
visit at the residential facility.  If the 
subject has left the residential facility 
where he or she participated in the 
trial, the 30-day safety follow-up visit 
will occur as a clinic visit at the 
investigator's site.
visit at either the investigator’s site or
residential facility, if institutionalized
30 (+ 2) days after the last dose of 
the IMP.  If the institutionalized
subject has left the residential facility 
where he or she participated in the 
trial, the subject should be seen atin
the investigator’s site.clinic or (if 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 study, all 
attempts will be made to collect 
mortality data by telephone contact 
with the subject’s caregiver at Week 
16.
Subjects who complete both the 12-
week double-blind treatment period 
and the 30-day safety follow-up visit 
are eligible to enroll into Trial 331-13-
211, which is a 2-month, 
observational, rollover trial to evaluate 
the safety of subjects with agitation 
associated with Alzheimer's disease 
who previously participated in Trial 
331-12-284.  For those subjects who 
plan to enroll into Trial 331-132-211, 
the 30-day safety follow-up visit for 
Trial 331-12-284 will occur as a clinic 
visit at either the investigator’s site or
residential facility, if institutionalized.  
If the institutionalized subject has left 
the residential facility where he or she 
participated in the trial, the 30-day 
safety follow-up visit will occur as a 
clinic visit at the investigator's site.
Synopsis
Subject Population
The subject population will include 
male and female subjects between 55 
and 90 years of age (inclusive), who 
are residing in a dementia unit, 
nursing home, assisted living facility, 
or any other residential care facility 
providing long-term care, with a 
diagnosis of probable Alzheimer’s 
disease according to the NINCDS-
ADRDA criteria. Subjects must have 
a previous magnetic resonance 
imaging (MRI) or computed 
tomography (CT) scan of the brain, 
which was performed after the onset 
of symptoms of dementia, with 
The subject population will include 
male and female subjects between 55 
and 90 years of age (inclusive), who 
are living in either an 
institutionalized setting (e.g., 
nursing home, dementia unit, 
assisted living facility, or any other 
residential care facility providing 
long term care) or in a non-
institutionalized setting where the 
subject is 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 
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findings consistent with a diagnosis of 
Alzheimer’s disease. Additionally, at 
both the screening and baseline visits, 
subjects must have a Mini-Mental 
State Examination (MMSE) score of 
5 to 22, inclusive, and a total score 
(frequency x severity) of ≥4 on the 
agitation/aggression item of the 
Neuropsychiatric Inventory—Nursing 
Home  (NPI-NH). ...
Subjects must have been residing at 
their current facility for at least 1 
month before screening and be 
expected to remain at the same facility 
for the duration of the trial.  Subjects 
may receive supervised day passes at 
the discretion of the investigator.  
Overnight passes will not be allowed 
for this trial.
A caregiver who is usually assigned to 
care for the subject on a regular basis, 
has sufficient contact to describe the 
subject’s symptoms, and has direct 
observation of the subject’s behavior 
must be identified during the 
screening period for participation in 
the interview for the CMAI, NPI-NH, 
and other applicable trial assessments.  
The identified caregiver will be a 
member of the residential facility or 
other individual (e.g., 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.
day for 4 days per week with the 
subject in order to assess changes in 
the subject’s condition in a 
dementia unit, nursing home, 
assisted living facility, or any other 
residential care facility providing 
long-term care, All subjects must 
havewith a diagnosis of probable 
Alzheimer’s disease according to the 
NINCDS-ADRDA criteria. Subjects 
must have a previous magnetic 
resonance imaging (MRI) or computed 
tomography (CT) scan of the brain, 
which was performed after the onset 
of symptoms of dementia, with 
findings consistent with a diagnosis of 
Alzheimer’s disease.  If a previous 
MRI or CT scan of the brain 
performed after the onset of the 
symptoms of dementia is not 
available, then an MRI/CT scan 
should be performed during 
screening. Additionally, at both the 
screening and baseline visits, subjects 
must have a Mini-Mental State 
Examination (MMSE) score of 5 to 
22, inclusive, and a total score 
(frequency x severity) of ≥4 on the 
agitation/aggression item of the 
Neuropsychiatric Inventory—Nursing 
Home  (NPI-NH).  The NPI-NH will 
be used for both institutionalized and 
non-institutionalized subjects; 
however, the Occupational 
Disruptiveness questions will not be 
answered for non-institutionalized 
subjects.  Instead, the Distress 
questions from the Neuropsychiatric 
Inventory (NPI) will replace the 
Occupational Disruptiveness 
questions for non-institutionalized 
subjects.  This neuropsychiatric 
assessment for non-institutionalized 
subjects based on the NPI/NPI-NH 
will hereafter be referred to as 
"NPI/NPI-NH”....
Subjects must have been residing at 
their current location facility for at 
least 14 days1 month before 
screening and be expected to remain at 
the same location facility for the 
duration of the trial.  Subjects from a 
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non-institutionalized setting who at 
any point during the double-blind 
treatment phase require permanent 
placement to a nursing home or 
assisted living facility will be 
withdrawn from the trial.  Subjects 
who at any point during the double-
blind treatment phase transfer from 
an institutionalized setting to a 
non-institutionalized setting will also 
be withdrawn from the trial.  In case 
of a change in the 
non-institutionalized address or 
institutionalized address, the 
investigator should consult with the 
medical monitor on a case-by-case 
basis.  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 INC Research 
medical monitor.  Subjects in an 
institutionalized setting subjects
may receive supervised day passes at 
the discretion of the investigator;
however, overnight passes will not be 
allowed for this trial.
A caregiver who is usually assigned 
to care for the subject on a regular 
basis, has sufficient contact to 
describe the subject’s symptoms, 
and has direct observation of the 
subject’s behavior must be 
identified during the screening 
period for participation in the 
interview for the CMAI, NPI-NH, 
and other applicable trial 
assessments.  Subjects in a non-
institutionalized setting may have a 
caretaker as well as a caregiver. The 
subject’s caretaker is the person who 
lives with and cares for the subject on 
a regular basis. The caretaker may 
be supported in providing care to the 
subject by a professional(s), friend(s), 
or family member(s).  Tthe subject’s 
caregiver is the person 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, NPI-NH, 
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NPI/NPI-NH, and other applicable 
trial assessments.  For subjects in an 
institutionalized setting, there is only 
one role defined and that is the role 
of caregiver.  The identified caregiver 
can be a staff member of the 
institutionalized setting will be a 
member of the residential facility or 
another individual (e.g., family 
member, family friend, hired 
professional caregiver) who meets the 
caregiver requirements 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, NPI-
NH, NPI/NPI-NH, and other 
applicable trial assessments.  The 
recommended minimum level of 
contact between the caregiver and the 
subject is 2 hours per day for 4 days 
per week in both the institutionalized 
and non-institutionalized settings.  
Synopsis
Trial Sites
It is planned that approximately 330 
subjects will be screened at 
approximately 30 trial centers 
worldwide so that 230 subjects will be 
randomized to treatment.
It is planned that approximately 330 
subjects will be screened at 
approximately 4630 trial centers 
worldwide so that 230 subjects will be 
randomized to treatment.
Synopsis
Investigational 
Medicinal Product, 
Dose, Formulation, 
Mode of Administration
All doses of brexpiprazole and 
matching placebo will be taken orally 
once daily, preferably in the morning, 
and can be administered without 
regard to meals.  Brexpiprazole should 
be taken at the same time each day, 
particularly prior to visits with 
pharmacokinetic sampling.
All doses of brexpiprazole and 
matching placebo will be taken orally 
once daily, preferably in the morning, 
and can be administered without 
regard to meals.  Brexpiprazole should 
be taken at approximately the same 
time each day, particularly prior to 
visits with pharmacokinetic sampling. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Synopsis
Criteria for Evaluation
Safety Variables
Pharmacokinetic samples for 
determination of brexpiprazole and its 
major metabolite, DM-3411, will be 
collected at the baseline visit and at 
the Week 8 and Week 12/ET trial 
visits, at the same time as the sample 
collection for the clinical laboratory 
tests.  For those subjects who have a 
separate signed ICF for the optional 
pharmacogenomic testing for 
determination of CYP2D6 metabolism 
status and other drug metabolizing 
enzymes and transporters, as 
necessary, a pharmacogenomic sample 
will be collected at the baseline visit.
Pharmacokinetic samples for 
determination of brexpiprazole and its 
major metabolite, DM-3411, will be 
collected at the baseline visit and at 
the Week 8 and Week 12/ET trial 
visits, at the same time as the sample 
collection for the clinical laboratory 
tests.  For those subjects who have a 
separate signed ICF for the optional 
pharmacogenomic testing for 
determination of cytochrome P450 
(CYP) 2D6 metabolism status and 
other drug metabolizing enzymes and 
transporters, as necessary, as well as 
banking for potential future analysis,
a pharmacogenomic sample will be 
collected at the baseline visit.
Synopsis
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 
(SD).  Tabulations of frequency 
distributions will be provided for 
categorical variables.  The primary 
endpoint will be analyzed using a 
mixed-effect model repeated measure 
(MMRM) methodology.  The model 
will include fixed class effect terms 
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 
(SD).  Tabulations of frequency 
distributions will be provided for 
categorical variables.  The primary 
endpoint will be analyzed using a 
mixed-effect model repeated measure 
(MMRM) methodology.  The model 
will include fixed class effect terms 
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for treatment, trial center, visit week, 
and an interaction term of treatment by 
visit week and include the interaction 
term of baseline by visit week as a 
covariate.  The primary efficacy 
outcome measure is the mean change 
from baseline to the endpoint in the 
CMAI total score. 
 
... The resulting sample size is 103 
subjects/arm.  To account for a portion 
of subjects who discontinue 
prematurely and whose data may 
potentially dilute the treatment effect, 
approximately an additional 10% of 
subjects was added to the sample size, 
resulting in a sample size of 115 
subjects/arm, which means the total 
sample size is 230 subjects.  
for treatment, trial center, visit week, 
and an interaction term of treatment by 
visit week and include the interaction 
term of baseline by visit week as a 
covariate.  The primary efficacy 
outcome measure is the mean change 
from baseline (Day 0 Visit) to the 
endpoint end of the double-blind 
treatment period (Week 12 visit) in 
the CMAI total score.  
 
 
 
... The resulting sample size is 103 
subjects/arm.  After allowance of 10% 
non-evaluable subjects, To account 
for a portion of subjects who 
discontinue prematurely and whose 
data may potentially dilute the 
treatment effect, approximately an 
additional 10% of subjects was 
added to the sample size, it resultsing
in a sample size of 115 subjects/arm, 
which means the total sample size is 
230 subjects.  
Synopsis
Trial Duration
The time from enrollment of the first 
subject to the last subject’s last trial 
visit will be approximately 4.5 years, 
of which approximately 4 years are 
allotted for recruitment of subjects.   
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 
will be followed up at a clinic visit or 
via telephone contact 30 (+ 2) days 
after the last dose of the IMP.  
The time from enrollment of the first 
subject to the last subject’s last trial 
visit will be approximately 4 3.5 years, 
of which approximately 4 3 years are 
allotted for recruitment of subjects.   
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 
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 study, all 
attempts will be made to collect 
mortality data by telephone contact 
with the subject’s caregiver at Week 
16.  
List of Abbreviations 
and Definition of Terms
--
--
--
ACR  Albumin-to-creatinine ratio
NPI  Neuropsychiatric Inventory 
 
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Section 1.3
Known and Potential 
Risks and Benefits
As of 20 Sep 2012, brexpiprazole has 
been studied in 33 clinical trials (25 
completed and 8 ongoing) conducted 
under US INDs for 3 indications 
(schizophrenia or schizoaffective 
disorder, major depressive disorder 
[MDD], and adult attention-
deficit/hyperactivity disorder 
[ADHD]) and 5 clinical trials (3 
completed and 2 ongoing) conducted 
outside of the US.
Brexpiprazole has been well tolerated 
by healthy volunteers at single doses 
up to 6 mg and at multiple doses up to 
2 mg/day.  In trials, brexpiprazole has 
been well tolerated at multiple doses 
up to 12 mg/day in subjects with 
schizophrenia or schizoaffective 
disorder, up to 4 mg/day in subjects 
with MDD who received concomitant 
ADT, and up to 4 mg/day in adults 
with ADHD who received 
concomitant stimulant therapy.  
Recently completed phase 2 clinical 
trials evaluated multiple oral doses up 
to 6 mg/day in subjects with 
schizophrenia; up to 2 mg/day when 
coadministered with marketed ADT in 
subjects with MDD; and up to 
2 mg/day when coadministered with 
marketed stimulant therapy in subjects 
with ADHD.
In the 25 completed brexpiprazole 
trials conducted under US 
Investigational New Drug Application 
(IND) (19 phase 1 trials, 1 phase 1b 
trial, and 5 phase 2 trials), 1204 of 
1773 (67.9%) subjects who received 
brexpiprazole either alone or 
coadministered with another marketed 
medication reported at least 
1 treatment-emergent adverse event 
(TEAE) compared with 325 of 520 
(62.5%) subjects who received 
placebo either alone or coadministered 
with another marketed medication.  
The most frequently reported TEAEs 
(incidence ≥ 5% of the total 
brexpiprazole group and more than 
total placebo group) in all subjects 
who received brexpiprazole were 
As of 20 Sep 2012, brexpiprazole 
has been studied in 33 clinical trials 
(25 completed and 8 ongoing) 
conducted under US INDs for 3 
indications (schizophrenia or 
schizoaffective disorder, major 
depressive disorder [MDD], and 
adult attention-deficit/hyperactivity 
disorder [ADHD]) and 5 clinical 
trials (3 completed and 2 ongoing) 
conducted outside of the US.
Brexpiprazole has been well 
tolerated by healthy volunteers at 
single doses up to 6 mg and at 
multiple doses up to 2 mg/day.  In 
trials, brexpiprazole has been well 
tolerated at multiple doses up to 
12 mg/day in subjects with 
schizophrenia or schizoaffective 
disorder, up to 4 mg/day in subjects 
with MDD who received 
concomitant ADT, and up to 
4 mg/day in adults with ADHD who 
received concomitant stimulant 
therapy.  Recently completed phase 
2 clinical trials evaluated multiple 
oral doses up to 6 mg/day in 
subjects with schizophrenia; up to 
2 mg/day when coadministered with 
marketed ADT in subjects with 
MDD; and up to 2 mg/day when 
coadministered with marketed 
stimulant therapy in subjects with 
ADHD.
In the 25 completed brexpiprazole 
trials conducted under US 
Investigational New Drug 
Application (IND) (19 phase 1 trials, 
1 phase 1b trial, and 5 phase 2 
trials), 1204 of 1773 (67.9%) 
subjects who received brexpiprazole 
either alone or coadministered with 
another marketed medication 
reported at least 1 treatment-
emergent adverse event (TEAE) 
compared with 325 of 520 (62.5%) 
subjects who received placebo either 
alone or coadministered with 
another marketed medication.  The 
most frequently reported TEAEs
(incidence ≥ 5% of the total 
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dizziness (8.7%), insomnia (7.0%), 
nausea (6.2%), and akathisia (5.8%).  
In the total placebo group, headache 
(9.8%) was the most frequently 
reported TEAE (incidence ≥ 5% of 
subjects).  In the total brexpiprazole 
group, 67 of 1773 (3.8%) subjects 
discontinued the study due to 1 or 
more TEAE, compared with 12 of 520 
(2.3%) of subjects in the total placebo 
group.
One death has been reported in the 25 
trials completed under the US INDs as 
of the 20 Sep 2012 cutoff date.  This 
death occurred 12 days after the 
subject received the last dose of 
brexpiprazole in the phase 2, double-
blind schizophrenia trial (Trial 331-
07-203), and the death was not 
considered by the investigator to be 
not related to the IMP.  One additional
death was reported in the ongoing, 
phase 2, open-label MDD trial 
(Trial 331-08-212).  The subject was 
reported to have died from progressive 
metastatic disease approximately 2 
months after the initial onset of the 
event (81 days after the last dose of 
the IMP).  The event was assessed as 
not related to the IMP by the 
investigator.
Serious TEAEs have been reported in 
20 of 1773 (1.1%) subjects who 
received brexpiprazole (either alone or 
coadministered with another 
medication) and 9 of 520 (1.7%) 
subjects who received placebo (either 
alone or coadministered with another 
medication) in combined 
brexpiprazole trials completed under 
the US INDs as of the 20 Sep 2012 
cutoff date.  Treatment with 
brexpiprazole does not appear to 
promote suicidal behavior in subjects 
with MDD or schizophrenia.
Brexpiprazole did not result in any 
consistent, clinically relevant changes 
in laboratory values, vital signs (blood 
pressure or heart rate), or ECG 
parameters in the completed phase 1 
brexpiprazole group and more than 
total placebo group) in all subjects 
who received brexpiprazole were 
dizziness (8.7%), insomnia (7.0%), 
nausea (6.2%), and akathisia 
(5.8%).  In the total placebo group, 
headache (9.8%) was the most 
frequently reported TEAE 
(incidence ≥ 5% of subjects).  In the 
total brexpiprazole group, 67 of 
1773 (3.8%) subjects discontinued 
the study due to 1 or more TEAE, 
compared with 12 of 520 (2.3%) of 
subjects in the total placebo group.
One death has been reported in the 
25 trials completed under the US 
INDs as of the 20 Sep 2012 cutoff 
date.  This death occurred 12 days 
after the subject received the last 
dose of brexpiprazole in the phase 2, 
double-blind schizophrenia trial 
(Trial 331-07-203), and the death 
was not considered by the 
investigator to be not related to the 
IMP.  One additional death was 
reported in the ongoing, phase 2, 
open-label MDD trial (Trial 331-08-
212).  The subject was reported to 
have died from progressive 
metastatic disease approximately 2 
months after the initial onset of the 
event (81 days after the last dose of 
the IMP).  The event was assessed as 
not related to the IMP by the 
investigator.
Serious TEAEs have been reported 
in 20 of 1773 (1.1%) subjects who 
received brexpiprazole (either alone 
or coadministered with another 
medication) and 9 of 520 (1.7%) 
subjects who received placebo 
(either alone or coadministered with 
another medication) in combined 
brexpiprazole trials completed 
under the US INDs as of the 20 Sep 
2012 cutoff date.  Treatment with 
brexpiprazole does not appear to 
promote suicidal behavior in 
subjects with MDD or 
schizophrenia.
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and 2 clinical trials in subjects with
MDD or schizophrenia.  Statistically 
significant increases in weight were 
observed with brexpiprazole relative 
to placebo in both sample populations.  
Brexpiprazole exhibited a favorable 
profile with respect to movement 
disorders in subjects with MDD at 
doses up to 3 mg/day (Trial 331-09-
221) and in subjects with 
schizophrenia at doses up to 
12 mg/day (Trial 331-08-205).  In the 
dose-ranging trial that enrolled 
subjects who were experiencing an 
acute exacerbation of schizophrenia 
(Trial 331-07-203), an increase in the 
incidence of EPS was observed at the 
highest dose (i.e., brexpiprazole 
5.0 1.0 mg/day).
Refer to the current Investigator’s 
Brochure for a summary of available 
nonclinical and clinical safety data.16
Based on the Investigator’s 
Brochure,16 combined data from the 
completed phase 1 clinical trials 
indicate that brexpiprazole is safe 
and well tolerated in healthy subjects 
at single oral doses of 0.2 to 6 mg and 
at multiple oral doses up to 2 mg/day.  
Data from the completed 
multiple-dose clinical trials indicate 
brexpiprazole is well tolerated at 
multiple oral doses up to 12 mg/day 
in subjects with schizophrenia or 
schizoaffective disorder; up to 
4 mg/day when coadministered with 
marketed ADT in subjects with 
MDD; and up to 4 mg/day when 
coadministered with marketed 
stimulant therapy in subjects with 
ADHD. 
Based on data from the 18 completed 
phase 1 clinical trials in healthy 
subjects or special populations 
(including healthy subjects from 2 
phase 1 trials conducted in special 
populations) (15 in the US, 2 in 
Japan, and 1 in Korea), the most 
frequently reported TEAEs 
(incidence ≥ 5% or more of all 
healthy subjects who received 
brexpiprazole and more than placebo, 
administered either alone or with 
another marketed drug) were:

Healthy subjects (N = 15 trials 
conducted in the US):  dizziness, 
headache, postural dizziness, 
nausea, somnolence, 
constipation, and diarrhoea

Healthy subjects (N = 3 trials 
conducted in Japan and Korea):  
nausea, orthostatic hypotension, 
somnolence, and dizziness
By indication, the most frequently 
reported TEAEs (incidence ≥ 5% or 
more of all subjects who received 
brexpiprazole and more than placebo, 
administered either alone or with 
another marketed therapy or drug 
(i.e., ADT, stimulant therapy, or 
antibiotic) in completed phase 1, 
phase 1b, and/or phase 2 double-
blind patient trials (excluding 
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subjects enrolled in phase 2 open-
label extension trials) conducted 
under US Investigation New Drug 
Applications (INDs) were:

Schizophrenia or schizoaffective 
disorder (N = 4 trials):  
headache, anxiety, akathisia, 
nausea, increased weight, and 
dizziness

MDD (N = 3 trials):  akathisia, 
increased weight, insomnia, 
upper respiratory tract infection, 
and nasopharyngitis

ADHD (N = 2 trials):  insomnia
In the single completed phase 1 trial 
in subjects with schizophrenia 
conducted in Japan, TEAEs reported 
in 3 or more subjects who received 
brexpiprazole (of 21 total subjects) 
were:

Schizophrenia (N = 1 trial): 
increased serum prolactin and 
increased serum creatine 
phosphokinase
Brexpiprazole did not result in any 
consistent, clinically relevant changes 
in laboratory values, vital signs (blood 
pressure or heart rate), or ECG 
parameters in the completed phase 1 
and 2 clinical trials in subjects with 
MDD or schizophrenia.  Statistically 
significant increases in weight were 
observed with brexpiprazole relative 
to placebo in both sample populations.  
Brexpiprazole exhibited a favorable 
profile with respect to movement 
disorders in subjects with MDD at 
doses up to 3 mg/day (Trial 331-09-
221) and in subjects with 
schizophrenia at doses up to 
12 mg/day (Trial 331-08-205).  In the 
dose-ranging trial that enrolled 
subjects who were experiencing an 
acute exacerbation of schizophrenia 
(Trial 331-07-203), an increase in the 
incidence of EPS was observed at the 
highest dose (i.e., brexpiprazole 
5.0 1.0 mg/day).
Two deaths have been reported in the 
30 completed clinical trials.  One 
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death was reported in the completed 
phase 2 double-blind trial in adult 
subjects with acute schizophrenia 
(Trial 331-07-203).  The second death 
was reported in the completed 
phase 2 open-label MDD trial (Trial 
331-08-212).  None of these subjects 
were taking IMP at the time of death 
and none of these fatal events were 
considered by the investigator to be 
related to IMP.  Additionally, 4 
deaths have been reported in 2 
ongoing phase 3 open-label trials of 
brexpiprazole.  One death was 
reported in an ongoing schizophrenia 
trial (331-10-237) and 3 deaths were 
reported in an ongoing MDD trial 
(331-10-238).  One of the deaths 
(completed suicide in Trial 331-10-
238) was considered by the 
investigator to be possibly related to 
IMP.
Serious TEAEs have been reported 
for 64 subjects who received 
brexpiprazole in the 30 completed 
trials.  In ongoing trials of 
brexpiprazole, 120 subjects receiving 
brexpiprazole had reported serious 
TEAEs. 
Refer to the current Investigator’s 
Brochure for a summary of available 
nonclinical and clinical safety data.16
Section 2.1
Trial Rationale
In light of the Food and Drug 
Administration (FDA) boxed warning 
of increased mortality with the use of 
antipsychotics in elderly subjects with 
dementia-related psychosis and similar 
caution advised by other regulatory 
authorities, the clinical trial will be 
conducted in an environment that 
allows for close safety monitoring, 
specifically in subjects who are 
residing in a dementia unit, nursing 
home, assisted living facility, or any 
other residential care facility providing 
long-term care.  The settings will 
provide the type of medically 
supervised environment needed to 
closely monitor trial participants, 
particularly for events related to 
cardiac and pulmonary disease that 
In light of the Food and Drug 
Administration (FDA) boxed warning 
of increased mortality with the use of 
antipsychotics in elderly subjects with 
dementia-related psychosis and similar 
caution advised by other regulatory 
authorities, the clinical trial will be 
conducted in an environment that 
allows for close safety monitoring, 
specifically in subjects who are living 
in either an institutionalized setting 
(e.g., nursing home, dementia unit, 
assisted living facility, or any other 
residential care facility providing 
long term care) or in a non-
institutionalized setting where the 
subject is not living alone and has a 
caregiver who can spend a 
minimum of 2 hours per day for 4 
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may contribute to the risk of increased 
death.  
days per week with the subject in 
order to assess changes in the 
subject’s condition in a dementia 
unit, nursing home, assisted living 
facility, or any other residential care 
facility providing long-term care.  
The settings will provide the type of 
medically supervised environment 
needed to closely monitor trial 
participants, particularly for events 
related to cardiac and pulmonary 
disease that may contribute to the 
risk of increased death.    
Section 3.1
Type/Design of Trial
... The trial population will include 
male and female subjects between 55 
and 90 years of age (inclusive), who 
are residing in a dementia unit, 
nursing home, assisted living facility, 
or any other residential care facility 
providing long-term care, with 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.
The trial comprises a 2- to 42-day 
screening period, a 12-week 
double-blind treatment period, and a 
30-day post-treatment follow-up 
period.  Subjects may receive 
supervised day passes at the discretion 
of the investigator.  Overnight passes 
will not be allowed for this trial.
... 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 (e.g., 
nursing home, dementia unit, 
assisted living facility, or any other 
residential care facility providing 
long term care) or in a non-
institutionalized setting where the 
subject is 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 the 
subject in order to assess changes in 
the subject’s condition in a 
dementia unit, nursing home,
assisted living facility, or any other 
residential care facility providing 
long-term care, All subjects must 
havewith 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.
The trial comprises a 2- to 42-day 
screening period, a 12-week 
double-blind treatment period, and a 
30-day post-treatment follow-up 
period.  In addition, for all subjects
who terminate early from the study, 
all attempts will be made to collect 
mortality data by telephone contact 
with the subject’s caregiver at Week 
16. Subjects may receive supervised 
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day passes at the discretion of the 
investigator.  Overnight passes will 
not be allowed for this trial.
Section 3.1
Type/Design of Trial
Screening Period
The patient’s daily behavior will be 
logged into an eDiary by the caregiver 
and/or facility staff.
The patient’s subject’s daily 
behavior will be logged into an eDiary 
by the caregiver and/or facility staff.
Section 3.1
Type/Design of Trial
12-week, Double-blind 
Treatment Period
The subjects’ condition will be 
evaluated routinely, including vital 
signs assessments, as per the local 
guidelines of the facility.  Subjects 
will be evaluated at Baseline and at 
Day 3 and Weeks 2, 4, 6, 8, 10, and 12 
during the double-blind treatment 
period.  Beginning at Week 3, the 
subject’s identified caregiver at the 
residential facility or other individual 
(e.g., family member, family friend, 
hired professional caregiver) will be 
contacted by telephone between the 
scheduled visits.  Trial-related 
efficacy and safety assessments will 
be performed as outlined in the 
Schedule of Assessments (Table 3.7-
1).
The subjects’ condition will be 
evaluated routinely, including vital 
signs assessments, as required per the 
local guidelines of the 
institutionalized setting or according 
to the discretion of the principal 
investigator the facility.  Subjects 
will be evaluated at Baseline, and at
Day 3, and at Weeks 2, 4, 6, 8, 10, and 
12 during the double-blind treatment 
period.  All study visits will take place 
as a clinic visit at either the 
investigator’s site (for non-
institutionalized subjects) or 
residential facility (for 
institutionalized subjects).  Beginning 
at Week 3, the subject’s identified 
caregiver at the residential facility 
or other individual (e.g., family 
member, family friend, hired 
professional caregiver) will be 
contacted by telephone between the 
scheduled visits.  In addition, the 
subject’s identified caregiver will be 
contacted by telephone every odd 
numbered week after Week 2 (i.e., 
Weeks 3, 5, 7, 9, 11) to assess 
compliance with IMP, confirm any 
changes to concomitant medications, 
and assure the subject’s well-being.  
Trial-related efficacy and safety 
assessments will be performed as 
outlined in the Schedule of 
Assessments (Table 3.7-1).
Section 3.1
Type/Design of Trial
Follow-up Period
All subjects, whether they complete 
the trial or are withdrawn prematurely 
for any reason, will be followed up for 
a safety evaluation at a clinic visit at 
the residential facility 30 (+ 2) days 
after the last dose of the IMP.  If the 
subject has left the residential facility 
where he or she participated in the 
trial, the subject should be seen in the 
investigator’s clinic or (if a clinic visit 
is not possible) assessed by telephone 
contact with the subject and a 
caregiver.
All subjects, whether they complete 
the trial or are withdrawn prematurely 
for any reason, will be followed up for 
a safety evaluation 30 (+ 2) days after 
the last dose of IMP during at a clinic 
visit at either the investigator’s site or
residential facility, if institutionalized
30 (+ 2) days after the last dose of 
the IMP.  If the institutionalized
subject has left the residential facility 
where he or she participated in the 
trial, the subject should be seen atin
the investigator’s site.clinic or (if If a 
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Subjects who complete both the 12-
week double-blind treatment period 
and the 30-day safety follow-up visit 
are eligible to enroll into Trial 331-13-
211, which is a 2-month, 
observational, rollover trial to evaluate 
the safety of subjects with agitation 
associated with Alzheimer's disease 
who previously participated in Trial 
331-12-284.  For those subjects who 
plan to enroll into Trial 331-12-211, 
the 30-day safety follow-up visit for 
Trial 331-12-284 will occur as a clinic 
visit at the residential facility.  If the 
subject has left the residential facility 
where he or she participated in the 
trial, the 30-day safety follow-up visit 
will occur as a clinic visit at the 
investigator's site.  
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 study, all 
attempts will be made to collect 
mortality data by telephone contact 
with the subject’s caregiver at Week 
16.
Subjects who complete both the 12-
week double-blind treatment period 
and the 30-day safety follow-up visit 
are eligible to enroll into Trial 331-13-
211, which is a 2-month, 
observational, rollover trial to evaluate 
the safety of subjects with agitation 
associated with Alzheimer's disease 
who previously participated in Trial 
331-12-284.  For those subjects who 
plan to enroll into Trial 331-132-211, 
the 30-day safety follow-up visit for 
Trial 331-12-284 will occur as a clinic 
visit either at the investigator’s site or
residential facility.  If the 
institutionalized subject has left the 
residential facility where he or she 
participated in the trial, the 30-day 
safety follow-up visit will occur as a 
clinic visit at the investigator's site.
Figure 3.1-1
Trial Design Schematic
--
 
 
 
 
 
 
 
Section 3.2
Treatments
Neither the investigator nor the subject 
will be aware of the treatment 
assignment.  All doses of 
brexpiprazole and matching placebo 
should be taken orally once daily, 
preferably in the morning, and can be 
administered without regard to meals.  
Brexpiprazole should be taken at the 
same time each day, particularly prior 
to visits with pharmacokinetic 
sampling.
Neither the investigator nor the subject 
will be aware of the treatment 
assignment.  All doses of 
brexpiprazole and matching placebo 
should be taken orally once daily, 
preferably in the morning, and can be 
administered without regard to meals.  
Brexpiprazole should be taken at 
approximately the same time each 
day, particularly prior to visits with 
pharmacokinetic sampling.
Section 3.3
The subject population will include 
The subject population will include 
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Trial Population
male and female subjects between 55 
and 90 years of age (inclusive), who 
are residing in a dementia unit, 
nursing home, assisted living facility, 
or any other residential care facility 
providing long-term care, with a 
diagnosis of probable Alzheimer’s 
disease according to the NINCDS-
ADRDA criteria.  Subjects must have 
a previous magnetic resonance 
imaging (MRI) or computed 
tomography (CT) scan of the brain, 
which was performed after the onset 
of symptoms of dementia, with 
findings consistent with a diagnosis of 
Alzheimer’s disease.  Additionally, at 
both the screening and baseline visits, 
subjects must have a Mini-Mental 
State Examination (MMSE) score of 
5 to 22, inclusive, and a total score 
(frequency x severity) of ≥4 on the 
agitation/aggression item of the 
NPI-NH. ... 
Subjects must have been residing at 
their current facility for at least 1 
month before screening and be 
expected to remain at the same facility 
for the duration of the trial. Subjects 
may receive supervised day passes at 
the discretion of the investigator.  
Overnight passes will not be allowed 
for this trial.
A caregiver who is usually assigned to 
care for the subject on a regular basis, 
has sufficient contact to describe the 
subject’s symptoms, and has direct 
observation of the subject’s behavior 
must be identified during the 
screening period for participation in 
the interview for the CMAI, NPI-NH, 
and other applicable trial assessments.  
The identified caregiver will be a 
member of the residential facility or 
other individual (e.g., family member, 
family friend, hired professional 
caregiver) who meets the caregiver 
requirements.  
...
It is planned that approximately 330 
subjects will be screened at 
approximately 30 trial centers 
male and female subjects between 55 
and 90 years of age (inclusive), who 
are living in either an 
institutionalized setting (e.g., 
nursing home, dementia unit, 
assisted living facility, or any other 
residential care facility providing 
long term care) or in a non-
institutionalized setting where the 
subject is 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 the 
subject in order to assess changes in 
the subject’s condition. in a 
dementia unit, nursing home, 
assisted living facility, or any other 
residential care facility providing 
long-term care, All subjects must 
havewith a diagnosis of probable 
Alzheimer’s disease according to the 
NINCDS-ADRDA criteria.  Subjects 
must have a previous magnetic 
resonance imaging (MRI) or computed 
tomography (CT) scan of the brain, 
which was performed after the onset 
of symptoms of dementia, with 
findings consistent with a diagnosis of 
Alzheimer’s disease. If a previous 
MRI or CT scan of the brain 
performed after the onset of the 
symptoms of dementia is not 
available, then an MRI/CT scan 
should be performed during 
screening.  Additionally, at both the 
screening and baseline visits, subjects 
must have a Mini-Mental State 
Examination (MMSE) score of 5 to 
22, inclusive, and a total score 
(frequency x severity) of ≥4 on the 
agitation/aggression item of the 
NPI-NH.  The NPI-NH will be used 
for both institutionalized and non-
institutionalized subjects; however, 
the Occupational Disruptiveness 
questions will not be answered for 
non-institutionalized subjects.  
Instead, the Distress questions from 
the Neuropsychiatric Inventory (NPI) 
will replace the Occupational 
Disruptiveness questions for non-
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worldwide in order to randomize 230 
subjects.
institutionalized subjects.  This 
neuropsychiatric assessment for non-
institutionalized subjects based on the 
NPI/NPI-NH will hereafter be 
referred to as "NPI/NPI-NH”. ... 
Subjects must have been residing at 
their current location facility for at 
least 14 days1 month before 
screening and be expected to remain at 
the same location facility for the 
duration of the trial.  Subjects from a 
non-institutionalized setting who at 
any point during the double-blind 
treatment phase require permanent 
placement to a nursing home or 
assisted living facility will be 
withdrawn from the trial.  Subjects 
who at any point during the double-
blind treatment phase transfer from 
an institutionalized setting to a 
non-institutionalized setting will also 
be withdrawn from the trial.  In case 
of a change in the 
non-institutionalized address or 
institutionalized address, the 
investigator should consult with the 
medical monitor on a case-by-case 
basis.  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 INC Research 
medical monitor.  Subjects in an 
institutionalized setting subjects
may receive supervised day passes at 
the discretion of the investigator; 
however, overnight passes will not be 
allowed for this trial.
A caregiver who is usually assigned 
to care for the subject on a regular 
basis, has sufficient contact to 
describe the subject’s symptoms, 
and has direct observation of the 
subject’s behavior must be 
identified during the screening 
period for participation in the 
interview for the CMAI, NPI-NH, 
and other applicable trial 
assessments.  The identified 
caregiver will be a member of the 
residential facility or other 
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individual (e.g., family member, 
family friend, hired professional 
caregiver) who meets the caregiver 
requirements.  
...
It is planned that approximately 330 
subjects will be screened at 
approximately 3046 trial centers 
worldwide in order to randomize 230 
subjects.
Section 3.3.1 Caregiver 
Requirements 
Null (new section)
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.  The caretaker may be 
supported in providing care to the 
subject by a professional(s), friend(s), 
or family member(s).
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, NPI-NH, NPI/NPI-NH, and 
other applicable trial assessments, 
including completion of the eDiary.  
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 
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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 the same individual who 
fulfills the role of caretaker 
depending on the circumstances of 
the subject.  The recommended 
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 and NPI-NH are 
administered unless other 
arrangements are made and approved 
by the sponsor.
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, NPI-NH, NPI/NPI-NH, 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 (e.g., 
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.
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Section 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 study.  Once these determinations 
are made by the investigator, the 
following options for obtaining 
informed consent from and/or on 
behalf of the subject must be followed:

If the subject is deemed capable 
by the investigator, written 
informed consent will be obtained 
from the subject prior to the 
initiation of any study protocol-
required procedures.  In such 
cases, acknowledgement from the 
subject’s legally acceptable 
representative (an individual, or 
judicial or other body, authorized 
under applicable law to consent to 
the subject’s participation in the 
clinical trial on behalf of that 
prospective subject) will also be 
obtained in accordance with state 
and/or local regulations prior to 
initiation of any study protocol-
required procedures.   

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 and/or local 
regulations prior to the initiation 
of any study protocol-required 
procedures.  
...

If the subject initially provided 
assent at study entry, but 
subsequent dissents to participate 
in the trial, the subject will be 
early terminated from the trial.
The investigator must assess the 
capacity of the subject to provide 
informed consent during the screening 
period and throughout the course of 
the study.  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 and/or on behalf of the subject 
must be followed:

If the subject is deemed capable 
by the investigator, written 
informed consent will be obtained 
from the subject prior to the 
initiation of any study protocol-
required procedures.  In such 
cases, acknowledgement from the 
subject’s legally acceptable 
representative (an individual, or 
judicial or other body, authorized 
under applicable law to consent to 
the subject’s participation in the 
clinical trial on behalf of that 
prospective subject) will also be 
obtained, if required, in 
accordance with state and/or local 
regulations prior to initiation of 
any study protocol-required 
procedures.   

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 and/or local regulations 
prior to the initiation of any 
study protocol-required 
procedures.  
...

If the subject initially provided 
assent at study 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 
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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 and/or local regulations 
prior to the initiation or 
continuation of any study 
protocol-required procedures.  
Table 3.4.2-1
Inclusion Criteria
#6  Subjects who are residing in a 
dementia unit, nursing home, assisted 
living facility, or any other residential 
care facility providing long-term care.  
Subjects who have been residing at 
their current facility for at least 1 
month before screening and are 
expected to remain at the same facility 
for the duration of the trial.
#6  Subjects who are residing at 
their current location for at least 14 
days before screening and are 
expected to remain at the same 
location for the duration of the trial.  
Subjects who are residing in a 
dementia unit, nursing home, 
assisted living facility, or any other 
residential care facility providing 
long-term care.  Subjects who have 
been residing at their current 
facility for at least 1 month before 
screening and are expected to 
remain at the same facility for the 
duration of the trial.
#7  Subjects must have an identified 
caregiver who is usually assigned to 
care for the subject on a regular basis, 
has sufficient contact to describe the 
subject’s symptoms, and has direct 
observation of the subject’s behavior.  
The identified caregiver will be a 
member of the residential facility or 
other individual (e.g., family member, 
family friend, hired professional 
caregiver) who meets the caregiver 
requirements.  
#7  Institutionalized Ssubjects with 
must have an identified caregiver who 
is usually assigned to care for the 
subject on a regular basis, has 
sufficient contact 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 will be a member of the 
residential facility or another 
individual (e.g., family member, 
family friend, hired professional 
caregiver) who meets the caregiver 
requirements.  
Non-institutionalized subjects may 
not be living alone (see Section 
3.3.1.1 for caretaker definition) and 
must have an identified caregiver 
who has sufficient contact to describe 
the subject’s symptoms and has direct 
observation of the subject’s behavior.
Table 3.4.3-1
Exclusion Criteria
#8  Subjects who have been diagnosed 
with an Axis I disorder (DSM-IV-TR 
criteria) including, but not limited to:
...
#8  Subjects who have been diagnosed 
with an Axis I disorder (DSM-IV-TR 
criteria) including, but not limited to:
...
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Current major depressive episode 
unless on a stable dose(s) of 
antidepressant medication(s) for the 30 
days prior to randomization.
Current major depressive disorder 
episode unless on a stable dose(s) 
of antidepressant medication(s) for the 
30 days prior to randomization.
#13  Subjects with insulin-dependent 
diabetes mellitus (IDDM) (i.e., any 
subjects using insulin) are excluded.  
Subjects with non-IDDM may be 
eligible for the trial if their condition 
is stable as determined by satisfying 
ALL of the following criteria: ...
#13  Subjects with insulin-dependent 
diabetes mellitus (IDDM) (i.e., any 
subjects using insulin) may be eligible 
for the trial if their condition is well 
controlled and if they do not have 
current microalbuminuria are 
excluded.  Subjects with non-IDDM 
may be eligible for the trial if their 
condition is stable as determined by 
satisfying ALL of the following 
criteria:...

Urine albumin-to-creatinine 
ratio (ACR) must be < 30 mg/g 
(calculated), AND
#14  Subjects with stage 3 or higher 
chronic kidney disease.
#14  Subjects with clinically 
significantstage 3 or higher chronic 
kidney disease based on the 
investigator’s judgment.
#27  Subjects who have significant 
risk of death within the next 6 months 
based on the investigator’s judgment.  
#27  Subjects who have significant 
risk of death within the next 6 
months based on the investigator’s 
judgment.  
#31  ...
In addition, subjects with the 
following laboratory test and ECG 
results at screening must be excluded 
from the trial:
...

QTcF 450 msec
#30 31  ...
In addition, subjects with the 
following laboratory test and ECG 
results at screening must be excluded 
from the trial:
...

ACR > 30 mg/g (calculated as 
urine albumin [mg/dL] / urine 
creatinine [g/dL])
...

QTcF 450 msec in men and 
470 msec in women (refer to 
Section 3.7.4.4 for further 
details)
#32  Sexually active females of 
childbearing potential (see 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 trial medication 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 
#31 32  Sexually active females of 
childbearing potential (see 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 trial medication 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 
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ligation, vaginal diaphragm, 
intrauterine device (IUD), birth 
control pill, birth control implant, birth 
control depot injections, condom, or 
sponge with spermicide.
ligation, vaginal diaphragm, 
intrauterine device (IUD), birth 
control pill, birth control implant, birth 
control depot injections, condom with 
spermicide, or sponge with 
spermicide.
#40  Subjects who participated in a 
clinical trial within the last 180 days 
or who participated in more than 
2 clinical trials within the past year.
#39 40  Subjects who participated in a 
clinical trial within the last 180 days 
or who participated in more than 
2 interventional clinical trials within 
the past year.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Section 3.7
Trial Procedures
The time from enrollment of the first 
subject to the last subject’s last trial 
visit will be approximately 4.5 years, 
of which approximately4 years are 
allotted for recruitment of subjects.   
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 
will be followed up at a clinic visit or 
via telephone contact 30 (+ 2) days 
after the last dose of the IMP.  
...
 
 the CST 
will perform regular quality reviews of 
CMAI data and will compare these 
data against other sources of 
behavioral information, including 
patterns of movement using actigraphy 
technology (refer to Section 3.7.3.6), 
daily behavior logs collected by 
caregivers through electronic diaries 
(refer to Section 3.7.3.7), and 
investigator progress notes.
Trial assessment time points are 
summarized in Table 3.7-1.  
The time from enrollment of the first 
subject to the last subject’s last trial 
visit will be approximately 3.5 4.5
years, of which approximately 4 3
years are allotted for recruitment of 
subjects. 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 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 study, 
all attempts will be made to collect 
mortality data by telephone contact 
with the subject’s caregiver at Week 
16.
...
 
, the CST 
will perform regular quality reviews of 
CMAI data and will compare these 
data against other sources of 
behavioral information, including 
patterns of movement using actigraphy 
technology (refer to Section 3.7.3.67), 
daily behavior logs collected by 
caregivers through electronic diaries 
(refer to Section 3.7.3.78), and 
investigator progress notes.
All study visits will take place as a 
clinic visit at either the investigator’s 
site (for non-institutionalized 
subjects) or residential facility (for 
institutionalized subjects).  Trial 
assessment time points are 
summarized in Table 3.7-1.   
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Table 3.7-1
Schedule of Assessments (truncated)
Assessment
Visit
Screeninga
Baseline 
(Day 0)
Day 3
Wk 2
Wk 4
Wk 6
Wk 8
Wk 10
Wk 12/ 
ETb
Between
clinic visit 
phone callc
FUdc
Wk 16d
EFFICACY
...
NPI-NH (for institutionalized 
subjects) or NPI/NPI-NH (for 
non-institutionalized subjects)
X
X
X
X
X
X
X
X
OTHER
 
 
 
...
SAFETY
...
Adverse eventsw
X
X
X
X
X
X
X
X
X
X
X
...
Concomitant medicationsz
X
X
X
X
X
X
X
X
X
X
X
Mortality assessmentaa
X
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Table 3.7-1
Schedule of Assessments (truncated)
Assessment
Visit
Screeninga
Baseline 
(Day 0)
Day 3
Wk 2
Wk 4
Wk 6
Wk 8
Wk 10
Wk 12/ 
ETb
Between
clinic visit 
phone callc
FUdc
Wk 16d
OTHER PROCEDURES
Register trial visit in IVRS/IWRS
X
X
X
X
X
X
X
X
X
Randomize eligible subjects via 
IVRS/IWRS
X
IMP dispensingaabb
X
X
X
X
X
X
X
IMP accountability
X
X
X
X
X
X
X
Telephone contactcc
ADDITIONAL ENTRANCE/HISTORY
MRI/CT scanbbdd
Xbbdd
Abbreviations: ... NPI = Neuropsychiatric Inventory; ...
cdAll subjects, whether they complete the trial or are withdrawn prematurely for any reason, will be followed up for a safety evaluation at 30 (+ 2) days after 
the last dose of IMP during a clinic visit at either the investigator’s site or residential facility 30 (+ 2) days after the last dose of IMP.  If the 
institutionalized subject has left the residential facility where he or she participated in the trial, the subject should be seen atin the investigator’s site.clinic
or (if If a clinic visit is not possible), the subject should be assessed by telephone contact with the subject and a caregiver.  Subjects who complete both the 
12-week double-blind treatment period and the 30-day safety follow-up visit are eligible to enroll into Trial 331-13-211, which is a 2-month, observational, 
rollover trial to evaluate the safety of subjects with agitation associated with Alzheimer's disease who previously participated in Trial 331-12-283.  For 
those subjects who plan to enroll into Trial 331-132-211, the 30-day safety follow-up visit for Trial 331-12-283 will occur as a clinic visit at either the 
investigator’s site or residential facility.  If the institutionalized subject has left the residential facility where he or she participated in the trial, the 30-day 
safety follow-up visit will occur as a clinic visit at the investigator's site.
dNote that this visit is 16 weeks postbaseline.
...
kAfter the ICF is signed during the screening visit, the actigraphy device will be put on the subject’s nondominant wrist and worn daily until Week 12/ET.  It 
is recommended that the Aactigraph must be checked daily to ensure that the subject is wearing it and that it continues to be operational.  
...
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pSubjects should must be fasting for a minimum of 8 hours prior to blood draws for screening laboratory assessments, if at all possible.  If fasting blood 
samples are not feasible at screening, nonfasting blood samples may be obtained initially for determining eligibility for the trial.
...
v
 
 
 
xPharmacokinetic samples will be obtained at baseline and at any time during the Week 8 and Week 12/ET visits.  If blood samples for clinical laboratory 
tests are not collected at the baseline visit, pharmacokinetic samples do not need to be obtained at baseline.  Every possible effort should be made to collect 
samples at the same time at each visit.  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 pharmacokinetic sampling.  The date and time of the last 2 doses prior to each pharmacokinetic blood draw will be recorded 
on the electronic case report form (eCRF).  Vital sign and ECG assessments should be completed before any blood samples are collected.
...
zAll medications taken within 30 days of screening (signing of ICF/assent) will be recorded.  In addition, all prescription and nonprescription medications 
taken during the trial will be recorded as concomitant medications.  Details of prohibited and restricted medications are provided in the protocol (refer to 
Section 4.1).  During the first 4 weeks of the randomized phase (baseline to Week 4 visit), benzodiazepines are allowed but limited to 4 days/week with a 
maximum dose of 2 mg/day of lorazepam (or equivalent) or less depending on dose-limiting side effects.  Benzodiazepines must not be administered 
within 12 hours prior to the efficacy and safety scales.  After the Week 4 visit, benzodiazepines are prohibited.
aaFor all subjects who terminate early from the study, all attempts will be made to collect mortality data by telephone contact with the subject’s caregiver 
at Week 16.  
aabbSubjects will start taking IMP from the new blister card the day after the clinic visit.
ccThe subject’s identified caregiver will be contacted by telephone every odd numbered week after Week 2 (i.e., Weeks 3, 5, 7, 9, 11) to assess compliance 
with IMP, confirm any changes to concomitant medications, and assure the subject’s well-being.
bbddIf 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 
 in order to confirm 
eligibility.  
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Section 3.7.1.1
Screening
At the time of subject’s screening 
visit, the caregiver will be provided a 
document which will outline all 
caregiver responsibilities and their 
role in this study.  The caregiver 
should acknowledge and agree to 
undertake all the tasks designated by 
this protocol at the time of the 
informed consent process.
Screening evaluations will include the 
following:
...

A standard 12-lead ECG will be 
performed after the subject has 
been supine and at rest for at least 
5 minutes.  Subjects with 
screening QTcF 450 msec will 
be excluded from the trial (see
Section 3.7.4.4).  The ECG is to 
be completed before any blood is 
drawn.
...

A qualified and certified rater will 
administer the CMAI and NPI-
NH to the caregiver.
...

After the ICF is signed during the 
screening visit, an actigraphy 
device will be put on the subject’s 
nondominant wrist. The 
actigraph will be worn 
continuously throughout the 
double-blind treatment period.  
The device must be checked daily 
to ensure that the subject is 
wearing it and that it continues to 
be operational.  At every study 
visit (except the Day 3 visit), 
subjects will take off the device 
so that site personnel can 
download the data stored in the 
device, and the device battery will 
be changed.  Once the download 
is complete, the device will be 
placed back on the subject.  If the 
screening period extends beyond 
4 weeks, the battery will need to 
be replaced once.  Once the 
download is complete, the device 
will be placed back on the 
subject.
At the time of subject’s screening 
visit, the caregiver will be provided a 
document which will outline all 
caregiver responsibilities and their 
role in this study.  The caregiver 
should acknowledge and agree to 
undertake all the tasks designated by 
this protocol at the time of the 
informed consent process.
Screening evaluations will include the 
following:

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 study.  The caregiver should 
acknowledge and agree to 
undertake all the tasks designated 
by this protocol at the time of the 
informed consent process.
...

A standard 12-lead ECG will be 
performed after the subject has 
been supine and at rest for at least 
5 minutes.  Subjects with screening 
QTcF 450 msec (males) or 
470 msec (females) will be 
excluded from the trial (see Section 
3.7.4.4).  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.  The 
ECG is to be completed before any 
blood is drawn.
...

Albumin-to-creatinine ratio 
(ACR) will be determined (must be 
< 30 mg/g; calculated as urine 
albumin [mg/dL] / urine 
creatinine [g/dL]).
...

A qualified and certified rater will 
administer the CMAI, and NPI-
NH, and NPI/NPI-NH to the 
caregiver.
...

After the ICF is signed during the 
screening visit, an actigraphy 
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
After the ICF has been signed, the 
caregiver and/or facility staff will 
enter daily into the electronic 
diary (eDiary) information 
regarding the subject's behavior.    
device will be put on the subject’s 
nondominant wrist. The actigraph 
will be worn continuously 
throughout the double-blind 
treatment period.  It is 
recommended that tThe 
actigraphdevice must be checked 
daily to ensure that the subject is 
wearing it and that it continues to 
be operational.  At every study visit 
(except the Day 3 visit), subjects 
will take off the device so that site 
personnel can download the data 
stored in the device, and the device 
battery will be changed.  Once the 
download is complete, the device 
will be placed back on the subject.  
If the screening period extends 
beyond 4 weeks, the battery will 
need to be replaced once.  Once 
the download is complete, the 
device will be placed back on the 
subject.    

After the ICF has been signed, 
the caregiver and/or facility staff 
will enter daily into the electronic 
diary (eDiary) information 
regarding the subject's behavior.    

The subject’s caregiver and/or 
facility staff will complete an 
electronic diary (eDiary) daily (if 
possible) after the ICF is signed, 
continuing through the Week 
12/ET.
Section 3.7.1.2
Baseline (Day 0)

A qualified and certified rater will 
administer the CMAI and NPI-
NH to the caregiver.
...
 
...

Daily eDiary recording will 
continue.

The subject will take the first 
dose of the IMP from the 
assigned blister card on Day 1 
(i.e., the day after the baseline 
visit).  The subject should take the 
IMP at the same time each day, 
preferably in the morning, 
without regard to meals.

A qualified and certified rater will 
administer the CMAI, and NPI-
NH, and NPI/NPI-NH to the 
caregiver.
...

 
 
 
 
...

Daily eDiary recording will 
continue.

The subject will take the first dose 
of the IMP from the assigned 
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blister card on Day 1 (i.e., 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
Section 3.7.1.3.1
Day 3

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 the same time each day, 
preferably in the morning, 
without regard to meals.
...

Daily eDiary recording will 
continue.

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.
...

Daily eDiary recording will 
continue.
Section 3.7.1.3.2
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.  Beginning at Week 3, the 
subject’s identified caregiver will be 
contacted by telephone between the 
scheduled visits.  The following 
evaluations will be performed at the 
Weeks 2, 4, 6, 8, and 10 visits.
...

A qualified and certified rater will 
administer the CMAI and NPI-
NH to the caregiver.
...

Daily eDiary recording will 
continue.
...

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 the same time each day, 
preferably in the morning, 
without regard to meals.
 
 
 
 
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.  
Beginning at Week 3, the subject’s 
identified caregiver will be contacted 
by telephone between the scheduled 
visits.  The following evaluations will 
be performed at the Weeks 2, 4, 6, 8, 
and 10 visits.
...

A qualified and certified rater will 
administer the CMAI, and NPI-
NH, and NPI/NPI-NH to the 
caregiver.
...

Daily eDiary recording will 
continue.
...

The subject will start taking the 
IMP from the assigned blister card 
the day after the clinic visit.  The 
subject should take the IMP at 
approximately the same time each 
day, preferably in the morning, 
without regard to meals.
 
 
 
 
 
 
 
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...
In addition, the subject’s identified 
caregiver will be contacted by 
telephone every odd numbered week 
after Week 2 (i.e., Weeks 3, 5, 7, 9, 11) 
to assess compliance with IMP, 
confirm any changes to concomitant 
medications, and assure the subject’s 
well-being.
Section 3.7.1.4
End of Treatment 
(Week 12/ET)
The following activities and 
assessments will occur at Week 12 (or 
at the ET visit, if applicable):

A qualified and certified rater will 
administer the CMAI and NPI-
NH to the caregiver.
...

 
The following activities and 
assessments will occur at Week 12 (or 
at the ET visit, if applicable):

A qualified and certified rater will 
administer the CMAI, and NPI-
NH, and NPI/NPI-NH to the 
caregiver.
...

 
 
 
 
 
Section 3.7.1.5
Follow-up
All subjects, whether they complete 
the trial or are withdrawn prematurely 
for any reason, will be followed up for 
a safety evaluation at a clinic visit at 
the residential facility 30 (+ 2) days 
after the last dose of the IMP.  If the 
subject has left the residential facility 
where he or she participated in the 
trial, the subject should be seen in the 
investigator’s clinic or (if a clinic visit 
is not possible) assessed by telephone 
with the subject and a caregiver.  All 
AEs and concomitant medications will
be recorded.  
All subjects, whether they complete the 
trial or are withdrawn prematurely for 
any reason, will be followed up for a 
safety evaluation 30 (+ 2) days after the 
last dose of IMP during at a clinic visit
at either the investigator’s site or
residential facility, if institutionalized
30 (+ 2) days after the last dose of the 
IMP.  If the institutionalized subject 
has left the residential facility where he 
or she participated in the trial, the 
subject should be seen atin the 
investigator’s site.clinic or (if 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 study, all 
attempts will be made to collect 
mortality data by telephone contact 
with the subject’s caregiver at Week 
16.
Section 3.7.2
Efficacy Assessments
It is required that adequately trained 
and experienced clinicians administer 
the CMAI, NPI-NH, CGI S, 
 
It is required that adequately trained 
and experienced clinicians administer 
the CMAI, NPI-NH, NPI/NPI-NH, 
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and 
  In addition, the raters 
must be certified for this trial to 
administer the CMAI and NPI-NH.  
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 who is usually assigned to 
care for the subject on a regular basis, 
has sufficient contact to describe the 
subject’s symptoms, and has direct 
observation of the subject’s behavior, 
must be identified during the 
screening period for participation in 
the interview for the CMAI, NPI-NH, 
and other applicable trial assessments.  
The recommended minimum level of 
contact between the caregiver and the 
subject is 2 hours per day for 4 days 
per week.  The identified caregiver 
will be a member of the residential 
facility or other individual (e.g., 
family member, family friend, hired 
professional caregiver) who meets the 
caregiver requirements.  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.  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 overview 
of the subject’s behavioral symptoms 
and condition. 
At the time of subject’s screening 
visit, the caregiver will be provided a 
document which will outline all 
caregiver responsibilities and their 
role in this study.  The caregiver 
should acknowledge and agree to 
undertake all the tasks designated by 
this protocol at the time of the 
informed consent process.  The 
recommended minimum level of 
CGI S, 
  In addition, 
the raters must be certified for this trial 
to administer the CMAI, and NPI-NH, 
and NPI/NPI-NH.  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 who is usually assigned to 
care for the subject on a regular 
basis, has sufficient contact to 
describe the subject’s symptoms, and 
has direct observation of the 
subject’s behavior, must be identified 
during the screening period for 
participation in the interview for the 
CMAI, NPI-NH, NPI/NPI-NH, and 
other applicable trial assessments.  The 
recommended minimum level of 
contact between the caregiver and 
the subject is 2 hours per day for 4 
days per week.  The identified 
caregiver will be a member of the 
residential facility staff or other 
individual (e.g., family member, 
family friend, hired professional 
caregiver) who meets the caregiver 
requirements.  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, Tthe 
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 
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 
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contact between the caregiver and the 
subject is 2 hours per day for 4 days 
per week.    
daily living.  Details on the caregiver 
requirements can be found in Section 
3.3.1
At the time of subject’s screening 
visit, the caregiver will be provided a 
document which will outline all 
caregiver responsibilities and their 
role in this study.  The caregiver 
should acknowledge and agree to 
undertake all the tasks designated by 
this protocol at the time of the 
informed consent process.  The 
recommended minimum level of 
contact between the caregiver and 
the subject is 2 hours per day for 4 
days per week.    
Section 3.7.2.6
Neuropsychiatric 
Inventory  (NPI)
Null (new section)
The NPI is a structured caregiver 
interview designed to obtain 
information on the presence of 
psychopathology in subjects with brain 
disorders, including Alzheimer’s 
disease and other dementias.31  The 
NPI differs from the NPI-NH in that it 
is tailored for use in non-institutional 
settings (as opposed to the nursing 
home).  Item domains are identical 
between the two scale versions.  Ten 
behavioral and two neurovegetative 
symptom domains comprise the NPI 
(including delusions, hallucinations, 
agitation/aggression, 
depression/dysphoria, anxiety, 
elation/euphoria, apathy/indifference, 
disinhibition, irritability, aberrant 
motor behavior, nighttime behavior 
disorders, and appetite/eating 
disorders).  Caregivers are instructed 
to indicate the frequency of a given 
behavior (on a scale of 1 to 4), its 
severity (on a scale of 1 to 3), and how 
much distress that behavior causes for 
him or her (on a scale of 0 to 5).  Each 
domain produces 4 scores:  frequency, 
severity, total (frequency x severity), 
and distress.  A total NPI score is 
calculated by adding the first 10 
domain total scores (frequency x 
severity scores) together.  All 12 
domain total scores can be summed in 
special circumstances where the 
neurovegetative symptoms are of 
particular importance.  Administering 
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the NPI generally takes about 15 
minutes.  The psychometric properties 
and factor structure of the NPI have 
been shown to have internal 
consistency, reliability, convergent 
validity, and discriminant validity.
A sample of the NPI is provided in 
Appendix 9.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 3.7.3.7
Actigraphy
3.7.3.6  Actigraphy
The CST will perform ongoing 
reviews of CMAI raters by reviewing 
CMAI data relative to other sources of 
behavioral information, including 
patterns of movement using 
3.7.3.67  Actigraphy
The CST will perform ongoing reviews 
of CMAI raters by reviewing CMAI 
data relative to other sources of 
behavioral information, including 
patterns of movement using actigraphy 
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actigraphy technology.  Motion will 
be collected through an actigraphy 
device resembling a wristwatch worn 
by the subject on their nondominant 
wrist for 24 hours/day during the 
screening and treatment periods.  If 
the subject decides not to wear the 
actigraph at any time after the consent 
is obtained, the assessment may be 
discontinued and continued study 
participation will not be affected.  
Study staff will be responsible for 
uploading actigraphy data from the 
device to the actigraphy vendor at 
regular intervals corresponding to the 
date of the CMAI.  
...
Since actigraphy data are tools to 
assist the CST in monitoring CMAI 
rater training, actigraphy information 
will not be made available to site 
personnel, and will not be statistically 
analyzed.
technology.  Motion will be collected 
through an actigraphy device 
resembling a wristwatch worn by the 
subject on their nondominant wrist for 
24 hours/day during the screening and 
treatment periods.  If the subject 
decides not to wear the actigraph at any 
time after the consent is obtained, the 
assessment may be discontinued and 
continued study participation will not 
be affected.  Study staff will be 
responsible for uploading The 
actigraphy data will be downloaded
from the device to the actigraphy 
vendor at regular intervals 
corresponding to the date of the CMAI.  
For non-institutionalized subjects, the 
caregiver will not be expected to 
change the actigraph watch battery or 
download the actigraph data; these 
duties will be completed by the site 
staff.  For institutionalized subjects, 
the caregiver or site staff may be 
responsible for changing the actigraph 
watch battery or downloading the 
actigraph data.
...
Since actigraphy data are tools to assist 
the CST in monitoring CMAI rater 
training, actigraphy information will 
not be made available to site 
personnel, and will not be statistically 
analyzed.
Section 3.7.3.8
Electronic Diary 
(eDiary)
3.7.3.7  Electronic Diary (eDiary)
The CST will perform ongoing 
reviews of CMAI raters by reviewing 
CMAI data relative to other sources of 
behavioral information, including 
daily behavior logs collected by 
caregivers and/or facility staff through 
eDiaries (refer to Appendix 17).  
Caregivers will record occurrence of 
the 29 behaviors listed in the CMAI as 
they occur using an eDiary.  All 29 
behaviors will be listed, and the 
caregiver will check the box next to 
the behavior when it occurs; there is 
no free text in the eDiary.  
Observations recorded using the 
eDiary will be transmitted wirelessly 
to the eDiary vendor.
...
3.7.3.78  Electronic Diary (eDiary)
The CST will perform ongoing reviews 
of CMAI raters by reviewing CMAI 
data relative to other sources of 
behavioral information, including daily
behavior logs collected by caregivers 
and/or facility staff through eDiaries 
(refer to Appendix 17).  Caregivers will 
record occurrence of the 29 behaviors 
listed in the CMAI as they occur using 
an eDiary.  All 29 behaviors will be 
listed, and the caregiver will check the 
box next to the behavior when it occurs; 
there is no free text in the eDiary.  
Observations recorded using the eDiary 
will be transmitted wirelessly to the 
eDiary vendor.
For subjects in a non-institutionalized 
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Since eDiary data are tools to assist 
the CST in monitoring CMAI rater 
training, eDiary information will not 
be made available to site personnel, 
and will not be statistically analyzed.
setting, one of the responsibilities of 
the caregiver is to complete the eDiary 
by noting the subject’s symptoms of 
agitation.  While it is preferred that 
eDiary data are collected 7 days a 
week, it is realized that eDiary 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.  
The caretaker may provide 
information to the caregiver to 
complete the eDiary on a daily basis, 
but this is not a requirement.  The 
responsibility of the caregiver for 
logging behaviors in the eDiary 
remains the same for subjects in an 
institutionalized setting.  However, 
more than one caregiver may use the 
eDiary for any given subject; whoever 
is providing care for the subject at a 
given time can log behaviors in the
eDiary.  
...
Since eDiary data are tools to assist the 
CST in monitoring CMAI rater training, 
eDiary information will not be made 
available to site personnel, and will 
not be statistically analyzed.
Table 3.7.4.2-1
Clinical Laboratory 
Assessments
--
Addition of albumin and creatinine 
under Urinalysis
Section 3.7.4.2
Clinical Laboratory 
Assessments
The following laboratory test results at 
screening are exclusionary:
The following laboratory test results at 
screening are exclusionary:
...

Urine albumin-to-creatinine ratio 
(ACR) > 30 mg/g (calculated as 
urine albumin [mg/dL] / urine 
creatinine [g/dL])
Section 3.7.4.3.1
Physical Examination
Waist circumference will be measured 
at each physical examination 
(screening, Week 6 and Week 12/ET).  
Waist circumference will be measured 
at each physical examination 
(screening, Week 6, and Week 12/ET), 
using the provided measuring tape.  
Section 3.7.4.4
ECG Assessments
A screening ECG finding of QTcF 
450 msec is exclusionary (see Table 
3.4.3-1).  In addition, subjects should 
be excluded if they have any other 
abnormal ECG finding at screening 
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 screening ECG with 
A screening ECG finding of QTcF 
450 msec is exclusionary (see Table 
3.4.3-1).  If, according to the 
investigator's judgment, any abnormal 
ECG finding is deemed medically 
significant (impacting the safety of the 
subject and/or the interpretation of the 
study results) or meets an exclusion 
criterion (see Table 3.4.3-1), the 
subject should be excluded from the 
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abnormal 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 5 for a list of 
potentially clinically relevant ECG 
abnormalities.
study. 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 
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.  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 study.  
In addition, subjects should be 
excluded if they have any other 
abnormal ECG finding at screening 
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 screening 
ECG with abnormal 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 5 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.
Section 3.7.5.1
Blood Collection 
Times
... Every possible effort should be 
made to collect pharmacokinetic 
samples at the same time at each visit.  
Furthermore, the subject should be 
advised to take the IMP at the same 
... Every possible effort should be made 
to collect pharmacokinetic samples at 
the same time at each visit.  
Furthermore, the subject should be 
advised to take the IMP at 
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time each day throughout the trial, but 
most importantly, prior to each 
pharmacokinetic 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 
will be recorded on the eCRF.
approximately the same time each day 
throughout the trial, but most 
importantly, prior to each 
pharmacokinetic 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 will 
be recorded on the eCRF.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
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Section 3.8.3
Individual Subject
In addition, subjects meeting any of 
the following criteria must be 
withdrawn from the trial:
...
4)  At the request of the subject, 
investigator, sponsor, or regulatory 
authority
...
 
 
 
 
 
The investigator will notify the 
sponsor promptly when a subject is 
withdrawn.  Subjects withdrawn prior 
to Week 12 must complete the Week 
12/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 
the residential facility.  If the subject 
has left the residential facility where 
In addition, subjects meeting any of the 
following criteria must be withdrawn 
from the trial:
...
4)  At the request of the subject, 
caregiver, legally acceptable 
representative, investigator, sponsor, or 
regulatory authority
...
10)  Subject from a non-
institutionalized setting requires 
permanent placement to a nursing 
home or assisted living facility, or 
subject transfers from an 
institutionalized setting to a non-
institutionalized setting.  In case of a 
change in the non-institutionalized 
address or institutionalized address, 
the investigator should consult with 
the medical monitor on a case-by-case 
basis.  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 INC Research 
medical monitor.
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he or she participated in the trial, the 
subject should be seen in the 
investigator’s clinic or (if a clinic visit 
is not possible) assessed by telephone 
contact with the subject and a 
caregiver.  
 
 
 
 
 
The investigator will notify the sponsor 
promptly when a subject is withdrawn.  
Subjects withdrawn prior to Week 12 
must complete the Week 12/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.  If the 
institutionalized subject has left the 
residential facility where he or she 
participated in the trial, the subject 
should be seen atin the investigator’s 
site. clinic or (iIf 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 study, 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.
Any subject who withdraws 
prematurely from the trial will not be 
eligible to roll-over into Trial 331-13-
211.  
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
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should be reported, and make a 
determination of subject continuation 
based on subject safety.  The 
investigator could consult with the 
medical monitor to determine subject 
continuation in the study.
Section 3.11
Definition of Subjects 
Lost to Follow-up
Subjects who cannot be contacted on 
or before the Week 12 visit during the 
treatment period and who do not have 
a known reason for discontinuation 
(e.g., withdrew consent or AE) will be 
classified as “lost to follow-up.”  If a 
subject leaves the residential facility 
in which he/she was residing before 
completion of the study, the site will 
make 3 attempts to contact the subject 
by telephone; 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.
Subjects who cannot be contacted on or 
before the Week 12 visit during the 
treatment period and who do not have a 
known reason for discontinuation (e.g., 
withdrew consent or AE) will be 
classified as “lost to follow-up.”  If an
institutionalized subject leaves the 
residential facility in which he/she was 
residing before completion of the study, 
the site will make 3 attempts to contact 
the subject by telephone; 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.  A similar procedure will 
be followed for non-institutionalized 
subjects who are lost to follow-up.
Section 3.12
Subject Compliance
Responsible trial personnel will 
dispense the IMP (i.e., brexpiprazole 
or matching placebo).  Accountability 
and compliance verification should be 
documented in the subject’s trial 
records.
Responsible trial personnel will 
dispense the IMP (i.e., 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.
For non-institutionalized subjects, the 
caretaker or caregiver may administer 
IMP to the subject, as long as the 
subject is compliant with IMP dosing 
requirements.
For institutionalized subjects, the 
caregiver will be responsible for 
administering IMP to the subject.  It 
may be possible that there is more than 
one caregiver for a subject.  The 
caregiver(s) should be appropriately 
instructed to ensure that the subject is 
compliant with IMP dosing 
requirements.
Section 5.7.4
Follow-up Mortality 
Assessment
Null (new section)
For all subjects who terminate early 
from the study, all attempts will be 
made to collect mortality data by 
telephone contact with the subject’s 
caregiver at Week 16.  Three attempts 
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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.
Section 7.1
Sample Size
... The resulting sample size is 103 
subjects/arm.  To account for a portion 
of subjects who discontinue 
prematurely and whose data may 
potentially dilute the treatment effect, 
approximately an additional 10% of 
subjects was added to the sample size, 
resulting in a sample size of 115 
subjects/arm, which means the total 
sample size is 230 subjects.  
... The resulting sample size is 103 
subjects/arm.  After allowance of 10% 
non-evaluable subjects, To account 
for a portion of subjects who 
discontinue prematurely and whose 
data may potentially dilute the 
treatment effect, approximately an 
additional 10% of subjects was added 
to the sample size, it resultsing in a 
sample size of 115 subjects/arm, which 
means the total sample size is 230 
subjects.  
Section 7.4.1
Primary Efficacy 
Analysis
The primary endpoint will be analyzed 
using a mixed-effect model repeated 
measure (MMRM) model.  The 
primary efficacy outcome measure is 
the mean change from baseline to the
endpoint in the CMAI total score.  
 
 
  The null hypothesis for the 
comparison of brexpiprazole flexible 
dose versus placebo is that there is no 
difference between the brexpiprazole 
treatment group and placebo in change 
from baseline to endpoint in CMAI 
total score.  The comparison will be 
made at the significance level of alpha 
= 0.05.
The statistical comparison will be 
performed by the MMRM analysis 
with an unstructured variance 
covariance matrix for the repeated 
measures in which the change from 
baseline to endpoint in CMAI total 
score will be the dependent variable 
based on the OC dataset.  The model 
will include fixed class-effect terms 
for treatment, trial center, visit week 
and an interaction term of treatment 
by visit week and include the 
interaction term of baseline by visit 
week as a covariate.  
The primary endpoint will be analyzed 
using a mixed-effect model repeated 
measure (MMRM) model.  The primary 
efficacy outcome measure is the mean 
change from baseline (Day 0 Visit) to 
the endpoint end of the double-blind 
treatment period (Week 12 visit) in the 
CMAI total score. 
 
 
  The null 
hypothesis for the comparison of 
brexpiprazole flexible dose versus 
placebo is that there is no difference 
between the brexpiprazole treatment 
group and placebo in change from 
baseline to endpoint in CMAI total 
score.  The comparison will be made at 
the significance level of alpha = 0.05.
The statistical comparison will be 
performed by the fitting a MMRM 
analysis with an unstructured variance 
covariance matrix for the repeated 
measures in which the change from 
baseline to endpoint (Day 0 Visit) 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 center, visit 
week and an interaction term of 
treatment by visit week and include 
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the interaction term of baseline by 
visit week as a covariate.  The model 
will also include a random effect for 
subject and the interaction term of 
baseline (Day 0 visit) by visit week as 
covariates.  The primary comparison 
between the brexpiprazole and the 
placebo groups at Week 12 will be 
estimated as the difference between the 
least squares (LS) means utilizing the 
computing software SAS procedure 
PROC MIXED.
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 1
Names of Sponsor 
Personnel
Primary Medical Contact
 
Development
Otsuka Pharmaceutical Development 
& Commercialization, Inc.
1 University Square Drive, Suite 500
Princeton, NJ 08540
Phone: 
Fax: 
Primary Medical Contacts
Otsuka Pharmaceutical Development & 
Commercialization, Inc.
1 University Square Drive, Suite 500
Princeton, NJ 08540
Phone:  
Fax:  
Otsuka Pharmaceutical Development 
& Commercialization, Inc.
1 University Square Drive, Suite 500
Princeton, NJ 08540
Phone:  
Fax:  
Appendix 2
Institutions Concerned 
With the Trial
Medical Monitors
Country
Safety Fax Line
United States
Canada
United 
Kingdom
France
Ukraine
Additional countries being 
considered for participation
Slovenia
Lithuania
Sweden
Austria
Finland
Ireland
* Please note that this is a partner 
CRO number, not INC.
Europe:
INC Research, LLC
UI. Emaus 5
30-201 Kraków, Poland
Office:  
Mobile:  
Fax:  
Country
Safety Fax Line
United States
Canada
United Kingdom
France
Ukraine
Additional countries being 
considered for participation
Slovenia
Lithuania
Sweden
Austria
Finland
Ireland
* Please note that this is a partner 
CRO number, not INC.
Europe:
 
INC Research, LLC
UI. Emaus 5
30-201 Kraków, Poland
Office:  
Mobile:  
Fax:  
Appendix 5
Criteria for Identifying 
ECG Measurements of 
Potential Clinical 
Relevance
Increase in 
QTc
QTcF 450 
msec
(men and 
women)
Increase in 
QTc
QTcF 450 
msec
(men and 
women)
QTcF 470 
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msec
(women)
Appendix 9
Neuropsychiatric 
Inventory  (NPI)
Null (new appendix)
Added NPI for subjects in a 
non-institutionalized setting (this 
resulted in renumbering of the 
subsequent appendices).
 
 
 
 
 
 
 
  
 
 
 
 
 
 
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Amendment Number:
3
Issue Date:
10 Sep 2015
PURPOSE:
The sponsor has determined the need for a third formal amendment.  This amendment 
serves to reflect clarifications and changes to trial procedures intended to enhance subject 
safety and accuracy of data, as well as to streamline the exclusion criteria.  In addition, 
administrative clarifications were made, including changes to text to enhance readability 
and consistency, and changes to correct typographical, punctuation, and formatting 
errors.  These changes were minor and do not change the design or content of the 
protocol, and therefore, are not summarized in this appendix.
The purpose of amending Protocol 331-12-284, issued 07 Jul 2014, was to:

Increase the number of screened subjects from 330 to 520 and the number of 
trial sites from 46 to 65.

Change the power from 80% to 85% and the resulting sample size from 
103 subjects/arm to 117 subjects/arm.  

Increase the total sample size from 230 subjects to 260 subjects (from 
115 subjects/arm to 130 subjects/arm).

Increase the time from enrollment of first subject to last subject’s last trial visit from 
3.5 to 4.5 years and the time for recruitment from 3 to 4 years.

Broaden the definition of subjects in an institutionalized setting and add overnight 
passes (at the investigator’s discretion) for these subjects.

Broaden the location of trial visits.

Add that the screening period can be extended or that subjects can be rescreened more 
than once with the approval of the medical monitor.

Modify inclusion criterion #8.

Modify exclusion criteria #1, 3, 7, 8, 11, 13, 18, 21, 23, 30, 33, 36, and 39, and 
remove exclusion criteria #4, 5, 9, 14, 17, 19, 20, 22, and 24-27.  These modifications 
resulted in the renumbering of the exclusion criteria. 

Remove HIV testing at screening.

Remove urinalysis, prolactin, and urine pregnancy testing at Week 4 and Week 8.


Add the AIMS at Weeks 2, 4, and 8 and remove the AIMS at Week 6.

Remove 
, physical examination, and 
neurological examination at Week 6. 

Change telephone contact to Weeks 3, 5, and 7 during the double-blind treatment 
period.
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
Change electronic diaries to paper diaries, as well as remove the diary line item from 
Table 3.7-1 (Schedule of Assessments), remove Section 3.7.3.8 (Electronic Diary), 
and remove Appendix 17 (Electronic Diary).

Remove actigraphy from the trial.

Modify the criteria during the double-blind treatment period for restricted/prohibited 
medications #1, 3, and 12 in Table 4.1-1.

Modify the other efficacy variables and add a section for exploratory efficacy 
variables.

Remove adverse events of interest from the safety variables.

Change the sponsor clinical contact and the North American medical monitor.

Update the address for all sponsor contacts, electronic data capture, and IVRS/IWRS.

Remove the eDiary, actigraphy, and rater surveillance vendors.

Add Bulgaria and Russia as participating countries and update the safety fax 
numbers.

Replace the NPI assessment with the NPI/NPI-NH assessment for 
non-institutionalized subjects.

 
BACKGROUND:
These changes to Protocol 331-12-284 Amendment 2 were made on the basis of 
adjustments considered important to ensure the safety of the subjects enrolled and to 
facilitate appropriate trial implementation and communication.
MODIFICATIONS TO PROTOCOL:
General Revisions:
All changes by section are provided below.
Sectional Revisions:
Note that the tabular format below follows the new protocol template and differs from the 
tabular format used for the previous 331-12-284 protocol amendments.
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Title Page
Manager, Clinical Management
Phone:  
Fax:  
E-mail:  
...
Associate Director, Clinical 
Management
Phone:  
Fax:  
E-mail:  
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Issue Dates:
Date of Amendment 2:  07 Jul 2014
...
Issue Dates:
Date of Amendment 2:  07 Jul 2014
Date of Amendment 3:  10 Sep 2015
Synopsis 
Trial Design
...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 
(e.g., nursing home, dementia unit, 
assisted living facility, or any other 
residential care facility providing long 
term care) or in a non-institutionalized 
setting where the subject is not living 
alone.
...
Screening Period:
The screening period will range from a 
minimum of 2 days to a maximum of 42 
days and will begin when the informed 
consent form (ICF) is signed, prior to the 
initiation of any procedures.  
...
12-week, Double-blind Treatment 
Period:
...
The subjects’ condition will be evaluated 
routinely, including vital signs 
assessments, as required per the local 
guidelines of the institutionalized setting 
or according to the discretion of the 
principal investigator.  Subjects will be 
evaluated at Baseline, Day 3, and at 
Weeks 2, 4, 6, 8, 10, and 12 during the 
double-blind treatment period.  All study 
visits will take place as a clinic visit at 
either the investigator’s site (for 
non-institutionalized subjects) or 
residential facility (for institutionalized 
subjects).  In addition, the subject’s 
identified caregiver will be contacted by 
telephone  every odd numbered week 
after Week 2 (i.e., Weeks 3, 5, 7, 9, 11) 
to assess compliance with IMP, confirm 
any changes to concomitant medications, 
and assure the subject’s well-being.  
Trial-related efficacy and safety 
assessments will be performed as 
outlined in the Schedule of Assessments.
Follow-up Period:
All subjects, whether they complete the 
trial or are withdrawn prematurely for 
any reason, will be followed up for a 
...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 the subject is not living 
alone.  
...
Screening Period:
The screening period will range from 2 
days to 42 days 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.
...
12-week, Double-blind Treatment 
Period:
...
Subjects will be evaluated at Baseline, 
Day 3, and at Weeks 2, 4, 6, 8, 10, and 
12 during the double-blind treatment 
period.  All trial visits will take place as 
a clinic visit at either the investigator’s 
site or residential facility, if applicable.  
All attempts should be made to 
maintain the subjects’ normal routine 
with regard to physician appointments.  
Individual circumstances that fall 
outside this general convention should 
be discussed with the medical monitor 
in order to determine appropriateness 
to proceed.  In addition, the subject’s 
identified caregiver will be contacted by 
telephone at Weeks 3, 5, and 7 to assess 
compliance with IMP, confirm any 
changes to concomitant medications, 
and assure the subject’s well-being. 
Trial-related efficacy and safety 
assessments will be performed as 
outlined in the Schedule of 
Assessments.
Follow-up Period:
All subjects, whether they complete the 
trial or are withdrawn prematurely for 
any reason, will be followed up for a 
safety evaluation 30 (+ 2) days after the 
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safety evaluation 30 (+ 2) days after the 
last dose of IMP during a clinic visit at 
either the investigator’s site or residential 
facility, if institutionalized. If the 
institutionalized subject has left the 
residential facility where he or she 
participated in the trial, the subject 
should be seen at the investigator’s site. 
...
... For those subjects who plan to enroll 
into Trial 331-13-211, the 30-day safety 
follow-up visit for Trial 331-12-284 will 
occur as a clinic visit at either the 
investigator’s site or residential facility, 
if institutionalized.  If the 
institutionalized subject has left the 
residential facility where he or she 
participated in the trial, the 30-day safety 
follow-up visit will occur as a clinic visit 
at the investigator's site.
last dose of IMP during a clinic visit at 
either the investigator’s site or 
residential facility, if applicable. ...
... For those subjects who plan to enroll 
into Trial 331-13-211, the 30-day safety 
follow-up visit for Trial 331-12-284 will 
occur as a clinic visit at either the 
investigator’s site or residential facility, 
if applicable.      
Synopsis
Subject Population
The subject population will include male 
and female subjects between 55 and 
90 years of age (inclusive), who are 
living in either an institutionalized setting 
(e.g., nursing home, dementia unit, 
assisted living facility, or any other
residential care facility providing long 
term care) or in a non-institutionalized 
setting where the subject is not living 
alone. ... Additionally, at both the 
screening and baseline visits, subjects 
must have a Mini-Mental State 
Examination (MMSE) score of 5 to 22, 
inclusive, and a total score (frequency × 
severity) of ≥4 on the 
agitation/aggression item of the 
Neuropsychiatric Inventory—Nursing 
Home (NPI-NH).  The NPI-NH will be 
used for both institutionalized and 
non-institutionalized subjects; however,
the Occupational Disruptiveness 
questions will not be answered for non-
institutionalized subjects.  Instead, the 
Distress questions from the 
Neuropsychiatric Inventory (NPI) will 
replace the Occupational Disruptiveness 
questions for non-institutionalized 
subjects.  This neuropsychiatric 
assessment for non-institutionalized 
subjects based on the NPI/NPI-NH will 
hereafter be referred to as "NPI/NPI-
NH”.
The subject 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 the subject is not living 
alone. ... Additionally, at both the 
screening and baseline visits, subjects 
must have a Mini-Mental State 
Examination (MMSE) score of 5 to 22, 
inclusive, and a total score (frequency x 
severity) of ≥4 on the 
agitation/aggression item of the 
Neuropsychiatric Inventory—Nursing 
Home (NPI-NH) or the 
Neuropsychiatric Assessment for 
Non-institutionalized Patients based on 
the NPI/NPI-NH (hereafter referred to 
as “NPI/NPI-NH”).  The NPI-NH will 
be used for institutionalized subjects and 
the NPI/NPI-NH will be used for 
non-institutionalized subjects.
... Subjects who at any point during the 
double-blind treatment phase transfer 
from an institutionalized setting to a 
non-institutionalized setting, or vice 
versa, will be withdrawn from the trial.   
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 
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... Subjects from a non-institutionalized 
setting who at any point during the 
double-blind treatment phase require 
permanent placement to a nursing home 
or assisted living facility will be 
withdrawn from the trial.  Subjects who 
at any point during the double-blind 
treatment phase transfer from an 
institutionalized setting to a 
non-institutionalized setting will also be 
withdrawn from the trial.  In case of a 
change in the non-institutionalized 
address or institutionalized address, the 
investigator should consult with the 
medical monitor on a case-by-case basis.   
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 
INC Research medical monitor.  Subjects 
in an institutionalized setting may receive 
supervised day passes at the discretion of 
the investigator; however, overnight 
passes will not be allowed for this trial.
... The subject’s caregiver is the person 
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, NPI-NH, NPI/NPI-NH, and 
other applicable trial assessments.
  
... The identified caregiver can be a staff 
member of the institutionalized setting or 
another individual (eg, family member, 
family friend, hired professional 
caregiver) 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, NPI-NH, 
NPI/NPI-NH, and other applicable trial 
assessments.  
medical monitor.  All attempts should 
be made to maintain the subjects’ 
normal routine with regard to 
appointments with physicians and 
overnight accommodations.  Subjects 
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 subjects’ normal routine.
... For purposes of this trial, the 
subject’s caregiver is the person 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, NPI/NPI-NH, and other 
applicable trial assessments. 
... The identified caregiver can be a staff 
member of the institutionalized setting 
or another individual (eg, family 
member, family friend, hired 
professional caregiver) 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, NPI-NH, and other 
applicable trial assessments.  
Synopsis
Inclusion/Exclusion 
Criteria
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, 
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 
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substance-induced dementia, 
normal pressure hydrocephalus, or 
any other specific 
non-Alzheimer’s-type dementia; 
subjects 55 years or older with a 
diagnosis of Down syndrome.
...

Subjects with a history of stroke, 
transient ischemic attack, or 
pulmonary or cerebral embolism.

Subjects with a history of clinically 
relevant traumatic brain injury with 
neurological sequelae.

Subjects with a history of a deep 
venous thrombosis within the 5 
years prior to the screening visit.

Subjects with delirium, unless 
resolved with no symptoms for at 
least 30 days prior to the screening 
visit.
...

Subjects considered in poor general 
health based on the investigator’s 
judgment.  
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.
...

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 30 days prior to 
the screening visit.
...

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.
Synopsis
Trial Sites
It is planned that approximately 330 
subjects will be screened at 
approximately 46 trial centers worldwide 
so that 230 subjects will be randomized 
to treatment.
It is planned that approximately 520
subjects will be screened at 
approximately 65 trial sites worldwide 
so that 260 subjects will be randomized 
to treatment.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Other Outcome Variables:
...
Safety Variables:
... Other safety variables will include the 
MMSE score 
 
 
 
 
 
 
and adverse events of interest 
(e.g., falls, sedation, diabetes, weight 
changes, QTc prolongation, or deaths).
Pharmacokinetic samples for 
determination of brexpiprazole and its 
major metabolite, DM-3411, will be 
collected at the baseline visit and at the 
Week 8 and Week 12/ET trial visits, at 
the same time as the sample collection 
for the clinical laboratory tests.  
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
:
...
Safety Variables:
... Other safety variables will include the 
MMSE score 
 
 
 
 
 
 
Pharmacokinetic samples for 
determination of brexpiprazole and its 
metabolite(s) will be collected at the 
baseline visit and at the Week 8 and 
Week 12/ET trial visits, at the same time 
as the sample collection for the clinical 
laboratory tests.  
 
 
 
 
 
Synopsis
Statistical Methods
The 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 the endpoint in the 
CMAI total score, to achieve 80% power 
at a 2-sided alpha level of 0.05.  The 
resulting sample size is 103 subjects/arm.  
The 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 the endpoint in the 
CMAI total score, to achieve 85% 
power at a 2-sided alpha level of 0.05.  
The resulting sample size is 
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After allowance of 10% non-evaluable 
subjects, it results in a sample size of 
115 subjects/arm, which means the total 
sample size is 230 subjects.  
117 subjects/arm.  After allowance of 
10% non-evaluable subjects, it results in 
a sample size of 130 subjects/arm, 
which means the total sample size is 
260 subjects.  
Synopsis
Trial Duration
The time from enrollment of the first 
subject to the last subject’s last trial visit 
will be approximately 3.5 years, of which 
approximately 3 years are allotted for 
recruitment of subjects.  
The time from enrollment of the first 
subject to the last subject’s last trial visit 
will be approximately 4.5 years, of 
which approximately 4 years are allotted 
for recruitment of subjects.  
Section 2.1
Trial Rationale
In light of the Food and Drug 
Administration (FDA) boxed warning of 
increased mortality with the use of 
antipsychotics in elderly subjects with 
dementia-related psychosis and similar 
caution advised by other regulatory 
authorities, the clinical trial will be 
conducted in an environment that allows 
for close safety monitoring, in subjects 
who are living in either an 
institutionalized setting (e.g., nursing 
home, dementia unit, assisted living 
facility, or any other residential care 
facility providing long term care) or in a 
non-institutionalized setting where the 
subject is not living alone and has a 
caregiver who can spend a minimum of 
2 hours per day for 4 days per week with 
the subject in order to assess changes in 
the subject’s condition.  
In light of the Food and Drug 
Administration (FDA) boxed warning of 
increased mortality with the use of 
antipsychotics in elderly subjects with 
dementia-related psychosis and similar 
caution advised by other regulatory 
authorities, the clinical trial will be 
conducted in an environment that allows 
for close safety monitoring, in subjects 
who are living in either an 
institutionalized setting or in a non-
institutionalized setting where the 
subject is not living alone and has a 
caregiver who can spend a minimum of 
2 hours per day for 4 days per week 
with the subject in order to assess 
changes in the subject’s condition.  
Section 3.1
Type/Design of 
Trial
... 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 
(e.g., nursing home, dementia unit, 
assisted living facility, or any other 
residential care facility providing long 
term care) or in a non-institutionalized 
setting where the subject is not living 
alone.  
... 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 the subject is not living 
alone.
Section 3.1
Type/Design of 
Trial
Screening Period
The screening period will range from a 
minimum of 2 days to a maximum of 42 
days and will begin when the informed 
consent form (ICF) is signed, prior to the 
initiation of any procedures.
...
In addition, the subject will be monitored 
through actigraphy and eDiary 
assessments as a means of corroborating 
information recorded on the CMAI.  
Both assessments will be initiated after 
the ICF is signed during the screening 
visit and followed through 
The screening period will range from 2 
days to 42 days 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.
...
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 and/or facility 
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Week 12/Early Termination (ET).  The 
subjects will be given an actigraph, 
which will record their physical activity, 
to wear on their nondominant wrist for 
24 hours/day.  If the subject decides not 
to wear the actigraph at any time after the 
consent is obtained, the assessment may 
be discontinued and study participation 
will not be affected.  The subject’s 
behavior will be logged into an eDiary by 
the caregiver and/or facility staff.
staff.  This diary data along with the 
collection of progress notes will be sent 
to the CST group on a routine basis in 
order to corroborate information 
recorded on the CMAI.  Since the diary 
data is a tool to assist the 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, 
and/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.
Section 3.1
Type/Design of 
Trial
12-week, 
Double-blind 
Treatment Period
The subjects’ condition will be evaluated 
routinely, including vital signs 
assessments, as required per the local 
guidelines of the institutionalized setting 
or according to the discretion of the 
principal investigator.  Subjects will be 
evaluated at Baseline, Day 3, and at 
Weeks 2, 4, 6, 8, 10, and 12 during the 
double-blind treatment period.  All study 
visits will take place as a clinic visit at 
either the investigator’s site (for non-
institutionalized subjects) or residential 
facility (for institutionalized subjects).  In 
addition, the subject’s identified 
caregiver will be contacted by telephone 
every odd numbered week after Week 2 
(i.e., Weeks 3, 5, 7, 9, 11) to assess 
compliance with IMP, confirm any 
changes to concomitant medications, and 
assure the subject’s well-being.  Trial-
related efficacy and safety assessments 
will be performed as outlined in the 
Schedule of Assessments (Table 3.7-1).
  
If a subject discontinues the trial 
prematurely, every effort will be made to 
complete the Week 12/ET evaluations 
Subjects will be evaluated at Baseline, 
Day 3, and at Weeks 2, 4, 6, 8, 10, and 
12 during the double-blind treatment 
period.  All trial visits will take place as 
a clinic visit at either the investigator’s 
site or residential facility, if applicable.  
All attempts should be made to 
maintain the subjects’ normal routine 
with regard to physician appointments.  
Individual circumstances that fall 
outside this general convention should 
be discussed with the medical monitor 
in order to determine appropriateness 
to proceed.  In addition, the subject’s 
identified caregiver will be contacted by 
telephone at Weeks 3, 5, and 7 to assess 
compliance with IMP, confirm any 
changes to concomitant medications, 
and assure the subject’s well-being. 
Trial-related efficacy and safety 
assessments will be performed as 
outlined in the Schedule of Assessments 
(Table 3.7-1).  
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prior to administering additional 
medications for the treatment of agitation 
or other prohibited medications.
Section 3.1
Type/Design of 
Trial
Follow-up Period
All subjects, whether they complete the 
trial or are withdrawn prematurely for 
any reason, will be followed up for a 
safety evaluation 30 (+ 2) days after the 
last dose of IMP during a clinic visit at 
either the investigator’s site or residential 
facility, if institutionalized.  If the 
institutionalized subject has left the 
residential facility where he or she 
participated in the trial, the subject 
should be seen at the investigator’s site.  
... For those subjects who plan to enroll 
into Trial 331-13-211, the 30-day safety 
follow-up visit for Trial 331-12-283 will 
occur as a clinic visit either at the 
investigator’s site or residential facility.  
If the institutionalized subject has left the 
residential facility where he or she 
participated in the trial, the 30-day safety 
follow-up visit will occur as a clinic visit 
at the investigator's site.
All subjects, whether they complete the 
trial or are withdrawn prematurely for 
any reason, will be followed up for a 
safety evaluation 30 (+ 2) days after the 
last dose of IMP during a clinic visit at 
either the investigator’s site or 
residential facility, if applicable.  
... For those subjects who plan to enroll 
into Trial 331-13-211, the 30-day safety 
follow-up visit for Trial 331-12-283 will 
occur as a clinic visit either at the 
investigator’s site or residential facility, 
if applicable.  
Figure 3.1-1
Trial Design 
Schema
Screening
Subjects with agitation associated with 
dementia of the Alzheimer’s type
(N = 330)
2 to 42 days
Days –42 to –2
Screening
Subjects with agitation associated with 
dementia of the Alzheimer’s type
(N = 520 screened)
2 to 42 days
Days –42 to –2
(with an option to extend with approval 
of the medical monitor)
12-week Double-blind Treatment Period
Brexpiprazole flexible dose
Dose range 0.5 mg/day to 2 mg/day 
(target dose is 1 mg/day)
(N = 115)
Placebo 
(N = 115)
Randomized (1:1)
(N = 230)
12-week Double-blind Treatment Period
Brexpiprazole flexible dose
Dose range 0.5 mg/day to 2 mg/day 
(target dose is 1 mg/day)
(N = 130)
Placebo
(N = 130)
Randomized (1:1)
(N = 260)
Section 3.3
Trial Population
The subject population will include male 
and female subjects between 55 and 
90 years of age (inclusive), who are 
living in either an institutionalized setting 
(e.g., nursing home, dementia unit, 
assisted living facility, or any other 
The subject 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 the subject is not living 
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residential care facility providing long 
term care) or in a non-institutionalized 
setting where the subject is not living 
alone. ... Additionally, at both the 
screening and baseline visits, subjects 
must have a Mini-Mental State 
Examination (MMSE) score of 5 to 22, 
inclusive, and a total score (frequency x 
severity) of ≥4 on the 
agitation/aggression item of the NPI-NH.  
The NPI-NH will be used for both 
institutionalized and non-institutionalized 
subjects; however, the Occupational 
Disruptiveness questions will not be 
answered for non-institutionalized 
subjects.  Instead, the Distress questions 
from the Neuropsychiatric Inventory 
(NPI) will replace the Occupational 
Disruptiveness questions for non-
institutionalized subjects.  This 
neuropsychiatric assessment for non-
institutionalized subjects based on the 
NPI/NPI-NH will hereafter be referred to 
as "NPI/NPI-NH”.
Subjects must have been residing at their 
current location for at least 14 days 
before screening and be expected to 
remain at the same location for the 
duration of the trial.  Subjects from a 
non-institutionalized setting who at any 
point during the double-blind treatment 
phase require permanent placement to a 
nursing home or assisted living facility 
will be withdrawn from the trial.  
Subjects who at any point during the 
double-blind treatment phase transfer 
from an institutionalized setting to a 
non-institutionalized setting will also be 
withdrawn from the trial.  In case of a 
change in the non-institutionalized 
address or institutionalized address, the 
investigator should consult with the 
medical monitor on a case-by-case basis.  
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 
INC Research medical monitor.  Subjects 
in an institutionalized setting may receive 
supervised day passes at the discretion of 
the investigator; however, overnight 
passes will not be allowed for this trial.
alone. ... Additionally, at both the 
screening and baseline visits, subjects 
must have a Mini-Mental State 
Examination (MMSE) score of 5 to 22, 
inclusive, and a total score (frequency x 
severity) of ≥4 on the 
agitation/aggression item of the NPI-NH 
or the Neuropsychiatric Assessment for 
Non-institutionalized Patients based on 
the NPI/NPI-NH (hereafter referred to 
as “NPI/NPI-NH”).  The NPI-NH will 
be used for institutionalized subjects and 
the NPI/NPI-NH will be used for 
non-institutionalized subjects.
Subjects must have been residing at 
their current location for at least 14 days 
before screening and be expected to 
remain at the same location for the 
duration of the trial.  Subjects who at 
any point during the double-blind 
treatment phase transfer from an 
institutionalized setting to a 
non-institutionalized setting, or vice 
versa, will be withdrawn from the trial.  
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.  All attempts should 
be made to maintain the subjects’ 
normal routine with regard to 
appointments with physicians and 
overnight accommodations.  Subjects 
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 subjects’ normal routine.
...
It is planned that approximately 520
subjects will be screened at 
approximately 65 trial sites worldwide 
in order to randomize 260 subjects.
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...
It is planned that approximately 330 
subjects will be screened at 
approximately 46 trial centers worldwide 
in order to randomize 230 subjects.
Section 3.3.1.1
Non-
institutionalized 
Subjects
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, NPI-NH, 
NPI/NPI-NH, and other applicable trial 
assessments, including completion of the 
eDiary. ... The caregiver is the person 
who should accompany the subject to all 
visits where the CMAI and NPI-NH are 
administered unless other arrangements 
are made and approved by the sponsor.  
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, NPI/NPI-NH, and other 
applicable trial assessments, including 
completion of the diary. ... The 
caregiver is the person who should 
accompany the subject to all visits 
where the CMAI and NPI/NPI-NH are 
administered unless other arrangements 
are made and approved by the sponsor. 
Section 3.3.1.2
Institutionalized 
Subjects
... 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, NPI-NH, NPI/NPI-NH, and 
other applicable trial assessments.  
... 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, NPI-NH, and other 
applicable trial assessments.  
Table 3.4.2-1
Inclusion Criteria
8. Subjects with a total score (frequency 
x severity) of ≥4 on the 
agitation/aggression item of the NPI-NH 
at the screening and baseline visits.
8. Subjects with a total score (frequency 
x severity) of ≥4 on the 
agitation/aggression item of the NPI-NH 
(for institutionalized subjects) or the 
NPI/NPI-NH (for non-institutionalized 
subjects) at the screening and baseline 
visits.
Table 3.4.3-1
Exclusion Criteria
1. Subjects with dementia or other 
memory impairment not due to 
Alzheimer’s disease, such as ... 
substance-induced dementia, normal 
pressure hydrocephalus, or any other 
specific non-Alzheimer’s-type dementia; 
subjects aged 55 years or older with a 
diagnosis of Down syndrome.
1. Subjects with dementia or other 
memory impairment not due to 
Alzheimer’s disease, such as ... 
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.
3. Subjects with a history of stroke, 
transient ischemic attack, or pulmonary 
or cerebral embolism.
3. Subjects with a history of stroke, 
well-documented transient ischemic 
attack, or pulmonary or cerebral 
embolism.
4. Subjects with a history of clinically 
relevant traumatic brain injury with 
neurological sequelae.
(this exclusion criterion was removed)
5. Subjects with a history of a deep 
venous thrombosis within the 5 years 
prior to the screening visit.
(this exclusion criterion was removed)
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7. Subjects with delirium, unless resolved 
with no symptoms for at least 30 days 
prior to the screening visit.
5. 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-IV-TR 
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 
disorderunless on a stable dose(s) 
of antidepressant medication(s) for 
the 30 days prior to randomization.  
Please note: antidepressant 
medications that are CYP2D6 or 
CYP3A4 inhibitors are prohibited 
(see Table 4.1-2 for prohibited 
antidepressant medications).

Eating disorder (including anorexia 
nervosa or bulimia)unless 
resolved with no symptoms for at 
least 1 year prior to screening

Obsessive-compulsive 
disorderunless resolved with no 
symptoms for at least 1 year prior to 
screening

Panic disorderunless resolved 
with no symptoms for at least 1 year 
prior to screening

Posttraumatic stress 
disorderunless resolved with no 
symptoms for at least 1 year prior to 
screening
6. Subjects who have been diagnosed 
with an Axis I disorder (DSM-IV-TR 
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 major depressive 
disorder are eligible provided that 
they have been on a stable dose(s) 
of antidepressant medication(s) for 
the 30 days prior to randomization.  
Please note: antidepressant 
medications that are CYP2D6 or 
CYP3A4 inhibitors are prohibited 
(see Table 4.1-2 for prohibited 
antidepressant medications).
9. Subjects with an Axis II (DSM-IV-TR 
criteria) diagnosis of borderline, 
antisocial, paranoid, schizoid, 
schizotypal, or histrionic personality 
disorder.
(this exclusion criterion was removed)
11. Subjects who currently have 
clinically significant neurological, 
hepatic, renal, metabolic, hematological, 
immunological, cardiovascular, 
pulmonary, or gastrointestinal disorders.  
8. Subjects who currently have clinically 
significant neurological, hepatic, renal, 
metabolic, hematological, 
immunological, cardiovascular, 
pulmonary, gastrointestinal, or 
psychiatric disorders.  
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13. Subjects with insulin-dependent 
diabetes mellitus (IDDM) (i.e., any 
subjects using insulin) may be eligible 
for the trial if their condition is 
well-controlled and if they do not have 
current microalbuminuria.  Subjects with 
non-IDDM may be eligible for the trial if 
their condition is stable as determined by 
satisfying ALL of the following criteria:

Glycosylated hemoglobin (HbA1c) < 
8.0%, AND

Screening glucose must be 
125 mg/dL (fasting) or 
< 200 mg/dL (non-fasting).  If the 
non-fasting screening glucose is 
200 mg/dL, subjects must be 
retested in a fasted state and the 
retest value must be 125 mg/dL, 
AND

Urine albumin-to-creatinine ratio 
(ACR) must be < 30 mg/g 
(calculated), AND

Subject has been maintained on a 
stable regimen of oral anti-diabetic 
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, 
AND

Subject has not had any 
hospitalizations within the 3 months 
prior to screening due to diabetes or 
complications related to diabetes.
Subjects with newly diagnosed diabetes 
during screening are excluded.
10. Subjects with diabetes mellitus may 
be eligible for the trial if their condition 
is stable and well-controlled as 
determined by satisfying ALL of the 
following criteria:

HbA1c < 8.0%, AND

Screening glucose must be 
125 mg/dL (fasting) or 
< 200 mg/dL (non-fasting).  If the 
non-fasting 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 IDDM (ie, any subjects 
using insulin) must also satisfy the 
below criterion:

No current microalbuminuria; ie, 
urine ACR must be < 30 mg/g 
(calculated).
Subjects with newly diagnosed diabetes 
during screening are excluded.
14. Subjects with clinically significant 
chronic kidney disease based on the 
investigator’s judgment.
(this exclusion criterion was removed)
17. Subjects with a clinical history 
consistent with a hypercoagulable state 
and/or evidence of a hypercoagulable 
state based on laboratory tests.
(this exclusion criterion was removed)
18. Subjects with human 
immunodeficiency virus (HIV) 
seropositive status/acquired 
immunodeficiency syndrome, or chronic 
hepatitis B or C.  
13. Subjects with seropositive status for 
hepatitis B (ie, HBsAg positive) or 
hepatitis C (ie, anti-HCV positive).  
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19. Subjects with clinically relevant 
sensory impairments such as visual or 
hearing loss that would limit subjects’ 
participation in the trial and ability to 
comply with the protocol requirements 
based on the investigator’s judgment.
(this exclusion criterion was removed)
20. Subjects with significant swallowing 
difficulties that would preclude taking 
oral medications in tablet form; subjects 
with clinically relevant dysphagia.
(this exclusion criterion was removed)
21. Subjects considered in poor general 
health based on the investigator’s 
judgment.  
14. 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.
22. Subjects with weight loss of more 
than 5% in the7 days prior to the baseline 
visit or more than 10% between the 
screening and baseline visits.
(this exclusion criterion was removed)
23. Subjects with weight < 40 kilograms.
15. Subjects with a BMI < 18.5 kg/m2.
24. Subjects with dehydration or 
hypovolemia, or a consistent or chronic 
pattern of poor fluid and/or nutritional 
intake, or with recent need for 
supplemental fluid via intravenous 
solution or supplemental nutrition via 
gastric tube. 
(this exclusion criterion was removed)
25. Subjects who are bedridden.
(this exclusion criterion was removed)
26. Subjects with recent clinically 
significant infection, as evidenced by 
treatment with intravenous antibiotics or 
hospitalization, within the 2 weeks prior 
to the screening visit. 
(this exclusion criterion was removed)
27. Subjects who are known to be poor 
CYP2D6 metabolizers.
(this exclusion criterion was removed)
30. ... Tests with abnormal results should 
be repeated to ensure reproducibility of 
the abnormality before excluding a 
subject based on the criteria noted above.
In addition, subjects with the following 
laboratory test and ECG results at 
screening must be excluded from the 
trial:

Platelets ≤ 120,000/mm3

Hemoglobin ≤ 10 g/dL for women, 
11 g/dL for men 

Neutrophils, absolute ≤ 1500/mm3

...

ACR > 30 mg/g (calculated as urine 
18. ...
In addition, subjects with the following 
laboratory test and ECG results at 
screening must be excluded from the 
trial:

Platelets ≤ 75,000/mm3

Hemoglobin ≤ 9 g/dL 

Neutrophils, absolute ≤ 1000/mm3

...

QTcF 450 msec in men and 470 
msec in women (see Section 3.7.4.4
for further details), unless due to 
ventricular pacing
Tests with exclusionary results should 
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albumin [mg/dL] / urine creatinine 
[g/dL])

...

QTcF 450 msec in men and 470 
msec in women (see Section 3.7.4.4
for further details)
be repeated (if ECG, 3 consecutive 
recordings) to ensure reproducibility of 
the abnormality before excluding a 
subject based on the criteria noted 
above.
33. Subjects who have a medical 
condition that requires treatment with an 
anticoagulant.
21. Subjects who have a current medical 
condition that requires treatment with an 
anticoagulant.
36. Subjects who received brexpiprazole 
in any prior clinical trial.
24. Subjects who received brexpiprazole 
in any prior clinical trial or 
commercially available brexpiprazole
(Rexulti®).
39. Subjects who participated in a 
clinical trial within the last 180 days or 
who participated in more than 
2 interventional clinical trials within the 
past year.
27. Subjects who participated in a 
clinical trial within the last 30 days.
Section 3.4.3
Exclusion Criteria
... In the event that a screen failure is 
rescreened after the 42-day screening 
period expires, a new ICF must be 
signed, a new screening number 
assigned, and all screening procedures 
repeated.
... 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.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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...
Section 3.5.6
Pharmacokinetic/ 
Pharmacodynamic 
Variables
Plasma concentrations will be 
determined for brexpiprazole and its 
major metabolite, DM-3411, and 
descriptive statistics will be calculated.  
Plasma concentrations will be 
determined for brexpiprazole and its 
metabolite(s) and descriptive statistics 
will be calculated.  
Section 3.7
Trial Procedures
The time from enrollment of the first 
subject to the last subject’s last trial visit 
will be approximately 3.5 years, of which 
approximately 3 years are allotted for 
recruitment of subjects.
...
 
t, the CST 
will perform regular quality reviews of 
CMAI data and will compare these data 
against other sources of behavioral 
information, including patterns of 
The time from enrollment of the first 
subject to the last subject’s last trial visit 
will be approximately 4.5 years, of 
which approximately 4 years are allotted 
for recruitment of subjects.  
...
 
the CST 
will perform regular quality reviews of 
CMAI data and will compare these data 
against other sources of behavioral 
information, including behavior logs 
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movement using actigraphy technology 
(refer to Section 3.7.3.7), behavior logs 
collected by caregivers through 
electronic diaries (refer to Section 
3.7.3.8), and investigator progress notes.
All study visits will take place as a clinic 
visit at either the investigator’s site (for 
non-institutionalized subjects) or 
residential facility (for institutionalized 
subjects). 
collected by caregivers through paper 
diaries and investigator progress notes.
All trial visits will take place as a clinic 
visit at either the investigator’s site or 
residential facility, if applicable.  All 
attempts should be made to maintain the 
subjects’ normal routine with regard to 
physician appointments.  Individual 
circumstances that fall outside this 
general convention should be 
discussed with the medical monitor in 
order to determine appropriateness to 
proceed.
Table 3.7-1
Schedule of 
Assessments
The changes to the Schedule of Assessments are presented below.
Bold and underlined text:  Changed or added text
Bold and strikethrough text:  Deleted text
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Table 3.7-1  Schedule of Assessments
Assessment
Visit
Screeninga
Baseline 
(Day 0)
Day 3
Wk 2
Wk 4
Wk 6
Wk 8
Wk 10
Wk 12/ ETb
FUc
ENTRANCE/HISTORY
Informed consente
X
Inclusion/exclusion criteriaf
X
X
Demography
X
Medical history
X
Psychiatric history
X
Neurological historyg
X
Prior medication washouth
X
NINCDS-ADRDA
X
Hachinski Ischemic Scale (Rosen 
Modification)g
X
HIV, HBsAg, and anti-HCV
X
Pre-Baseline Packeti
X
EFFICACY
CMAI
X
X
X
X
X
X
X
X
CGI-Sj
X
X
X
X
X
X
X
X
NPI-NH (for institutionalized subjects) or 
NPI/NPI-NH (for non-institutionalized 
subjects)
X
X
X
X
X
X
X
X
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Table 3.7-1  Schedule of Assessments
Assessment
Visit
Screeninga
Baseline 
(Day 0)
Day 3
Wk 2
Wk 4
Wk 6
Wk 8
Wk 10
Wk 12/ ETb
FUc
OTHER
 
Actigraphyk
-----------------------------------------------------X-------------------------------------------------
Electronic diariesl
-----------------------------------------------------X-------------------------------------------------
SAFETY
Physical examinationmk
X
X
X
Neurological examinationnl
X
X
X
Vital signsom
X
X
X
X
X
X
X
X
X
Clinical laboratory tests (hematology, serum 
chemistry, urinalysis)pn
X
Xqo
Xp
Xp
X
Prolactin (blinded)pn
X
X
X
X
TSH with reflex to free T4 if abnormalpn
X
X
HbA1c
pn
X
X
PT, aPTT, and INRpn
X
X
ACTH and cortisolpn
X
X
Urine pregnancy test (women of childbearing 
potential) onlyrq
X
X
X
X
ECGsr
X
X
X
X
X
Blood alcoholt,us,t
X
Urine drug screent,us,t
X
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Table 3.7-1  Schedule of Assessments
Assessment
Visit
Screeninga
Baseline 
(Day 0)
Day 3
Wk 2
Wk 4
Wk 6
Wk 8
Wk 10
Wk 12/ ETb
FUc
Wk 16d
MMSE
X
X
X
Adverse eventswv
X
X
X
X
X
X
X
X
X
X
Pharmacokinetic samplingxw
X
X
X
Concomitant medicationszy
X
X
X
X
X
X
X
X
X
X
OTHER PROCEDURES
Register trial visit in IVRS/IWRS
X
X
X
X
X
X
X
X
X
Randomize eligible subjects via IVRS/IWRS
X
IMP dispensingbbaa
X
X
X
X
X
X
X
IMP accountability
X
X
X
X
X
X
X
Telephone contactccbb
ADDITIONAL ENTRANCE/HISTORY
MRI/CT scanddcc
Xddcc
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Table 3.7-1
Schedule of 
Assessments, footnotes
aScreening begins when the ICF is 
signed.  Screening procedures must be 
initiated between Day −42 and Day 
−2.  
aScreening begins when the ICF is 
signed.  Screening procedures must be 
initiated between Day −42 and Day −2.  
The screening period may be extended 
after discussion with and approval by 
the medical monitor.  
cAll subjects, whether they complete 
the trial or are withdrawn prematurely 
for any reason, will be followed up for 
a safety evaluation 30 (+ 2) days after 
the last dose of IMP during a clinic 
visit at either the investigator’s site or 
residential facility.  If the 
institutionalized subject has left the 
residential facility where he or she 
participated in the trial, the subject 
should be seen at the investigator’s 
site. ... For those subjects who plan to 
enroll into Trial 331-13-211, the 
30-day safety follow-up visit for Trial 
331-12-284 will occur as a clinic visit 
at either the investigator’s site or
residential facility.  If the 
institutionalized subject has left the 
residential facility where he or she 
participated in the trial, the 30-day 
safety follow-up visit will occur as a 
clinic visit at the investigator's site.
cAll subjects, whether they complete 
the trial or are withdrawn prematurely 
for any reason, will be followed up for 
a safety evaluation 30 (+ 2) days after 
the last dose of IMP during a clinic visit 
at either the investigator’s site or 
residential facility, if applicable. ... For 
those subjects who plan to enroll into 
Trial 331-13-211, the 30-day safety 
follow-up visit for Trial 331-12-284 
will occur as a clinic visit at either the
investigator’s site or residential facility, 
if applicable.  
kAfter the ICF is signed during the 
screening visit, the actigraphy device 
will be put on the subject’s 
nondominant wrist and worn daily 
until Week12/ET.  It is recommended 
that the actigraph be checked daily to 
ensure that the subject is wearing it 
and that it continues to be operational.  
At every study visit (except the Day 3 
visit), subjects will take off the watch 
so that site personnel can download 
the data stored in the device, and the 
device battery will be changed.  If the 
screening period extends beyond 
4 weeks, the battery will need to be 
replaced once.  Once the download is 
complete, the device will be placed 
back on the subject.
(this footnote was removed)
lElectronic diary (eDiary) information 
will be entered by the caregiver and/or 
facility staff after the ICF is signed.
(this footnote was removed)
mPhysical examination includes 
measurement of height and waist 
circumference at screening and waist 
circumference at Weeks 6 and 12/ET.
kPhysical examination includes 
measurement of height and waist 
circumference at screening and waist 
circumference at Week 12/ET.
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nA detailed neurological examination 
will be performed by a physician at 
screening, Week 6, Week 12/ET, and 
as needed during the trial for new 
onset neurological symptoms.  
lA detailed neurological examination 
will be performed by a physician at 
screening, Week 12/ET, and as needed 
during the trial for new onset 
neurological symptoms.  
(new footnote)
pUrinalysis is not required at Week 4 or 
Week 8.
s... Any screening ECG with abnormal 
result(s) considered to be clinically 
significant should be repeated to 
confirm the finding(s) before 
excluding the subject from the trial.  
r... Any screening ECG with abnormal 
result(s) considered to be clinically 
significant should be repeated (with 3 
consecutive ECG recordings) to 
confirm the finding(s) before excluding 
the subject from the trial.  
ccThe subject’s identified caregiver 
will be contacted by telephone every 
odd numbered week after Week 2 
(i.e., Weeks 3, 5, 7, 9, 11) to assess 
compliance with IMP, confirm any 
changes to concomitant medications, 
and assure the subject’s well-being.
bbThe subject’s identified caregiver will 
be contacted by telephone at Weeks 3, 
5, and 7 to assess compliance with IMP, 
confirm any changes to concomitant 
medications, and assure the subject’s 
well-being.
Section 3.7.1.1
Screening
The screening period begins after 
written informed consent has been 
obtained.  Subjects will participate in 
screening activities for a minimum of 
2 days and a maximum of 42 days. ...
Screening evaluations will include the 
following:
...

A standard 12-lead ECG will be 
performed after the subject has 
been supine and at rest for at least 
5 minutes.  Subjects with 
screening QTcF 450 msec 
(males) or 470 msec (females) 
will be excluded from the trial 
(see Section 3.7.4.4). ...  

Blood samples will be drawn for 
human immunodeficiency virus 
(HIV) serology and the presence 
of hepatitis B surface antigen 
(HBsAg) and antibodies to 
hepatitis C (anti-HCV).
...

Albumin-to-creatinine ratio 
(ACR) will be determined (must 
be < 30 mg/g; calculated as urine 
albumin [mg/dL] / urine 
creatinine [g/dL]).
...

A qualified and certified rater will 
administer the CMAI, NPI-NH, 
and NPI/NPI-NH to the caregiver.
The screening period begins after 
written informed consent has been 
obtained.  Subjects will participate in 
screening activities for 2 days to
42 days.  The screening period may be 
extended after discussion and approval 
of the medical monitor. ... 
Screening evaluations will include the 
following:
...

A standard 12-lead ECG will be 
performed after the subject has 
been supine and at rest for at least 
5 minutes.  Subjects with screening 
QTcF 450 msec (males) or 470 
msec (females) will be excluded 
from the trial, unless due to 
ventricular pacing (see Section 
3.7.4.4). ...

Blood samples will be drawn for 
the presence of hepatitis B surface 
antigen (HBsAg) and antibodies to 
hepatitis C (anti-HCV).
...

Urine albumin-to-creatinine ratio 
(ACR) will be determined only for 
subjects with insulin-dependent 
diabetes mellitus (IDDM) (must be 
< 30 mg/g; calculated as urine 
albumin [mg/dL]/urine creatinine 
[g/dL]).
...
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...

After the ICF is signed during the 
screening visit, the actigraphy 
device will be put on the subject’s 
nondominant wrist.  The 
actigraph will be worn 
continuously throughout the 
double-blind treatment period.  It 
is recommended that the 
actigraph be checked daily to 
ensure that the subject is wearing 
it and that it continues to be 
operational.  At every study visit 
(except the Day 3 visit), subjects 
will take off the device so that site 
personnel can download the data 
stored in the device, and the 
device battery will be changed.  
Once the download is complete, 
the device will be placed back on 
the subject.  If the screening 
period extends beyond 4 weeks, 
the battery will need to be 
replaced once.

The subject’s caregiver and/or 
facility staff will complete an 
electronic diary (eDiary) daily (if 
possible) after the ICF is signed, 
continuing through Week 12/ET.

A qualified and certified rater will 
administer the CMAI and NPI-NH 
(for institutionalized subjects) or 
NPI/NPI-NH (for non-
institutionalized subjects) to the 
identified caregiver.
...

The subject’s caregiver and/or 
facility staff will complete a paper 
diary daily (if possible) after the 
ICF is signed, continuing through 
Week 12/ET.
Section 3.7.1.2
Baseline (Day 0)
If the subject is found to be eligible 
for the trial during the screening 
period, the following procedures will 
be performed at the baseline visit:
...

A qualified and certified rater will 
administer the CMAI, NPI-NH, 
and NPI/NPI-NH to the caregiver.
...

 
 
 
 
 
 
 
 
If the subject is found to be eligible for 
the trial during the screening period, the 
following procedures will be performed 
at the baseline visit:
...

A qualified and certified rater will 
administer the CMAI and NPI-NH 
(for institutionalized subjects) or 
NPI/NPI-NH (for non-
institutionalized subjects) to the 
identified caregiver.
...

 
 
 
  
 
 
 
 
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...

Actigraphy recording will 
continue.

eDiary recording will continue.
 
 
 
 
 
 
 
...

Diary recording will continue.
Section 3.7.1.3.1
Day 3
This visit is to occur within + 2 days 
of the target visit date.  At the Day 3 
visit the following evaluations will be 
performed:
...

Actigraphy recording will 
continue.

eDiary recording will continue.
This visit is to occur within + 2 days of 
the target visit date.  At the Day 3 visit 
the following evaluations will be 
performed:
...

Diary recording will continue.
Section 3.7.1.3.2
Weeks 2, 4, 6, 8, and 
10
... The following evaluations will be 
performed at the Weeks 2, 4, 6, 8, and 
10 visits.
...

A qualified and certified rater will 
administer the CMAI, NPI-NH, 
and NPI/NPI-NH to the caregiver.
...

 
...

At each visit, subjects will take 
off the actigraph so that site 
personnel can download the data 
stored in the device, and the 
device battery will be changed.  
Once the download is complete, 
the device will be placed back on 
the subject.

eDiary recording will continue.
...
The following additional evaluations 
will be performed at the designated 
visits:

A complete physical examination 
... The following evaluations will be 
performed at the Weeks 2, 4, 6, 8, and 
10 visits.
...

A qualified and certified rater will 
administer the CMAI and NPI-NH 
(for institutionalized subjects) or 
NPI/NPI-NH (for non-
institutionalized subjects) to the 
identified caregiver.
...

Diary recording will continue.
...
The following additional evaluations 
will be performed at the designated 
visits:

 

A fasting blood draw for clinical 
laboratory tests (hematology and 
serum chemistry) will be obtained 
at Weeks 4 and 8 only.  Vital sign 
and ECG assessments should be 
completed before any blood 
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(including waist circumference) 
will be performed at Week 6 only.

A detailed neurological 
examination, which will consist 
of an evaluation of the subject’s 
mental status, cranial nerves, 
motor system (e.g., motor 
strength, muscle tone, reflexes), 
cerebellar system (e.g., 
coordination), gait and station, 
and sensory system, will be 
performed by a physician at Week 
6 only.

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A fasting blood draw for clinical 
laboratory tests (hematology and 
serum chemistry, including 
prolactin [blinded]) will be 
obtained and urine will be 
collected for urinalysis at Weeks 
4 and 8 only.  Vital sign and ECG 
assessments should be completed 
before any blood samples are 
collected.
...

Women of childbearing potential 
will be given a urine pregnancy 
test at Weeks 4 and 8 only.  Any 
positive result must be confirmed 
by a serum pregnancy test.  
Subjects with positive urine and 
serum test results must 
discontinue trial medication and 
be withdrawn from the trial.
samples are collected.
...
In addition, the subject’s identified 
caregiver will be contacted by 
telephone at Weeks 3, 5, and 7 to assess 
compliance with IMP, confirm any 
changes to concomitant medications, 
and assure the subject’s well-being.
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In addition, the subject’s identified 
caregiver will be contacted by 
telephone every odd numbered week 
after Week 2 (i.e., Weeks 3, 5, 7, 9, 
11) to assess compliance with IMP, 
confirm any changes to concomitant 
medications, and assure the subject’s 
well-being.
Section 3.7.1.4
End of Treatment 
(Week 12/ET)
The following activities and 
assessments will occur at Week 12 (or 
at the ET visit, if applicable):

A qualified and certified rater will 
administer the CMAI, NPI-NH, 
and NPI/NPI-NH to the caregiver.

An adequately trained and 
experienced clinician will 
administer the CGI-S, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
...

The actigraphy device will be 
taken off, the data will be 
downloaded to the computer, and
the actigraphy monitoring will be 
stopped.

eDiary recording will be stopped.
The following activities and 
assessments will occur at Week 12 (or 
at the ET visit, if applicable):

A qualified and certified rater will 
administer the CMAI and NPI-NH 
(for institutionalized subjects) or 
NPI/NPI-NH (for non-
institutionalized subjects) to the 
identified caregiver.

An adequately trained and 
experienced clinician will 
administer the CGI-S, 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.
...

Diary recording will be stopped.
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Section 3.7.1.5
Follow-up
All subjects, whether they complete 
the trial or are withdrawn prematurely 
for any reason, will be followed up for 
a safety evaluation 30 (+ 2) days after 
the last dose of IMP during a clinic 
visit at either the investigator’s site or 
residential facility, if institutionalized.  
If the institutionalized subject has left 
the residential facility where he or she 
participated in the trial, the subject 
should be seen at the investigator’s 
site.  
... For those subjects who plan to 
enroll into Trial 331-13-211, the 30-
day safety follow-up visit for Trial 
331-12-283 will occur as a clinic visit 
at either the investigator’s site or 
residential facility.  If the 
institutionalized subject has left the 
residential facility where he or she 
participated in the trial, the 30-day 
safety follow-up visit will occur as a 
clinic visit at the investigator's site.  
All subjects, whether they complete the 
trial or are withdrawn prematurely for 
any reason, will be followed up for a
safety evaluation 30 (+ 2) days after the 
last dose of IMP during a clinic visit at 
either the investigator’s site or 
residential facility, if applicable.  
... For those subjects who plan to enroll 
into Trial 331-13-211, the 30-day safety 
follow-up visit for Trial 331-12-283 
will occur as a clinic visit at either the 
investigator’s site or residential facility, 
if applicable.  
Section 3.7.2.1
Cohen-Mansfield 
Agitation Inventory 
(CMAI)
The primary efficacy variable is the 
change from baseline to Week 12/ET 
in the CMAI total score.  
 
 
 
  
The primary efficacy variable is the 
change from baseline to Week 12/ET in 
the CMAI total score.  
 
 
 
 
Section 3.7.2.5
Neuropsychiatric 
Inventory-Nursing 
Home (NPI-NH)
The NPI-NH questionnaire is used to 
interview the caregiver about the 
subject’s possible neuropsychiatric 
symptoms (i.e., delusions, 
hallucinations, agitation/aggression, 
depression/dysphoria, anxiety, 
elation/euphoria, apathy/indifference, 
disinhibition, irritability, aberrant 
motor behavior, nighttime behaviors, 
and appetite/eating behaviors).  The 
NPI-NH gives an insight into the 
frequency (1 to 4), severity (1 to 3), 
and occupational disruption (0 to 5) of 
each of the 12 separate behavioral 
domains.
The NPI-NH questionnaire is used to 
interview the identified caregiver about 
the institutionalized subject’s possible 
neuropsychiatric symptoms (ie, 
delusions, hallucinations, 
agitation/aggression, 
depression/dysphoria, anxiety, 
elation/euphoria, apathy/indifference, 
disinhibition, irritability, aberrant motor 
behavior, nighttime behaviors, and 
appetite/eating behaviors).  The NPI-
NH gives an insight into the frequency 
(on a scale of 1 to 4), severity (on a 
scale of 1 to 3), and occupational 
disruption (on a scale of 0 to 5) of each 
of the 12 separate behavioral domains.
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Section 3.7.2.6
Neuropsychiatric 
Inventory (NPI)
Section 3.7.2.6  Neuropsychiatric 
Inventory (NPI)
The NPI is a structured caregiver 
interview designed to obtain 
information on the presence of 
psychopathology in subjects with 
brain disorders, including Alzheimer’s 
disease and other dementias.31  The 
NPI differs from the NPI-NH in that it 
is tailored for use in non-institutional 
settings (as opposed to the nursing 
home).  Item domains are identical 
between the two scale versions.  
Ten behavioral and two 
neurovegetative symptom domains 
comprise the NPI (including 
delusions, hallucinations, 
agitation/aggression, 
depression/dysphoria, anxiety, 
elation/euphoria, apathy/indifference, 
disinhibition, irritability, aberrant 
motor behavior, nighttime behavior 
disorders, and appetite/eating 
disorders).  Caregivers are instructed 
to indicate the frequency of a given 
behavior (on a scale of 1 to 4), its 
severity (on a scale of 1 to 3), and how 
much distress that behavior causes for 
him or her (on a scale of 0 to 5).  Each 
domain produces 4 scores:  frequency, 
severity, total (frequency x severity), 
and distress.  A total NPI score is 
calculated by adding the first 
10 domain total scores (frequency x 
severity scores) together.  All 
12 domain total scores can be summed 
in special circumstances where the 
neurovegetative symptoms are of 
particular importance.  Administering 
the NPI generally takes about 15 
minutes.  The psychometric properties 
and factor structure of the NPI have 
been shown to have internal 
consistency, reliability, convergent 
validity, and discriminant validity.
A sample of the NPI is provided in 
Appendix 9.
Section 3.7.2.6  Neuropsychiatric 
Assessment for Non-institutionalized 
Patients Based on the NPI/NPI-NH 
(NPI/NPI-NH)
The NPI/NPI-NH is a structured 
caregiver interview designed to obtain 
information on the presence of 
psychopathology in non-
institutionalized subjects with brain 
disorders, including Alzheimer’s 
disease and other dementias.31  The 
NPI/NPI-NH differs from the NPI-NH 
in that questions referring to 
“Occupational Disruptiveness” from the 
NPI-NH have been replaced with 
questions referring to “Distress” from 
the Neuropsychiatric Inventory (NPI).  
Item domains are identical between the 
NPI/NPI-NH and NPI-NH.  
Ten behavioral and two neurovegetative 
symptom domains comprise the 
NPI/NPI-NH (ie, delusions, 
hallucinations, agitation/aggression, 
depression/dysphoria, anxiety, 
elation/euphoria, apathy/indifference, 
disinhibition, irritability, aberrant motor 
behavior, nighttime behavior disorders, 
and appetite/eating disorders).  The 
identified caregivers are instructed to 
indicate the frequency (on a scale of 1 
to 4), severity (on a scale of 1 to 3), and 
distress (on a scale of 0 to 5) of each of 
the 12 separate behavioral domains.  
Therefore, for each behavioral domain, 
there are 4 scores:  frequency, severity, 
total (frequency x severity), and 
distress.  A total NPI/NPI-NH score is 
calculated by adding the first 10 domain 
total scores (frequency x severity 
scores) together.  All 12 domain total 
scores can be summed in special 
circumstances where the 
neurovegetative symptoms are of 
particular importance.  Administering 
the NPI/NPI-NH generally takes about 
15 minutes.  
A sample of the NPI/NPI-NH is 
provided in Appendix 9.
 
 
 
 
 
 
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Section 3.7.3.7
Actigraphy
The CST will perform ongoing 
reviews of CMAI raters by reviewing 
CMAI data relative to other sources of 
behavioral information, including 
patterns of movement using 
actigraphy technology.  Motion will 
be collected through an actigraphy 
device resembling a wristwatch worn 
by the subject on their nondominant 
wrist for 24 hours/day during the 
screening and treatment periods.  If 
the subject decides not to wear the 
actigraph at any time after the consent 
is obtained, the assessment may be 
discontinued and continued study 
participation will not be affected.  The 
actigraphy data will be downloaded 
from the device to the actigraphy 
vendor at regular intervals 
corresponding to the date of the 
CMAI.  For non-institutionalized 
subjects, the caregiver will not be 
expected to change the actigraph 
watch battery or download the 
actigraph data; these duties will be 
completed by the site staff.  For 
institutionalized subjects, the 
caregiver or site staff may be 
responsible for changing the actigraph 
watch battery or downloading the 
actigraph data.  
Actigraphy uses a portable 
Motionlogger device (actigraph) that 
records movement over extended 
periods of time and that most 
commonly is worn on the wrist (refer 
to Appendix 16).  The actigraph 
accelerometers samples physical 
activity 32 times a second to detect 
wrist movement.  These data are 
stored within the actigraph for up to 
several weeks.  The length of time the 
actigraph is able to record data is 
typically dependent on the actigraph’s 
epoch length (15 seconds, in this 
study).  The subject is advised to wear 
the actigraph continuously all times, 
including during sleep.  If the subject 
must remove the device for any 
reason, the subject is instructed to 
place it back on the wrist as soon as 
possible.  The device is able to detect 
(this section was removed)
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when it is not on the subject’s wrist, 
and it tracks the time that it is not 
being worn.  An event marker on the 
device can be used to mark the 
occurrence of significant events such 
as bedtime, or the time of a rating 
(e.g., such as the CMAI).  The 
actigraphy data will be downloaded, 
verified, and transferred to Clinilabs’ 
core laboratory at each study visit 
(except the Day 3 visit) from the 
device by attaching it to a docking 
station connected to a computer that 
allows communication with the 
software program on the computer.  
The computer program summarizes 
these data and can display and print a 
histogram (called an actogram), which 
shows the subject’s activity levels for 
each epoch during successive 24-hour 
periods.  The computer program 
provides validated algorithms that 
summarize activity data.  The data are 
then reviewed for active periods and 
rest periods.  The actigraph will be put 
on the subject after the ICF/assent is 
signed and taken off at the Week 
12/ET visit.
Investigator progress notes, as well as 
other efficacy data, will be reviewed 
by the CST as part of this in-trial 
CMAI data quality oversight method.  
Any clinically relevant findings 
generated by this review suggesting 
rater training or other issues will be 
discussed with the sites, and measures 
may be taken to enhance training 
when needed.  Details of this CMAI 
quality review may be found in the 
Operations Manual.
Since actigraphy data are tools to 
assist the CST in monitoring CMAI 
rater training, actigraphy information 
will not be statistically analyzed.
Section 3.7.3.8
Electronic Diary 
(eDiary)
3.7.3.8  Electronic Diary (eDiary)
The CST will perform ongoing 
reviews of CMAI raters by reviewing 
CMAI data relative to other sources of 
behavioral information, including 
behavior logs collected by caregivers 
(this section was removed)
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and/or facility staff through eDiaries 
(refer to Appendix 17).  Caregivers 
will record occurrence of the 29 
behaviors listed in the CMAI as they 
occur using an eDiary.  All 29 
behaviors will be listed, and the 
caregiver will check the box next to 
the behavior when it occurs; there is 
no free text in the eDiary.  
Observations recorded using the 
eDiary will be transmitted wirelessly 
to the eDiary vendor.
For subjects in a non-institutionalized 
setting, one of the responsibilities of 
the caregiver is to complete the eDiary 
by noting the subject’s symptoms of 
agitation.  While it is preferred that 
eDiary data are collected 7 days a 
week, it is realized that eDiary 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.  
The caretaker may provide 
information to the caregiver to 
complete the eDiary on a daily basis, 
but this is not a requirement.  The 
responsibility of the caregiver for 
logging behaviors in the eDiary 
remains the same for subjects in an 
institutionalized setting.  However, 
more than one caregiver may use the 
eDiary for any given subject; whoever 
is providing care for the subject at a 
given time can log behaviors in the 
eDiary.
...
Since eDiary data are tools to assist 
the CST in monitoring CMAI rater 
training, eDiary information will not 
be statistically analyzed.
Table 3.7.4.2-1
Clinical Laboratory 
Assessments
Urinalysis
Albumin
Creatinine
Additional Tests (Screening Only)
HIV
HBsAg
Anti-HCV
Urinalysis
(these asessments were removed)
Additional Tests (Screening Only)
HBsAg
Anti-HCV
Urine albumin (only for subjects with 
IDDM)
Urine creatinine (only for subjects with 
IDDM)
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Section 3.7.4.2
Clinical Laboratory
Assessments
Urine will be collected and blood will 
be drawn from each subject during 
screening prior to treatment with the 
IMP.  If fasting blood samples are not 
feasible at screening, nonfasting blood 
samples may be obtained initially for 
determining eligibility for the trial. ...  
Additional urine and blood samples 
may be collected for further 
evaluation of safety as warranted by 
the investigator’s judgment.  Subjects 
should be fasting for a minimum of 8 
hours prior to the blood draws, if 
possible.  
...
The following laboratory test results at 
screening are exclusionary:

Platelets 120,000/mm3

Hemoglobin ≤ 10 g/dL for 
women, 11 g/dL for men 

Neutrophils, absolute 1500/mm3
...

Urine albumin-to-creatinine ratio 
(ACR) > 30 mg/g (calculated as 
urine albumin [mg/dL] / urine 
creatinine [g/dL])
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. ... Additional 
urine and blood samples may be 
collected for further evaluation of 
safety as warranted by the 
investigator’s judgment.
...
The following laboratory test results at 
screening are exclusionary:

Platelets 75,000/mm3

Hemoglobin ≤ 9 g/dL 

Neutrophils, absolute 1000/mm3
...

Subjects with IDDM (ie, any 
subjects using insulin) must also 
satisfy the following criterion:  no 
current microalbuminuria; ie, urine 
ACR must be < 30 mg/g 
(calculated).
Section 3.7.4.3.1
Physical Examination
... Repeat measurement of height is 
not required at the physical 
examinations scheduled for the Weeks 
6 and 12/ET visits.  Waist
circumference will be measured at 
each physical examination (screening, 
Week 6, and Week 12/ET), using the 
provided measuring tape.
... Repeat measurement of height is not 
required at the physical examinations 
scheduled for the Week 12/ET visits.  
Waist circumference will be measured 
at each physical examination (screening 
and Week 12/ET), using the provided 
measuring tape.  
Section 3.7.4.3.2
Neurological 
Examination
A detailed neurological examination 
will be performed by a physician at 
screening, Week 6, Week 12/ET, and 
as needed during the trial for new 
onset neurological symptoms.  
A detailed neurological examination 
will be performed by a physician at 
screening, Week 12/ET, and as needed 
during the trial for new onset 
neurological symptoms.  
Section 3.7.4.4
ECG Assessments
... Based on the QT interval as 
corrected 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.
... Based on the QT interval as corrected 
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.  
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Section 3.8.3
Individual Subject
9) Subject from a non-institutionalized 
setting requires permanent placement 
to a nursing home or assisted living 
facility, or subject transfers from an 
institutionalized setting to a non-
institutionalized setting.  In case of a 
change in the non-institutionalized 
address or institutionalized address, 
the investigator should consult with 
the medical monitor on a case-by-case 
basis.  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 INC Research 
medical monitor.  
...
... 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.  If the institutionalized subject 
has left the residential facility where 
he or she participated in the trial, the 
subject should be seen at the 
investigator’s site.  If a clinic visit is 
not possible, the subject should be 
assessed by telephone contact with the 
subject and a caregiver. ... 
9) 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.  
...
... 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, if applicable.  If a clinic visit is 
not possible, the subject should be 
assessed by telephone contact with the 
subject and a caregiver. ...  
Section 3.9
Screen Failures
... 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 once at a 
later date.  The medical monitor must 
be contacted before rescreening any 
subjects who initially failed screening 
due to a positive blood alcohol test or 
positive drug screens resulting from 
... 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 
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use of prescription or OTC 
medications or products.  In the event 
that the subject is rescreened for trial 
participation after the 42-day 
screening period expires, a new ICF 
must be signed, a new screening 
number assigned, and all screening 
procedures repeated.
screening due to a positive blood 
alcohol test or 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.  
Table 4.1-1
List of Restricted and 
Prohibited Medications
1. Medications to treat Alzheimer’s 
disease (cholinesterase inhibitors, 
memantine, and/or other cognitive 
enhancers)  
Allowed provided that the dose has 
been stable for 90 days prior to 
randomization
1. Medications to treat Alzheimer’s 
disease (cholinesterase inhibitors, 
memantine, and/or other cognitive 
enhancers)  
Subject should remain on the same dose 
throughout the duration of the trial, 
except when medically indicated due to 
a change in the underlying medical 
condition.
3. Antidepressants
Subject will remain on the same dose 
throughout the duration of the trial.
3. Antidepressants
Subject should remain on the same dose 
throughout the duration of the trial, 
except when medically indicated due to 
a change in the underlying medical 
condition.
12. Medications to treat other medical 
conditions, such as hypertension, 
hypercholesterolemia, etc., and anti-
platelet agents  
Subject will remain on the same dose 
throughout the duration of the trial.
12. Medications to treat other medical 
conditions, such as hypertension, 
hypercholesterolemia, etc., and anti-
platelet agents  
Subject should remain on the same dose 
throughout the duration of the trial, 
except when medically indicated due to 
a change in the underlying medical 
condition.
Section 6
Pharmacokinetic 
Analysis
Pharmacokinetic samples will be 
analyzed for brexpiprazole (OPC-
34712) and its major metabolite, 
DM-3411, and descriptive statistics 
will be calculated.  
Pharmacokinetic samples will be 
analyzed for brexpiprazole (OPC-
34712) and its metabolite(s) and 
descriptive statistics will be calculated.  
Section 7.1
Sample Size
The 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 the 
endpoint in the CMAI total score, to 
achieve 80% power at a 2-sided alpha 
level of 0.05.  The resulting sample 
size is 103 subjects/arm. After 
allowance of 10% non-evaluable 
subjects, it results in a sample size of 
115 subjects/arm, which means the 
total sample size is 230 subjects.  
The 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 the endpoint in 
the CMAI total score, to achieve 85% 
power at a 2-sided alpha level of 0.05.  
The resulting sample size is 
117 subjects/arm.  After allowance of 
10% non-evaluable subjects, it results 
in a sample size of 130 subjects/arm, 
which means the total sample size is 
260 subjects.  
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Section 7.6.1
Adverse Events
The incidence of AEs of interest (e.g., 
falls, sedation, diabetes, weight 
changes, QTc prolongation, or deaths) 
will be summarized by treatment 
group.
(this text was deleted)
 
 
 
 
 
 
 
...
Appendix 1
Names of Sponsor 
Personnel
(address change for all sponsor 
contacts)
Otsuka Pharmaceutical Development 
& Commercialization, Inc.
1 University Square Drive, Suite 500
Princeton, NJ 08540
(address change for all sponsor 
contacts)
Otsuka Pharmaceutical Development & 
Commercialization, Inc.
508 Carnegie Center
Princeton, NJ 08540
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Primary Medical Contact:
 
Primary Medical Contact:
 
Clinical Contact:
Otsuka Pharmaceutical Development 
& Commercialization, Inc.
1 University Square Drive, Suite 500
Princeton, NJ 08540
Phone:  
Mobile:  
Clinical Contact:
 
Otsuka Pharmaceutical Development & 
Commercialization, Inc.
2440 Research Blvd
Rockville, MD 20850
Phone:  
Fax:  
Appendix 2
Institutions Concerned 
With the Trial
United States  
...
United Kingdom  
...
Slovenia 
Finland  
United States  
 or 
...
United Kingdom  
...
Slovenia 
Finland  
Bulgaria  
Russia  
Medical Monitors
North America:
INC Research, LLC
3201 Beechleaf Court, Suite 600
Raleigh, NC 27604 USA
Phone: 
Mobile: 
Europe:
Medical Monitors
North America
INC Research, LLC
3201 Beechleaf Court, Suite 600
Raleigh, NC 27604 USA
Office:  
Mobile:  
Fax:  
Europe:
Plasma Sample Storage Facility
FBS.customer.service@thermofisher.c
om
Plasma Sample Storage Facility
(email address was removed)
Electronic Data Capture
Medidata Solutions Worldwide
79 Fifth Avenue, 8th Floor
New York, NY 10003
USA
Electronic Data Capture
Medidata Solutions, Inc.
350 Hudson Street, 9th Floor
New York, NY 10014
USA
IVRS/IWRS
S-Clinica Inc.
33 Wood Avenue South
Suite 600
Iselin, NJ 08830
USA
IVRS/IWRS
S-Clinica Inc.
41 University Drive
Suite 400
Newtown, PA 18940
USA
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eDiary
eResearch Technology
1818 Market Street, Suite 1000
Philadelphia, PA 19103
USA
Actigraphy
Clinilabs, Inc.
423 West 55th Street
New York, NY 10019
USA
Rater Surveillance
CROnos
1800 East State Street
Suite 144B
Hamilton, NJ 08609
USA
(these vendors were removed)
Appendix 9
Neuropsychiatric 
Assessment for Non-
Institutionalized 
Patients Based on the 
NPI/NPI-NH
Appendix 9  Neuropsychiatric 
Inventory (NPI)
Appendix 9  Neuropsychiatric 
Assessment for Non-Institutionalized 
Patients Based on the NPI/NPI-NH
Appendix 16
Actigraphy 
Description
Actigraphy utilizes a portable device 
(actigraph) that records movement 
with a piezoelectric accelerometer 
over extended periods of time and is 
worn most commonly on the 
nondominant wrist.  The actigraph 
accelerometers samples physical 
activity 32 times a second to detect
wrist movement.  These data are 
stored within the actigraph for up to 
several weeks.  The length of time the 
actigraph is able to record data are 
typically dependent on the actigraph’s 
epoch length (15 seconds, in this 
study).  The subject is advised to wear 
the actigraph continuously, at all 
times, including during sleep 
beginning after the informed consent 
is signed to Week 12/ET.  If the 
subject must remove the device for 
any reason, the subject is instructed to 
place it back on the wrist as soon as 
possible.  The device is able to detect 
when it is not on the subject’s wrist, 
and it tracks the time that it is not 
being worn.  The actigraphy data will 
be downloaded from the device, 
verified, and transferred to Clinilabs’ 
core laboratory at each study visit 
(this appendix was removed)
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(except the Day 3 visit)  by attaching 
it to a docking station connected to a 
computer that allows communication 
with the software program on the 
computer.  A computer program 
summarizes these data and can display 
and print a histogram (called an 
actogram), which shows the subject’s 
activity levels for each epoch over 
successive 24-hour periods.  The 
computer program provides validated 
algorithms that summarize activity 
data.  The data are then reviewed for 
active periods and rest periods.
In addition, activity will be analyzed 
over each 24-hour period (“Daily” 
intervals) for maximum, total and 
average activity levels to understand 
the amount of day time movement 
from the subject and to evaluate 
restlessness, agitation, and increased 
random movements like those seen in 
akathisia.  Raw activity data will also 
be generated that allows the total 
number of epochs with zero activity 
counts to be calculated during baseline 
and treatment period for both groups 
over each 24-hour period.  In addition, 
for non-zero epochs, the mean activity 
can be calculated over each 24-hour 
period.
To evaluate the diurnal activity 
patterns, the activity counts for one-
hour blocks at 8:00 am, 12:00 pm, 
4:00 pm, and 8:00 pm will be 
provided.  This will provide for the 
possibility of measuring “time of day” 
specific activity related to agitation.  
Since actigraphy will be collected 
twenty four hours per day for 
extended periods of time, sleep 
parameters will be evaluated as a 
continuous evaluation of these 
multiple day indices.  Sleep-wake 
patterns are estimated from periods of 
activity and inactivity based on this 
movement during the rest period.  
Actigraphy is based on the principle 
that there is reduced movement during 
sleep and increased movement during 
wake.  The computer programs can 
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estimate sleep and wake based upon 
computer algorithm-defined 
thresholds of activity.  Thus, the 
estimated sleep-wake parameters such 
as sleep latency, total sleep time, 
number and frequency of awakenings, 
sleep efficiency can be derived.  
Circadian rhythm parameters, such as 
the amplitude (peak-to-nadir 
difference) or acrophase (time of peak 
activity), can also be typically 
obtained.  
Source: Littner M, Kushida C, 
Anderson WM, Bailey D, Berry RB, 
Davila DG, et al. Practice parameters 
for the role of actigraphy in the study 
of sleep and circadian rhythms: an 
update for 2002. Sleep. 2003;26(3): 
337-41.
Appendix 17
Electronic Diary 
(eDiary)
Once caregivers and/or facility staff 
log in, they will be prompted to select 
from the 29 behaviors listed in the 
CMAI: 
1) –Biting
2) –Grabbing onto people or things 
inappropriately
3) –Hitting (including self)
4) –Hurting self or other
5) –Kicking
6) –Making physical sexual advances 
or exposing genitals
7) –Pushing
8) –Scratching
9) –Spitting (including while feeding)
10) –Tearing things or destroying 
property
11) –Throwing things
12) –Eating or drinking inappropriate 
substances
13) –General restlessness
14) –Handling things inappropriately 
(e.g., playing with food, fecal 
smearing)
15) –Hiding things
16) –Hoarding things
17) –Inappropriate dressing or 
disrobing
18) –Intentional falling
19) –Pacing and aimless wandering
20) –Performing repetitious 
mannerisms
(this appendix was removed)
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21) –Trying to get to a different place
22) –Complaining
23) –Constant unwarranted request for 
attention or help
24) –Cursing or verbal aggression
25) –Making verbal sexual advances
26) –Negativism
27) –Repetitive sentences or questions
28) –Screaming
29) –Making strange noises
If the caregivers click on “Help”, they 
will be able to view the definitions of 
the behaviors within their selected 
category.
After the caregivers select a behavior, 
they will be taken to a screen where 
they can enter the time the behavior 
occurred.
Appendix 23
Handling and 
Shipment of 
Bioanalytical Samples
Pharmacokinetic Sample Collection
...
The sample must be stored at −70°C, 
if available, or −20°C or below.  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 
pharmacokinetic sample should be 
shipped on dry ice to the central 
laboratory on the day of collection.  
The backup sample can be refrigerated 
(2 to 8°C) for up to 48 hours prior to 
shipment on dry ice to the central 
laboratory.
Pharmacokinetic Sample Collection
...
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.  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 
pharmacokinetic samples must be 
shipped on dry ice in the same box to 
the central laboratory on the day of 
collection.  
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
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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 Research 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 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 Paragraph I of the sponsor's Clinical 
Research 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 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 protocol 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 5 working days. Administrative 
changes to the protocol will be transmitted to the IRB/IEC for informational purposes only.
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 Research 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 prior to publication of efficacy and safety results on an individual basis.
________________________________________________
Principal or Coordinating Investigator Signature and Date
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Otsuka Pharmaceutical Development & Commercialization, Inc.
This page is a manifestation of an electronically captured signature
                                                                                                                                
SIGNATURE PAGE
Document Name:
Document Number:
Document Version:
Signed by
Meaning of Signature
Server Date
(dd-MMM-yyyy HH:mm ‘GMT’Z)
OPC-34712
Protocol_331-12-284_Amend 3
0001191988
2.0
Biostatistics Approval
11-Sep-2015 03:33 GMT+00
Clinical Approval
11-Sep-2015 13:38 GMT+00
Clinical Pharmacology
11-Sep-2015 13:51 GMT+00
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SAP_001.pdf: 
Protocol 331-12-284
• Protocol number: 331-12-284
• Document title: 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
• Version number: 1.0
• Date of the document: 22 March 2017
• NCT number: NCT01922258
Confidential -Proprieta1y Info1mation 


SAP 331-12-284
Confidential - Proprietary Information  
1
March 22, 2017
Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigational Medicinal Product
Brexpiprazole (OPC-34712)
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
Protocol No. 331-12-284
IND No. 115,960
EudraCT No. 2013-000503-17
Statistical Analysis Plan
Version: Final
Date: 22 March, 2017
CONFIDENTIAL - PROPRIETARY INFORMATION
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Otsuka Pharmaceutical Development & Commercialization, Inc.


SAP 331-12-284
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March 22, 2017
Table of Contents
1
Introduction ..........................................................................................5
2
Trial Objectives ....................................................................................5
3
Trial Design...........................................................................................5
4
Sample Size and Power Justification..................................................7
5
Data Sets for Analysis and Missing Data...........................................7
5.1
Data Sets for analysis ..........................................................................................7
5.2
Handling of Missing Data ...................................................................................8
6
Study Conduct ......................................................................................9
6.1
Subject Disposition and Reasons for Discontinuations.......................................9
6.2
Treatment Compliance ........................................................................................9
6.3
Protocol Deviation...............................................................................................9
7
Baseline Characteristics.......................................................................9
7.1
Baseline Definition..............................................................................................9
7.2
Demographic Characteristics.............................................................................10
7.3
Disease History..................................................................................................10
7.4
Baseline Disease Characteristics.......................................................................10
8
Efficacy Analysis.................................................................................11
8.1
Primary Efficacy Endpoint ................................................................................11
8.1.1
Primary Efficacy Analysis ..............................................................................11
8.1.2
Technical Computation Details for Primary Efficacy Analysis......................12
8.1.3
Sensitivity Analyses for Primary Efficacy Endpoint ......................................13
8.1.4
Subgroup Analyses for Primary Efficacy Endpoint........................................15
8.2
Key Secondary Analysis....................................................................................15
8.3
15
8.4
.16
8.5
18
8.6
19
8.7
Actigraphy and eDiary Data ..............................................................................20
9
Safety Analysis....................................................................................20
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9.1
Adverse Events..................................................................................................20
9.2
Clinical Laboratory Tests ..................................................................................22
9.2.1
Change from Baseline in Lab Tests................................................................22
9.2.2
Potentially Clinically Relevant Values...........................................................22
9.2.3
Potentially Liver Injury Related Laboratory Test ...........................................22
9.2.4
Metabolic Change...........................................................................................22
9.3
Physical and Neurological Examination and Vital Signs..................................23
9.4
12-Lead ECG.....................................................................................................23
9.5
Body Weight, Waist Circumference and Body Mass Index (BMI)...................24
9.6
25
9.7
Mini-Mental State Examination (MMSE).........................................................25
9.8
25
9.9
Concomitant Medications..................................................................................26
9.10
Extent of Exposure............................................................................................26
10
Conventions.........................................................................................26
10.1
Study Visit Windows.........................................................................................26
10.2
Pooling of small centers ....................................................................................27
10.3
Scales: Rules for Scoring and Handling of Missing Data .................................28
10.3.1
Cohen-Mansfield Agitation Inventory (CMAI)..............................................28
10.3.2
Clinical Global Impression-Severity of Illness Scale (CGI-S) .......................28
10.3.3
.29
10.3.4
.29
10.3.5
Neuro-psychiatric Inventory ...........................................................................29
10.3.6
30
10.3.7
.30
10.3.8
.31
10.3.9
National Institute of Neurological and Communicative Disorders and 
Stroke and the Alzheimer’s Disease and Related Disorders Association 
(NINCDS-ADRDA) .......................................................................................32
10.3.10
Hachinski Ischemic Scale (Rosen Modification)............................................32
10.3.11
32
10.3.12
32
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10.3.13
.33
10.3.14
.33
10.3.15
Mini-Mental State Examination (MMSE)......................................................33
11
References............................................................................................35
12
Potential Clinical Relevance Criteria from Protocol......................36
13
Proposed List of Summary Tables....................................................40
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1
Introduction
This statistical analysis plan (SAP) documents the statistical methodology and data 
analysis algorithms and conventions to be applied for statistical analysis and reporting of 
efficacy and safety data of study 331-12-284.  All amendments to the protocol and 
Addendum to protocol amendment are taken into consideration in developing this SAP.
2
Trial Objectives
Primary: To compare the efficacy of flexible dosing of brexpiprazole (dose range of 0.5 to 
2 mg/day) with placebo in subjects with agitation associated with dementia of the 
Alzheimer’s type, as assessed by the Cohen-Mansfield Agitation Inventory (CMAI) after 
12 weeks of treatment.
Secondary: To evaluate the safety and tolerability of flexible dosing of brexpiprazole 
(dose range of 0.5 to 2 mg/day) compared with placebo in subjects with agitation 
associated with dementia of the Alzheimer’s type after 12 weeks of treatment.
3
  Trial Design
This is a phase 3, 12-week, multicenter, randomized, double-blind, placebo-controlled, 
2-arm, flexible-dose trial designed to assess the efficacy, safety, and tolerability of 
brexpiprazole (dose range of 0.5 mg/day to 2 mg/day) in the treatment of subjects with 
agitation associated with dementia of the Alzheimer’s type. 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 (e.g., nursing home, dementia unit, assisted 
living facility, or any other residential care facility providing long term care) or in a non-
institutionalized setting where the subject is 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 the subject in order to assess 
changes in the subject’s condition. 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. 
The trial comprises a 2- to 42-day screening period, a 12-week double-blind treatment 
period, and a 30-day post-treatment follow-up period. In addition, for all subjects who 
terminate early from the study, all attempts will be made to collect mortality data by 
telephone contact with the subject’s caregiver at Week 16.


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This trial will be monitored under the supervision of an independent Data Monitoring 
Committee (DMC). The DMC will monitor safety periodically, based on a predetermined 
schedule. 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 to 42 days 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 
interactive voice response system (IVRS) or interactive web response system (IWRS) will
be used to obtain the subject study identification number for each subject with a signed 
ICF.
12-week, Double-blind Treatment Period
Based on a randomization scheme, eligible subjects will be allocated in a 1:1 ratio at 
randomization to 1 of the following 2 treatment groups:

Brexpiprazole

Placebo
Subjects will be titrated to a target dose of 1 mg/day of brexpiprazole over a 2-week 
period, using the recommended titration schedule. 
Subjects unable to tolerate 0.5 mg/day of the IMP (or matching placebo) will be 
discontinued from the trial.
Subjects will be evaluated at Baseline, Day 3, and Weeks 2, 4, 6, 8, 10, and 12 during the 
double-blind treatment period. 
All attempts should be made to maintain the subjects’ normal routine with regard to 
physician appointments. Individual circumstances that fall outside this general convention 
should be discussed with the medical monitor in order to determine appropriateness to 
proceed. In addition, the subject’s identified caregiver will be contacted by telephone at 
Weeks 3, 5, and 7 to assess compliance with IMP, confirm any changes to concomitant 
medications, and assure the subject’s well-being. Trial-related efficacy and safety 
assessments will be performed as outlined in the study protocol.
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All subjects, whether they complete the trial or are withdrawn prematurely for any reason, 
will be followed up for a safety evaluation 30 (+ 2) days after the last dose of the IMP 
during a clinic visit at either the investigator’s site or residential facility, if applicable.  If 
a clinic visit is not possible, the subject should be assessed by telephone contact with the 
subject and a caregiver. For all subjects who terminate early from the study, all attempts 
will be made to collect mortality data by telephone contact with the subject’s caregiver at 
Week 16.
Subjects who complete both the 12-week double-blind treatment period and the 30-day 
safety follow-up visit are eligible to enroll into Trial 331-13-211, which is a 2-month, 
observational, rollover trial to evaluate the safety of subjects with agitation associated 
with Alzheimer's disease who previously participated in Trial 331-12-284. For those 
subjects who plan to enroll into Trial 331-13-211, the 30-day safety follow-up visit for 
Trial 331-12-284 will occur as a clinic visit at either the investigator’s site or residential 
facility, if applicable.
4
Sample Size and Power Justification
The sample size was calculated based on the treatment effect of 6.5 points with a standard 
deviation (SD) of 16.5 in the change from baseline (Day 0 visit) to the end of the 
double-blind treatment period (Week 12 visit) in the CMAI total score, to achieve 85% 
power at a 2-sided alpha level of 0.05.  The resulting sample size is 117 subjects/arm.  
After allowance of 10% non-evaluable subjects, it results in a sample size of 130
subjects/arm, which means the total sample size is 260 subjects.  The sample size was 
estimated based on 1:1 randomization ratio (brexpiprazole:placebo).  The randomization 
will be stratified by center.
5
Data Sets for Analysis 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 IVRS 
at the end of Screening Period. A subject receiving trial treatment outside of the IVRS 
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, 
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trial drug. If a subject is dispensed trial medication 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 the IMP and have a baseline and at least 
one 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.  However, as described below, in order to handle missing 
data and restrictions imposed by different types of analyses (eg, change from baseline 
analysis), other datasets derived from the ITT population will be used for the efficacy 
analyses.
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.
 
 
 
 
 
The primary efficacy variable is the change from baseline to Week 12 in the CMAI total 
score. 
In general, missing data will be handled by analysis of Mixed effect Model Repeat 
Measurement (MMRM) methodology based on observed-case (OC) data from protocol-
specified visits in the ITT population under the assumption of missing at random (MAR).
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The OC dataset consists of actual observations recorded at each visit during the double-
blind acute treatment phase, and no missing data will be imputed. 
 
 
 
 
 
 
 
 
6
Study 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
Based on the Study Medication panel of the CRF, compliance in taking study medication 
is calculated by dividing the number of tablets taken by the total number of tablets the 
subjects were scheduled to take during the study period. For lost-to-follow up subjects, 
last study medication end date record will be used as the treatment end date.  
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 study medication.
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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; 
 CGI-S score, NPI total 
score; NPI-AA item score; MMSE score; 
Number of subjects with presence of psychotic symptoms will be summarized at baseline 
using NPI Delusion and Hallucination score. The counts will be provided for the 
following categories:  NPI item score >=4, >=5, >=6 on either hallucination or delusion 
score.
All patients randomized under the original protocol and amendment 1 are assumed to be 
institutionalized and will be included in the institutionalized subgroup. 
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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. 
Statistical comparisons are based on 2-sided, 0.05 significance levels.
NPI endpoints are collected using NPI-NH for institutionalized subjects and NPI/NPI-NH 
for non-institutionalized subjects. Since each score derivation of the NPI items is based 
on the frequency and severity scores only, no distinction will be made due to the 
instrument used. All analysis of NPI based endpoints will be based on totality of data, 
unless specified otherwise. 
8.1
Primary Efficacy Endpoint
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.  
8.1.1 Primary Efficacy Analysis
The primary endpoint will be analyzed using a mixed-effect model repeated measure 
(MMRM) model.  The primary efficacy outcome measure is the mean change from 
baseline (Day 0 visit) to the end of the double-blind treatment period (Week 12 visit) in 
the CMAI total score.  The primary statistical comparison of interest is brexpiprazole 
flexible dose versus placebo.  The null hypothesis is that there is no difference between 
the brexpiprazole treatment group and placebo in change from baseline to endpoint in 
CMAI total score.  The comparison will be made at the significance level of alpha = 0.05 
(2-sided).
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. The primary efficacy analysis will be 
performed by fitting a MMRM analysis 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 set.  The model will include 
fixed class-effect terms for treatment (brexpiprazole and placebo), trial center, 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 covariates. The primary 
comparison between a brexpiprazole and the placebo arm at Week 12 will be estimated as 


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the difference between Least Squares (LS) means from the interaction term of treatment 
by visit week utilizing the computing software SAS procedure PROC MIXED. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.1.2
 
 
 
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8.1.3
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.1.4 Subgroup Analyses for Primary Efficacy Endpoint
Subgroup analyses of change from baseline in CMAI Total Score to every study week in 
the double blind treatment period will be performed by the following factors:

Gender

Race (White and All Other Races)

Age group (<65; >=65 and <75; or >=75)

Region (North America and Other)
 
 
 
 
 
 
8.2
Key Secondary Analysis 
The key secondary efficacy variable is the change from baseline to endpoint 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, based on the Efficacy Sample.  
In order to control the overall 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 at 0.05.  Thus, if the primary efficacy analysis for the CMAI total score 
yields a statistically significant result at 0.05 (2-sided) for the comparison of 
brexpiprazole versus placebo, then the comparison for key secondary efficacy variable 
(CGI-S score) will be tested at an alpha level of 0.05 (2-sided).
8.3
 
 
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
 
 
 
 
 
 
8.4
 
 
 
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
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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
 
 
 
Summary statistics will be provided by treatment groups. Statistical comparisons will be 
evaluated using the same MMRM model described in the primary analysis at a nominal 
0.05 level (two-sided).
8.5
 
 
 
 
 
 
 
 
 
 
 
 
 
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
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.6
 
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8.7
Actigraphy and eDiary Data
Since actigraphy and eDiary are tools to assist the CST in monitoring CMAI rater 
training, actigraphy and eDiary information will not be made available to site personnel, 
will not be included in the clinical database, and will not be statistically analyzed. 
9
Safety Analysis
Standard safety variables to be analyzed include AEs, clinical laboratory tests, vital signs, 
ECGs, body weight, waist circumference and physical examination.  In addition, data 
from the following safety scales will be evaluated:  MMSE score, 
 
 
 
 
 
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. 
9.1
Adverse Events 
All adverse events will be coded by primary system organ class (SOC) and Medical 
Dictionary for Regulatory Activities (MedDRA version 19.0 ) preferred term (PT).  AEs 
that are gender-specific, e.g., ovarian cancer, will have their incidence rates evaluated for 
the specific gender. The incidence of the following events will be summarized by 
treatment group:
a) Treatment-emergent AEs (TEAE) by SOC and PT
b) TEAEs at least 5% in the brexpiprazole group and twice greater than placebo
c) TEAEs at least 2% in the brexpiprazole group and greater than placebo
d) TEAEs by severity
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e) Potentially drug-related TEAEs
f)
TEAEs with an outcome of death
g) Serious TEAEs
h) TEAEs leading to discontinuations
i)
EPS-related AEs
j)
EPS-related AEs by time
k) AEs of special interest
l)
TEAEs by gender, race, age and region
EPS-related AEs will be grouped into five categories.
1) Dystonic Events, which include cervical spasm, dystonia, emprosthotonos, muscle 
contractions involuntary, muscle rigidity, muscle spasms, muscle spasticity, 
myotonia, nuchal rigidity, oculogyration, opisthotonos, pleurothotonus, risus 
sardonicus, torticollis, and trismus;
2) Parkinsonian Events, which include akinesia, asterixis, athetosis, bradykinesia, 
cogwheel rigidity, essential tremor, extrapyramidal disorder, freezing 
phenomenon, gait festinating, hypertonia, hypokinesia, hypokinesia neonatal, 
intention tremor, masked facies, parkinson’s disease, parkinsonian crisis, 
parkinsonian gait, parkinsonian rest tremor, parkinsonism, tremor, and tremor 
neonatal;
3) Akathisia Events, which include akathisia, hyperkinesia, and psychomotor 
hyperactivity;
4) Dyskinetic Events, which include ballismus, buccoglossal syndrome, 
choreoathetosis, clumsiness, dyskinesia, dyskinesia neonatal, dyskinesia 
oesophageal, fumbling, nodding of head, on and off phenomenon, and tardive 
dyskinesia;
5) Residual Events, which include chorea, huntington’s chorea, muscle twitching, 
and myoclonus.
 
The following AEs of special interest will be summarized by PT terms only:
1) Fall 
2) Orthostatic hypotension 
3) Syncope
4) Dizziness
Treatment-emergent AEs are defined as AEs with an onset date on or after the start of 
double-blind treatment. In more detail, TEAEs are all adverse events which started after 
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start of double blind study drug treatment; or if the event was continuous from baseline 
and was worsening, serious, study drug related, or resulted in death, discontinuation, 
interruption or reduction of study therapy. Adverse Events occurring up to 30 days after 
the last day of double-blind dosing will be included in the summary tables. 
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 (PT, aPTT, 
and INR), HbA1c, cortisol, ACTH, and TSH will be provided by treatment and by visit.  
9.2.2 Potentially Clinically Relevant Values
In addition, the incidence of treatment-emergent potentially clinically relevant (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.
9.2.3 Potentially Liver Injury Related Laboratory Test
Total bilirubin level will be checked for any subjects with increased ALT or 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. The corresponding listing will be provided as well.

AST or ALT ≥3 x ULN and 

T_Bili ≥2 x 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.
Criteria for Treatment-Emergent Significant Change in Lipids and Glucose
LAB PARAMETER
BASELINE*
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 
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Criteria for Treatment-Emergent Significant Change in Lipids and Glucose
LAB PARAMETER
BASELINE*
ANYTIME POST BASELINE     
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   
* Baseline is calculated from day 0; if day 0 is unavailable screen visit will be used
Criteria for Treatment-Emergent Metabolic Syndrome
DESCRIPTION
ANYTIME POST BASELINE*     
Central Obesity        
                       
Dyslipidemia           
                       
Dyslipidemia           
                       
Supine Blood Pressure  
                       
Glucose Fasting, Serum
Waist Circumference >=102cm(MALE), >=88cm (FEMALE)    
                                                     
Triglycerides >= 150mg/dl                            
                                                     
HDL < 40mg/dl (MALE), <50mg/dl (FEMALE)              
                                                     
Systolic>=130mmHg and Diastolic>=85mmHg              
                                                     
>=100mg/dl                                           
Metabolic Syndrome         
Met 3 Or More of the Above Criteria at a Visit
* 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 
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In addition, the incidence of treatment-emergent potentially clinically relevant (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:
1) QTcB is the length of the QT interval corrected for heart rate by the Bazett 
formula: QTcB=QT/(RR)0.5 and
2) QTcF is the length of the QT interval corrected for heart rate by the Fridericia 
formula: QTcF=QT/(RR)0.33
3) 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 following criteria:
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.
QTc *
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
* QTc categorical change criteria apply to QTcB, QTcF and QTcN.
9.5
Body Weight, Waist Circumference and Body Mass Index (BMI)
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 (OC) and the last visit in 
the double blind treatment period in body weight will be tabulated and analyzed using 
ANCOVA. The ANCOVA models will include the baseline as a covariate and the 
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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 Cochran-
Mantel-Haenszel (CMH) General Association Test. 
9.6
 
 
 
 
 
 
 
 
 
 
9.7
Mini-Mental State Examination (MMSE)
The mean changes from baseline to Week 12 (OC) and the last visit in the double blind 
treatment period in MMSE will be tabulated and analyzed by treatment group using 
ANCOVA. The ANCOVA model for the OC data set will include the baseline item score 
as covariate and treatment group as main effect. The ANCOVA model for last visit will 
include the baseline item score as covariate, and study center, treatment group as main 
effects. The analyses will be performed for Safety Sample.
9.8
 
 
 
 
 
 
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9.9
Concomitant Medications
Number and proportion of subjects taking concomitant medications prior to study 
therapy, during the double blind treatment period, and after study therapy are tabulated by 
drug classification using the WHO drug dictionary.
9.10 Extent of Exposure
The start date of double-blind study therapy - brexpiprazole or placebo - will be the first 
day of double-blind dosing. The number and percentage of subjects, who receive double-
blind study medication, will be presented by week and by treatment group. Each dosing 
week will be based on the actual week; i.e., Day 1-7 in Week 1, Day 8-14 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 study. 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 
treatment group the number of subjects receiving double-blind study medication, and the 
mean and range of the mean daily dose for each week.
The number and percentage of subjects will be presented by modal dose, by final dose
and by treatment group.
10 Conventions
10.1 Study Visit Windows
Study visit windows will be used to map visits using study day intervals. This visit 
window convention applies to tables and listings for all efficacy and safety scales. In
listings it will be listed along with the CRF study visit.
Table below shows classifications for study day intervals in the double-blind period. The 
variable “target day” is defined using the number of days since the start of double-blind 
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dosing. The first day of double-blind dosing is defined as “Day 1”. If more than one 
observation falls within a particular study day interval, then the last observation within 
that interval is used. 
 
 
Study Day and Visit Window
Week
Target Day a
Study Day Interval a
1
7
2-10
2
14
11-17
3
21
18-24
4
28
25-31
5
35
32-38
6
42
39-45
7
49
46-52
8
56
53-59
9
63
60-66
10
70
67-73
11
77
74-80
12
84
81-91 b
a Relative to the first day of IMP in the double blind treatment period.
 
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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10.3 Scales: Rules for Scoring and Handling of Missing Data
10.3.1 Cohen-Mansfield Agitation Inventory (CMAI)
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.
 
 
 
 
 
 
 
.
10.3.2 Clinical Global Impression-Severity of Illness Scale (CGI-S)
The severity of agitation for each subject will be rated using the 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 
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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
 
 
 
 
 
  
 
 
 
10.3.4
 
 
 
 
 
 
 
 
 
10.3.5 Neuro-psychiatric Inventory
The NPI consists of 12 items. For each item there is a screening question to determine if 
the behavioral change is present (rated 1) or absent (rated 0). For each item there are three 
scores: frequency, severity, and caregiver distress (NPI/NPI-NH) or occupational 
disruptiveness (NPI-NH). Frequency is rated on a 1 to 4 scale, severity is rated on a 1 to 3 
scale and the caregiver distress is rated on a 0 to 5 scale. The individual item score is 
calculated as presence x frequency x severity and has a range from 0 to 12. If presence is 
zero, the individual item score and caregiver distress score will be set to zero. For all 
items, low scores are ’better’ than high scores. 
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The NPI Total Score is calculated by adding the individual item scores of the 12 items
together. The possible total scores are from 0 to 144. The NPI Total Score will be
unevaluable if less than 10 of the 12 items are recorded. If 10 or 11 of the 12 items are
available then the total score is the mean of the available scores times 12. All imputed
scores are rounded to the first decimal place.
  
 
  
 
10.3.6
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.3.7
 
 
 
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10.3.8
 
 
 
 
 
 
 
 
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10.3.9 National Institute of Neurological and Communicative Disorders and 
Stroke and the Alzheimer’s Disease and Related Disorders 
Association (NINCDS-ADRDA)
The NINCDS-ADRDA, which has shown good reliability and validity, provides criteria 
for the possible and probable diagnosis of Alzheimer’s disease. 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.
10.3.10 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.
10.3.11
 
 
 
10.3.12
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10.3.14
 
  
 
 
 
 
 
 
 
 
 
 
 
  
10.3.15 Mini-Mental State Examination (MMSE)
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
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missing items could contribute more than 6 points to the total score then the total score
will be set to missing. Otherwise a mean non-missing items score will be calculated by
summing the non-missing items and dividing them by the maximum score possible from
the non-missing items. For missing items with possible scores from 0 to 1, the mean score 
will be imputed for each missing item. If item 14 is missing, two times this mean will be 
imputed for item 14. If items 11, 13, or 16 are missing three times this mean for will be 
imputed each missing item. If item 12 is missing 5 times then this mean will be imputed 
for item 12. After all by-item imputation has been done, the individual item scores will be 
added and this sum will be rounded to the first decimal place to arrive at an imputed total 
score. In other terms, the MMSE Total Score is simply the mean non-missing items score 
multiplied by 30, and then rounded to the first decimal place.


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11
References
1
Siddiqui O, Hung JHM, O'Neill R. MMRM vs. LOCF:  A comprehensive comparison 
based on simulation study and 25 NDA datasets. J Biopharmaceutical Stats. 2009; 
19(2):227-46.
2
Diggle P, Kenward MG. Informative drop-out in longitudinal data analysis. Applied 
Statistics. 1994;43:49-93.
3
Little RJA. Pattern-mixture models for multivariate incomplete data. J Am Stat 
Assoc. 1993;88:125-34.
4
Little RJA. Modeling the drop-out mechanism in repeated measures studies. J Am 
Stat Assoc. 1995;90:1112-21.
5
Hedeker D, Gibbons RD. Application of random effects pattern-mixture models for 
missing data in longitudinal studies. Psychological Methods. 1997;2:64-78.
6
Ali MW, Siddiqui O. Multiple imputation compared with some information dropout 
procedures in the estimation and comparison of rates of change in longitudinal 
clinical trials with dropouts. J Biopharmaceutical Stats. 2000;10(2):165-81.
7
Wu MC, Bailey KR. Estimation and comparison of changes in the presence of 
informative right censoring:  Conditional linear model. Biometrics. 1989; 45:939-55.
8     Rabinowitz J, Davidson M, Paul De Deyn P, Katz I, Brodaty H, Cohen-Mansfield J. 
Factor Analysis of the Cohen-Mansfield Agitation Inventory in Three Large Samples 
of Nursing Home Patients With Dementia and Behavioral Disturbance. The American 
Journal of Geriatric Psychiatry. 2005; 13(11): 991-998.
9  Brunner C, Spiegel R. Eine Validierungsstudie mit der NOSGER (Nurses' Observation 
Scale for Geriatric Patients), einem neuen Beurteilungsinstrument für die 
Psychogeriatrie. Zeitschrift für Klinische Psychologie. 1990; 19:211-229.


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12 Potential Clinical Relevance Criteria from Protocol
Appendix 1
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance
Laboratory Tests
Criteria
Chemistry
AST (SGOT)
3 x upper limit of normal (ULN)
ALT (SGPT)
3 x ULN
Alkaline phosphatase
3 x ULN
LDH
3 x 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 x 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


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Laboratory Tests
Criteria
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
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
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 study 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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Otsuka Pharmaceutical Development & Commercialization, Inc.
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OPC-34712
P331-10-284_SAP
0001263438
2.0
Clinical Approval
21-Mar-2017 18:14 GMT+00
Biostatistics Approval
21-Mar-2017 18:49 GMT+00
PPD