A Phase 2/3 Multicenter, Placebo-controlled, Randomized, Double-blind, Parallel-group Comparison Trial to Evaluate the Efficacy and Safety of Brexpiprazole (OPC-34712) in the Treatment of Patients With Agitation Associated With Dementia of the Alzheimer's Type
Phase: PHASE2
Conditions: Agitation Associated With Dementia of the Alzheimer's Type
Sponsor: Otsuka Pharmaceutical Co., Ltd.

 
 
CLINICAL STUDY PROTOCOL 
 
 
 
A multicenter, randomized, double-blind, placebo-controlled, parallel-group comparison trial to 
evaluate the efficacy and safety of brexpiprazole (OPC-34712) in the treatment of patients with 
agitation associated with dementia of the Alzheimer’s type 
 
 
 
 
NCT Number: NCT03620981 
Protocol No. 331-102-00088 
Version Date: 24 Nov 2022 (Version 6.0) 

Protocol 331-102-00088 
Confidential - Proprietary Information 
1 
Protocol Version 6.0, 24 Nov 2022 
Otsuka Pharmaceutical Co., Ltd. 
 
Investigational Medicinal Product 
Brexpiprazole (OPC-34712) 
 
CLINICAL PROTOCOL 
 
A multicenter, randomized, double-blind, placebo-controlled, parallel-group comparison 
trial to evaluate the efficacy and safety of brexpiprazole (OPC-34712) in the treatment of 
patients with agitation associated with dementia of the Alzheimer’s type 
 
Protocol No. 331-102-00088 
 
CONFIDENTIAL – PROPRIETARY INFORMATION 
 
Clinical Development Phase:  
2/3 
Sponsor: 
Otsuka Pharmaceutical Co., Ltd. 
Immediately Reportable Event: 
 
 
 
 
 
 
Issue Date: 
29 May 2018 
Date of Amendment 1: 
24 Aug 2018 
Date of Amendment 2: 
05 Mar 2020 
Date of Amendment 3: 
03 Feb 2021 
Date of Amendment 4: 
27 Apr 2022 
Date of Amendment 5: 
24 Nov 2022 
Version No.: 
6.0 
 
(Date of Translation: 
12 Jan 2023) 

Protocol 331-102-00088 
Confidential - Proprietary Information 
2 
Protocol Version 6.0, 24 Nov 2022 
Protocol Synopsis 
Name of Sponsor: Otsuka Pharmaceutical 
Co., Ltd. 
Name of Investigational Medicinal Product: 
Brexpiprazole (OPC-34712) 
Protocol No.: 331-102-00088 
 
Protocol title: 
A multicenter, randomized, double-blind, placebo-controlled, 
parallel-group comparison trial to evaluate the efficacy and safety of 
brexpiprazole (OPC-34712) in the treatment of patients with 
agitation associated with dementia of the Alzheimer’s type 
Clinical phase/ 
type of trial: 
Phase 2/3 
Confirmatory study 
Treatment 
indication: 
Agitation associated with dementia of the Alzheimer’s type 
Objectives: 
To evaluate the superiority of brexpiprazole 1 or 2 mg over placebo 
after a 10-week treatment regimen for agitation associated with 
dementia of the Alzheimer’s type in patients who require medication, 
to investigate the safety of brexpiprazole, and to identify the 
optimum dose of brexpiprazole 
Trial design: 
Multicenter, randomized, double-blind, placebo-controlled, parallel-
group comparison 
Subject 
population: 
A total of 407 male or female patients aged ≥ 55 to ≤ 90 years old 
with a diagnosis of dementia of the Alzheimer’s type according to 
the Diagnostic and Statistical Manual of Mental Disorders Fifth 
Edition (DSM-5) and the National Institute of Neurological and 
Communicative Disorders and Stroke–Alzheimer’s Disease and 
Related Disorders Association (NINCDS-ADRDA) who require 
medication, who have symptoms of agitation that have persisted or 
shown frequent recurrence during each 2-week period before the 
screening examination and baseline evaluation, respectively, and 
whose condition can be observed by a caregiver in at least 4 days per 
week for 4 hours or more a day 
Inclusion/exclusi
on criteria: 
The main inclusion criteria are as follows: 
• Patients who meet both of the following diagnostic criteria: 
− Diagnosis of “Dementia due to Alzheimer’s Disease” 
according to DSM-5. 
− Diagnosis of “Probable Alzheimer’s Disease” according to 
NINCDS-ADRDA. 
• Patients who are ≥ 55 and ≤ 90 years of age at the time of 
obtaining informed consent. 
• Patients who can be followed in the same environment (as 
described below) from at least 3 weeks before baseline evaluation 
up to the completion of the examinations scheduled at the 
completion or discontinuation of investigational medicinal 
product (IMP) administration 

Protocol 331-102-00088 
Confidential - Proprietary Information 
3 
Protocol Version 6.0, 24 Nov 2022 
− Patients who will be hospitalized in the same medical facility. 
− Patients who will be institutionalized in the same care facility. 
− Patients who will continue to receive care at home. 
For patients receiving day care or day service, those patients 
who will visit the same care facility at the same frequency 
during the above-mentioned period will be included. 
• Patients whose caregiver can properly collect the necessary 
information (the main caregiver must observe the patient’s 
condition in at least 4 days per week for 4 hours or more a day). 
Patients receiving home care must live with a specific caregiver 
and must not live alone. 
• Patients who have agitation that interferes with daily activities 
and is persistent/recurs frequently during the 2 weeks each before 
the screening examination and baseline evaluation. Agitation is 
defined according to the “Consensus provisional definition of 
agitation in cognitive disorders” from the International 
Psychogeriatric Association (IPA).a 
• Patients who have shown verbal aggression or physical 
aggression for 3 times or more during the 2 weeks before 
baseline evaluation. Examples of verbal aggression and physical 
aggression include the following symptoms in the “Consensus 
provisional definition of agitation in cognitive disorders” of IPA.a 
− Verbal aggression: yelling, speaking in an excessively loud 
voice, using profanity, screaming, shouting, etc. 
− Physical aggression: grabbing, shoving, pushing, resisting, 
hitting others, kicking objects or people, scratching, biting, 
throwing objects, self-hitting, slamming doors, tearing things, 
destroying property, etc. 
The main exclusion criteria are as follows: 
• Patients who have dementia or memory impairment other than 
dementia of the Alzheimer’s type, such as the following: 
Frontotemporal dementia, Lewy body dementia, vascular 
dementia, dementia secondary to head trauma, substance-induced 
persistent dementia, dementia due to human immunodeficiency 
virus infection, dementia due to prion disease, dementia due to 
Parkinson’s disease (including Parkinsonian diseases such as 
progressive supranuclear palsy and basal ganglion degeneration), 
dementia due to Huntington’s disease, dementia due to other 
general medical conditions (eg, subdural hematoma, normal 
pressure hydrocephalus, brain tumor, endocrine disorders, 
 
a Cummings J, Mintzer J, Brodaty H, Sano M, Banerjee S, Devanand DP, et al. Agitation in cognitive 
disorders: International Psychogeriatric Association provisional consensus clinical and research definition. 
International Psychogeriatrics. 2015;27:7–17. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
4 
Protocol Version 6.0, 24 Nov 2022 
nutritional disorders, or infections), dementia due to multiple 
diseases, and dementia not otherwise specified. 
• Patients diagnosed with delirium between 30 days before the 
screening examination and baseline evaluation according to 
DSM-5. 
• Patients diagnosed with any of the following disorders according 
to DSM-5: 
− Schizophrenia spectrum and other psychotic disorders 
− Bipolar and related disorders 
− Major depressive disorder 
However, patients who have major depressive disorder but 
whose condition is stable and asymptomatic within 30 days 
before the screening examination may be included. In regard 
to patients whose condition has been stabilized by 
medication, it should be noted that the use of antidepressants 
is prohibited from 7 days before baseline evaluation up to the 
completion of the examinations scheduled at the completion 
or discontinuation of IMP administration. 
Trial sites: 
Approximately 120 sites in Japan 
Investigational 
medicinal 
products, dose, 
dosage regimen, 
treatment period, 
formulation, 
mode of 
administration: 
The IMP will be administered orally as one tablet once a day for 10 
weeks. The doses of brexpiprazole for each group are as follows: 
Group 
Day 1–7 
Day 8–14 
Day 15–70 
Brexpiprazole 2 mg group 
0.5 mg 
1 mg 
2 mg 
Brexpiprazole 1 mg group 
0.5 mg 
1 mg 
1 mg 
Placebo group 
0 mg 
0 mg 
0 mg 
The dose will be increased to 1 mg after evaluation at Week 1 (Day 8) and to 2 
mg after evaluation at Week 2 (Day 15). 
Trial 
assessments: 
Efficacy: Cohen-Mansfield Agitation Inventory (CMAI), 
Clinical Global Impression–Severity of 
Illness (CGI-S), and CGI-Global Improvement (CGI-I) 
Safety: Adverse events, laboratory tests, 12-lead electrocardiogram, 
vital signs, body weight, physical examination, pregnancy test, Drug-
Induced Extrapyramidal Symptoms Scale, Abnormal Involuntary 
Movement Scale, Barnes Akathisia Rating Scale, and Sheehan 
Suicidality Tracking Scale 
Pharmacokinetics: Blood sampling for the measurement of the 
plasma drug concentration 
Screening and other tests: Mini-Mental State Examination, height, 
medications and therapies, blood sampling for the evaluation of 
pharmacogenomics, blood sampling for DNA storage, blood 
sampling for biomarker exploration samples storage, Alzheimer’s 
Disease Cooperative Study–Activities of Daily Living, and EuroQol 
5-dimension 5-level health questionnaire 

Protocol 331-102-00088 
Confidential - Proprietary Information 
5 
Protocol Version 6.0, 24 Nov 2022 
Criteria for 
evaluation 
Primary endpoint:  
Change in CMAI total score from baseline to Week 10 
Secondary endpoints: 
• Changes in CMAI subscales (Aggressive Behavior, Physically 
Non-aggressive Behavior, and CMAI Verbally Agitated 
Behavior) from baseline to Week 10 
• Change in CGI-S from baseline to Week 10 
• CGI-I at Week 10 
Statistical 
methods: 
Primary endpoint: 
The primary analysis will be conducted on the full analysis set by 
using mixed models for repeated measures analysis on the basis of 
the observed cases data set. For the analysis model, the treatment 
group (brexpiprazole 1 mg group, brexpiprazole 2 mg group, or 
placebo group), time point (Weeks 2, 4, 6, 8, or 10), medical care 
category (hospitalized or outpatient), prior use of antipsychotics (yes 
or no), and interaction between treatment group and time point will 
be included as factors, the baseline and interaction between the 
baseline and time point will be included as covariates, and the error 
variance and covariance structure will be unstructured. The 
Kenward–Roger method will be used to determine the degrees of 
freedom. 
Between-group comparison will be performed by calculating the 
difference of the least squares mean between each of the 
brexpiprazole groups and the placebo group at Week 10. The fixed 
sequence procedure will be used to adjust the multiplicity of testing 
due to the performance of two comparisons (ie, the brexpiprazole 1 
mg group versus the placebo group and the brexpiprazole 2 mg group 
versus the placebo group) to control the overall type I error rate. 
Initially, the brexpiprazole 2 mg group will be compared with the 
placebo group. Only if the difference is statistically significant at a 
significance level of 5% (two sided), the brexpiprazole 1 mg group 
will be compared with the placebo group at a significance level of 
5% (two sided). 
The least squares mean for each treatment group and the difference 
of the least squares mean between each brexpiprazole group and the 
placebo group, as well as their two-sided 95% confidence intervals, 
will be calculated at each time point. 
Rationale for setting the target sample size: 
In Trial 331-12-283, which was performed outside Japan, the 2 mg 
fixed-dose group showed superiority over the placebo group in 
patients with aggressive behavior at baseline, thus suggesting that it 
may also be the optimum dose for Japanese patients. Efficacy was 
not observed in the 1 mg fixed-dose group, but in Trial 331-12-284, 
the efficacy of a dose less than 2 mg was suggested by the results 

Protocol 331-102-00088 
Confidential - Proprietary Information 
6 
Protocol Version 6.0, 24 Nov 2022 
obtained in patients from the flexible-dose (0.5 to 2 mg) group, who 
had aggressive behavior at baseline. 
In this trial, a power of detection ≥ 80% will be achieved for 
comparison between the placebo group and the 1 mg group to allow 
evaluation of superiority over the placebo group if equivalent 
efficacy is demonstrated in the 1 and 2 mg groups. For comparison 
between the 2 mg group (possible optimum dose) and the placebo 
group, a more sufficient power of detection will be obtained by 
changing the randomization ratio. In this trial, it is assumed that the 
difference between the 2 mg group and the placebo group in the 
change in the CMAI total score from baseline to Week 10 is −5.35, 
and the standard deviation (calculated from the standard error of the 
difference between the 2 mg and placebo groups and the number of 
subjects at baseline) is 15.06 on the basis of the results of Trial 331-
12-283. By setting the number of subjects in the 2 mg group, 1 mg 
group, and placebo group as 148, 111, and 148, respectively 
(randomization ratio of 4:3:4), the power of detection is 86.1% for 
the comparison between the 2 mg group and the placebo group and is 
80.5% for the comparison between the 1 mg group and the placebo 
group in a test with a significance level of 5% (two sided). 
On the basis of the above considerations, the number of subjects will 
be set at 148 in the 2 mg group, 111 in the 1 mg group, and 148 in 
the placebo group (randomization ratio of 4:3:4). 
Trial duration: 
August 2018 to June 2023 (planned) 
The duration of participation in the trial by each subject will be up to 
20 weeks. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
7 
Protocol Version 6.0, 24 Nov 2022 
Table of Contents 
Protocol Synopsis ........................................................................................... 2 
Table of Contents ........................................................................................... 7 
List of In-text Tables ................................................................................... 13 
List of In-text Figures .................................................................................. 14 
List of Appendices........................................................................................ 15 
List of Abbreviations and Definitions of Terms ....................................... 16 
1 
Introduction .......................................................................................................18 
1.1 
Background .....................................................................................................18 
1.2 
Nonclinical Data .............................................................................................20 
1.3 
Clinical Data ...................................................................................................21 
1.3.1 
 
 .............................................................21 
1.3.1.1 
 .........................................................................................21 
1.3.1.2 
 .......................................................................................23 
1.3.1.3 
 ......................................................................................25 
1.4 
Known and Potential Risks and Benefits ........................................................26 
2 
Trial Rationale and Objectives ..........................................................................27 
2.1 
Trial Rationale ................................................................................................27 
2.2 
Rationale for CYP2D6 Genetic Testing and DNA Storage ............................28 
2.3 
Rationale of Sample Storage for Biomarker Exploration ...............................29 
2.4 
Trial Objectives ..............................................................................................30 
3 
Trial Design .......................................................................................................30 
3.1 
Type/Design of Trial .......................................................................................30 
3.2 
Trial Treatments ..............................................................................................32 
3.2.1 
Dosing and Regimen ...................................................................................32 
3.2.2 
Rationale for Dosing and Regimen .............................................................32 
3.2.3 
Rationale for Duration of Treatment ...........................................................34 
3.3 
Trial Population ..............................................................................................34 
3.3.1 
Number of Subjects and Trial Population ...................................................34 
3.3.2 
Subject Number Assignment ......................................................................34 
3.4 
Eligibility Criteria ...........................................................................................35 

Protocol 331-102-00088 
Confidential - Proprietary Information 
8 
Protocol Version 6.0, 24 Nov 2022 
3.4.1 
Informed Consent ........................................................................................35 
3.4.2 
Inclusion Criteria .........................................................................................36 
3.4.3 
Exclusion Criteria........................................................................................38 
3.5 
Requirements for Caregivers ..........................................................................41 
3.6 
Endpoints ........................................................................................................42 
3.6.1 
Primary Endpoint ........................................................................................42 
3.6.2 
Secondary Endpoints ...................................................................................42 
3.6.3 
Exploratory Endpoints ................................................................................42 
3.6.4 
Safety Endpoints .........................................................................................42 
3.6.5 
Pharmacokinetic Endpoint ..........................................................................43 
3.6.6 
Pharmacogenomic Endpoint .......................................................................43 
3.6.7 
Other Endpoints ..........................................................................................43 
3.7 
Measures to Minimize/Avoid Bias .................................................................43 
3.8 
Trial Procedures ..............................................................................................45 
3.8.1 
Schedule of Assessments ............................................................................47 
3.8.1.1 
Screening Period ......................................................................................47 
3.8.1.2 
Day of Baseline Examination ..................................................................49 
3.8.1.3 
Randomization .........................................................................................49 
3.8.1.4 
Seven Days After Administration (Week 1, Day 8) to Seventy 
Days After Administration (Week 10, Day 71) .......................................50 
3.8.1.5 
Examination at Discontinuation ..............................................................50 
3.8.1.6 
Follow-up Observation (Twenty-eight Days After Completion or 
Discontinuation of IMP Administration) .................................................50 
3.8.2 
Efficacy Assessments ..................................................................................50 
3.8.2.1 
Cohen-Mansfield Agitation Inventory ....................................................51 
3.8.2.2 
Clinical Global Impression–Severity of Illness .......................................51 
3.8.2.3 
Clinical Global Impression–Global Improvement ..................................51 
3.8.2.4 
 ..........................................................................................51 
3.8.2.5 
 ...................................................................52 
3.8.3 
Safety Assessments .....................................................................................52 
3.8.3.1 
Adverse Events ........................................................................................52 

Protocol 331-102-00088 
Confidential - Proprietary Information 
9 
Protocol Version 6.0, 24 Nov 2022 
3.8.3.2 
Clinical Laboratory Assessments ............................................................52 
3.8.3.3 
Physical Examination ..............................................................................54 
3.8.3.4 
Vital Signs (Blood Pressure and Pulse Rate) ..........................................54 
3.8.3.5 
Height and Body Weight .........................................................................54 
3.8.3.6 
Twelve-lead Electrocardiography ...........................................................54 
3.8.3.7 
Pregnancy Test ........................................................................................55 
3.8.3.8 
Other Safety Assessments .......................................................................56 
3.8.3.8.1 
Drug-induced Extrapyramidal Symptoms Scale ..................................56 
3.8.3.8.2 
Abnormal Involuntary Movement Scale ..............................................56 
3.8.3.8.3 
Barnes Akathisia Rating Scale .............................................................56 
3.8.3.8.4 
Sheehan Suicidality Tracking Scale .....................................................56 
3.8.4 
Pharmacokinetic Assessment, Pharmacogenomic Assessment, and 
Biomarker Exploration ................................................................................56 
3.8.4.1 
Pharmacokinetic Assessment ..................................................................57 
3.8.4.2 
Pharmacogenomic Assessment ...............................................................57 
3.8.4.2.1 
CYP2D6 Genetic Testing ....................................................................57 
3.8.4.2.2 
DNA Storage ........................................................................................58 
3.8.4.3 
Storage of Samples for Biomarker Exploration ......................................60 
3.8.5 
Other Endpoints ..........................................................................................62 
3.8.5.1 
Alzheimer's Disease Cooperative Study–Activities of Daily Living ......62 
3.8.5.2 
Mini-Mental State Examination ..............................................................62 
3.8.5.3 
EuroQol 5-Dimension 5-Level Health Questionnaire .............................63 
3.8.6 
Medications and Therapies .........................................................................63 
3.8.7 
End of Trial .................................................................................................63 
3.8.8 
Independent Data Monitoring Committee ..................................................64 
3.8.9 
Raters ..........................................................................................................64 
3.9 
Stopping Rules, Withdrawal Criteria, and Procedures ...................................65 
3.9.1 
Entire Trial ..................................................................................................65 
3.9.2 
Individual Site .............................................................................................65 
3.9.3 
Individual Subject Discontinuation .............................................................65 
3.9.3.1 
Treatment Discontinuation ......................................................................65 
3.9.3.2 
Documenting Reasons for Discontinuation .............................................66 
3.9.3.3 
Withdrawal of Consent ............................................................................67 

Protocol 331-102-00088 
Confidential - Proprietary Information 
10 
Protocol Version 6.0, 24 Nov 2022 
3.9.3.4 
Procedures to Encourage Continued Trial Participation .........................68 
3.10 
Screen Failures ................................................................................................68 
3.11 
Definition of Completed Subjects ..................................................................69 
3.12 
Definition of Subjects Lost to Follow-up .......................................................69 
3.13 
Subject Compliance ........................................................................................69 
3.14 
Protocol Deviations ........................................................................................70 
4 
Restrictions ........................................................................................................70 
4.1 
Prohibited Medications ...................................................................................70 
4.2 
Restricted Medications ...................................................................................71 
4.3 
Restricted Therapies .......................................................................................72 
4.4 
Other Restrictions ...........................................................................................73 
5 
Reporting of Adverse Events ............................................................................73 
5.1 
Definitions ......................................................................................................73 
5.2 
Eliciting and Reporting Adverse Events .........................................................75 
5.3 
Immediately Reportable Events ......................................................................75 
5.4 
Potential Drug-induced Liver Injury ..............................................................76 
5.5 
Pregnancy .......................................................................................................76 
5.6 
Procedure for Breaking the Blind ...................................................................78 
5.7 
Follow-up of Adverse Events .........................................................................78 
5.7.1 
Follow-up of Nonserious Adverse Events ..................................................78 
5.7.2 
Follow-up of Serious Adverse Events and Immediately Reportable 
Events ..........................................................................................................78 
5.7.3 
Follow-up and Reporting of Serious Adverse Events and Immediately 
Reportable Events Occurring After the End of Trial Date (Final Day 
of Observation) ...........................................................................................79 
6 
Statistical Analysis ............................................................................................79 
6.1 
Determination of Sample Size ........................................................................79 
6.2 
Datasets for Analysis ......................................................................................80 
6.2.1 
Pharmacokinetic Analysis Set .....................................................................80 
6.2.2 
Full Analysis Set .........................................................................................80 
6.2.3 
Safety Analysis Set .....................................................................................80 
6.3 
Handling of Missing Data ...............................................................................80 
6.4 
Primary and Secondary Endpoint Analyses ...................................................81 

Protocol 331-102-00088 
Confidential - Proprietary Information 
11 
Protocol Version 6.0, 24 Nov 2022 
6.4.1 
Primary Endpoint Analyses.........................................................................81 
6.4.2 
Secondary Endpoint Analyses.....................................................................81 
6.4.3 
Exploratory Endpoint Analyses ..................................................................82 
6.4.4 
Interim Analysis ..........................................................................................82 
6.4.5 
Subgroup Analyses .....................................................................................82 
6.5 
Analysis of Demographic and Baseline Characteristics .................................83 
6.6 
Safety Analysis ...............................................................................................83 
6.6.1 
Adverse Events ...........................................................................................83 
6.6.2 
Clinical Laboratory Data .............................................................................84 
6.6.3 
Physical Examination and Vital Signs Data ...............................................84 
6.6.4 
Electrocardiogram Data ..............................................................................84 
6.6.5 
Other Safety Data ........................................................................................85 
6.6.5.1 
Body Weight and Body Mass Index ........................................................85 
6.6.5.2 
DIEPSS, AIMS, and BARS .....................................................................85 
6.6.5.3 
S-STS .......................................................................................................85 
6.7 
Analysis of Pharmacokinetic Endpoints .........................................................86 
6.8 
Analysis of Pharmacogenomic Endpoints ......................................................86 
6.9 
Genomic/Genetic Analysis .............................................................................86 
6.10 
Biomarker Exploration Analysis ....................................................................86 
6.11 
Analysis of Other Endpoints ...........................................................................86 
7 
Management of Investigational Medicinal Product ..........................................87 
7.1 
Packaging and Labeling ..................................................................................87 
7.2 
Storage ............................................................................................................87 
7.3 
Accountability .................................................................................................87 
7.4 
Returns and Destruction .................................................................................87 
7.5 
Reporting of Product Quality Complaints ......................................................87 
7.5.1 
Eliciting and Reporting Product Quality Complaints .................................88 
7.5.2 
Information Required for Reporting Product Quality Complaints .............88 
7.5.3 
Return Process for Product Quality Complaints .........................................88 
7.5.4 
Assessment/Evaluation ...............................................................................89 
8 
Records Management ........................................................................................89 
8.1 
Source Documents ..........................................................................................89 
8.2 
Data Collection ...............................................................................................89 

Protocol 331-102-00088 
Confidential - Proprietary Information 
12 
Protocol Version 6.0, 24 Nov 2022 
8.3 
File Management at the Trial Site ..................................................................90 
8.4 
Record Retention at the Trial Site ..................................................................90 
9 
Quality Control and Quality Assurance ............................................................91 
9.1 
Monitoring ......................................................................................................91 
9.2 
Auditing ..........................................................................................................91 
10 
Ethics and Responsibility ..................................................................................91 
11 
Confidentiality ...................................................................................................91 
12 
Amendment Policy ............................................................................................92 
13 
Publication Authorship Requirements ...............................................................92 
14 
References .........................................................................................................93 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
13 
Protocol Version 6.0, 24 Nov 2022 
List of In-text Tables 
Table 1.3.1.1-1 
 ........................................... 21 
Table 1.3.1.2-1 
 ............................... 23 
Table 1.3.1.2-2 
 ........................... 24 
Table 3.2.1-1 
Doses of IMPs ............................................................................... 32 
Table 3.4.2-1 
Inclusion Criteria .......................................................................... 36 
Table 3.4.3-1 
Exclusion Criteria ......................................................................... 38 
Table 3.8-1 
Schedule of Assessments .............................................................. 45 
Table 3.8-2 
Allowable Time Windows for Evaluations, Tests, and 
Observations ................................................................................. 47 
Table 3.8.3.2-1 
Clinical Laboratory Assessments .................................................. 53 
Table 3.8.9-1 
Raters of Evaluation Scales .......................................................... 65 
Table 4.1-1 
Prohibited Medications ................................................................. 70 
Table 4.1-2 
Prohibited Concomitant CYP2D6 Inhibitors, CYP3A4 
Inhibitors, and CYP3A4 Inducers (Except for External Use) ....... 71 
Table 4.2-1 
Restricted Medications.................................................................. 71 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
14 
Protocol Version 6.0, 24 Nov 2022 
List of In-text Figures 
Figure 3.1-1 
Trial Design .................................................................................. 32 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
15 
Protocol Version 6.0, 24 Nov 2022 
List of Appendices 
Appendix 1 
 ........................ 96 
Appendix 2 
 .......................................................... 99 
Appendix 3 
Protocol Amendments/Administrative Changes ......................... 103 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
16 
Protocol Version 6.0, 24 Nov 2022 
List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
5-HT 
5-Hydroxytryptamine 
5-HT1A 
5-Hydroxytryptamine 1A  
5-HT2A 
5-Hydroxytryptamine 2A 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study–Activities of Daily Living 
AIMS 
Abnormal Involuntary Movement Scale  
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance  
APTT 
Activated partial thromboplastin time  
AST 
Aspartate aminotransferase 
BARS 
Barnes Akathisia Rating Scale  
BMI 
Body mass index  
BPSD 
Behavioral and Psychological Symptoms of Dementia  
BUN 
Blood urea nitrogen  
CGI-I 
Clinical Global Impression–Global Improvement 
CGI-S 
Clinical Global Impression–Severity of Illness 
CMAI 
Cohen-Mansfield Agitation Inventory 
CMH 
Cochran Mantel Haenszel  
CPK 
Creatine phosphokinase 
CYP 
Cytochrome P450 
D2 
Dopamine D2 
DBP 
Diastolic blood pressure 
DIEPSS 
Drug-Induced Extrapyramidal Symptoms Scale  
DNA 
Deoxyribonucleic acid 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders Fifth Edition 
EDTA 
Ethylenediaminetetraacetic acid 
EQ-5D-5L 
EuroQol 5-dimension 5-level health questionnaire 
FAS 
Full analysis set  
FT4 
Free thyroxine  
GCP 
Good Clinical Practice  
HbA1c 
Glycosylated hemoglobin 
HBsAg 
Hepatitis B surface antigen  
HCG 
Human chorionic gonadotropin  
HCV Ab 
Hepatitis C virus antibodies  
HDL 
High-density lipoprotein  
HIV 
Human immunodeficiency virus  
IB 
Investigator brochure 
ICH 
The International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICMJE 
International Committee of Medical Journal Editors  
IDMC 
Independent data monitoring committee 
INR 
International normalized ratio  
IPA 
International Psychogeriatric Association  
IRB 
Institutional review board  

Protocol 331-102-00088 
Confidential - Proprietary Information 
17 
Protocol Version 6.0, 24 Nov 2022 
Abbreviation 
Definition 
IRE 
Immediately reportable event 
IUD 
Intrauterine device  
IWRS 
Interactive web response system  
LDH 
Lactate (lactic acid) dehydrogenase  
LDL 
Low-density lipoprotein 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities  
MMRM 
Mixed models for repeated measures  
MMSE 
Mini-Mental State Examination  
NGSP 
The National Glycohemoglobin Standardization Program 
NINCDS-ADRDA 
National Institute of Neurological and Communicative Disorders and Stroke–
Alzheimer’s Disease and Related Disorders Association 
 
 
 
 
 
 
 
 
 
 
 
 
OC 
Observed cases  
PQC 
Product quality complaint 
PT 
Prothrombin time  
PV 
Pharmacovigilance  
QTc 
QT corrected for heart rate 
QTcB 
QT corrected for heart rate by Bazett’s formula 
QTcF 
QT corrected for heart rate by Fridericia’s formula 
QTcN 
QT corrected for heart rate by FDA Neuropharmacological Division formula 
SBP 
Systolic blood pressure 
S-STS 
Sheehan Suicidality Tracking Scale 
TEAE 
Treatment-emergent adverse event 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal  
WOCBP 
Women of childbearing potential 
γ-GTP 
γ-glutamyl transpeptidase 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
18 
Protocol Version 6.0, 24 Nov 2022 
1 
Introduction 
1.1 
Background 
Due to a recent increase in the elderly population, the number of patients with dementia is 
increasing. According to the Ministry of Health, Labour and Welfare (MHLW), Japanese 
patients with dementia account for 10% (approximately 2.42 million people) of the 
population aged ≥ 65 years, and the number is estimated to increase to 3.25 million 
people by 2020.1 A recent epidemiology study showed that dementia of the Alzheimer’s 
type is the most common form of dementia.1 
Symptoms of dementia of the Alzheimer’s type are categorized into core symptoms such 
as memory impairment and impaired cognitive function and peripheral symptoms.2 
Peripheral symptoms are referred to as the behavioral and psychological symptoms of 
dementia (BPSD) or neuropsychiatric symptoms, and agitation is included in peripheral 
symptoms.3,4 According to the definition given by the International Psychogeriatric 
Association (IPA) Working Group, agitation is a state in which the patient exhibits at 
least one of the symptoms of excessive motor activity, verbal aggression, and physical 
aggression, is not attributable solely to another psychiatric disorder or living 
environment, and causes impairment in the ability to perform or participate in daily living 
activities, other aspects of social functioning, or interpersonal relationships.5 About 40% 
to 80% of patients with dementia of the Alzheimer’s type present with agitation.6,7 
Agitation has been reported to be related to cognitive decline,8 decline in activities9 and 
function8 of daily living, progression to severe dementia of the Alzheimer’s type,10 and 
death.10 Moreover, agitation has been reported to be related to the burden imposed on 
caregivers,11,12 increases in care time and observation time,13 early admission to a care 
facility,8,14,15 and increased healthcare costs,16 this being an issue for patients, caregivers, 
and medical resources. 
The Practice Guideline for Dementia 2017 instructs as follows for agitation: “Person-
centered-care is the basis. The reason(s) and cause(s) of symptoms should be considered 
and measures to resolve them should be sought. Another effective approach is for 
caregivers to learn appropriate skills for conversing with patients with dementia and to 
exercise these skills. As nonmedication therapies, the efficacy of group activities, music 
therapy, tactile care, and massage has been demonstrated, and use of these therapies 
should also be considered” and “if the patient does not respond adequately to 
nonmedication therapies, medication should be considered.”17 This clearly implies that if 

Protocol 331-102-00088 
Confidential - Proprietary Information 
19 
Protocol Version 6.0, 24 Nov 2022 
agitation does not respond adequately to nonmedication therapies, medication needs to be 
considered. While the guideline states that “medication should be introduced only after 
sufficient efforts have been made to reduce BPSD with nonmedication therapies,” it lists 
“aggression that endangers self or others” as one of the “exceptions to preferentially 
introduce medication.”18 According to the guideline, immediate consideration of 
medication cannot be avoided in some patients with aggressive agitation associated with 
dementia of the Alzheimer’s type. 
However, in Japan there are no drugs indicated for agitation and all drugs are 
administered as off-label use. Although it is off-label use, the Practice Guideline for 
Dementia 2017 states the following regarding medication: “The efficacy of atypical 
antipsychotics such as risperidone and aripiprazole has been demonstrated. Use of 
Yokukansan, tiapride, carbamazepine, sertraline, escitalopram and trazodone should also 
be considered.”17 The results of a meta-analysis of dementia patients in clinical trials of 
atypical antipsychotics, for which efficacy has been demonstrated according to the 
guideline, showed a mortality rate 1.54-fold higher in the atypical antipsychotic group 
compared with the rate in the placebo group,19 showing a risk of death. These findings 
show that sufficient evidence is lacking for all medications indicated for agitation and the 
use of atypical antipsychotics needs to be considered despite the reported safety risk. Due 
to these circumstances, there are unmet needs for a drug-based approach to the treatment 
of agitation. 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
20 
Protocol Version 6.0, 24 Nov 2022 
 
 
 
 
On the basis of these background factors, Otsuka considered that the development of 
brexpiprazole could make a significant contribution to the treatment of agitation 
associated with dementia of the Alzheimer’s type and accordingly planned this clinical 
trial. 
1.2 
Nonclinical Data 
 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
21 
Protocol Version 6.0, 24 Nov 2022 
1.3 
Clinical Data 
1.3.1 
 
1.3.1.1 
 
 
 
Table 1.3.1.1-1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
22 
Protocol Version 6.0, 24 Nov 2022 
Table 1.3.1.1-1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
23 
Protocol Version 6.0, 24 Nov 2022 
1.3.1.2 
 
 
 
 
 
Table 1.3.1.2-1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
24 
Protocol Version 6.0, 24 Nov 2022 
 
 
 
 
 
 
 
 
 
 
Table 1.3.1.2-2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
25 
Protocol Version 6.0, 24 Nov 2022 
 
1.3.1.3 
 
 
 
 
 
 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
26 
Protocol Version 6.0, 24 Nov 2022 
 
 
 
 
 
 
 
. 
1.4 
Known and Potential Risks and Benefits 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
27 
Protocol Version 6.0, 24 Nov 2022 
 
 
 
 
 
 
2 
Trial Rationale and Objectives 
2.1 
Trial Rationale 
It is considered that neurotransmitters such as serotonin, dopamine and noradrenaline are 
involved in agitation. Brexpiprazole, which regulates the serotonin-dopaminergic system, 
is expected to improve agitation in patients with dementia of the Alzheimer’s type while 
suppressing expression of extrapyramidal symptoms. 
Based on the results of the 2 overseas confirmatory trials in agitation associated with 
dementia of the Alzheimer's type (Trial 331-12-283 and Trial 331-12-284), and because 

Protocol 331-102-00088 
Confidential - Proprietary Information 
28 
Protocol Version 6.0, 24 Nov 2022 
the PK of brexpiprazole is not affected by ethnicity, it is considered that brexpiprazole 
will also show efficacy in Japanese patients with agitation associated with dementia of 
the Alzheimer's type. 
In the overall population of Trial 331-12-284, no statistically significant differences were 
noted in the flexible-dose brexpiprazole group compared with the placebo group, but the 
results of an additional analysis showed the efficacy of brexpiprazole in patients with 
aggression. 
On the basis of these findings, a multicenter, placebo-controlled, randomized, double-
blind, parallel-group comparison trial to verify the superiority of brexpiprazole over 
placebo, evaluate the safety of brexpiprazole, and confirm an optimal dose in Japanese 
patients with aggression in agitation associated with dementia of the Alzheimer’s type 
was planned. The doses of brexpiprazole were determined with reference to the data of 
the 2 overseas trials, and two doses were selected: a dose of 2 mg, which showed a 
statistically significant improvement compared with the placebo group in Trial 331-12-
283 and might be an optimal dose in Japanese patients, and a dose of 1 mg to obtain the 
dose-response relationship in Japanese patients. Duration of treatment was set to 10 
weeks. 
Furthermore, on the basis of the report19 of the risk of death associated with atypical 
antipsychotics, criteria to exclude patients at high risk of cerebrovascular disorder, 
cardiac disorder, pneumonia, and other infections, which were the causes of death 
associated with atypical antipsychotics, were established to minimize the risk to subjects 
during the trial and an Independent Data Monitoring Committee (IDMC) was established 
to monitor safety during the trial, as measures to ensure subject safety. 
Since there are no drugs indicated for “agitation associated with dementia of the 
Alzheimer’s type” in Japan, obtaining marketing approval for the indication through this 
trial would contribute to medical practice by providing another therapeutic option. 
On the basis of what has been described above, the conduct of this trial was judged to be 
scientifically and ethically justifiable. 
2.2 
Rationale for CYP2D6 Genetic Testing and DNA Storage 
The metabolism of brexpiprazole was shown to be mainly mediated by CYP3A4 and 
CYP2D6 according to in vitro metabolism studies, and CYP2D6 is known to have 
multiple genotypes with different enzyme activities. It has been clarified that CYP2D6 
genotypes affect the pharmacokinetics of brexpiprazole. Therefore, the examination of 
CYP2D6 genotypes will be performed in this trial to investigate the influence of 
CYP2D6 genotypes on the safety and efficacy of brexpiprazole, 

Protocol 331-102-00088 
Confidential - Proprietary Information 
29 
Protocol Version 6.0, 24 Nov 2022 
 
 
 
 
2.3 
Rationale of Sample Storage for Biomarker Exploration 

Protocol 331-102-00088 
Confidential - Proprietary Information 
30 
Protocol Version 6.0, 24 Nov 2022 
 
 
 
 
 
2.4 
Trial Objectives 
The objective of the trial is to evaluate the superiority of brexpiprazole 1 or 2 mg over 
placebo after a 10-week treatment regimen for agitation associated with dementia of the 
Alzheimer’s type in patients who require medication, to investigate the safety of 
brexpiprazole, and to identify the optimum dose. 
3 
Trial Design 
3.1 
Type/Design of Trial 
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group 
comparison trial to evaluate the efficacy and safety of brexpiprazole in patients with 
agitation associated with dementia of the Alzheimer’s type who require medication. The 
overview of the trial design is shown in Figure 3.1-1. 
The trial consists of a screening period, a treatment period, and a follow-up period. The 
investigator or subinvestigator will explain the details of the trial to a prospective subject 
(if the investigator or subinvestigator judges that the subject is incapable of providing 
informed consent or if the subject is hospitalized for reasons related to medical 
protection, the subject’s legally acceptable representative must provide written consent, 
and even when written consent is obtained from the legally acceptable representative, the 
subject should be given an explanation appropriate to his or her level of understanding 
and, if possible, should also provide written consent) and their caregivers using the 
explanatory materials and informed consent form (ICF) and obtain written consent for 

Protocol 331-102-00088 
Confidential - Proprietary Information 
31 
Protocol Version 6.0, 24 Nov 2022 
participation in the trial from the patient (or their legally acceptable representatives) and 
caregivers. The subject’s clinical course will be followed in the same environment (see 
Section 3.4.2 Inclusion Criteria, 4) such as hospitalization in the same medical facility, 
institutionalization in the same care facility, and continued care at home from at least 3 
weeks before baseline evaluation up to the completion of the examinations scheduled at 
the completion or discontinuation of IMP administration. After obtaining consent from 
the patient (or their legally acceptable representatives) and caregiver, the investigator or 
subinvestigator will perform the specified observations, tests, and investigations to 
confirm the subject’s eligibility before IMP allocation. Subjects who are judged to be 
eligible in the screening examination and baseline evaluation will be randomized to the 
brexpiprazole 1 mg, brexpiprazole 2 mg, or placebo group. The IMP allocation will be 
performed using a dynamic allocation method to minimize bias in background factors 
(medical care category, prior use of antipsychotics, CMAI total score in baseline 
assessment) among the treatment groups. Duration of IMP treatment is 10 weeks. The 
subject will receive brexpiprazole or placebo for 10 weeks according to Section 3.2 Trial 
Treatments, and undergo periodic observations, tests, and investigations to assess 
efficacy and safety. The subject will return to the trial site 28 days after the completion of 
IMP administration for follow-up observation. Discontinued subjects will also undergo 
follow-up observation. 
For subjects who discontinued the trial during the treatment period, the examination at 
discontinuation will be performed. 
The trial period of each subject is from the date of informed consent to the end date of 
follow-up observation. If subjects have transitioned to the extension trial and commenced 
IMP administration, follow-up observation will not be performed. In such a case, the trial 
period is until the end date of evaluation at Week 10 (Day 71). 

Protocol 331-102-00088 
Confidential - Proprietary Information 
32 
Protocol Version 6.0, 24 Nov 2022 
 
Figure 3.1-1 
Trial Design 
Follow-up observation will not be performed for subjects who have transitioned to the extension trial 
and commenced IMP administration. 
 
3.2 
Trial Treatments 
3.2.1 
Dosing and Regimen 
The IMP will be administered orally as one tablet once a day for 10 weeks. The doses of 
brexpiprazole for each group is shown in Table 3.2.1-1. Although the temporal 
relationship between IMP administration and meals will not be considered, subjects 
should take the IMP at the specified time in so far as possible. Dose reduction is not 
allowed during the trial, and if there are tolerability issues, administration of the IMP will 
be discontinued. 
Table 3.2.1-1 
Doses of IMPs 
Group 
Day 1–7 
Day 8–14 
Day 15–70 
Brexpiprazole 2 mg 
0.5 mg 
1 mg 
2 mg 
Brexpiprazole 1 mg 
0.5 mg 
1 mg 
1 mg 
Placebo 
0 mg 
0 mg 
0 mg 
The dose will be increased to 1 mg after evaluation at Week 1 (Day 8) and to 2 mg after evaluation at 
Week 2 (Day 15) 
 
3.2.2 
Rationale for Dosing and Regimen 
Doses and regimen were determined on the basis of the results of the 2 overseas trials 
(Trial 331-12-283 and Trial 331-12-284), as no significant differences due to ethnicity 
have been observed in the PK of brexpiprazole. 
Screening
period
Follow-up
period
Treatment period
1 week
2 mg
Brexpiprazole 2 mg (148 subjects)
1 week
1 mg
0.5 mg
1 mg
Brexpiprazole 1 mg (111 subjects)
0.5 mg
Placebo (148 subjects)
Day −42 to
Day −2
Day 28
Baseline Week 1 Week 2
Week 4
Week 6
Week 8
Week 10

Protocol 331-102-00088 
Confidential - Proprietary Information 
33 
Protocol Version 6.0, 24 Nov 2022 
In Trial 331-12-283, the brexpiprazole 2 mg group showed a statistically significant 
improvement in change from baseline in CMAI total score compared with the placebo 
group. In patients with aggression in the baseline evaluation in Trial 331-12-283, 
improvement in the 2 mg group was greater than that in the placebo group. 
These findings suggested that 2 mg might be the optimal dose in Japanese patients. 
Therefore, 2 mg was selected to verify superiority over the placebo group. 
On the other hand, although the 1 mg group in Trial 331-12-283 did not demonstrate 
improvement greater than that in the placebo group among either the overall population 
or patients with aggression, in Trial 331-12-284, which was conducted using flexible 
doses, the 0.5 to 2 mg group showed greater efficacy than the placebo group among 
patients with aggression, raising the possibility that doses lower than 2 mg might be 
effective. On the basis of these findings, a 1 mg group was included so that information 
on the dose-response relationships in Japanese patients could be obtained and superiority 
over the placebo group can be confirmed if the 1 mg group demonstrates efficacy similar 
to that in the 2 mg group. 
In the 2 overseas trials, a dose titration method with a low starting dose and gradual dose 
increase was used in consideration of safety in elderly subjects, who were the target 
subjects of those trials. In the 2 overseas trials, a dose titration method in which dosing 
started from 0.25 mg and was increased to the maximum dose of 2 mg over 4 weeks was 
used, and no apparent safety problems were noted up to 2 mg. Since this trial will be 
conducted in patients with aggression who have a strong need for medication among 
patients with agitation, a dose titration method in which the dose will be started from 0.5 
mg, increased to 1 mg at Week 1 (after evaluation at Week 1 [Day 8]) and to 2 mg at 
Week 2 (after evaluation at Week 2 [Day 15]) was selected to reach 2 mg (which may 
become the optimal dose) as quickly as possible. The starting dose of 0.5 mg is 1/2 of the 
starting dose (1 mg) of brexpiprazole in schizophrenia, and conforms to the precautions 
and principles for medication in elderly patients with dementia described in the Practice 
Guideline for Dementia 201726: “depending on the type of medication, starting treatment 
at lower doses such as 1/2 to 1/4 of the doses recommended for younger patients should 
be considered.” Trial visits were set to 1 week after the start of trial treatment before a 
dose increase to 1 mg and 2 weeks after the start of trial treatment before a dose increase 
to 2 mg, and dose titration will be performed with confirmation of subject safety. 
The dosing regimen is oral administration once daily based on the PK and the 2 overseas 
trials. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
34 
Protocol Version 6.0, 24 Nov 2022 
3.2.3 
Rationale for Duration of Treatment 
Duration of treatment was determined on the basis of the clinical position of 
brexpiprazole therapy and taking the results of the 2 overseas trials into consideration. 
Brexpiprazole is positioned as symptomatic treatment for patients who require 
medication. The Practice Guideline for Dementia 201717 states that atypical 
antipsychotics including brexpiprazole “should not be continued without a compelling 
reason even if their efficacy is recognized.” Therefore, long-term administration as 
maintenance therapy after improvement of symptoms is not considered.  
However, in a repeated-dose trial in Japanese patients with schizophrenia, steady-state 
was reached from Day 10 onward, and thus a certain period is necessary to confirm if 
efficacy is sufficient after increasing the dose to 2 mg. 
In the 2 overseas trials, after the brexpiprazole dose had been increased to 2 mg 
(maximum dose), brexpiprazole was continued for 8 weeks (12 weeks in total, including 
the 4-week dose titration period) until sufficient efficacy was confirmed, and the efficacy 
of brexpiprazole 2 mg had been demonstrated. Therefore, as in the 2 overseas trials, it 
was decided that for this trial administration would be continued for 8 weeks after 
reaching the maximum dose of 2 mg. As described in Section 3.2.2 Rationale for Dosing 
and Regimen, as administration of brexpiprazole will reach the maximum dose of 2 mg at 
2 weeks, a total of 10 weeks was set as the duration of treatment. 
3.3 
Trial Population 
3.3.1 
Number of Subjects and Trial Population 
A total of 407 male and female patients (brexpiprazole 2 mg, 148 subjects; brexpiprazole 
1 mg, 111 subjects; placebo 148 subjects) with agitation associated with dementia of the 
Alzheimer’s type who require medication will be enrolled in the trial. 
3.3.2 
Subject Number Assignment 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
35 
Protocol Version 6.0, 24 Nov 2022 
3.4 
Eligibility Criteria 
3.4.1 
Informed Consent 
Written informed consent will be obtained from all subjects (or their legally acceptable 
representatives) on their voluntary decision. If the investigator or subinvestigator judges 
that the subject is incapable of providing informed consent or is hospitalized for reasons 
related to medical protection, the subject does not have to provide informed consent, but 
the subject’s legally acceptable representative must provide written consent. Even when 
written consent is obtained from the legally acceptable representative, the subject should 
be given an explanation appropriate to his or her level of understanding and, if possible, 
should also provide written consent. Consent will be documented on a written informed 
consent form (ICF) with the subject’s signature. The ICF will be approved by the same 
institutional review board (IRB) that approves this protocol. 
The ICF for subjects and their representatives will comply with the International Council 
for Harmonisation (ICH) Good Clinical Practice (GCP) Guideline27 and regional 
regulatory requirements. 
Investigators or subinvestigators may discuss the possibility for entry with a potential 
subject (or their legally acceptable representative) without first obtaining consent. 
However, informed consent must be obtained and documented before initiating any 
procedure that will be performed solely for the purpose of determining eligibility for this 
trial, including withdrawal from current medication(s). 
Furthermore, to facilitate management of patient compliance with the treatment regimen 
and the collection of patient information during the trial via the cooperation of their 
caregivers, the investigator or subinvestigator will explain the details of the trial to the 
caregivers of potential subjects by using explanatory materials designed for caregivers 
and obtain their written informed consent to cooperate in the trial. Potential subjects (or 
their legally acceptable representatives) and caregivers are free to refuse participation in 
the trial or withdraw from the trial at any time, without justification, and there will be no 
consequences to the further care of said patients. 
After the investigator or subinvestigator (or designee) has provided appropriate essential 
information to the subject (or their legally acceptable representative), has fully explained 
the information in plain language, has provided them with the opportunity to ask 
questions, and has made a record indicating that these procedures were followed, the 
IRB-approved written ICF will be signed and dated by the subject (or their legally 
acceptable representative), caregiver, and person obtaining the consent (investigator, 
subinvestigator, or designee). If a trial collaborator has provided supplemental 

Protocol 331-102-00088 
Confidential - Proprietary Information 
36 
Protocol Version 6.0, 24 Nov 2022 
explanation, the IRB-approved written ICF will also be signed and dated by the trial 
collaborator. The subject (or their legally acceptable representative) and the subject’s 
caregiver will receive a copy of the signed ICF; the original shall be kept on file by the 
investigator or subinvestigator. 
Subjects (or their legally acceptable representatives) and their caregivers may be asked to 
sign additional ICFs if the protocol is amended to significantly add or change procedures. 
The investigator or subinvestigator will enter information on subjects for whom informed 
consent has been obtained into an interactive web response system (IWRS). 
For CYP2D6 genetic testing, DNA storage, and biomarker sample storage, a separate ICF 
will be used for explanation, and written informed consent will be obtained from subjects 
(or their legally acceptable representatives) on their voluntary decision in a similar 
manner. CYP2D6 genetic testing is mandatory, and if subjects (or their legally acceptable 
representatives) have not consented to CYP2D6 genetic testing, they cannot participate in 
the trial. On the other hand, DNA storage and biomarker sample storage are optional, and 
the refusal of subjects (or their legally acceptable representatives) to allow DNA storage 
and/or biomarker sample storage will not affect trial participation. 
3.4.2 
Inclusion Criteria 
Subjects must meet the inclusion criteria described in Table 3.4.2-1. 
Table 3.4.2-1 
Inclusion Criteria 
1 
Patients who have provided written informed consent (or whose legally acceptable representative has 
provided written informed consent). If the investigator or subinvestigator judges that the patient is 
incapable of providing informed consent or is hospitalized for reasons related to medical protection, 
the patient’s legally acceptable representative must provide written consent. 
2 
Patients who meet both of the following diagnostic criteria: 
• 
Diagnosis of “Dementia due to Alzheimer’s Disease” according to the Diagnostic and Statistical 
Manual of Mental Disorders Fifth Edition (DSM-5). 
• 
Diagnosis of “Probable Alzheimer’s Disease” according to the National Institute of 
Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related 
Disorders Association (NINCDS-ADRDA). 
3 
Patients who are ≥ 55 and ≤ 90 years of age at the time of obtaining informed consent. 
4 
Patients who can be followed in the same environment (as described below) from at least 3 weeks 
before baseline evaluation up to the completion of the examinations scheduled at the completion or 
discontinuation of investigational medicinal product (IMP) administration. 
• 
Patients who will be hospitalized in the same medical facility. 
• 
Patients who will be institutionalized in the same care facility. 
• 
Patients who will continue to receive care at home. 
For patients receiving day care or day service, those patients who will visit the same care facility 
at the same frequency during the above-mentioned period will be included. 
5 
Patients whose caregiver can properly collect the necessary information (the main caregiver must 
observe the patient’s condition in at least 4 days per week for 4 hours or more a day) Patients 
receiving home care must live with a specific caregiver and must not live alone. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
37 
Protocol Version 6.0, 24 Nov 2022 
Table 3.4.2-1 
Inclusion Criteria 
6 
Patients with a Mini-Mental State Examination (MMSE) total score of ≥ 1 to ≤ 22 at screening. 
7 
 
 
 
8 
Patients who have agitation that interferes with daily activities and is persistent/recurs frequently 
during the 2 weeks each before the screening examination and baseline evaluation. Agitation is 
defined according to the “Consensus provisional definition of agitation in cognitive disorders” from 
the International Psychogeriatric Association (IPA).a 
9 
Patients who have shown verbal aggression or physical aggression for 3 times or more during the 2 
weeks before baseline evaluation. Examples of verbal aggression and physical aggression include the 
following symptoms in the “Consensus provisional definition of agitation in cognitive disorders” of 
IPA.a 
• 
Verbal aggression: yelling, speaking in an excessively loud voice, using profanity, screaming, 
shouting, etc. 
• 
Physical aggression: grabbing, shoving, pushing, resisting, hitting others, kicking objects or 
people, scratching, biting, throwing objects, self-hitting, slamming doors, tearing things, 
destroying property, etc. 
10 
Patients who show significant improvement (of two grades or more) in CGI-S from screening to 
baseline evaluation. 
11 
Patients who show inadequate response to nonpharmacological therapy for agitation associated with 
dementia of the Alzheimer’s type or who are otherwise judged to be in need of pharmacological 
therapy. 
12 
Patients who are either capable of walking on their own or are able to move about with the use of a 
walking aid (a walker or wheelchair) and whose vision and hearing are sufficient to enable the 
required tests and observations for the trial (the use of glasses, hearing aids, etc, is acceptable).  
a Cummings J, Mintzer J, Brodaty H, Sano M, Banerjee S, Devanand DP, et al. Agitation in cognitive 
disorders: International Psychogeriatric Association provisional consensus clinical and research 
definition. International Psychogeriatrics. 2015;27:7–17. 
 
[Rationale for inclusion criteria] 
1. 
This criterion is specified for ethical considerations. 
2. 
This criterion is specified because DSM-5 is recommended in the Practice Guideline for Dementia 
2017, and NINCDS-ADRDA is widely used in clinical trials for dementia of the Alzheimer’s type. 
These standards have been established as the diagnostic standards for dementia of the Alzheimer’s 
type. 
3. 
Although it is known that most patients with dementia of the Alzheimer’s type are above the age of 
65, there is a small number of patients below the age of 65. Past trials have suggested that patients 
of ages 55 and above may be suitable for such trials. Thus, the lower age limit was set at 55. On the 
other hand, given that patients aged over 90 could interfere with the evaluations set for this trial and 
in consideration of safety, 20 the upper age limit was set at 90. 
4. 
These patients were included because the target subjects of this trial, namely, patients with agitation 
associated with dementia of the Alzheimer’s type, may not necessarily be hospitalized patients but 
may be receiving care at nursing homes or at home. This criterion was also set for the appropriate 
assessment of the safety and efficacy of brexpiprazole.  
5 to 12. These criteria are specified for the appropriate assessment of the safety and efficacy of 
brexpiprazole in the treatment of agitation associated with dementia of the Alzheimer’s type. 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
38 
Protocol Version 6.0, 24 Nov 2022 
3.4.3 
Exclusion Criteria 
Subjects will be excluded if they fall under any of the exclusion criteria described in 
Table 3.4.3-1. 
Table 3.4.3-1 
Exclusion Criteria 
1 
Patients who have dementia or memory impairment other than dementia of the Alzheimer’s type, 
such as the following: 
• 
Frontotemporal dementia 
• 
Lewy body dementia 
• 
Vascular dementia 
• 
Dementia secondary to head trauma 
• 
Substance-induced persistent dementia 
• 
Dementia due to human immunodeficiency virus infection 
• 
Dementia due to prion disease 
• 
Dementia due to Parkinson’s disease (including Parkinsonian diseases such as progressive 
supranuclear palsy and basal ganglion degeneration) 
• 
Dementia due to Huntington’s disease 
• 
Dementia due to other general medical conditions (eg, subdural hematoma, normal pressure 
hydrocephalus, brain tumor, endocrine disorders, nutritional disorders, or infections) 
• 
Dementia due to multiple diseases 
• 
Dementia not otherwise specified 
2 
Patients diagnosed with delirium between 30 days before the screening examination and baseline 
evaluation according to DSM-5. 
3 
Patients diagnosed with any of the following disorders according to DSM-5: 
• 
Schizophrenia spectrum and other psychotic disorders 
• 
Bipolar and related disorders 
• 
Major depressive disorder 
However, patients who have major depressive disorder but whose condition is stable and 
asymptomatic within 30 days before the screening examination may be included. In regard to 
patients whose condition has been stabilized by medication, it should be noted that the use of 
antidepressants is prohibited from 7 days before baseline evaluation up to the completion of the 
examinations scheduled at the completion or discontinuation of IMP administration (see Section 4.1 
Prohibited Medications). 
4 
Patients with psychological symptoms or behavioral problems clearly due to other diseases or a drug 
substance. 
5 
• 
Patients with a complication or history of stroke or transient ischemic attack. 
• 
Patients with a complication of pulmonary embolism. 
However, patients with asymptomatic cerebral infarction or uncertain transient ischemic attack may 
be included. 
In regard to history of stroke or transient ischemic attack, a patient may be included if a medical 
monitor checks the patient’s symptoms and judges that they will have no influence on the efficacy 
and safety of the IMP. 
6 
Patients with a complication or history of convulsive disorders, such as epilepsy, not including 
patients with febrile seizures, posttraumatic seizures, alcohol withdrawal seizures, or other seizures. 
7 
Patients with clinically significant nervous, hepatic, renal, metabolic, immunological, hematological, 
cardiovascular, pulmonary, or digestive abnormality. 
8 
Patients with heart failure of New York Heart Association Class III or higher. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
39 
Protocol Version 6.0, 24 Nov 2022 
Table 3.4.3-1 
Exclusion Criteria 
9 
Patients who require pharmacological therapy for arrhythmia or ischemic heart disease, not 
including patients for whom the investigator or subinvestigator judges pharmacological therapy to be 
the primary prevention of ischemic heart disease. 
10 
Patients who test positive for hepatitis B surface antigen (HBsAg) or hepatitis C virus antibodies 
(HCV Ab). 
11 
Patients with a diagnosis of substance use disorder according to DSM-5, constituting substance 
abuse or substance dependence, including alcohol and benzodiazepines (but not including caffeine 
or nicotine), within 6 months prior to the acquisition of informed consent 
12 
Patients with a complication or history of neuroleptic malignant syndrome, tardive dyskinesia, 
paralytic ileus, or rhabdomyolysis 
13 
Patients who are unable to take oral medication due to severe dysphagia 
14 
Patients meeting any of the following criteria: 
• 
Patients with type 1 diabetes mellitus or patients with type 2 diabetes mellitus being treated with 
insulin 
• 
Patients with type 2 diabetes mellitus who have not been maintained on a stable regimen of 
antidiabetic medication(s) or have not undergone diet/exercise therapy for at least 28 days prior 
to screening 
• 
Patients meeting either of the following criteria for poor blood glucose control at screening 
(assessed on the basis of the results from the central laboratory) 
− 
Glycosylated hemoglobin (HbA1c) of ≥ 8.0% according to the global standard value 
(NGSP value) 
− 
Fasting blood glucose level of ≥ 126 mg/dL or nonfasting blood glucose level of 
≥ 200 mg/dL 
15 
Patients whose QTcF values based on the results from the central ECG laboratory at screening 
match the following criteria (if the criteria are matched in 2 out of 3 measurements), not including 
ventricular pacing: 
• 
Men: ≥ 450 ms; women: ≥ 470 ms 
16 
Patients whose (supine or sitting) blood pressure values at screening match the following criteria: 
• 
Poorly controlled hypertension (diastolic blood pressure [DBP] > 95 mmHg) 
17 
Patients meeting any of the following criteria at screening: 
• 
Hypotension with symptoms 
• 
Orthostatic hypotension in which blood pressure after at least 3 minutes of standing is 
≥ 30 mmHg lower for systolic blood pressure (SBP) or ≥20 mmHg lower for DBP compared 
with pressures in the supine position before standing 
18 
Patients with the following abnormal laboratory test values at screening (assessed on the basis of the 
results from the central laboratory): 
• 
Platelet count: ≤ 75,000/mm3 
• 
Hemoglobin: ≤ 9 g/dL 
• 
Neutrophil count: ≤ 1000/mm3 
• 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT): > 2 times the upper 
limit of normal (ULN) 
• 
Creatine phosphokinase (CPK): > 3 times ULN (however, this does not apply if the medical 
monitor judges that there will be no medically significant problems) 
• 
Albumin: < 3 g/dL 
19 
Patients whose body weight at screening or baseline evaluation is < 30 kg 

Protocol 331-102-00088 
Confidential - Proprietary Information 
40 
Protocol Version 6.0, 24 Nov 2022 
Table 3.4.3-1 
Exclusion Criteria 
20 
Patients whose Sheehan Suicidality Tracking Scale (S-STS) score at screening or baseline evaluation 
matches any of the following criteria or who are judged by the investigator or subinvestigator to be 
at high risk of suicide: 
• 
Patients with a score of 3 or 4 on any of S-STS Questions 2, 3, 4, 5, 6, or 11 
• 
Patients with a score of 2 or more on any of S-STS Questions 1a, 7, 8, 9, 10, or 12  
21 
The following patients falling under the contraindications in the package insert for REXULTI®: 
• 
Patients in a coma 
• 
Patients under the strong influence of central nervous system depressants, including barbiturate 
analogs/anesthetics 
• 
Patients receiving adrenaline 
• 
Patients with a history of hypersensitivity to the components of REXULTI® 
22 
Patients with thyroid disease (not including patients whose condition has been kept stable via drug 
therapy for at least 3 months prior to the acquisition of informed consent) or patients who show 
abnormal values for thyroid-stimulating hormone (TSH) and free thyroxine (FT4) in the screening 
examination 
23 
Patients who are likely to require any prohibited medications during the trial period  
24 
Patients who have previously taken brexpiprazole 
25 
Patients who have previously received antipsychotic medication for agitation associated with 
dementia of the Alzheimer’s type and whose condition has been judged to be treatment resistant. 
Cases in which treatment has to be stopped owing to adverse events are not counted as treatment 
resistant. 
26 
Patients who have undergone disease-modifying treatment for dementia of Alzheimer’s type (eg, 
amyloid β vaccine) within 6 months before the start of IMP administration 
27 
Patients who have taken any investigational drug within 30 days prior to informed consent 
28 
Patients who are bedridden and require assistance for excretion, eating, and changing clothes 
29 
Women who are nursing before the administration of IMP or have a positive pregnancy test result at 
screening 
30 
Sexually active men or sexually active women of childbearing potential who will not agree to 
practice 2 different methods of birth control or to remain abstinent during the trial and for 30 days 
after the final IMP administration. For birth control, two of the following methods must be used:  
vasectomy, tubal ligation, vaginal diaphragm, intrauterine contraceptive device (IUD), oral 
contraceptives, or condom with spermicide. 
31 
Patients who otherwise were judged by the investigator or subinvestigator to be unsuitable for 
participation in the trial 
 
Men without the ability to procreate are defined as those who have had bilateral 
orchidectomy, and women who are incapable of pregnancy are defined as those who have 
had bilateral oophorectomy or hysterectomy or who have been postmenopausal for at 
least 12 months. 
Subjects must agree to the restrictions described in Section 4 Restrictions. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
41 
Protocol Version 6.0, 24 Nov 2022 
[Rationale for the exclusion criteria] 
1 to 4 These criteria are specified to exclude patients who would be inappropriate for this trial. 
5 to 21 These criteria are specified in view of safety. 
22 to 27, 31 These criteria are specified for the appropriate assessment of safety and efficacy. 
28 This criterion is specified for the appropriate assessment of efficacy and in view of safety.20 
29, 30 These criteria are specified in consideration of safety, as the safety of brexpiprazole during 
pregnancy or while breastfeeding has not yet been established. 
 
3.5 
Requirements for Caregivers 
A caregiver who meets the following criteria will be designated as the main caregiver in 
the trial: 
• Is able to obtain the patient information required for evaluation (24-hour information 
wherever possible on the patient’s activities including toilet use, eating, bathing, 
changing, and other daily activities) during the trial period and provide this 
information during the inquiries on trial evaluation items; and 
• Provides the patient with care and can observe the patient’s condition in at least 4 
days per week for 4 hours or more a day, starting from 14 days before the day of 
baseline evaluations to the completion of the examinations scheduled at the 
completion or discontinuation of IMP administration. 
If there are multiple caregivers in charge of the patient’s care, the main caregiver will not 
only provide patient information from his or her own observations but also obtain from 
the other caregivers information on the patient’s condition during those periods when the 
patient was not under his or her observation and provide all patient information required 
for evaluations during the inquiries on the trial evaluation items.  
To the extent possible, the same main caregiver will respond to queries on the trial 
evaluation items from 14 days before the day of baseline evaluations to the completion of 
examinations scheduled at the completion or discontinuation of IMP administration. If 
the main caregiver is unable to respond to queries, a substitute caregiver is allowed to 
respond to queries on the trial evaluation items. However, to the extent possible, queries 
on the trial evaluation items at the time of baseline evaluation and at the completion or 
discontinuation of IMP administration should be answered by the person who was 
designated as the main caregiver at the start of the trial. A substitute caregiver should be 
able to obtain patient information required for evaluations from other caregivers and 
provide the same information as would have been provided by the main caregiver during 
inquiries on the trial evaluation items, and should be selected from among the caregivers 
in charge of the patient’s care. Queries at the conclusion of follow-up observation to be 
performed 28 days after the completion or discontinuation of IMP administration will 
also be answered by a caregiver who is in charge of the patient’s care and is able to 
provide patient information required for evaluations. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
42 
Protocol Version 6.0, 24 Nov 2022 
3.6 
Endpoints 
3.6.1 
Primary Endpoint 
The primary endpoint is change in CMAI total score from baseline to Week 10. 
The CMAI is a scale to assess the frequency of specific agitation symptoms. The Practice 
Guideline for Dementia 2017 recommends the NPI, Behavioral Pathology in Alzheimer’s 
Disease, and CMAI for assessment of BPSD. The CMAI evaluates the frequency of 
occurrence of specific agitation for the preceding 2 weeks and is used globally for 
assessment of agitation.22,28 Therefore, the CMAI is the most appropriate scale for 
evaluating the efficacy of brexpiprazole for agitation associated with dementia of the 
Alzheimer’s type, which is the primary objective of the trial. Furthermore, the CMAI was 
adopted as the primary endpoint in the 2 overseas trials (Trial 331-12-283 and Trial 331-
12-284). 
3.6.2 
Secondary Endpoints 
• Changes in CMAI subscales (Aggressive Behavior, Physically Non-aggressive 
Behavior, and CMAI Verbally Agitated Behavior) from baseline to Week 10 
• Change in Clinical Global Impression–Severity of Illness (CGI-S) from baseline to 
Week 10 
• Clinical Global Impression–Global Improvement (CGI-I) at Week 10 
 
3.6.3 
Exploratory Endpoints 
• 
 
• 
 
• 
 
• 
 
• 
 
 
• 
 
• 
 
• 
 
 
3.6.4 
Safety Endpoints 
• Adverse events 
• Physical examinations 

Protocol 331-102-00088 
Confidential - Proprietary Information 
43 
Protocol Version 6.0, 24 Nov 2022 
• Laboratory tests 
• Vital signs 
• Body weight 
• Twelve-lead electrocardiogram (ECG) 
• Pregnancy test (for women of childbearing potential [WOCBP] only) 
• Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) 
• Abnormal Involuntary Movement Scale (AIMS) 
• Barnes Akathisia Rating Scale (BARS) 
• Sheehan Suicidality Tracking Scale (S-STS) 
 
3.6.5 
Pharmacokinetic Endpoint 
Plasma concentrations of OPC-34712 at Week 10 of brexpiprazole administration  
3.6.6 
Pharmacogenomic Endpoint 
CYP2D6 genotype 
3.6.7 
Other Endpoints 
• Alzheimer's Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) 
• MMSE 
• EuroQol 5-dimension 5-level health questionnaire (EQ-5D-5L) 
 
3.7 
Measures to Minimize/Avoid Bias 
Subjects who meet all the inclusion criteria and do not fall under any of the exclusion 
criteria will be randomly assigned to the brexpiprazole 1 mg/day group, the brexpiprazole 
2 mg/day group, or placebo group at a randomization ratio of 3:4:4. The IMP allocation 
will be performed using a dynamic allocation method. The details of the randomization 
method will be described in a separately produced procedural guide for dynamic 
allocation. 
This is a double-blind trial. The IMP allocation manager will prepare a “Table of 
randomization scheme and codes” (hereinafter randomization table) and conduct IMP 
coding according to the operating procedures for randomization. The IMP allocation 
manager will prepare an emergency code list for emergencies, such as when an SAE 
occurs. 
The treatment assignment code will be revealed to neither the subject (including any 
representatives or caregivers) nor the investigator. The sponsor’s staff involved in the 

Protocol 331-102-00088 
Confidential - Proprietary Information 
44 
Protocol Version 6.0, 24 Nov 2022 
trial (except for those of the Department of Pharmacovigilance [PV department]), 
including contract research organizations (excluding the bioanalytical laboratory, genetic 
analysis laboratory, and IDMC), will also remain blind to the treatment assignment codes 
for the duration of the trial. Prior to the start of the trial, those who are involved in 
packaging the IMP and the sponsor will confirm that the IMP is not identifiable. The 
randomization table will be strictly retained until unblinding is performed after 
finalization of all the case report forms (CRFs) and database. 
The emergency code break information will be managed by the IWRS until the 
completion of the trial. In the event that a subject has a medical emergency and the 
knowledge of the treatment assignment code is necessary for treatment, the emergency 
key may be opened for the subject in question (see Section 5.6 Procedure for Breaking 
the Blind). 
The results of CYP2D6 genotyping and plasma drug concentration measurements should 
not be disclosed until unblinding at the end of the trial. The CYP2D6 genotyping and 
plasma drug concentration measurements should be performed at the designated 
laboratories and not at the clinical laboratories of the trial sites. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
45 
Protocol Version 6.0, 24 Nov 2022 
3.8 
Trial Procedures 
The schedule of assessments is shown in Table 3.8-1, and the allowable time windows for 
observations, tests, and assessments are shown in Table 3.8-2. 
Table 3.8-1 
Schedule of Assessments 
Item 
Screening 
Period 
Treatment Period 
Follow-up 
Perioda 
Day -42 to 
Day -2 
Baseline 
evaluation 
(Day 1)b 
Week 1 
(Day 8) 
Week 2 
(Day 15) 
Week 4 
(Day 29) 
Week 6 
(Day 43) 
Week 8 
(Day 57) 
Week 10 
(Day 71)  
At 
discontinu-
ation 
28 days 
after 
completion/ 
discontinu-
ation 
Same environment 
Before Day -21 ←------------------------------------------------------------------------------→ 
 
Informed consent 
• 
 
 
 
 
 
 
 
 
Subject background 
information 
• 
 
 
 
 
 
 
 
 
Subject diary 
From Day -14 ←-------------------------------------------------------------------------------→ 
 
Inclusion/exclusion 
criteria 
• 
• 
 
 
 
 
 
 
 
Compliance status 
 
 
• 
• 
• 
• 
• 
• 
 
Efficacy endpoints 
CMAI 
 
• 
 
• 
• 
• 
• 
• 
 
CGI-S 
• 
• 
 
• 
• 
• 
• 
• 
 
CGI-I 
 
 
 
• 
• 
• 
• 
• 
 
c 
•d 
• 
 
 
• 
 
 
• 
 
e 
 
• 
 
 
• 
 
 
• 
 
Safety endpoints 
Adverse events 
←-----------------------------------------------------------------------------------------------------------------→ 
Confirmation of 
medications and 
therapies 
←-----------------------------------------------------------------------------------------------------------------→ 
Height 
• 
 
 
 
 
 
 
 
 
Body weight 
• 
• 
 
 
 
 
 
• 
 
Physical 
examination 
• 
• 
• 
• 
• 
• 
• 
• 
 
Laboratory tests 
• 
•f 
 
 
• 
 
 
• 
 
Vital signs 
•g 
• 
• 
• 
• 
• 
• 
• 
 
12-lead ECG 
•h 
• 
 
• 
• 
 
 
• 
 
Pregnancy testi 
• 
 
 
 
 
 
 
• 
 
DIEPSS 
 
• 
• 
• 
• 
• 
• 
• 
• 
AIMS 
 
• 
 
 
 
 
 
• 
• 
BARS 
 
• 
 
 
 
 
 
• 
• 
S-STS 
• 
• 
 
 
• 
 
 
• 
 
Other endpoints 
ADCS-ADL 
 
• 
 
 
 
 
 
• 
• 
MMSE 
• 
 
 
 
 
 
 
• 
• 
EQ-5D-5L (subject 
and caregiver) 
 
• 
 
 
 
 
 
• 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
46 
Protocol Version 6.0, 24 Nov 2022 
Table 3.8-1 
Schedule of Assessments 
Item 
Screening 
Period 
Treatment Period 
Follow-up 
Perioda 
Day -42 to 
Day -2 
Baseline 
evaluation 
(Day 1)b 
Week 1 
(Day 8) 
Week 2 
(Day 15) 
Week 4 
(Day 29) 
Week 6 
(Day 43) 
Week 8 
(Day 57) 
Week 10 
(Day 71)  
At 
discontinu-
ation 
28 days 
after 
completion/ 
discontinu-
ation 
Blood sampling for 
measurement of 
plasma drug 
concentration 
 
 
 
 
 
 
 
•j 
 
Blood sampling for 
CYP2D6 
genotyping 
 
•k 
 
 
 
 
 
 
 
Blood sampling for 
DNA storage 
 
 
 
 
•l, m 
 
 
 
 
Blood sampling for 
biomarker sample 
storage 
 
•l 
 
 
 
 
 
 
 
aFollow-up observation will not be performed for subjects who have transitioned to the extension trial 
and commenced IMP administration. 
bAll baseline observations, tests, and evaluations will be performed on the day before the start of IMP 
administration (Day -1) and the day of starting IMP administration (Day 1). CMAI, CGI-S, 
, and 
must be performed on the same day. 
c
. 
d
. 
e
 
 
fPerforming laboratory tests at baseline is not necessary if fasting blood sample collection was 
performed at screening and within 14 days before baseline evaluation. 
gBlood pressure and pulse rate will be measured in the order of supine, sitting, and standing positions. 
hEligibility will be assessed based on consecutive triplicate ECG measurements (central reading). The 
third measurement can be omitted if neither the first nor second measurement (central reading) meets 
the exclusion criteria. 
iPregnancy test (HCG test) will be performed for WOCBP only. If urinary test is positive, serum test 
will be performed. 
jBlood sampling will be performed before IMP administration if the IMP is administered in Week 10 but 
does not need to be performed at the time of discontinuation. 
kIf blood sampling is not performed for any other test item or for some reason cannot be performed at 
the time of baseline evaluation, or if blood resampling is necessary, blood sampling will be performed 
during the trial period. 
lOptional 
mIf for some reason it is not possible to perform blood sampling at this time or if blood resampling is 
necessary, blood sampling will be performed during the trial period. 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
47 
Protocol Version 6.0, 24 Nov 2022 
Table 3.8-2 
Allowable Time Windows for Evaluations, Tests, and 
Observations 
Test Point 
Base Date 
Allowable Time Window From 
the Base Date 
Screening period 
At the start of screening 
Day -42 to Day -2 
Baseline evaluation date 
Day 1 
Day -1 or Day 1 
Week 1 
Day 8 
Day 6 to Day 10 
Week 2 
Day 15 
Day 13 to Day 17 
Week 4 
Day 29 
Day 27 to Day 31 
Week 6 
Day 43 
Day 40 to Day 46 
Week 8 
Day 57 
Day 54 to Day 60 
Week 10 
Day 71 
Day 68 to Day 78 
Follow-up perioda 
28 days after the final 
administration of IMP 
23 to 35 days after the final 
administration of IMP 
aFollow-up observation will not be performed for subjects who have transitioned to the extension trial 
and commenced IMP administration. 
The date of starting IMP administration is designated as Day 1. 
All baseline observations, tests, and evaluations will be performed on the day before the start of IMP 
administration (Day -1) and the day of starting IMP administration (Day 1). CMAI, CGI-S, 
, and 
must be performed on the same day. 
 
3.8.1 
Schedule of Assessments 
The investigator or subinvestigator will perform observations, tests, and assessments 
within the allowable windows shown in Table 3.8-2 according to the schedule of 
assessments shown in Table 3.8-1. Special consideration should be given to 
environmental factors (eg, physical restraint [including isolation] and transfer to a 
different ward or room, staying out overnight, and outings during 
hospitalization/institutionalization) that may affect assessments. The investigation of 
subject background information, clinical laboratory tests, and other investigation/test 
items that can be performed by the trial collaborator may be performed by the trial 
collaborator under supervision of the investigator. 
The methods employed for observations, tests, and assessments are shown in 
Section 3.8.2 Efficacy Assessments to Section 3.8.5 Other Endpoints. 
The date and time of observations, tests, and assessments and the results will be recorded 
in the source document and case report form (CRF). 
3.8.1.1 
Screening Period 
To confirm that the subject meets the inclusion criteria and does not fall under the 
exclusion criteria, observations, tests, and assessments will be performed, and the results 
will be recorded after the date of informed consent but before the baseline assessment. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
48 
Protocol Version 6.0, 24 Nov 2022 
The caregivers will be provided with the subject diary for the period up to the baseline 
evaluation and be given an explanation on how to complete the subject diary, and 
instructed to record the required information in the subject diary from 14 days before the 
baseline evaluation until the baseline evaluation. In the subject diary, occurrence of daily 
symptoms will be recorded to evaluate the frequency of occurrence of agitation 
associated with dementia of the Alzheimer’s type (CMAI). 
The investigator or subinvestigator will record subject information related to the 
enrollment criteria, which had been collected during screening, in the eligibility form 
specified by the sponsor and submit to the medical monitor for confirmation of the 
subject’s eligibility. The medical monitor will confirm the content of the eligibility form, 
and if there is any doubt regarding the subject’s eligibility, he/she will consult with the 
investigator or subinvestigator to determine the subject’s eligibility before the baseline 
examination. 
The investigator or subinvestigator will investigate subject background and other 
information as follows and record it in the source document and CRF. 
• Date of visit 
• Date of informed consent by the subject (or their legally acceptable representatives) 
and caregivers 
• Subject background information 
− Sex, date of birth, race, ethnicity, and trial country 
− Possibility of getting pregnant in women of childbearing potential (WOCBP) (see 
Section 5.5 Pregnancy) (if there is no childbearing potential, record the reason) 
− Diagnosis of dementia of the Alzheimer’s type (diagnostic criteria of DSM-5 and 
NINCDS-ADRDA) 
− Timepoint of onset of dementia of the Alzheimer’s type 
− Timepoint of diagnosis of dementia of the Alzheimer’s type 
− Timepoint of onset of agitation associated with dementia of the Alzheimer’s type 
− Complications 
− Medical history (for the 2 years preceding informed consent; however, medical 
history related to the inclusion/exclusion criteria is not limited to the preceding 2 
years.) 
− Medical care category (inpatient or outpatient; if outpatient, institutionalized or 
care at home) 
− Classification of the main caregiver specified at the start of the trial (hospital staff, 
care facility staff, family, or other), care status over the 2 weeks prior to the visit 
(amount of care time per day and days of care in a week)  
− Prior medications and therapies 

Protocol 331-102-00088 
Confidential - Proprietary Information 
49 
Protocol Version 6.0, 24 Nov 2022 
• Confirmation of eligibility 
 
3.8.1.2 
Day of Baseline Examination 
To confirm that the subject meets the inclusion criteria and does not fall under the 
exclusion criteria before starting IMP administration, the investigator or subinvestigator 
will perform the observations, tests, and assessments shown in Table 3.8-1 and the 
investigation of the following items and record the results. 
• Date of visit 
• Confirmation of eligibility 
 
3.8.1.3 
Randomization 
The investigator or subinvestigator will select subjects who meet the inclusion criteria 
and do not fall under the exclusion criteria on the basis of the results of the screening 
examination and baseline evaluation. For the clinical laboratory test and 12-lead ECG, 
the subject’s eligibility will be judged on the basis of the results obtained by the central 
laboratory and central ECG laboratory at the time of screening. 
The investigator or subinvestigator will enter information on eligible subjects in the 
IWRS. Subjects whose registration was confirmed in the IWRS will be randomized to the 
brexpiprazole 1 mg, brexpiprazole 2 mg, or placebo group using a dynamic 
randomization method to minimize bias between the treatment groups regarding the 
following background factors. The date of randomization and randomization number will 
be recorded in the CRF. 
• Medical care category (inpatient or outpatienta) 
• Prior use of antipsychoticsb (yes or no) 
• CMAI total score (≥ 56 or < 56) in the baseline evaluation 
aSubjects who are institutionalized or receiving care at home and visit the trial site as outpatients 
bReceiving antipsychotics in the 6 months prior to the day of baseline evaluation will be considered as 
“yes.” 
The investigator or subinvestigator will provide the IMP and subject diary needed for the 
period up until the next assessment on the basis of the drug number assigned to the 
subject in the IWRS and give instructions to bring unused IMPs and the completed 
subject diary to the next assessment. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
50 
Protocol Version 6.0, 24 Nov 2022 
3.8.1.4 
Seven Days After Administration (Week 1, Day 8) to Seventy 
Days After Administration (Week 10, Day 71) 
The investigator or subinvestigator will perform the observations, tests, and assessments 
shown in Table 3.8-1 and record the results and date of visit. 
At visits where blood is collected for measurement of plasma drug concentrations, the 
date and time of last IMP administration will be recorded. 
At visits from 7 days after administration (Week 1, Day 8) until 56 days after 
administration (Week 8, Day 57), the investigator or subinvestigator will provide the IMP 
and subject diary needed up until the next assessment on the basis of the drug number 
assigned to the subject in IWRS and give instructions to bring unused IMPs and the 
completed subject diary to the next assessment. 
3.8.1.5 
Examination at Discontinuation 
At discontinuation, the investigator or subinvestigator will perform the observations, 
tests, and assessments shown in Table 3.8-1 as promptly as possible, within the same day 
if possible, after discontinuation has been decided and will record the results along with 
the date of visit. If at time of discontinuation, the subject or caregiver refuses any of the 
tests or if the investigator or subinvestigator judges that tests cannot be performed due to 
an emergency, only those observations, tests, and assessments that are feasible will be 
performed. 
3.8.1.6 
Follow-up Observation (Twenty-eight Days After Completion or 
Discontinuation of IMP Administration) 
The investigator or subinvestigator will perform the observations, tests, and assessments 
shown in Table 3.8-1 and record the results and date of visit. These observations, tests, 
and assessments will also be performed in discontinued subjects unless the subject or 
caregiver refuses any of the tests or the investigator or subinvestigator judges that tests 
cannot be performed due to an emergency. Follow-up observation will not be performed 
for subjects who have transitioned to the extension trial and commenced IMP 
administration. 
3.8.2 
Efficacy Assessments 
The rater for each of the assessment items should refer to Section 3.8.9 Raters. The 
results and the date and time of assessments should be recorded in the source documents 
and the CRF. The schedule for each of the assessment items is shown in Table 3.8-1. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
51 
Protocol Version 6.0, 24 Nov 2022 
3.8.2.1 
Cohen-Mansfield Agitation Inventory 
The rater will use CMAI to determine how often each of the 29 agitated behaviors 
associated with dementia of the Alzheimer’s type occurred with each behavior rated on a 
7-point scale of frequency through an interview with the caregiver. The evaluation will be 
made on the basis of information on the subject from 14 days before each assessment day 
and the frequency of agitation will be evaluated on the basis of the information contained 
in the subject diary. However, records in the subject diary are supplementary data for 
assessment, and the investigator or subinvestigator will perform the final assessment 
based not only on the information contained in the subject diary but also the information 
collected through an interview with the caregiver. 
[29 agitated behaviors]  
“Pace, aimless wandering,” “inappropriate dressing or disrobing,” “spitting (include at 
meal),” “cursing or verbal aggression,” “constant unwarranted request for attention or 
help,” “repetitive sentences or questions,” “hitting (including self), ” “kicking,” 
“grabbing onto people,” “pushing,” “throwing things,” “strange noises (weird laughter or 
crying),” “screaming,” “biting,” “scratching,” “trying to get to a different place (e.g., out 
of the room, building),” “intentional falling,” “complaining,” “negativism,” 
“eating/drinking inappropriate substances,” “hurt self or other (cigarette, hot water, etc.),” 
“handling things inappropriately,” “hiding things,” “hoarding things,” “tearing things or 
destroying property,” “performing repetitious mannerisms,” “making verbal sexual 
advances,” “making physical sexual advances,” and “general restlessness” 
3.8.2.2 
Clinical Global Impression–Severity of Illness 
The rater will assess (by time point evaluation) the severity of agitation associated with 
dementia of the Alzheimer’s type on an 8-point scale using the CGI-S. 
3.8.2.3 
Clinical Global Impression–Global Improvement 
The rater will assess (by time point evaluation in comparison with the date of baseline 
evaluation) improvement of agitation associated with dementia of the Alzheimer’s type 
on an 8-point scale using the CGI-I. 
3.8.2.4 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
52 
Protocol Version 6.0, 24 Nov 2022 
 
 
 
 
3.8.2.5 
 
 
 
 
3.8.3 
Safety Assessments 
Evaluation points for each item are shown in Table 3.8-1. 
3.8.3.1 
Adverse Events 
Refer to Section 5 Reporting of Adverse Events. 
3.8.3.2 
Clinical Laboratory Assessments 
In this trial, the clinical laboratory tests shown in Table 3.8.3.2-1 will be conducted by 
central analysis. Blood and urine samples will be collected from each subject, and the 
date and time of blood sampling, the date of urine sampling, and the verification of 
whether blood sampling was performed when the subject was in a fasted state (having 
fasted for at least 8 hours) will be recorded in the source documents and the CRF. Subject 
eligibility will be verified using the clinical laboratory test values determined at the 
central laboratory. For appropriate procedures for the collection, handling, and shipment 

Protocol 331-102-00088 
Confidential - Proprietary Information 
53 
Protocol Version 6.0, 24 Nov 2022 
of samples, the separately prepared procedures should be followed. The total amount of 
blood to be collected for clinical laboratory tests during the trial period will be described 
in the ICF and explanatory materials. 
The central laboratory will report the results of tests to the investigator or subinvestigator. 
The investigator or subinvestigator will confirm the results of tests and date and sign the 
clinical laboratory test report to make it an official document. The results of laboratory 
tests, which will be reported directly from the central laboratory to the sponsor as an 
electronic file, do not need to be recorded in the source documents or the CRF. 
Table 3.8.3.2-1 
Clinical Laboratory Assessments 
Hematology: 
Red blood cell count 
White blood cell count 
Differential count of white blood cells (neutrophils, 
eosinophils, basophils, monocytes, and lymphocytes) 
Platelet count 
Hemoglobin 
Hematocrit 
Prothrombin time (PT) 
PT (international normalized ratio [INR]) 
Activated partial thromboplastin time (APTT) 
 
Urinalysis: 
pH 
Protein 
Glucose 
Occult blood 
Urobilinogen 
Specific gravity 
Ketone body 
Serum chemistry: 
ALT 
AST 
Alkaline phosphatase (ALP) 
Lactic dehydrogenase (LDH) 
Gamma-glutamyl transpeptidase (γ-GTP) 
Total protein 
Total bilirubin 
Albumin 
Cholesterol (total cholesterol, low-density 
lipoprotein [LDL] cholesterol, and high-density 
lipoprotein [HDL] cholesterol) 
Triglycerides 
Blood urea nitrogen (BUN) 
Creatinine 
Uric acid 
CPK 
Blood electrolytes (Na, K, Cl, Mg, Ca, P,) 
Blood glucose (fasting or nonfasting) 
HbA1c (NGSP value) 
Folatea 
Vitamin B12a 
  
Endocrinology: 
Serum prolactin 
Insulin 
FT4a 
TSHa 
 
Immunology 
HBsAga 
HCV Aba 
aPerformed only at screening 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
54 
Protocol Version 6.0, 24 Nov 2022 
3.8.3.3 
Physical Examination 
The investigator or subinvestigator will conduct a physical examination for HEENT 
(head, eye, ear, nose, and throat), chest, abdomen, urogenital organs, extremities, nerves, 
and skin/mucosa. 
In the screening examination, all the physical findings obtained on the evaluation day and 
up to the observation day will be recorded in the source document and CRF. From the 
baseline evaluation, only information on whether an observation occurred or not and date 
and time of observation will be recorded in the source document and CRF. Clinically 
significant physical findings obtained in and after the baseline evaluation will be recorded 
as AEs in the source document and CRF. 
3.8.3.4 
Vital Signs (Blood Pressure and Pulse Rate) 
After the subject has been rested, the investigator or subinvestigator will measure vital 
signs in accordance with the methods specified by the trial site. In the screening 
examination, SBP, DBP, and pulse rate will be measured in the order of supine, sitting, 
and standing positions. The results, date and time of measurement will be recorded in the 
source document and CRF. Blood pressure and pulse rate will be measured in the order of 
supine, sitting, and standing positions after maintaining each position for at least 3 
minutes. From the baseline evaluation, blood pressure and pulse rate will be measured in 
a sitting position. If the subject complained of symptoms of orthostatic hypotension 
before evaluation in or after the baseline evaluation, measurement should be performed in 
the supine and sitting positions in so far as possible in the order of the supine, sitting, and 
standing positions in the same manner as the screening examination. 
3.8.3.5 
Height and Body Weight 
Height and body weight will be measured using a standard measurement method (no 
shoes, with clothes on). 
The date and results of measurements will be recorded in the source document and CRF 
(body weight in increments of 0.1 kg, height in increments of 0.1 cm). 
3.8.3.6 
Twelve-lead Electrocardiography 
After the subject has been placed in a resting position, the subject’s ECG will be recorded 
using a 12-lead electrocardiograph supplied by the central ECG laboratory. At screening, 
the subject’s eligibility will be assessed based on consecutive triplicate ECG 
measurements (central reading) obtained during screening. ECG examination will be 
performed at appropriate intervals after the subject’s resting state is confirmed. The third 

Protocol 331-102-00088 
Confidential - Proprietary Information 
55 
Protocol Version 6.0, 24 Nov 2022 
measurement can be omitted if neither the first nor second measurement (central reading) 
meets the exclusion criteria (≥ 450 ms for men, ≥ 470 ms for women). 
The investigator or subinvestigator will check the ECG and assess whether the result is 
normal or abnormal and will record the date and time of ECG, normal/abnormal 
judgment, and abnormal findings in the source documents and the CRF. The original of 
the 12-lead ECG chart will be kept in the medical record or the investigator’s file. The 
central ECG laboratory will collect 12-lead ECG data and measure the heart rate, PR 
interval, RR interval, QRS interval, QT interval, and QT corrected for heart rate (QTc) 
[QTcB = QT interval/(RR interval)1/2, QTcF = QT interval/(RR interval)1/3], and the 
physician of the central ECG laboratory will assess the data.  
The central ECG laboratory will report the results of analysis to the investigator or 
subinvestigator. The investigator or subinvestigator will confirm the results of analysis 
and date and sign the analysis result report to make it an official document. The 
investigator or subinvestigator will reconfirm the normal/abnormal judgment with 
reference to the analysis result report sent from the central ECG laboratory. As the results 
of analysis by the central ECG laboratory are reported directly from the central ECG 
laboratory to the sponsor as an electronic file, they do not need to be recorded in the 
source documents or the CRF. 
3.8.3.7 
Pregnancy Test 
A urine pregnancy test will be performed in WOCBP (see Section 5.5 Pregnancy), and 
the date of urine sampling and the result of the test will be recorded in the source 
documents and the CRF. The result of the pregnancy test performed at screening must be 
obtained before starting IMP administration. If the urine test is positive, another 
pregnancy test will be performed using serum, and the date of blood sampling will be 
recorded in the source documents and the CRF. A serum pregnancy test will be 
performed by the central laboratory selected by the sponsor. For appropriate procedures 
for the collection, handling, and shipment of samples, separately documented procedures 
will be prepared and provided prior to the start of the trial. The central laboratory will 
report the results of tests to the investigator or subinvestigator. The investigator or 
subinvestigator will confirm the results of tests and date and sign the clinical laboratory 
test report to make it an official document. The results of serum tests, which will be 
reported directly from the central laboratory to the sponsor as an electronic file, do not 
need to be recorded in the source documents or the CRF. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
56 
Protocol Version 6.0, 24 Nov 2022 
3.8.3.8 
Other Safety Assessments 
The investigator or subinvestigator will record the results and the date and time of the 
assessments in the source documents and the CRF. The schedule for each of the 
assessment items is shown in Table 3.8-1. 
3.8.3.8.1 
Drug-induced Extrapyramidal Symptoms Scale 
By using DIEPSS, the investigator or subinvestigator will assess 9 items related to 
extrapyramidal symptoms on a 5-point scale on the basis of the subject’s information 
from the previous assessment (baseline assessment will be based on the subject’s 
information from the initial screening examination). 
Nine items related to extrapyramidal symptoms: 
Gait, bradykinesia, sialorrhea, muscle rigidity, tremor, akathisia, dystonia, dyskinesia, 
and overall severity 
3.8.3.8.2 
Abnormal Involuntary Movement Scale 
By using AIMS, the investigator or subinvestigator will assess the severity of abnormal 
involuntary movement at 7 sites and 3 global judgment items on a 5-point scale and 
assess the dental status items “current problems with teeth and/or dentures” and “Dose 
patient wear dentures” as either “yes” or “no” (assessment at specified time points). 
Seven sites: 
“Muscles of facial expression,” “lips and perioral area,” “jaw,” “tongue,” “upper (arms, 
wrists, hands, fingers),” “lower (legs, knees, ankles, toes),” and “neck, shoulders, hips” 
3.8.3.8.3 
Barnes Akathisia Rating Scale 
By using BARS, the investigator or subinvestigator will assess the “objective,” 
“subjective—awareness of restlessness,” and “subjective—distress related to 
restlessness” for akathisia on a 4-point scale and a “global clinical assessment of 
akathisia” on a 6-point scale.  
3.8.3.8.4 
Sheehan Suicidality Tracking Scale 
By using S-STS, the investigator or subinvestigator will assess suicidal attempt and 
behavior on the basis of 22 question items. At screening, assessment will cover the period 
spanning the previous 6 months, and for subsequent visits, the assessment will cover the 
period since the previous visit.  
3.8.4 
Pharmacokinetic Assessment, Pharmacogenomic Assessment, 
and Biomarker Exploration 
The schedule for each of the assessment items is shown in Table 3.8-1. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
57 
Protocol Version 6.0, 24 Nov 2022 
3.8.4.1 
Pharmacokinetic Assessment 
Plasma brexpiprazole concentrations will be measured by validated high performance 
liquid chromatography/tandem mass spectrometry method. Metabolites that are not 
presented in the protocol may be measured on the basis of newly obtained information. 
The bioanalytical laboratory will measure drug concentrations only for the samples 
collected from subjects in the brexpiprazole groups after recording the use of the 
randomization table. Access to the documents containing treatment assignment codes will 
be strictly controlled and will not be disclosed to anyone other than those who need them 
to perform trial-related activities in the opinion of the person responsible for drug 
concentration measurements. The bioanalytical laboratory will hold the results of the 
drug concentration measurements in strict confidence and submit an electronic file 
containing these results to the sponsor after unblinding. Therefore, there is no need to 
record the results of assessment in the source documents and CRF. 
1)  Timing of Blood Sampling 
Blood samples will be collected before IMP administration if the IMP is administered 
in Week 10. The date and time of blood sampling and the date and time of the most 
recent IMP administration before blood sampling will be recorded in the source 
documents and the CRF. 
2) Blood Samples for Pharmacokinetic Assessment 
Details of the sample collection, handling, and shipping methods are provided in 
Appendix 1. 
3.8.4.2 
Pharmacogenomic Assessment 
3.8.4.2.1 
CYP2D6 Genetic Testing 
CYP2D6 genotypes and phenotypes will be analyzed. CYP2D6 genetic testing is 
mandatory. 
The CYP2D6 genotype will be determined for each subject on the basis of the CYP2D6 
genotyping table (Appendix 2). In addition, on the basis of the CYP2D6 genotype, the 
phenotype will be classified into the following 4 types: extensive metabolizer (EM), 
intermediate metabolizer (IM), poor metabolizer (PM), and unknown. In principle, the 
results of CYP2D6 genetic testing will not be disclosed to subjects. 
The genetic analysis laboratory will extract DNA only from the blood samples of the 
brexpiprazole groups after recording the use of the randomization table. The blood 
samples collected from subjects in the placebo group will be discarded in accordance 
with the procedure specified by the genetic analysis laboratory. Access to the documents 
containing treatment assignment codes will be strictly controlled and will not be 

Protocol 331-102-00088 
Confidential - Proprietary Information 
58 
Protocol Version 6.0, 24 Nov 2022 
disclosed to anyone except for those who need them to perform trial-related activities in 
the opinion of the person responsible for genetic testing. The genetic analysis laboratory 
will hold the results of CYP2D6 genetic testing in strict confidence and submit an 
electronic file containing these results to the sponsor after unblinding. Therefore, there is 
no need to record the results of the assessment in the source documents and CRF. 
1) Timing of Blood Sampling 
Blood samples will be collected before IMP administration on the day of baseline 
evaluation. If blood sampling is not performed for any other test item or for some 
reason cannot be performed at the time of baseline evaluation, or if blood resampling 
is necessary, blood sampling will be performed during the trial period. The date and 
time of blood sampling will be recorded in the source documents and the CRF. 
2) Samples for CYP2D6 Genetic Testing 
Details of the sample collection, handling, and shipping methods are provided in 
Appendix 1. 
3.8.4.2.2 
DNA Storage 
 
 
 
 
 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
59 
Protocol Version 6.0, 24 Nov 2022 
 
 
 
 
 
 
 
 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
60 
Protocol Version 6.0, 24 Nov 2022 
 
 
 
 
 
3.8.4.3 
Storage of Samples for Biomarker Exploration 
 
 
 
. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
61 
Protocol Version 6.0, 24 Nov 2022 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
62 
Protocol Version 6.0, 24 Nov 2022 
 
 
 
 
3.8.5 
Other Endpoints 
The rater for each of the assessment items should refer to Section 3.8.9 Raters. The 
results and the date and time of assessments should be recorded in the source documents 
and the CRF. The schedule for each of the assessment items is shown in Table 3.8-1. 
3.8.5.1 
Alzheimer's Disease Cooperative Study–Activities of Daily 
Living 
The rater will review the answers to the 19 questions on the dementia patient’s activities 
of daily living through an interview with the caregiver using the ADCS-ADL severe 
dementia version and will record the results. The evaluation will be made on the basis of 
information for the period from 28 days before each evaluation day. If the caregiver 
cannot come to the trial site for a compelling reason, an interview by telephone is 
acceptable for the follow-up observation only. 
3.8.5.2 
Mini-Mental State Examination 
The rater will assess each of 11 cognitive function items for the subject at the time of 
evaluation using the MMSE and will record the results. 
[11 cognitive function items] 
“Orientation to time,” “orientation to place,” “registration,” “attention and calculation,” 
“recall,” “naming,” “repetition,” “comprehension,” “reading,” “writing,” and “drawing” 

Protocol 331-102-00088 
Confidential - Proprietary Information 
63 
Protocol Version 6.0, 24 Nov 2022 
3.8.5.3 
EuroQol 5-Dimension 5-Level Health Questionnaire 
The caregiver will assess the health of the subject and caregiver in relation to 5 health 
domains at the time of evaluation on a 5-level scale using the EQ-5D-5L. Health will be 
assessed using a 100 mm visual analogue scale (0 = the worst health imaginable, 100 = 
the best health imaginable). 
In the subject assessment, the caregiver will evaluate the subject’s health using the EQ-
5D-5L proxy version and will record the results. In the caregiver self-evaluation, the 
caregiver will evaluate his/her own health using the EQ-5D-5L and record the results. 
The caregiver self-evaluation will be performed only when the caregiver in the baseline 
evaluation and the caregiver in subsequent evaluations are the same person. 
[5 domains] 
“Mobility,” “self-care,” “usual activities,” “pain/discomfort,” and “anxiety/depression” 
3.8.6 
Medications and Therapies 
The investigator or subinvestigator will investigate medications and therapies 
administered during the periods below. If any medication is used during the periods, the 
name of the drug, purpose of use, dose, frequency, route of administration, and start date 
and end date of treatment will be investigated. If any therapy is performed, the name of 
the therapy, purpose of therapy, and start date and end date of treatment will be 
investigated. The results of the investigation will be recorded in the source document and 
CRF. 
• Antipsychotics: from 6 months before the date of baseline evaluation through to the 
trial end date 
• Antidementia drugs: from 3 months before the date of baseline evaluation through to 
the trial end date 
• Prohibited concomitant drugs other than antipsychotics and restricted concomitant 
drugs other than antidementia drugs: from 30 days before the date of informed 
consent or date of baseline evaluation, whichever is earlier, through to the trial end 
date 
• Other medications and therapies: from the date of informed consent through to the 
trial end date 
 
3.8.7 
End of Trial 
The end of the trial date is defined as the date of completion or discontinuation of the trial 
as recorded on the trial completion page or the date of last visit or contact or date of final 

Protocol 331-102-00088 
Confidential - Proprietary Information 
64 
Protocol Version 6.0, 24 Nov 2022 
contact attempt as recorded on the follow-up page of the CRF prepared for the last 
subject completing or withdrawing from the trial. 
3.8.8 
Independent Data Monitoring Committee 
The IDMC will be established to avoid exposing subjects to all potential risks (including 
the risk of death) during the trial period and to ensure the safe conduct of the trial. The 
IDMC will meet regularly and as needed to review the subject demographics and AEs 
and to give advice on the appropriateness of continuing the trial or the necessity of 
modifying the protocol. 
The sponsor will designate the following as IDMC members: 
. 
The IDMC members, their roles, and other details will be specified in a separate 
procedure. 
3.8.9 
Raters 
Table 3.8.9-1 shows persons who are authorized to evaluate each evaluation scale. While 
the 
, 
, ADCS-ADL, and MMSE are allowed to be 
evaluated by persons other than the investigator or subinvestigator, the investigator or 
subinvestigator will check the content and decide whether the data should be adopted. For 
EQ-5D-5L, as described in Section 3.8.5.3 EuroQol 5-Dimension 5-Level Health 
Questionnaire, the caregiver will evaluate the subject and himself/herself. 
For CMAI, the same rater will evaluate the same subject throughout the trial period. For 
CGI-S, CGI-I, DIEPSS, AIMS, BARS, S-STS, 
, 
, 
ADCS-ADL, and MMSE, the same rater will evaluate the same subject throughout the 
trial period whenever possible. 
Evaluations using the CMAI, 
, and 
will be conducted 
by a rater who has been trained and certified for the trial. Evaluations using the CGI-S, 
CGI-I, DIEPSS, AIMS, BARS, S-STS, ADCS-ADL, and MMSE will be conducted by 
the rater who has been trained for the trial. 
The investigator or subinvestigator will check how evaluations are being conducted and 
their content after receiving training for the trial. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
65 
Protocol Version 6.0, 24 Nov 2022 
Table 3.8.9-1 
Raters of Evaluation Scales 
 
Investigator or 
Subinvestigator 
Clinical 
Psychologist 
(Including Clinical 
Psychological 
Technologist) 
Occupational 
Therapist 
Speech-
language-
Hearing 
Therapist 
Nurse 
CMAI 
○ 
 
 
 
 
  
 
○ 
○ 
○ 
 
 
CGI-S 
○ 
 
 
 
 
CGI-I 
○ 
 
 
 
 
DIEPSS 
○ 
 
 
 
 
AIMS 
○ 
 
 
 
 
BARS 
○ 
 
 
 
 
S-STS 
○ 
 
 
 
 
ADCS-ADL 
○ 
○ 
○ 
 
 
MMSE 
○ 
○ 
○ 
○ 
○ 
 
3.9 
Stopping Rules, Withdrawal Criteria, and Procedures 
3.9.1 
Entire Trial 
In the event of sponsor termination or suspension of the trial for any reason, prompt 
notification will be given to the heads of the trial sites and regulatory authorities in 
accordance with the regulatory requirements. 
3.9.2 
Individual Site 
Individual trial site participation may be discontinued by the sponsor, the investigator, or 
the IRB for medical, safety, regulatory, ethical, or other reasons consistent with 
applicable laws, regulations, and GCP. The head of the trial site will notify the sponsor 
promptly if the trial is terminated by the investigator or the IRB at the site. 
3.9.3 
Individual Subject Discontinuation 
3.9.3.1 
Treatment Discontinuation 
After randomization, a subject may stop treatment permanently for a variety of reasons. 
Treatment discontinuations may be initiated by a subject who is not satisfied with the 
treatment or may become medically necessary due to AEs, required treatment with a 
disallowed medication or therapy, or other issues, as determined by the investigator or 
subinvestigator. Regardless, each investigator or subinvestigator must comprehensively 
review the circumstances and offer the subject options for continued treatment to the 
degree possible as described in Section 3.9.3.4 Procedures to Encourage Continued Trial 
Participation. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
66 
Protocol Version 6.0, 24 Nov 2022 
3.9.3.2 
Documenting Reasons for Discontinuation 
All subjects have the right to withdraw, and the investigator or subinvestigator can 
discontinue a subject’s participation in the trial at any time if medically necessary. In 
addition, subjects meeting the following criteria must be withdrawn from the trial. Only 
one main reason for discontinuation will be recorded in the CRF. 
• Adverse event 
− Death 
− Continuation of IMP would place the subject at undue risk, as determined by the 
investigator or subinvestigator (eg, there is a safety concern possibly, probably, or 
likely related to IMP). 
• SAE 
− The subject experiences worsening of agitation, and the investigator or 
subinvestigator judges that the subject should be withdrawn from the trial 
(worsening of agitation is to be reported as an AE). 
− The subject decides to discontinue the treatment because of annoyance or 
discomfort due to a nonserious AE that is not otherwise determined to be an 
undue hazard. 
• Subjects becoming bedridden and requiring assistance for excretion, eating, and 
changing clothes 
• Subject’s withdrawal of informed consent 
• Legally acceptable representative’s withdrawal of informed consent 
• Caregiver’s withdrawal of informed consent 
• Marked noncompliance with the IMP regimen (compliance rate of < 65% during the 
interval between the previous date of compliance verification and the current date of 
compliance verification) 
• Protocol deviation (other than marked noncompliance with the IMP regimen) 
− The subject is discovered to have not met the inclusion/exclusion criteria. 
− The subject has received any prohibited concomitant drugs or therapies or is 
judged to be in need of prohibited drugs or therapies. 
− The subject requires a change in care environmenta (for reasons other than AE 
occurrence) before the completion of the examinations at the end of IMP 
administration. 
• Lost to follow-up 
• Lack of efficacy 
• Pregnancy (see Section 5.5 Pregnancy) 
• Termination of all or part of the trial by the sponsor 
• Investigator or subinvestigator’s judgment (for reasons other than occurrence of AE) 
• Other 

Protocol 331-102-00088 
Confidential - Proprietary Information 
67 
Protocol Version 6.0, 24 Nov 2022 
a A change in the environment under which the subject’s condition is being followed, as specified in 
Inclusion Criterion 4 (see Section 3.4.2 Inclusion Criteria). 
 
If the subject discontinues IMP due to an AE, the investigator, subinvestigator, or other 
trial personnel will make every effort to follow the event until the event is resolved or 
stabilized, or the subject is lost to follow up or has died. Follow-up procedures in 
Section 3.9.3.1 Treatment Discontinuation must be followed. 
3.9.3.3 
Withdrawal of Consent 
All subjects (including their legal representatives and caregivers) have the right to 
withdraw their consent from further participation in the trial at any time without 
prejudice. Subjects cannot withdraw consent for use of data already collected as part of 
the trial, but only for future participation. The investigator or subinvestigator can also 
discontinue a subject’s participation in the trial at any time if medically necessary. Unless 
the subject provides their written withdrawal of consent or there is other written 
documentation by the investigator or subinvestigator confirming the subject’s verbal 
intent to completely withdraw from the trial, subjects should be followed for all protocol-
specified evaluations and assessments, if possible. 
Complete withdrawal of consent requires refusal by a subject of ALL of the following 
methods of follow up (these methods of follow up will also be noted in the trial ICF): 
• Participation in all follow-up procedures specified in the protocol (whether in-clinic, 
by telephone, or by an in-home visit). 
• Participation in a subset of protocol specified follow-up procedures (by a frequency 
schedule and method, as agreed by subject and staff). 
• Contact of the subject by trial personnel, even if only by telephone, to assess current 
medical condition, and to obtain necessary medical or laboratory reports relevant to 
the trial’s objectives. 
• Contact of alternative person(s) who have been designated in source documents as 
being available to discuss the subject’s medical condition, even if only by telephone, 
mail, or e-mail (eg, family, spouse, partner, legal representative, friend, neighbor, or 
physician). 
• Access to medical information from alternative sources (eg, hospital/clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, social media sources). 
Withdrawal of consent is a critical trial event and therefore should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent. 
The reasons of a subject for an intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial. 
A subject may initially express their desire to discontinue IMP administration, which is 

Protocol 331-102-00088 
Confidential - Proprietary Information 
68 
Protocol Version 6.0, 24 Nov 2022 
not equivalent to a complete withdrawal of consent for further participation (see 
Section 3.9.3.1 Treatment Discontinuation). A subject may, however, indicate that further 
trial participation is creating a burden on their work or social schedule. Therefore, the 
investigator or subinvestigator should follow the procedures outlined in Section 3.9.3.2 
Documenting Reasons for Discontinuation to determine if the subject can continue 
participation in the trial if modifications to his/her treatment and/or schedule of 
assessments can be accommodated. Only subjects who withdraw their permission for all 
of the above degrees of follow-up are considered to have completely withdrawn their 
consent to participate in the trial. 
3.9.3.4 
Procedures to Encourage Continued Trial Participation 
In all cases of impending IMP discontinuation or consent withdrawal, investigators or 
subinvestigators will be given instructions to meet and discuss with the subject their 
options of continuing in the trial, preferably on therapy. The investigator or 
subinvestigator should ensure understanding and documentation of the reasons why the 
subject wishes to withdraw consent. 
3.10 
Screen Failures 
A screen failure subject is one from whom informed consent is obtained and is 
documented in writing (ie, subject has signed an ICF), but who has not been randomized 
or has not been assigned to a treatment group. For screen failures, the following 
information will be recorded in the CRF: 
• Subject ID  
• Date of informed consent 
• Date of visit 
• Subject demographics (date of investigation, date of birth, sex, race, ethnicity, and 
country where trial is performed) 
• Results of eligibility criteria assessment 
• Date of assessment as screen failure 
• Reason for screening failure 
Subjects participating in this trial who fall under any of the exclusion criteria in the 
screening examination may undergo rescreening only if there is a change in the particular 
exclusion criterion that they met. If rescreening can be performed within the allowable 
time window for the screening period, there is no need to obtain reconsent, and only the 
tests relevant to the item that has changed need to be performed. If rescreening cannot be 
performed within the allowable time window for the screening period, written informed 

Protocol 331-102-00088 
Confidential - Proprietary Information 
69 
Protocol Version 6.0, 24 Nov 2022 
consent must be newly obtained, and a new subject ID must be assigned prior to the 
screening examination. 
3.11 
Definition of Completed Subjects 
The treatment period is defined as the time period during which subjects are evaluated for 
the primary and/or secondary objectives of the trial (corresponding to the treatment 
period in this trial) irrespective of whether the subject has received 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 the purposes of this trial, subjects who are evaluated at 
Week 10 will be defined as trial completers. 
3.12 
Definition of Subjects Lost to Follow-up 
Subjects who can no longer be contacted during the treatment period, who do not have a 
known reason for discontinuation (eg, withdrew consent or AE), and for whom a survival 
status at the end of the trial cannot be determined will be classified as “lost to follow-up.” 
Survival status can be determined from a variety of sources, either by obtaining 
acceptable documentation for death (ie, death certificate, medical records, public records, 
statement by a family member or primary care physician) or acceptable documentation 
for life (ie, direct contact with the subject, medical records, successful telephone contact 
with the subject, statement by a family member or primary care physician, or public 
records). 
The investigator, subinvestigator, or designee will make 3 documented attempts to 
contact the subject by telephone and in the event that the site is unable to reach the 
subject by telephone, the site will attempt to contact the subject via certified mail or an 
alternative similar method where appropriate, before assigning a “lost to follow-up” 
status. When a subject is lost to follow-up, the results of the investigation (whether or not 
the subject could be contacted and the date and method of contact) will be recorded in the 
source documents and the CRF. 
3.13 
Subject Compliance 
For this trial, subjects will receive care under the same environment from at least 3 weeks 
before the date of baseline evaluations to the completion of the examinations scheduled at 
the completion or discontinuation of IMP administration. If a change in the subject’s care 
environment is unavoidable, the subject’s participation in the trial should be 
discontinued. In the case of discontinuation, the necessary measures must be followed in 
accordance with Section 3.9 Stopping Rules, Withdrawal Criteria, and Procedures. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
70 
Protocol Version 6.0, 24 Nov 2022 
3.14 
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 therapy criteria), the investigator, subinvestigator, or designee will contact 
the sponsor at the earliest possible time by telephone. The investigator or subinvestigator 
and sponsor will come as quickly as possible to a joint decision regarding the subject’s 
continuation in the trial. The process of the decision for trial continuation will be 
documented by the investigator or subinvestigator and the sponsor, and reviewed by the 
site monitor. For major deviations, the date on which the deviation occurred and the 
details of the deviation will be recorded in the CRF. 
4 
Restrictions 
4.1 
Prohibited Medications 
Drugs shown in Table 4.1-1 except for brexpiprazole are prohibited until completion of 
the examinations scheduled at the completion or discontinuation of IMP administration. 
Brexpiprazole is prohibited until completion of follow-up observation. 
Table 4.1-1 
Prohibited Medications 
Drug Type 
Prohibited Period 
Before Baseline 
Evaluation 
Remarks 
Antipsychotics 
 
 
• 
Clozapine 
30 days 
Brexpiprazole is prohibited until 
completion of follow-up 
observation 
• 
Sustained release injections 
1.5 cycles 
• 
Brexpiprazole 
Any past use 
 
• 
Other antipsychotics 
7 days 
 
Antidepressants 
7 days 
 
Mood stabilizers 
7 days 
 
Psychostimulants 
7 days 
 
Narcotic analgesics for agitation 
7 days 
 
Yokukansan and other herbal medicines and 
supplements for treatment of BPSD 
7 days 
 
Adrenaline 
7 days 
 
Antiepileptic drugs 
7 days 
 
Antiparkinson drugs 
7 days 
 
Varenicline 
7 days 
 
Benzodiazepines 
7 days 
 
Belsomra 
7 days 
 
Lemborexant 
7 days 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
71 
Protocol Version 6.0, 24 Nov 2022 
Table 4.1-1 
Prohibited Medications 
Drug Type 
Prohibited Period 
Before Baseline 
Evaluation 
Remarks 
Drugs (β-blockers) for extrapyramidal 
symptoms 
7 days 
If administration is necessary due 
to AEs that occur after IMP 
administration, use will be 
permitted in accordance with the 
stipulations for restricted drugs. 
CYP2D6 inhibitors, CYP3A4 inhibitors and 
inducersa 
7 days 
 
asee Table 4.1-2 
 
Table 4.1-2 
Prohibited Concomitant CYP2D6 Inhibitors, CYP3A4 
Inhibitors, and CYP3A4 Inducers (Except for External Use) 
CYP2D6 
inhibitors 
 
CYP3A4 
inhibitors 
 
 
CYP3A4 
inducers 
 
 
 
4.2 
Restricted Medications 
Use of drugs listed in Table 4.2-1 from the baseline evaluation to the completion of the 
examinations scheduled at the completion or discontinuation of IMP administration is 
permitted under the prescribed restrictions. If the following restrictions cannot be 
complied with, restricted drugs should be discontinued before the day prior to the first 
day of IMP administration. 
Table 4.2-1 
Restricted Medications 
Drug Type 
Restriction 
Remarks 
Antidementia 
drugs 
These drugs can be continued if the dose and regimen have not been 
changed for 3 months before the baseline evaluation. The dose and 
regimen should remain the same until the completion of the 
examinations scheduled at the completion or discontinuation of IMP 
administration. 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
72 
Protocol Version 6.0, 24 Nov 2022 
Table 4.2-1 
Restricted Medications 
Drug Type 
Restriction 
Remarks 
Narcotic 
analgesics 
If not used for agitation (eg, pain control, tooth extraction), the use of 
these drugs is permitted from the baseline evaluation to the 
completion of the examinations scheduled at the completion or 
discontinuation of IMP administration. 
 
β-Blockers 
• 
Treatment of complications (eg, cardiovascular diseases) other 
than psychiatric diseases 
These drugs can be continued if they have been used before the 
acquisition of informed consent and the dose and regimen have 
not been changed for  30 days before the baseline evaluation. 
The type, dose, and regimen should remain the same until 
completion of the examinations scheduled at the completion or 
discontinuation of IMP administration (discontinuation or dose 
reduction are permitted only when these actions are necessary due 
to AEs caused by β-blockers and for remission of symptoms). 
• 
Treatment of extrapyramidal symptoms reported as AEs after 
IMP administration 
If medication is necessary, the use at a dose up to the equivalent 
of 60 mg/day of propranolol is permitted. These drugs are 
prohibited within 12 hours prior to efficacy and safety 
assessments. 
 
Hypnotics 
• 
Ultra-short-acting nonbenzodiazepine hypnotics (zolpidem, 
zopiclone, eszopiclone), ramelteon 
These drugs can be continued if the dose and regimen have not 
been changed for  30 days before the baseline evaluation. The 
type, dose, and regimen should remain the same until completion 
of the examinations scheduled at the completion or 
discontinuation of IMP administration (discontinuation and dose 
reduction are permitted only when these actions are necessary due 
to AEs caused by hypnotics and for remission of the symptoms of 
insomnia). These drugs are prohibited within 8 hours prior to 
efficacy and safety assessments. 
• 
Treatment of insomnia reported as an AE after IMP 
administration 
If medication is necessary, one (change of the type is permitted) 
ultra-short-acting nonbenzodiazepine hypnotic (zolpidem, 
zopiclone or eszopiclone) can be used. These drugs are prohibited 
within 8 hours prior to efficacy and safety assessments. 
 
 
4.3 
Restricted Therapies 
Starting new cognitive function training, cognitive stimulation, cognitive rehabilitation, 
exercise therapy, music therapy, and reminiscence therapy, as nonmedication therapies 
for dementia, and other nonmedication therapies which are judged by the investigator or 
subinvestigator to affect the efficacy and safety assessments is prohibited from baseline 
evaluation until completion of the examinations scheduled at the completion or 
discontinuation of IMP administration. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
73 
Protocol Version 6.0, 24 Nov 2022 
4.4 
Other Restrictions 
 
5 
Reporting of Adverse Events 
5.1 
Definitions 
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. Adverse events would not include information recorded 
as complications at screening for preplanned procedures for which the underlying 
condition was known and no worsening occurred. An adverse drug reaction is any 
untoward and unintended response to an IMP related to any dose administered. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE. For the purpose of Investigational New Drug safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal relationship between 
the IMP and the AE. Suspected adverse reaction implies a lesser degree of certainty about 
causality. 
An SAE includes any event that results in any of the following outcomes: 
• Death 
• Life-threatening; ie, the subject was, in the opinion of the investigator or 
subinvestigator, at immediate risk of death from the event as it occurred. It does not 
include an event that, had it occurred in a more severe form, might have caused death. 
• Persistent or significant incapacity/disability or substantial disruption of the ability to 
conduct normal life functions. 
• Requires inpatient hospitalization or prolongs hospitalization 
− Hospitalization itself should not be reported as an SAE; whenever possible the 
reason for the hospitalization should be reported. 
− Hospitalizations or prolonged hospitalizations for social admissions (ie, those 
required for reasons of convenience or other nonmedical need) are not considered 
SAEs. 
• Congenital anomaly/birth defect. 
• Other medically significant events that, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above, eg, allergic bronchospasm requiring 
intensive treatment in an emergency room or home, blood dyscrasias or convulsions 

Protocol 331-102-00088 
Confidential - Proprietary Information 
74 
Protocol Version 6.0, 24 Nov 2022 
that do not result in hospitalization, or the development of drug dependency or drug 
abuse. 
Nonserious AEs are all AEs that do not meet the criteria for a “serious” AE. 
 
Immediately Reportable Event (IRE): 
• Any SAE 
• Any AE related to occupational exposure. 
• Potential drug-induced liver injury (see Section 5.4 Potential Drug-induced Liver 
Injury). 
• Pregnancies are also defined as IREs. Although normal pregnancy is not an AE, it 
will mandate IMP discontinuation and must be reported on an IRE form to the 
sponsor. Pregnancy will only be recorded in the AE section of the CRF if there is an 
abnormality or complication. 
 
Clinical Laboratory Assessment Value Changes: It is the investigator’s or 
subinvestigator’s responsibility to review the results of all laboratory tests as they become 
available. This review will be documented by the investigator’s or subinvestigator’s dated 
signature on the laboratory report. For each abnormal laboratory test result, the 
investigator or subinvestigator needs to determine whether this is an abnormal (ie, 
clinically relevant) 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 or subinvestigator may repeat the laboratory test or request 
additional tests to verify the results of the original laboratory tests. If this laboratory value 
is considered medically relevant by the investigator or subinvestigator (subject is 
symptomatic, requiring corrective treatment or further evaluation), or if the laboratory 
value leads to discontinuation or meets the criteria for an SAE, this is considered an AE. 
 
Severity: Adverse events will be graded on a 3-point scale. The intensity of an AE 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. 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
75 
Protocol Version 6.0, 24 Nov 2022 
IMP Causality: Assessment of causal relationship between an AE and the IMP: 
Related:  
There is a reasonable possibility of a temporal and causal relationship 
between the IMP and the AE. 
Not related:  There is no temporal or reasonable relationship between the IMP and the 
AE. 
5.2 
Eliciting and Reporting Adverse Events 
The investigator or subinvestigator will periodically assess subjects for the occurrence of 
AEs. To avoid bias in eliciting AEs, subjects should be asked the non-leading question: 
“How have you felt since your last visit?” All AEs (serious and nonserious) reported by 
the subject must be recorded in the source documents and CRFs provided by the sponsor. 
The event name, date and time of onset, date and time of recovery, seriousness, severity, 
causal relationship to IMP, actions taken regarding IMP administration, and outcome 
thereof will be recorded in the CRF. The period for AE and SAE collection is defined as 
the period from after a subject has signed the ICF to the date of trial completion. 
Use medical terminology in AE reporting. Adverse events should be reported as a single 
unifying diagnosis whenever possible or, in the absence of a unifying diagnosis, as 
individual signs or symptoms. Exacerbation or disease progression should be reported as 
an AE only if there are unusual or severe clinical features that were not present, or 
experienced earlier, or not expected on the basis of the course of the condition. 
Worsening of severity and seriousness of reported AEs must be reported as new AEs in 
the CRF. 
In addition, the sponsor must be notified immediately by e-mail of any IREs according to 
the procedure outlined below, in Section 5.3 Immediately Reportable Events. Special 
attention should be paid to recording hospitalization and concomitant medications. 
5.3 
Immediately Reportable Events 
The investigator, subinvestigator, or designee must report any and all IREs (see 
Section 5.1 Definitions) to the sponsor by e-mail (using the contact information on the 
title page of this protocol) immediately after either the investigator, subinvestigator, or 
designee becomes aware of the event. An IRE form must be sent by e-mail to the 
sponsor. Please note that the IRE form is NOT the AE section of the CRF. Due 
consideration must be given to the subject’s privacy when an IRE form is sent by e-mail. 
For subjects experiencing SAEs or IREs, such events should be followed until the events 
are resolved or clinically stabilized, or the subject is lost to follow-up. Resolved means 

Protocol 331-102-00088 
Confidential - Proprietary Information 
76 
Protocol Version 6.0, 24 Nov 2022 
that the subject has returned to the baseline state of health, and stabilized means that the 
investigator or subinvestigator does not expect any further improvement or worsening of 
the subject’s condition. It is expected that the investigator or subinvestigator will provide 
or arrange appropriate supportive care for the subject and will provide prompt updates on 
the subject’s status to the sponsor. 
5.4 
Potential Drug-induced Liver Injury 
For a subject who experiences an elevation in aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) that is  3 times the ULN, total bilirubin level should 
also be evaluated. If the total bilirubin is ≥ 2 times the ULN, complete the IRE form and 
so on with all values listed and also report as an AE in the CRF. 
5.5 
Pregnancy 
Women of childbearing potential are defined as female subjects for whom menstruation 
has started and who are not documented as sterile (ie, have had a bilateral oophorectomy 
and/or hysterectomy or who have been postmenopausal for at least 12 months). 
For WOCBP and for men who are sexually active, there must be a documented 
agreement that the subject and/or their partner will take effective measures 
(ie, double-barrier method) to prevent pregnancy during the course of the trial and for 
30 days after the final administration of IMP. Unless the subject or their partner is sterile 
(ie, women who have had a bilateral oophorectomy and/or hysterectomy or who have 
been postmenopausal for at least 12 consecutive months; or men who have had a bilateral 
orchidectomy) or remains abstinent, 2 of the following precautions must be used: 
vasectomy, tubal ligation, vaginal diaphragm, IUD, oral contraceptives, or condom with 
spermicide. Any single method of birth control, including vasectomy and tubal ligation, 
may fail, leading to pregnancy. The contraceptive method will be documented at each 
trial visit. 
Before enrolling WOCBP in this clinical trial, investigators or subinvestigators must 
review the below guidelines about trial participation with all WOCBP. The topics should 
generally include: 
• General information 
• Informed consent form 
• Pregnancy prevention information 
• Drug interactions with hormonal contraceptives 
• Contraceptives in current use 
• Guidelines for the follow-up of a reported pregnancy 

Protocol 331-102-00088 
Confidential - Proprietary Information 
77 
Protocol Version 6.0, 24 Nov 2022 
 
Before trial enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy. The subject must sign an informed consent form stating that the above-
mentioned risk factors and the consequences were discussed with her. 
All WOCBP must undergo a urine or serum pregnancy test (human chorionic 
gonadotropin [HCG] test) at screening. If a urine test is performed and is positive, the 
investigator or subinvestigator will follow up with a confirmatory serum test. 
During the trial, all WOCBP should be instructed to contact the investigator or 
subinvestigator immediately if they suspect they might be pregnant (eg, missed or late 
menstrual cycle). 
If a subject is suspected to be pregnant before the start of IMP administration, the IMP 
administration must be withheld until the results of pregnancy tests are available. If the 
pregnancy is confirmed, the subject must not receive the IMP and must not be enrolled in 
the trial. If pregnancy is suspected while the subject is taking IMP, the IMP must be 
withheld immediately (if reasonable, taking into consideration any potential withdrawal 
risks) until the result of the serum pregnancy test 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 will be withdrawn from the trial. (Exceptions 
to trial discontinuation may be considered for life-threatening conditions only after 
consultations with the PV department [see the cover page of this protocol for contact 
information].) 
The investigator or subinvestigator must immediately notify the sponsor of any 
pregnancy associated with IMP exposure during the trial and for 30 days after the final 
administration of IMP, and record the event on the IRE form, and forward it to the 
sponsor. The sponsor will forward Pregnancy Surveillance Form(s) for monitoring the 
outcome of the pregnancy. The same applies to the pregnancy of a subject’s partner. 
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 or subinvestigator must report to the sponsor, on appropriate Pregnancy 
Surveillance Form(s), follow-up information regarding the course of the pregnancy, 
including perinatal and neonatal outcome. Infants will be followed for a minimum of 
6 months from the date of birth. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
78 
Protocol Version 6.0, 24 Nov 2022 
5.6 
Procedure for Breaking the Blind 
Only in the event that a subject has a medical emergency and knowledge of the treatment 
assignment code is necessary for treatment, the investigator or subinvestigator may obtain 
the emergency key code for the subject in question through the IWRS, in accordance with 
the separately specified procedures. When emergency key code opening is performed, the 
sponsor will receive automatic notification from the IWRS via e-mail. If the emergency 
key code is opened, the PV department must be notified immediately (see the cover page 
of this protocol for contact information).  
Documentation of emergency key code opening should be recorded in the subject’s 
medical record with the date and time of opening and the names of the personnel 
involved. Once a subject’s emergency key code is opened, IMP administration may not 
be reinitiated for that subject. 
5.7 
Follow-up of Adverse Events 
5.7.1 
Follow-up of Nonserious Adverse Events 
Nonserious AEs that are identified at any time during the trial must be recorded in the AE 
section of the CRF, with the current status (ongoing or resolved/recovered) noted. All 
nonserious events (other than IREs) that are ongoing at the end of trial date (final day of 
observation) will be recorded as ongoing in the CRF. For any AE having been identified 
throughout the trial, during data analysis, additional relevant medical history information 
may be requested by the sponsor to further ascertain causality (including, but not limited 
to, information such as risk-related behavior, family history, and occupation). The 
follow-up information after the end of trial date (final day of observation) will be 
recorded in the subject’s medical record. 
5.7.2 
Follow-up of Serious Adverse Events and Immediately 
Reportable Events 
This trial requires that subjects be actively monitored for SAEs and IREs up to the end of 
trial date (final day of observation). 
Serious AEs and IREs that are identified or ongoing at the end of trial date must be 
recorded in the AE section of the CRF. Between the end of trial date for the individual 
subject and the end of trial date for the last subject, if any new information regarding an 
SAE or IRE becomes available (eg, the event is resolved), this must be reported to the 
sponsor using the IRE form and so on, and the information must be recorded in the AE 
section of the CRF. The investigator or subinvestigator will follow SAEs and IREs, and 
will continue to report any significant information to the sponsor until the events are 

Protocol 331-102-00088 
Confidential - Proprietary Information 
79 
Protocol Version 6.0, 24 Nov 2022 
resolved or stabilized, or the subject is lost to follow-up or has died, using the IRE form 
and so on. 
5.7.3 
Follow-up and Reporting of Serious Adverse Events and 
Immediately Reportable Events Occurring After the End of Trial 
Date (Final Day of Observation) 
Any new SAEs or IREs reported to the investigator or subinvestigator, which occur after 
the end of trial date (final day of observation) and are determined by the investigator or 
subinvestigator to be associated with the use of the IMP, should be reported to the 
sponsor. This includes SAEs and IREs that are captured on follow-up telephone contact 
or at any other time point after the defined trial period. The investigator or 
subinvestigator will follow SAEs and IREs identified after the defined trial period and 
continue to report any significant follow-up information to the sponsor until the events 
are resolved or stabilized, or the subject is lost to follow-up or has died, using the IRE 
form and so on. 
6 
Statistical Analysis 
The definitions of the datasets for analysis and the analysis methods for the specified 
endpoints are described below. The statistical analysis plan details are described in a 
separate Statistical Analysis Plan. The Statistical Analysis Plan will be finalized prior to 
data lock. 
6.1 
Determination of Sample Size 
In Trial 331-12-283, which was performed outside Japan, the 2 mg fixed-dose group 
showed superiority over the placebo group in patients with aggression (patients with 
aggressive behavior at baseline), thus suggesting that it may also be the optimum dose for 
Japanese patients. Efficacy was not observed in the 1 mg fixed-dose group, but in Trial 
331-12-284, the efficacy of a dose less than 2 mg was suggested by the results obtained 
in patients from the flexible-dose (0.5 to 2 mg) group, who had aggression. 
In this trial, a power of detection ≥ 80% will be achieved for comparison between the 
placebo group and the 1 mg group to allow evaluation of superiority over the placebo 
group if equivalent efficacy is demonstrated in the 1 and 2 mg groups. For comparison 
between the 2 mg group (possible optimum dose) and the placebo group, a more 
sufficient power of detection will be obtained by changing the randomization ratio. In this 
trial, it is assumed that the difference between the 2 mg group and the placebo group in 
the change in the CMAI total score from baseline to Week 10 is −5.35, and the standard 
deviation (calculated from the standard error of the difference between the 2 mg and 
placebo groups and the number of subjects at baseline) is 15.06 on the basis of the results 

Protocol 331-102-00088 
Confidential - Proprietary Information 
80 
Protocol Version 6.0, 24 Nov 2022 
of Trial 331-12-283. By setting the number of subjects in the 2 mg group, 1 mg group, 
and placebo group as 148, 111, and 148, respectively (randomization ratio of 4:3:4), the 
power of detection is 86.1% for the comparison between the 2 mg group and the placebo 
group and is 80.5% for the comparison between the 1 mg group and the placebo group in 
a test with a significance level of 5% (two sided). 
On the basis of the above considerations, the number of subjects will be set at 148 in the 
2 mg group, 111 in the 1 mg group, and 148 in the placebo group (randomization ratio of 
4:3:4). 
6.2 
Datasets for Analysis 
6.2.1 
Pharmacokinetic Analysis Set 
The pharmacokinetic analysis set will comprise subjects who have been treated with 
brexpiprazole and for whom plasma drug concentration data have been obtained, other 
than those deemed as “not analyzed” or “not determined.” 
6.2.2 
Full Analysis Set 
The full analysis set (FAS) will comprise subjects who, after randomization, have 
received at least 1 dose of the IMP, and from whom CMAI total scores have been 
obtained at baseline and at least 1 time point after initiation of the treatment. 
6.2.3 
Safety Analysis Set 
The safety analysis set will comprise subjects who, after randomization, have received at 
least 1 dose of the IMP. 
6.3 
Handling of Missing Data 
The primary analysis of the primary endpoint will be performed in the observed cases 
(OC) dataset by mixed models for repeated measures (MMRM) without data imputation 
for missing data under the “missing at random” assumption. As a sensitivity analysis for 
the handling of missing data, placebo multiple imputation and tipping point analysis will 
be performed under the “missing not at random” assumption. Details are described in the 
statistical analysis plan. 
For efficacy and safety analyses, the last observation carried forward (LOCF) method (in 
which missing post-dose data are imputed by the last observed data after initiation of IMP 
treatment) will be used as needed. 
For pharmacokinetic analysis, no imputation will be performed for missing data. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
81 
Protocol Version 6.0, 24 Nov 2022 
6.4 
Primary and Secondary Endpoint Analyses 
6.4.1 
Primary Endpoint Analyses 
The primary endpoint will be change in CMAI total score from baseline to Week 10. 
The primary analysis will be conducted on the FAS by using MMRM analysis on the 
basis of the OC data set. For the analysis model, the treatment group (brexpiprazole 1 mg 
group, brexpiprazole 2 mg group, or placebo group), time point (Weeks 2, 4, 6, 8, or 10), 
medical care category (hospitalized or outpatient), prior use of antipsychotics (yes or no), 
and interaction between treatment group and time point will be included as factors, the 
baseline and interaction between the baseline and time point will be included as 
covariates, and the error variance and covariance structure will be unstructured. The 
Kenward–Roger method will be used to determine the degrees of freedom. 
Between-group comparison will be performed by calculating the difference of the least 
squares mean between each of the brexpiprazole groups and the placebo group at 
Week 10. The fixed sequence procedure will be used to adjust the multiplicity of testing 
due to the performance of two comparisons (ie, the brexpiprazole 1 mg group versus the 
placebo group and the brexpiprazole 2 mg group versus the placebo group) to control the 
overall type I error rate. Initially, the brexpiprazole 2 mg group will be compared with the 
placebo group. Only if the difference is statistically significant at a significance level of 
5% (two sided), the brexpiprazole 1 mg group will be compared with the placebo group 
at a significance level of 5% (two sided). 
The least squares mean for each treatment group and the difference of the least squares 
mean between each brexpiprazole group and the placebo group, as well as their two-sided 
95% CIs, will be calculated at each time point. 
If any problems in convergence status arise in the estimation of variance components of 
MMRM, heterogeneous Toeplitz, heterogeneous autoregressive of order 1, and 
heterogeneous compound symmetry, which are error variance-covariance structures, will 
be applied in this order, and the first structure that achieves convergence will be used in 
the primary analysis. If anything other than an unstructured variance-covariance structure 
is selected, a sandwich estimator for standard errors will be used. 
6.4.2 
Secondary Endpoint Analyses 
The secondary endpoint analysis will be performed on the FAS. 
• Changes in CMAI subscales (Aggressive Behavior, Physically Non-aggressive 
Behavior, and Verbally Agitated Behavior) from baseline at Week 10 
• Change in CGI-S related to agitation from baseline to Week 10 

Protocol 331-102-00088 
Confidential - Proprietary Information 
82 
Protocol Version 6.0, 24 Nov 2022 
The same MMRM analysis as that for the primary endpoint will be performed using the 
OC dataset. 
• CGI-I at Week 10 
Each brexpiprazole group will be compared with the placebo group by the Cochran 
Mantel Haenszel (CMH) Row Mean Scores test with medical care category (inpatient or 
outpatient) and prior use of antipsychotics (yes or no) as strata using the LOCF dataset. 
Mean values in each treatment group, differences in mean values between each 
brexpiprazole group and the placebo group, and their two-sided 95% CIs will be 
calculated. 
6.4.3 
Exploratory Endpoint Analyses 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
 
 
 
• 
 
• 
 
 
 
 
6.4.4 
Interim Analysis 
Safety will be evaluated by the IDMC when approximately 25%, 50%, and 75% of the 
target number of subjects have completed or discontinued the trial. 
6.4.5 
Subgroup Analyses 
The same MMRM analysis as that for the primary endpoint will be performed on the 
change in CMAI total score from baseline to Week 10 for each of the subgroup 

Protocol 331-102-00088 
Confidential - Proprietary Information 
83 
Protocol Version 6.0, 24 Nov 2022 
categories within each of the following items using the OC dataset (in the subgroup 
analyses of medical care category and prior use of antipsychotics, those particular factors 
will be excluded from the respective analysis models). 
• Medical care category (inpatient or outpatient) 
• Prior use of antipsychotics (yes or no) 
• Type of caregiver (hospital staff, care facility staff, family, or other)  
• Sex (male or female)  
• Age (< 80 or ≥ 80) 
• CMAI total score at baseline (< 56 or ≥ 56) 
• 
 
• Body weight (≤ median or > median) 
• Body mass index (BMI) (≤ median or > median) 
 
6.5 
Analysis of Demographic and Baseline Characteristics 
Descriptive statistics or frequency distribution of demographic and other baseline 
characteristics will be determined for each treatment group and for the overall 
brexpiprazole group in each analysis dataset. 
6.6 
Safety Analysis 
Safety analysis will be performed using the safety analysis set. Baseline is defined as the 
last data obtained prior to initiation of IMP treatment in the trial. 
6.6.1 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The incidence of the following events will be summarized by treatment 
group and by the overall brexpiprazole group, according to system organ class and 
preferred term. 
• Adverse events occurring after initiation of IMP administration (treatment-emergent 
adverse events [TEAEs]) 
• TEAEs by severity 
• TEAEs with an outcome of death 
• Serious TEAEs 
• TEAEs leading to discontinuation of the IMP 
TEAEs potentially causally related to the IMP will also be summarized in the same 
manner. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
84 
Protocol Version 6.0, 24 Nov 2022 
6.6.2 
Clinical Laboratory Data 
For each quantitative laboratory parameter, descriptive statistics of actual measurements 
and changes from baseline at each time point will be calculated for each treatment group 
and for the overall brexpiprazole group. 
For each laboratory parameter (excluding qualitative parameters), actual measurements 
will be classified as “lower than the lower limit of the reference range,” “within the 
reference range,” and “higher than the upper limit of the reference range” using the 
reference range specified by the central laboratory, and a shift table from baseline will be 
produced for each treatment group and for the overall brexpiprazole group. 
For each qualitative laboratory parameter, a shift table from baseline will be produced for 
each treatment group and for the overall brexpiprazole group. 
Numbers and proportions of subjects with potentially clinically significant laboratory test 
values will be determined for each treatment group and for the overall brexpiprazole 
group. 
6.6.3 
Physical Examination and Vital Signs Data 
Physical examination data will be provided in a listing. 
For each vital sign parameter, descriptive statistics of actual measurements and changes 
from baseline at each time point will be calculated for each treatment group and for the 
overall brexpiprazole group. 
Numbers and proportions of subjects with potentially clinically significant vital signs will 
be determined for each treatment group and for the overall brexpiprazole group. 
6.6.4 
Electrocardiogram Data 
For heart rate, PR interval, RR interval, QRS interval, QT interval, and QTc, descriptive 
statistics of actual measurements and changes from baseline at each time point will be 
calculated for each treatment group and for the overall brexpiprazole group. 
A shift table from baseline for normal/abnormal 12-lead ECG will be produced for each 
treatment group and for the overall brexpiprazole group. 
Numbers and proportions of subjects with actual measurements of corrected QT interval 
(QTcF, QTcB, and QTcN) at each time point of > 450 msec, > 480 msec, and > 500 msec 
will be determined for each treatment group and for the overall brexpiprazole group. 
Numbers and proportions of subjects with changes from baseline of > 30 msec and 
> 60 msec will be determined for each treatment group and for the overall brexpiprazole 
group. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
85 
Protocol Version 6.0, 24 Nov 2022 
Numbers and proportions of subjects with ECG results meeting the criteria for potentially 
clinically significant ECG data will be determined for each treatment group and for the 
overall brexpiprazole group. 
6.6.5 
Other Safety Data 
6.6.5.1 
Body Weight and Body Mass Index 
For body weight and BMI, descriptive statistics of actual measurements and changes 
from baseline at each time point will be calculated for each treatment group and for the 
overall brexpiprazole group. 
In addition, using the LOCF data set, analysis will be performed by the analysis of 
covariance (ANCOVA) model with treatment group, medical care category (hospitalized 
or outpatient), and prior use of antipsychotics (yes or no) as factors and baseline as a 
covariate. Least square means of each treatment group and differences in least square 
means between each brexpiprazole group and the placebo group, as well as the two-sided 
95% CIs will be determined. 
Numbers and proportions of subjects with results meeting the criteria for potentially 
clinically significant body weight gain or loss will be determined for each treatment 
group and for the overall brexpiprazole group. 
6.6.5.2 
DIEPSS, AIMS, and BARS 
For DIEPSS total score (total of scores for items 1 through 8) and score for each DIEPSS 
item, AIMS total score (total of scores for items 1 through 7) and score for each of the 3 
global judgment items (items 8 through 10), and BARS, descriptive statistics of actual 
measurements and changes from baseline at each time point will be calculated for each 
treatment group and for the overall brexpiprazole group. 
In addition, using the LOCF data set, analysis will be performed by the ANCOVA model 
with treatment group, medical care category (hospitalized or outpatient), and prior use of 
antipsychotics (yes or no) as factors and baseline as a covariate. Least square means of 
each treatment group and differences in least square means between each brexpiprazole 
group and the placebo group, as well as the two-sided 95% CIs will be determined. 
6.6.5.3 
S-STS 
For each item of S-STS, descriptive statistics of actual measurements and changes from 
baseline at each time point will be calculated for each treatment group and for the overall 
brexpiprazole group. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
86 
Protocol Version 6.0, 24 Nov 2022 
In addition, using the LOCF data set, analysis will be performed by the ANCOVA model 
with treatment group, medical care category (hospitalized or outpatient), and prior use of 
antipsychotics (yes or no) as factors and baseline as a covariate. Least square means of 
each treatment group and differences in least square means between each brexpiprazole 
group and the placebo group, as well as the two-sided 95% CIs will be determined. 
6.7 
Analysis of Pharmacokinetic Endpoints 
Descriptive statistics of plasma drug concentration at the time of blood sampling 
(Week 10) will be calculated for each dose group. 
6.8 
Analysis of Pharmacogenomic Endpoints 
A list of data obtained from CYP2D6 genetic assessment will be provided without 
summarization. 
6.9 
Genomic/Genetic Analysis 
See Section 3.8.4.2.2 5) Genomic/Genetic Analysis for genomic/genetic analysis. 
6.10 
Biomarker Exploration Analysis 
See Section 3.8.4.3 5) Biomarker Exploration for biomarker exploration analysis. 
6.11 
Analysis of Other Endpoints 
Analysis of other endpoints will be performed using the safety analysis set. Baseline is 
defined as the last data obtained prior to initiation of IMP treatment in the trial. 
• ADCS-ADL 
• MMSE 
• EQ-5D-5L 
 
For ADCS-ADL total score, MMSE total score and each item of EQ-5D-5L, descriptive 
statistics of actual measurements and changes from baseline at each time point will be 
calculated for each treatment group and for the overall brexpiprazole group. 
In addition, using the LOCF data set, analysis will be performed by the ANCOVA model 
with treatment group, medical care category (hospitalized or outpatient), and prior use of 
antipsychotics (yes or no) as factors and baseline as a covariate. Least square means of 
each treatment group and differences in least square means between each brexpiprazole 
group and the placebo group, as well as the two-sided 95% CIs will be determined. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
87 
Protocol Version 6.0, 24 Nov 2022 
7 
Management of Investigational Medicinal Product 
Refer to the investigator’s brochure on brexpiprazole and the separately-specified manual 
for details regarding IMP management. 
7.1 
Packaging and Labeling 
The IMP will be provided to the IMP manager by the sponsor or designated agent. The 
IMP will be supplied as 
used in the dosing period will be 
labeled to clearly indicate that the drug is for clinical trial use and to disclose the subject 
ID, compound ID, the protocol number, sponsor’s name and address, route of 
administration, manufacturing number, expiry date, storage conditions, etc. 
7.2 
Storage 
The IMP will be stored in a securely locked cabinet or enclosure. Access will be limited 
to the IMP manager. The IMP manager may not provide IMP to any subject not 
participating in this protocol. 
The IMP is to be stored at room temperature. The clinical site staff will maintain a 
temperature log in the drug storage area recording the temperature at least once each 
working day. 
7.3 
Accountability 
The IMP manager must maintain an inventory record of IMP received, dispensed, 
administered, or returned. 
7.4 
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. 
All IMP returned to the sponsor must be accompanied by appropriate documentation and 
be identified by protocol number and trial site number on the outermost shipping 
container. Returned supplies should be in the 
 
The assigned trial 
monitor will facilitate the return of unused and/or partially used IMP. 
7.5 
Reporting of Product Quality Complaints 
A Product Quality Complaint (PQC) regarding the IMP 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 

Protocol 331-102-00088 
Confidential - Proprietary Information 
88 
Protocol Version 6.0, 24 Nov 2022 
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) 
• 
 
• Product defect (eg, odor, chipped, broken, embossing illegible) 
• Loss or theft of product 
 
7.5.1 
Eliciting and Reporting Product Quality Complaints 
The investigator, subinvestigator, or designee must record all PQCs identified through 
any means from the receipt of the IMP from the sponsor, or sponsor’s designee, through 
and including reconciliation and up to destruction, including subject dosing. The 
investigator, subinvestigator, or designee must notify the sponsor (or sponsor’s designee) 
via e-mail immediately after becoming aware of the PQC according to the procedure 
outlined in Section 7.5.2 Information Required for Reporting Product Quality 
Complaints. (
) 
Identification of a PQC by the subject should be reported to the investigator or 
subinvestigator, who should then follow the reporting mechanisms listed above. 
7.5.2 
Information Required for Reporting Product Quality Complaints 
• Description of complaint 
• Reporter identification (eg, subject, investigator or subinvestigator, site information, 
etc) 
• Reporter contact information (eg, address, phone number, e-mail address) 
• ID of material (product/compound name, drug number) 
• Clinical protocol reference (protocol number or trial name) 
• Dosage form/strength (if known) 
• Pictures (if available) 
• Complaint sample availability for return 
 
7.5.3 
Return Process for Product Quality Complaints 
Indicate during the report of the PQC if the complaint sample is available for return. If 
the complaint sample is available for return, the sponsor will provide instructions for 
complaint sample return, when applicable. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
89 
Protocol Version 6.0, 24 Nov 2022 
It must be documented in the site accountability record that a complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation. 
7.5.4 
Assessment/Evaluation 
Assessment and evaluation of PQCs will be handled by the sponsor. 
8 
Records Management 
8.1 
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, medical 
records, electronic data, screening logs, and recorded data from automated instruments. 
All source documents pertaining to this trial will be maintained by the trial site and made 
available for direct inspection by authorized persons. Investigator(s)/trial site(s) will 
permit trial-related monitoring, audits, IRB review, and regulatory inspection(s) by 
providing direct access to source data/documents by authorized persons as defined in the 
ICF. In all cases, subject confidentiality must be maintained in accordance with regional 
regulatory requirements. 
8.2 
Data Collection 
During each subject’s visit to the trial site, an investigator or subinvestigator will 
document all significant observations and findings in the medical records. At a minimum, 
these records will contain: 
• Documentation of the informed consent process, including any revised consents; 
• Documentation of the investigator’s or subinvestigator’s decision to enroll the subject 
into the trial, the review of all inclusion/exclusion criteria prior to commencement of 
IMP administration, and confirmation of the subject’s actual participation in the trial; 
• The date of the visit and the corresponding Visit or Day in the trial schedule; 
• General subject status remarks, including any significant medical findings. The 
severity, frequency, duration, action taken, and outcome of any AEs and the 
investigator's or subinvestigator’s assessment of relationship to IMP must also be 
recorded; 
• Any changes in concomitant medications or dosages; 
• A general reference to the procedures completed; 
• The signature (or initials) and date of each clinician (or designee) who made an entry 
in the medical records. 
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the medical records as 

Protocol 331-102-00088 
Confidential - Proprietary Information 
90 
Protocol Version 6.0, 24 Nov 2022 
described above. Any changes to information in the medical records and other source 
documents will be initialed and dated on the day the change is made by a trial site staff 
member authorized to make the change. Changes will be made by striking a single line 
through erroneous data (so as not to obliterate the original data), and clearly entering the 
correct data (eg, wrong data right data). If the reason for the change is not apparent, a 
brief explanation for the change will be written in the source documentation by the 
investigator or subinvestigator. If electronic data systems are being utilized, a full audit 
trail of changes must be maintained. 
Information from the medical records and other source documents will be entered by trial 
site personnel directly onto electronic CRFs in the sponsor’s electronic data capture 
system. Changes to the data will be captured by an automatic audit trail. 
Subject diaries collected by caregivers (original documents) will be kept by the study site. 
8.3 
File Management at the Trial Site 
The head of the trial site will ensure that the trial site file is maintained in accordance 
with Section 8 of the ICH GCP Guideline E6 and as required by applicable local 
regulations. The trial site will take measures to prevent accidental or premature 
destruction of these documents. 
8.4 
Record Retention at the Trial Site 
The trial site will retain all the trial-related documents and records for whichever is the 
longer of the four periods indicated below. However, if the sponsor requires a longer 
period of archiving, the head of the trial site will consult with the sponsor on the period 
and procedures of record retention. 
• Until the date 2 years after manufacturing and marketing approval date; however, if 
the head of the trial site receives notification from the sponsor that development has 
been terminated or that results of the trial will not be submitted with the approval 
application, until the date 3 years after receipt of such notification. 
• Until the date 3 years after termination or completion of the trial. 
• Until the date on which it is decided to end DNA storage 
• Until the date on which it is decided to end biomarker sample storage 
The trial site must not dispose of any records relevant to this trial without either 
1) written permission from the sponsor or 2) providing an opportunity for the sponsor to 
collect such records. The trial site will be responsible to maintain adequate and accurate 
electronic or hard copy source documents of all observations and data generated during 
the trial. Such documentation is subject to inspection by the sponsor and relevant 
regulatory authorities. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
91 
Protocol Version 6.0, 24 Nov 2022 
9 
Quality Control and Quality Assurance 
9.1 
Monitoring 
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, ICH E6 GCP: Consolidated Guidance, and 
applicable regional regulatory requirements and laws. As part of a concerted effort to 
fulfill these obligations (maintain current personal knowledge of the progress of the trial), 
the sponsor’s monitors will visit the site during the trial, as well as communicate 
frequently via telephone, e-mail, and written communications. In addition, all 
investigators or subinvestigators and trial site clinical personnel will undergo initial and 
ongoing training for this particular trial, and this training will be clearly documented. 
9.2 
Auditing 
The sponsor’s Quality Assurance Unit (or representative) may conduct trial site audits. 
Audits will include, but are not limited to, IMP supply, presence of required documents, 
the informed consent process, and comparison of CRFs with source documents. The 
investigator agrees to participate with audits. 
Regulatory authorities may inspect the trial site during or after the trial. The investigator 
will cooperate with such inspections and will contact the sponsor immediately if such an 
inspection occurs. 
10 
Ethics and Responsibility 
This trial must be conducted in compliance with the protocol, ICH GCP Guideline (E6), 
international ethical principles derived from the Declaration of Helsinki and Council for 
International Organizations of Medical Science guidelines, and applicable local laws and 
regulations. Each trial site will seek approval/favorable opinion by an IRB according to 
the requirements of each region, and the trial site will provide that documentation to the 
sponsor. The IRB will evaluate the ethical, scientific, and medical appropriateness of the 
trial. Further, in preparing and handling CRFs and IRE forms, the investigator or 
subinvestigator and their staff will take measures to ensure adequate care in protecting 
subject privacy. To this end, a subject number or subject ID will be used to identify each 
subject. Financial aspects, subject insurance, and publication policy for the trial will be 
documented in the agreement between the sponsor and the trial site. 
11 
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 

Protocol 331-102-00088 
Confidential - Proprietary Information 
92 
Protocol Version 6.0, 24 Nov 2022 
written permission. Subject confidentiality requirements of the region where the trial is 
conducted will be met. However, authorized regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy the records, 
consistent with local requirements. All IMPs, subject bodily fluids, and 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 a unique subject ID in the CRFs. If further subject 
identification is required, subjects’ full names may be made known to a regulatory 
agency or other authorized officials if necessary, subject to local regulations. 
12 
Amendment Policy 
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval/favorable opinion by the IRB. 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, as required by local regulations. 
Except for “administrative” or “nonsubstantial” amendments, investigators or 
subinvestigators will wait for IRB approval/favorable opinion of the amended protocol 
before implementing the change(s). Administrative amendments are defined as having no 
effect on the safety of subjects, conduct or management of the trial, trial design, or the 
quality or safety of IMP(s) used in the trial. A protocol change intended to eliminate an 
apparent immediate hazard to subjects should be implemented immediately, followed by 
IRB notification within local applicable timelines. The sponsor will submit protocol 
amendments to the applicable regulatory agency within local applicable timelines. 
When the IRB, investigators, or the sponsor concludes that the protocol amendment 
substantially alters the trial design or increases the potential risk to the subject, the 
currently approved written ICF will require similar modification. In such cases, after 
approval/favorable opinion of the new ICF by the IRB, repeat written informed consent 
will be obtained from subjects enrolled in the trial before expecting continued 
participation and before the amendment-specified changes in the trial are implemented. 
13 
Publication Authorship Requirements 
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 
criteria (http://www.icmje.org/recommendations). According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met: 

Protocol 331-102-00088 
Confidential - Proprietary Information 
93 
Protocol Version 6.0, 24 Nov 2022 
1) Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND 
2) Drafting the work or revising it critically for important intellectual content; AND 
3) Final approval of the version to be published; AND 
4) Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved. 
 
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors. 
Investigators or other trial participants who do not qualify for authorship may be 
acknowledged in publications resulting from the trial. By agreeing to participate in the 
trial, investigators or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct. 
14 
References 
1 
Ministry of Health, Labour and Welfare. Let’s start with knowing—Comprehensive 
Website on Everyone's Mental Health:  Website regarding mental health, mental 
illnesses, support and service. [Internet]. Tokyo: Ministry of Health, Labour and 
Welfare; Accessed on 09 Jan 2018. Access: 
http://www.mhlw.go.jp/kokoro/speciality/detail_recog.html. 
2 
Honma A, Usui M. Basic knowledge on dementia. Monthly Shiho Shoshi. 
2011;472:11-6. 
3 
Kudo T, Takeda M. General theory on BPSD. Japanese Journal of Geriatric 
Psychiatry. 2005;16:9-15. 
4 
Cerejeira J, Lagarto L, Mukaetova-Ladinska EB. Behavioral and psychological 
symptoms of dementia. Front Neurol. 2012;3:73. 
5 
Cummings J, Mintzer J, Brodaty H, Sano M, Banerjee S, Devanand DP, et al. 
Agitation in cognitive disorders: International Psychogeriatric Association 
provisional consensus clinical and research definition. Int Psychogeriatr. 2015;27:7-
17. 
6 
Shimabukuro J, Awata S, Matsuoka H. Behavioral and psychological symptoms of 
dementia characteristic of mild Alzheimer patients. Psychiatry Clin Neurosci. 
2005;59:274-9. 
7 
Tractenberg RE, Weiner MF, Patterson MB, Teri L, Thal LJ. Comorbidity of 
psychopathological domains in Community-dwelling persons with Alzheimer’s 
disease. J Geriatr Psychiatry Neurol. 2003;16:94-9. 
8 
Scarmeas N, Brandt J, Blacker D, Albert M, Hadjigeorgiou G, Dubois B, et al. 
Disruptive Behavior as a Predictor in Alzheimer Disease. Arch Neurol. 
2007;64:1755-61. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
94 
Protocol Version 6.0, 24 Nov 2022 
9 
D’Onofrio1 G, Sancarlo D, Panza F, Copetti M, Cascavilla L, Paris F, et al. 
Neuropsychiatric Symptoms and Functional Status in Alzheimer’s Disease and 
Vascular Dementia Patients. Curr Alzheimer Res. 2012;9:759-71. 
10 Peters ME, Schwartz S, Han D, Rabins PV, Steinberg M, Tschanz JT, et al. 
Neuropsychiatric symptoms as predictors of progression to severe Alzheimer’s 
dementia and death: The Cache County Dementia Progression Study. Am J 
Psychiatry. 2015;172:460-5. 
11 Cheng ST. Dementia Caregiver Burden: a Research Update and Critical Analysis. 
Curr Psychiatry Rep. 2017;19:64. 
12 Hiyoshi-Taniguchi K, Becker CB, Kinoshita A. What Behavioral and Psychological 
Symptoms of Dementia Affect Caregiver Burnout?. Clin Gerontol. 2018;41:249-54. 
13 Okura T, Langa KM. Caregiver Burden and Neuropsychiatric Symptoms in Older 
Adults with Cognitive Impairment: The Aging, Demographics, and Memory Study 
(ADAMS). Alzheimer Dis Assoc Disord. 2011;25:116-21. 
14 Gilley DW, Bienias JL, Wilson RS, Bennett DA, Beck TL, Evans DA. Influence of 
behavioral symptoms on rates of institutionalization for persons with Alzheimer’s 
disease. Psychol Med. 2004;34:1129-35. 
15 Knapp M, Chua KC, Broadbent M, Chang CK, Fernandez JL, Milea D, et al. 
Predictors of care home and hospital admissions and their costs for older people with 
Alzheimer’s disease: findings from a large London case register. BMJ Open. 
2016;6:e013591. 
16 Morris S, Patel N, Baio G, Kelly L, Lewis-Holmes E, Omar RZ, et al. Monetary costs 
of agitation in older adults with Alzheimer's disease in the UK: prospective cohort 
study. BMJ Open. 2015;5:e007382. 
17 Committee on Practice Guideline for Dementia. Practice Guideline for Dementia 
2017. Japanese Society of Neurology. Tokyo: Igaku Shoin; 2017. CQ 3B-2, What are 
the effective non-pharmacological and pharmacological therapies for agitation?; p.74-
6. 
18 Committee on Practice Guideline for Dementia. Practice Guideline for Dementia 
2017. Japanese Society of Neurology. Tokyo: Igaku Shoin; 2017. CQ 3A-2, How to 
perform non-pharmacological therapy, pharmacological therapy and care when 
treating dementia; p.56-8. 
19 Schneider LS, Dagerman KS, Insel P. Risk of Death with Atypical Antipsychotic 
Drug Treatment for Dementia. JAMA. 2005;294:1934-43. 
20 Arai H, Nakamura Y, Taguchi M, Kobayashi H, Yamauchi K, Schneider LS, et al. 
Mortality risk in current and new antipsychotic Alzheimer's disease users: Large scale 
Japanese study. Alzheimer Dement. 2016;12:823-30. 
21 Liu KY, Stringer AE, Reeves SJ, Howard RJ. The neurochemistry of agitation in 
Alzheimer's disease: a systematic review. Ageing Res Rev. 2018;43:99-107. 
22 Rabinowitz J, Davidson M, De Deyn PP, Katz I, Brodaty H, Cohen-Mansfield J. 
Factor Analysis of the Cohen-Mansfield Agitation Inventory in Three Large Samples 
of Nursing Home Patients with Dementia and Behavioral Disturbance. Am J Geriatr 
Psychiatry. 2005;13:991-8. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
95 
Protocol Version 6.0, 24 Nov 2022 
23 Cohen-Mansfield J. INSTRUCTION MANUAL FOR THE COHEN-MANSFIELD 
AGITATION INVENTORY (CMAI). [Internet]. [cited Accessed on January 9, 
2018]. Available from: 
https://www.pdx.edu/ioa/sites/www.pdx.edu.ioa/files/CMAI_Manual%20(1).pdf 
24 Otsuka Pharmaceutical. Summary of application data for REXULTI 1 mg tablets and 
REXULTI 2 mg tablets. [Internet]. Tokyo: PMDA; Accessed on 08 May 2018. 
Access: http://www.pmda.go.jp/drugs/2018/P20180207001/index.html. 
25 Regarding Clinical Studies Utilizing Pharmacogenomics: PFSB/ELD Notification 
No. 0930007, 30 Sep 2008.  
26 Committee on Practice Guideline for Dementia. Practice Guideline for Dementia 
2017. Japanese Society of Neurology. Tokyo: Igaku Shoin; 2017. CQ 3A-3, What are 
the precautions and principles of pharmacological therapy for elderly patients with 
dementia?; p. 59-60. 
27 International Conference on Harmonisation. Guideline for Good Clinical Practice: 
E6(R1). Geneva, Switzerland: International Conference on Harmonisation; 1996. 
28 Schreiner AS, Yamamoto E, Shiotani H. Agitated Behavior in Elderly Nursing Home 
Residents With Dementia in japan. J Gerontol B Psychol Sci Soc Sci. 2000;55:P180-
6. 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
96 
Protocol Version 6.0, 24 Nov 2022 
Appendix 1 
 
 
 
 
 
 
 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
97 
Protocol Version 6.0, 24 Nov 2022 
 
 
 
 
 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
98 
Protocol Version 6.0, 24 Nov 2022 
 
 
 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
99 
Protocol Version 6.0, 24 Nov 2022 
Appendix 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2

Protocol 331-102-00088 
Confidential - Proprietary Information 
100 
Protocol Version 6.0, 24 Nov 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
101 
Protocol Version 6.0, 24 Nov 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
102 
Protocol Version 6.0, 24 Nov 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
103 
Protocol Version 6.0, 24 Nov 2022 
Appendix 3 
Protocol Amendments/Administrative Changes 
 
Amendment: Number: 1 
Issue Date: 
24 Aug 2018 
 
PURPOSE: 
 
 
BACKGROUND: 
 
 
MODIFICATIONS TO PROTOCOL: 
Sectional Revisions: 
Location 
Before Change 
After Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
104 
Protocol Version 6.0, 24 Nov 2022 
Location 
Before Change 
After Change 
 
 
 
 
 
 
 
 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
105 
Protocol Version 6.0, 24 Nov 2022 
Location 
Before Change 
After Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
106 
Protocol Version 6.0, 24 Nov 2022 
Location 
Before Change 
After Change 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
ADDITIONAL RISK TO THE SUBJECT 
 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
107 
Protocol Version 6.0, 24 Nov 2022 
Amendment: Number: 2 
Issue Date: 
05 Mar 2020 
 
PURPOSE: 
 
 
BACKGROUND: 
 
 
 
MODIFICATIONS TO PROTOCOL: 
Sectional Revisions: 
Location 
Before Change 
After Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
108 
Protocol Version 6.0, 24 Nov 2022 
Location 
Before Change 
After Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
109 
Protocol Version 6.0, 24 Nov 2022 
Location 
Before Change 
After Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
110 
Protocol Version 6.0, 24 Nov 2022 
Location 
Before Change 
After Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
111 
Protocol Version 6.0, 24 Nov 2022 
Location 
Before Change 
After Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
112 
Protocol Version 6.0, 24 Nov 2022 
Location 
Before Change 
After Change 
 
 
 
 
 
 
 
 
 
ADDITIONAL RISK TO THE SUBJECT 
 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
113 
Protocol Version 6.0, 24 Nov 2022 
Amendment: Number: 3 
Issue Date: 
03 Feb 2021 
 
PURPOSE: 
 
 
BACKGROUND: 
 
 
MODIFICATIONS TO PROTOCOL: 
Sectional Revisions: 
Location 
Before Change 
After Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADDITIONAL RISK TO THE SUBJECT 
. 

Protocol 331-102-00088 
Confidential - Proprietary Information 
114 
Protocol Version 6.0, 24 Nov 2022 
Amendment: Number: 4 
Issue Date: 
27 Apr 2022 
 
PURPOSE: 
 
 
BACKGROUND: 
 
 
MODIFICATIONS TO PROTOCOL: 
Sectional Revisions: 
Location 
Before Change 
After Change 
 
 
 
 
 
 
 
ADDITIONAL RISK TO THE SUBJECT 
 
 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
115 
Protocol Version 6.0, 24 Nov 2022 
Amendment: Number: 5 
Issue Date: 
24 Nov 2022 
 
PURPOSE: 
 
 
BACKGROUND: 
 
 
MODIFICATIONS TO PROTOCOL: 
Sectional Revisions: 
Location 
Before Change 
After Change 
 
 
 
 
 
 
 
ADDITIONAL RISK TO THE SUBJECT 
 

Protocol 331-102-00088 
Confidential - Proprietary Information 
116 
Protocol Version 6.0, 24 Nov 2022 
Agreement 
I, the undersigned principal investigator, have read and understand the protocol 
(including the Investigator's Brochure) and agree that it contains all the ethical, legal and 
scientific information necessary to conduct this trial in accordance with the principles of 
Good Clinical Practices and as described herein and in the sponsor's (or designee's) 
Clinical Trial Agreement. 
I will provide copies of the protocol to all physicians, nurses, and other professional 
personnel to whom I delegate trial responsibilities. I will discuss the protocol with them 
to ensure that they are sufficiently informed regarding the investigational new drug, 
OPC-34712, the concurrent medications, the efficacy and safety parameters and the 
conduct of the trial in general. I am aware that this protocol must be approved by the 
Institutional Review Board (IRB) responsible for such matters in the clinical trial facility 
where OPC-34712 will be tested prior to commencement of this trial. I agree to adhere 
strictly to the attached protocol (unless amended in the manner set forth in the sponsor's 
Clinical Trial Agreement, at which time I agree to adhere strictly to the protocol as 
amended). 
I understand that this IRB-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 trial sites, whenever applicable. I agree to allow sponsor and 
designee monitors and auditors full access to all medical records at the trial site for 
subjects screened or enrolled in the trial. 
I agree to await IRB approval before implementation of any substantial amendments to 
this protocol. If, however, there is an immediate hazard to subjects, I will implement the 
amendment immediately, and provide the information to the IRB within the required 
local applicable timelines. Administrative changes to the protocol will be transmitted to 
the IRB for informational purposes only, if required by local regulations. 
I agree to provide all subjects with informed consent forms, as required by the applicable 
regulations and by ICH guidelines. I agree to report to the sponsor any adverse events in 
accordance with the terms of the sponsor's Clinical Trial Agreement and the relevant 
regional regulation(s) and guideline(s). I further agree to provide all required information 
regarding financial certification or disclosure to the sponsor for all investigators and 
subinvestigators in accordance with the terms of the relevant regional regulation(s). I 
understand that participation in the protocol involves a commitment to publish the data 
from this trial in a cooperative publication before publication of efficacy and safety 

Protocol 331-102-00088 
Confidential - Proprietary Information 
117 
Protocol Version 6.0, 24 Nov 2022 
results on an individual basis may occur, and I consent to be acknowledged in any such 
cooperative publications that result. 
 
 
 
 
 
 
   
 
 
 
 
 
 
Principal Investigator’s Name 
  Name of Trial Site 
 
___________________________________   
 
Signature 
 
 
 
 
Date 
 
The sponsor’s signature for this Agreement is provided as an electronic signature. The 
electronic signature page is attached to this Agreement.