Clinical trial NCT03724942
Conditions: Agitation Associated With Dementia of the Alzheimer's Type
Sponsor: Otsuka Pharmaceutical Co., Ltd.
Start date: 2018-11-09; Completion date: 2022-01-05
Enrollment: 164 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To evaluate the safety of brexpiprazole 1 mg or 2 mg after a 14 week treatment regimen for agitation associated with dementia of the Alzheimer's type patients who completed in a double-blind trial, and to investigate the efficacy of brexpiprazole.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Brexpiprazole
Intervention descriptions: intervention 1: Brexpiprazole 1mg or 2mg will be orally once daily for 14 weeks

Protocol documents:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
A multicenter, uncontrolled, open-label trial to evaluate the safety of extended treatment with 
brexpiprazole (OPC-34712) in patients with agitation associated with dementia of 
 the Alzheimer’s type 
 
 
 
NCT Number: NCT03724942 
Protocol No. 331-102-00184 
Version Date: 03 Feb 2021  (Version 4.0) 


Protocol 331-102-00184 
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Protocol Version 4.0, 03 Feb 2021 
Otsuka Pharmaceutical Co., Ltd. 
 
Investigational Medicinal Product 
Brexpiprazole (OPC-34712) 
 
CLINICAL PROTOCOL 
(Translation of Japanese Original) 
 
A multicenter, uncontrolled, open-label trial to evaluate the safety of extended treatment 
with brexpiprazole (OPC-34712) in patients with agitation associated with dementia of 
the Alzheimer’s type 
 
Protocol No. 331-102-00184 
 
CONFIDENTIAL – PROPRIETARY INFORMATION 
 
Clinical Development Phase: 
3 
Sponsor: 
Otsuka Pharmaceutical Co., Ltd. 
 
Immediately Reportable Event: 
 
 
 
e-mail address: 
 
 
Issue Date: 
24 Aug 2018 
Date of Amendment 1: 
01 Oct 2018 
Date of Amendment 2: 
05 Mar 2020 
Date of Amendment 3: 
03 Feb 2021 
Version No.: 
4.0 
(Date of Translation: 
13 Apr 2021) 


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Protocol Synopsis 
Name of Sponsor: Otsuka Pharmaceutical 
Co., Ltd. 
Name of Investigational Medicinal Product: 
Brexpiprazole (OPC-34712) 
Protocol No.: 331-102-00184 
 
Protocol title: 
A multicenter, uncontrolled, open-label trial to evaluate the 
safety of extended treatment with brexpiprazole (OPC-34712) 
in patients with agitation associated with dementia of the 
Alzheimer’s type 
Clinical phase/ 
type of trial: 
Phase 3 
Long-term study 
Treatment indication: 
Agitation associated with dementia of the Alzheimer’s type 
Objectives: 
To evaluate the safety of brexpiprazole 1 or 2 mg administered 
for 14 weeks in patients with agitation associated with 
dementia of the Alzheimer’s type who have completed the 
treatment period of a double-blind trial (Trial 331-102-00088), 
and to explore the efficacy of extended treatment with 
brexpiprazole. 
Trial design: 
Multicenter, uncontrolled, open-label 
Subject population: 
A total of 157 male and female patients with agitation 
associated with dementia of the Alzheimer’s type who have 
completed the 10-week treatment period of Trial 331-102-
00088 and whose condition can be observed by a caregiver in 
at least 4 days per week for 4 hours or more a day. 
Inclusion/exclusion 
criteria: 
The main inclusion criteria are as follows: 
 Patients who have completed the 10-week treatment period 
of Trial 331-102-00088, as well as all observations, tests, 
and assessments at Week 10. 
 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 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). 
The main exclusion criteria are as follows: 
 Patients who experienced any serious adverse events 
(SAEs) that were judged to be related to the investigational 
medicinal product (IMP) by the investigator or 
subinvestigator in Trial 331-102-00088. 


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 Patients who experienced episodes of delirium during Trial 
331-102-00088. 
 Patients who had clinically significant nervous, hepatic, 
renal, metabolic, immunological, hematological, 
cardiovascular, pulmonary, or digestive abnormalities 
during Trial 331-102-00088. 
Trial sites: 
Approximately 120 sites in Japan 
Investigational 
medicinal products, 
dose, dosage regimen, 
treatment period, 
formulation, mode of 
administration: 
Brexpiprazole will be administered orally as one tablet once a 
day for 14 weeks. IMP administration will be initiated at 
0.5 mg, and 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). However, if the investigator or subinvestigator 
judges that dose increase is difficult for safety reasons, the dose 
may be maintained at 1 mg. After Week 2 (Day 15), the dose 
may be reduced or increased to 1 or 2 mg if the investigator or 
subinvestigator decides that dose adjustment is necessary. 
Trial assessments: 
Safety: adverse events, laboratory tests, 12-lead 
electrocardiogram, vital signs, body weight, physical 
examination, pregnancy test, Drug-Induced Extrapyramidal 
Symptoms Scale (DIEPSS), Abnormal Involuntary Movement 
Scale (AIMS), Barnes Akathisia Rating Scale (BARS), and 
Sheehan Suicidality Tracking Scale (S-STS) 
Efficacy: Cohen-Mansfield Agitation Inventory (CMAI), 
Neuropsychiatric Inventory, Clinical Global Impression–
Severity of Illness (CGI-S), CGI–Global Improvement (CGI-I) 
Other tests: Mini-Mental State Examination and Alzheimer's 
Disease Cooperative Study–Activities of Daily Living 
Criteria for evaluation: 
Safety endpoints: adverse events, laboratory tests, 12-lead 
electrocardiogram, vital signs, body weight, physical 
examination, pregnancy test, DIEPSS, AIMS, BARS, and S-
STS 
Efficacy endpoints: CMAI total score, CGI-S, CGI-I, 
 
Statistical methods: 
Safety analysis: 
The incidence of adverse events occurring after initiation of 
IMP administration (treatment-emergent adverse events 
[TEAEs]) will be determined. 
Descriptive statistics of actual measurements and changes from 
baseline at each time point and the final assessment (Week 14 
last observation carried forward [LOCF]) will be calculated. 


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Efficacy Analysis: 
Descriptive statistics of actual measurements and changes from 
baseline at each time point and the final assessment (Week 14 
LOCF) will be calculated. 
Rationale for setting the target sample size: 
This trial aims to include 100 completers of brexpiprazole 
treatment from Trial 331-102-00088 as subjects who will 
continue to receive brexpiprazole for more than 10 weeks. 
Since patients are assigned to the 1 mg group, the 2 mg group, 
or the placebo group at a ratio of 3:4:4 in Trial 331-102-00088, 
the target sample size for this trial (331-102-00184) has been 
determined to be 157 subjects, taking into account the fact that 
some of them would have received placebo in the previous 
trial. 
Trial duration: 
November 2018 to February 2022 (planned) 
The duration of participation in the trial by each subject will be 
up to 20 weeks. 
 
 


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Table of Contents 
Protocol Synopsis ........................................................................................... 2 
Table of Contents ........................................................................................... 5 
List of In-text Tables ................................................................................... 10 
List of In-text Figures .................................................................................. 11 
List of Appendices........................................................................................ 12 
List of Abbreviations and Definitions of Terms ....................................... 13 
1 
Introduction .......................................................................................................15 
1.1 
Background .....................................................................................................15 
1.2 
Nonclinical Data .............................................................................................17 
1.3 
Clinical Data ...................................................................................................18 
1.3.1 
 ..................................................................................18 
1.3.1.1 
.......................................................................................18 
1.3.1.2 
 .......................................................................................20 
1.3.1.3 
 ......................................................................................20 
1.3.2 
 .......................................................................................22 
1.4 
Known and Potential Risks and Benefits........................................................23 
2 
Trial Rationale and Objectives ..........................................................................24 
2.1 
Trial Rationale ................................................................................................24 
2.2 
Trial Objectives ..............................................................................................26 
3 
Trial Design .......................................................................................................26 
3.1 
Type/Design of Trial .......................................................................................26 
3.2 
Trial Treatments ..............................................................................................27 
3.2.1 
Dosing, Regimen, and Duration of Treatment ............................................27 
3.2.2 
Rationale for Dosing and Regimen .............................................................28 
3.2.3 
Rationale for Duration of Treatment ...........................................................29 
3.3 
Trial Population ..............................................................................................29 
3.3.1 
Number of Subjects and Trial Population ...................................................29 
3.3.2 
Subject Number Assignment ......................................................................30 
3.4 
Eligibility Criteria ...........................................................................................30 


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3.4.1 
Informed Consent ........................................................................................30 
3.4.2 
Inclusion Criteria .........................................................................................31 
3.4.3 
Exclusion Criteria........................................................................................32 
3.5 
Requirements for Caregivers ..........................................................................33 
3.6 
Endpoints ........................................................................................................34 
3.6.1 
Safety Endpoints .........................................................................................34 
3.6.2 
Efficacy endpoints .......................................................................................35 
3.6.3 
Other Endpoints ..........................................................................................35 
3.7 
Measures to Minimize/Avoid Bias .................................................................35 
3.8 
Trial Procedures ..............................................................................................35 
3.8.1 
Schedule of Assessments ............................................................................38 
3.8.1.1 
Date of Informed Consent .......................................................................38 
3.8.1.2 
Day of Baseline Assessment ...................................................................39 
3.8.1.3 
Environment Investigation (Day of Baseline Evaluation to Week 
14 [Day 99]) ............................................................................................40 
3.8.1.4 
Seven Days After Administration (Week 1 [Day 8]) to 98 Days 
After Administration (Week 14 [Day 99]) ..............................................40 
3.8.1.5 
Examination at Discontinuation ..............................................................40 
3.8.1.6 
Follow-up Observation (Twenty-eight Days After Completion or 
Discontinuation of IMP Administration) .................................................41 
3.8.2 
Safety Assessments .....................................................................................41 
3.8.2.1 
Adverse Events ........................................................................................41 
3.8.2.2 
Clinical Laboratory Assessments ............................................................41 
3.8.2.3 
Physical Examination ..............................................................................42 
3.8.2.4 
Vital Signs (Blood Pressure and Pulse Rate) ..........................................42 
3.8.2.5 
Body Weight ............................................................................................43 
3.8.2.6 
Twelve-lead Electrocardiography ...........................................................43 
3.8.2.7 
Pregnancy Test ........................................................................................44 
3.8.2.8 
Other Safety Assessments .......................................................................44 
3.8.2.8.1 
Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) ................44 
3.8.2.8.2 
Abnormal Involuntary Movement Scale (AIMS) ................................44 
3.8.2.8.3 
Barnes Akathisia Rating Scale (BARS) ...............................................45 
3.8.2.8.4 
Sheehan Suicidality Tracking Scale (S-STS) ......................................45 


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3.8.3 
Efficacy Assessments ..................................................................................45 
3.8.3.1 
Cohen-Mansfield Agitation Inventory (CMAI) ......................................45 
3.8.3.2 
Clinical Global Impression–Severity of Illness (CGI-S) .........................46 
3.8.3.3 
Clinical Global Impression–Global Improvement (CGI-I) .....................46 
3.8.3.4 
..........................................................46 
3.8.3.5 
 ...........................................46 
3.8.4 
Other Endpoints ..........................................................................................47 
3.8.4.1 
Alzheimer's Disease Cooperative Study–Activities of Daily Living 
(ADCS-ADL) ..........................................................................................47 
3.8.4.2 
Mini-Mental State Examination (MMSE) ...............................................47 
3.8.5 
Concomitant Medications and Therapies ....................................................47 
3.8.6 
End of Trial .................................................................................................48 
3.8.7 
Independent Data Monitoring Committee (IDMC) ....................................48 
3.8.8 
Raters...........................................................................................................48 
3.9 
Stopping Rules, Withdrawal Criteria, and Procedures ...................................49 
3.9.1 
Entire Trial ..................................................................................................49 
3.9.2 
Individual Site .............................................................................................49 
3.9.3 
Individual Subject Discontinuation .............................................................49 
3.9.3.1 
Treatment Discontinuation ......................................................................49 
3.9.3.2 
Documenting Reasons for Discontinuation .............................................49 
3.9.3.3 
Withdrawal of Consent ............................................................................51 
3.9.3.4 
Procedures to Encourage Continued Trial Participation .........................52 
3.10 
Screen Failures ................................................................................................52 
3.11 
Definition of Completed Subjects ..................................................................53 
3.12 
Definition of Subjects Lost to Follow-up .......................................................53 
3.13 
Subject Compliance ........................................................................................53 
3.14 
Protocol Deviations ........................................................................................54 
4 
Restrictions ........................................................................................................54 
4.1 
Prohibited Medications ...................................................................................54 
4.2 
Restricted Medications ...................................................................................55 
4.3 
Other Restrictions ...........................................................................................56 


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Reporting of Adverse Events ............................................................................56 
5.1 
Definitions ......................................................................................................56 
5.2 
Eliciting and Reporting Adverse Events .........................................................58 
5.3 
Immediately Reportable Events ......................................................................59 
5.4 
Potential Drug-induced Liver Injury ..............................................................59 
5.5 
Pregnancy .......................................................................................................59 
5.6 
Procedure for Breaking the Blind ...................................................................61 
5.7 
Follow-up of Adverse Events .........................................................................61 
5.7.1 
Follow-up of Nonserious Adverse Events ..................................................61 
5.7.2 
Follow-up of Serious Adverse Events and Immediately Reportable 
Events ..........................................................................................................61 
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)............................................................................................62 
6 
Statistical Analysis ............................................................................................62 
6.1 
Determination of Sample Size ........................................................................62 
6.2 
Datasets for Analysis ......................................................................................62 
6.2.1 
Efficacy Analysis Set ..................................................................................63 
6.2.2 
Safety Analysis Set .....................................................................................63 
6.3 
Handling of Missing Data ...............................................................................63 
6.4 
Efficacy Endpoint Analyses ...........................................................................63 
6.4.1 
Interim Analysis ..........................................................................................64 
6.5 
Analysis of Demographic and Baseline Characteristics .................................64 
6.6 
Safety Analysis ...............................................................................................64 
6.6.1 
Adverse Events............................................................................................64 
6.6.2 
Clinical Laboratory Data .............................................................................65 
6.6.3 
Physical Examination and Vital Signs Data................................................65 
6.6.4 
Electrocardiogram Data ..............................................................................65 
6.6.5 
Other Safety Data ........................................................................................66 
6.6.5.1 
Body Weight and Body Mass Index ........................................................66 
6.6.5.2 
DIEPSS, AIMS, and BARS .....................................................................66 
6.6.5.3 
S-STS .......................................................................................................66 
6.7 
Analysis of Other Endpoints ...........................................................................66 


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Management of Investigational Medicinal Product ..........................................66 
7.1 
Packaging and Labeling ..................................................................................66 
7.2 
Storage ............................................................................................................67 
7.3 
Accountability .................................................................................................67 
7.4 
Returns and Destruction .................................................................................67 
7.5 
Reporting of Product Quality Complaints ......................................................67 
7.5.1 
Eliciting and Reporting Product Quality Complaints .................................68 
7.5.2 
Information Required for Reporting Product Quality Complaints .............68 
7.5.3 
Return Process for Product Quality Complaints .........................................68 
7.5.4 
Assessment/Evaluation ...............................................................................68 
8 
Records Management ........................................................................................69 
8.1 
Source Documents ..........................................................................................69 
8.2 
Data Collection ...............................................................................................69 
8.3 
File Management at the Trial Site ..................................................................70 
8.4 
Record Retention at the Trial Site ..................................................................70 
9 
Quality Control and Quality Assurance ............................................................71 
9.1 
Monitoring ......................................................................................................71 
9.2 
Auditing ..........................................................................................................71 
10 
Ethics and Responsibility ..................................................................................71 
11 
Confidentiality ...................................................................................................71 
12 
Amendment Policy ............................................................................................72 
13 
Publication Authorship Requirements...............................................................72 
14 
References .........................................................................................................73 
 


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List of In-text Tables 
Table 1.3.1.1-1 
 ........................................... 18 
Table 1.3.1.2-1 
......................................................................... 20 
Table 3.2.1-1 
Doses of IMP ................................................................................ 28 
Table 3.4.2-1 
Inclusion Criteria .......................................................................... 31 
Table 3.4.3-1 
Exclusion Criteria ......................................................................... 32 
Table 3.8-1 
Schedule of Assessments .............................................................. 36 
Table 3.8-2 
Allowable Time Windows for Evaluations, Tests, and 
Observations ................................................................................. 38 
Table 3.8.2.2-1 
Clinical Laboratory Assessments .................................................. 42 
Table 3.8.8-1 
Raters of Evaluation Scales .......................................................... 48 
Table 4.1-1 
Prohibited Medications ................................................................. 54 
Table 4.1-2 
Prohibited Concomitant CYP2D6 Inhibitors, CYP3A4 
Inhibitors, and CYP3A4 Inducers (Except for External Use)....... 55 
Table 4.2-1 
Restricted Medications.................................................................. 55 
 
 


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List of In-text Figures 
Figure 3.1-1 
Trial Design .................................................................................. 27 
 
 


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List of Appendices 
Appendix 1 
Protocol Amendments/Administrative Changes ........................... 76 
 


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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 
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 
CPK 
Creatine phosphokinase 
CYP 
Cytochrome P450 
D2 
Dopamine D2 
DIEPSS 
Drug-Induced Extrapyramidal Symptoms Scale 
GCP 
Good Clinical Practice 
HbA1c 
Glycosylated hemoglobin 
HCG 
Human chorionic gonadotropin 
HDL 
High-density lipoprotein 
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 
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 
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 
 
 


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Abbreviation 
Definition 
 
 
 
 
 
 
 
 
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 
S-STS 
Sheehan Suicidality Tracking Scale 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limits of normal 
γ-GTP 
γ-Glutamyl transpeptidase 
 


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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 


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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. 
 


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. 
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 a double-blind 
trial (331-102-00088) in Japan ahead of this trial. Trial 331-102-00088 is intended 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 
Japanese patients, to investigate the safety of brexpiprazole, and to identify the optimum 
dose. In real-world clinical settings, however, a certain proportion of patients with 
dementia of the Alzheimer’s type are receiving antipsychotics for more than 10 weeks,20 
which is the treatment duration in Trial 331-102-00088. Given this fact, Otsuka 
considered it necessary to provide safety data on brexpiprazole when administered for 
more than 10 weeks and planned this clinical trial to evaluate the safety and efficacy of 
brexpiprazole when given for more than 10 weeks. 
1.2 
Nonclinical Data 
 


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1.3 
Clinical Data 
1.3.1 
 
1.3.1.1 
 
 
 
Table 1.3.1.1-1 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1.3.1.1-1 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.3.1.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.3.1.3 
 


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1.3.2 
 
 
 
 


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. 
1.4 
Known and Potential Risks and Benefits 
. 


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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, 


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is expected to improve agitation in patients with dementia of the Alzheimer’s type while 
suppressing expression of extrapyramidal symptoms. 
In Trial 331-102-00088 in Japanese patients with agitation associated with dementia of 
the Alzheimer’s type, which is scheduled to be conducted ahead of this trial, the 
superiority of brexpiprazole 1 or 2 mg over placebo after a 10-week treatment regimen 
will be evaluated, the safety of brexpiprazole will be investigated, and the optimum dose 
will be determined. Given that the Practice Guideline for Dementia 2017 states17 that 
atypical antipsychotics “should not be continued without a compelling reason even if 
their efficacy is recognized, and appropriate dose reduction or temporary cessation in 
response to symptom improvement should be considered to reduce the incidence of 
adverse drug reactions,” it is considered that brexpiprazole will not be used for long-term 
maintenance therapy after improvement of symptoms. Therefore, brexpiprazole does not 
fall under the group of drugs that need to be evaluated for long-term administration as 
specified in “Regarding the Extent of Population Exposure to Assess Clinical Safety for 
Drugs Intended for Long-Term Treatment of Non-Life-Threatening Conditions” 
(Yakushin Notification No. 592 dated 24 May 1995). In real-world clinical settings, 
however, a certain proportion of patients with dementia of the Alzheimer’s type are 
receiving antipsychotics for more than 3 months.20 When an additional indication of 
brexpiprazole is approved, the drug may possibly be administered to patients for longer 
than the treatment period of 10 weeks used in Trial 331-102-00088. Otsuka therefore 
decided to provide safety data on brexpiprazole when administered for longer than 10 
weeks. This trial will enroll subjects rolled over from Trial 331-102-00088, and the safety 
of brexpiprazole when administered for a maximum of 24 weeks (including the treatment 
period of Trial 331-102-00088) will be evaluated. The trial will also explore the efficacy 
of brexpiprazole. The dose level of brexpiprazole in the trial will be up to 2 mg, the 
maximum dose used in Trial 331-102-00088, and may be reduced or increased to 1 or 
2 mg, both of which are doses used in Trial 331-102-00088, depending on the subject’s 
condition. 
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 disorders, 
cardiac disorders, pneumonia, and other infections, which were the causes of death 
associated with atypical antipsychotics, are in place to minimize the risk to subjects 
during the trial. In addition, to ensure subject safety, the Independent Data Monitoring 
Committee (IDMC) established in Trial 331-102-00088 will monitor subject safety 
during this trial (331-102-00184) as well. 


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On the basis of what has been described above, the conduct of this trial was judged to be 
scientifically and ethically justifiable. 
2.2 
Trial Objectives 
The objective of the trial is to evaluate the safety of brexpiprazole 1 or 2 mg administered 
for 14 weeks in patients with agitation associated with dementia of Alzheimer’s type who 
have completed the treatment period of a double-blind trial (Trial 331-102-00088), and to 
explore the efficacy of extended treatment with brexpiprazole. 
3 
Trial Design 
3.1 
Type/Design of Trial 
This is a multicenter, uncontrolled, open-label 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 prospective subjects 
(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 main caregivers using the 
explanatory materials and informed consent form (ICF) and obtain written consent for 
participation in the trial from the prospective subjects (or their legally acceptable 
representatives) and caregivers during Trial 331-102-00088 between the dates of 
evaluation at Week 4 and Week 10. The investigator or subinvestigator will assess the 
eligibility of subjects to participate in the trial based on observations, tests, and 
investigations performed during the treatment period of Trial 331-102-00088. All 
subjects judged to be eligible based on the results of observations, tests, and 
investigations in Trial 331-102-00088 will skip the follow-up observation of Trial 331-
102-00088 and be rolled over into the treatment period of this trial (331-102-00084). 
Subjects will receive brexpiprazole for 14 weeks, starting at 0.5 mg, followed by dose 
titration, and then at either 1 or 2 mg, according to Section 3.2 Trial Treatments, and will 
undergo periodic observation, tests, and investigations to assess efficacy and safety. IMP 
administration will begin no later than 10 days after the date of evaluation at Week 10 of 
Trial 331-102-00088. The subject will return to the trial site 28 days after the completion 


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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 for each subject is from completion of evaluation at Week 10 of Trial 
331-102-0008 to the end of follow-up observation. 
 
Figure 3.1-1 
Trial Design 
Double-blind trial = Trial 331-102-00088, Extension trial = Trial 331-102-00184, Brex = brexpiprazole, 
BL = baseline 
 
3.2 
Trial Treatments 
3.2.1 
Dosing, Regimen, and Duration of Treatment 
Brexpiprazole will be administered orally as one tablet once a day for 14 weeks. 
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. The 
IMP doses are shown in Table 3.2.1-1. IMP administration will be initiated at 0.5 mg and 
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). If the investigator or subinvestigator judges that dose 
increase to 2 mg is difficult for safety reasons based on the subject’s condition after 
evaluation at Week 2 (Day 15), the dose may be maintained at 1 mg (see Section 3.2.1 1) 
Dose Maintenance at 1 mg). From Week 2 (Day 15), the dose may be reduced or 
increased to 1 or 2 mg if the investigator or subinvestigator decides that dose adjustment 
is necessary (see Section 3.2.1 2) Dose Change). In cases where dose reduction to lower 
than 1 mg is required, the trial should be discontinued. 
Trial 331-102-00088
Informed consent
Day 28
up to 10 days
Treatment period
Trial 331-102-00184
Screening period
Brex：0.5 mg
Brex: 1 or 2 mg
Brex：1 mg
1 week
Follow-up
period
1 week
Dose adjustment as appropriate
Double-blind trial
Week 10
(BL of extension trial)
Double-blind trial
Week 4
Start of IMP 
administration
(Day 1)
Week 1
(Day 8)
Week 2
(Day 15)
Week 14
(Day 99)


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Table 3.2.1-1 
Doses of IMP 
Day 1–7 
Day 8–14 
Day 15–98 
0.5 mg 
1 mg 
1 or 2 mg 
 
1) Dose Maintenance at 1 mg 
If the investigator or subinvestigator decides that dose increase to 2 mg is difficult 
due to the occurrence of an AE identified from the evaluation at Week 2 (Day 15), the 
dose will be maintained at 1 mg. The AE for which this judgement was made will be 
recorded in the case report form (CRF). 
2) Dose Change 
If the investigator or subinvestigator decides that dose adjustment is necessary based 
on the subject’s condition, the dose will be reduced or increased to 1 or 2 mg. 
If the investigator or subinvestigator decides that the current dose is not sufficiently 
effective, the dose will be increased to 2 mg. If either of the following cases applies, 
the dose will be reduced to 1 mg and the reason for dose reduction will be recorded in 
the CRF. In the event that both of the following cases apply, the AE should be 
recorded as the reason for dose reduction. When the occurrence of an AE necessitates 
dose reduction, enter “dose reduction” in the CRF as the action taken for the AE in 
relation to IMP administration. 
 The dose may be reduced to 1 mg in the following cases: 
 Dose reduction is necessary because an AE has occurred. 
 Dose reduction is necessary because symptoms have improved. 
 
3.2.2 
Rationale for Dosing and Regimen 
Since this is an extension trial following Trial 331-102-00088, Otsuka considered it 
appropriate to administer brexpiprazole within the dose range used in Trial 331-102-
00088 and selected 0.5, 1, and 2 mg for this trial. 
As the subjects who were assigned to placebo in Trial 331-102-00088 were not exposed 
to brexpiprazole in that trial, for those subjects the dose of brexpiprazole in this trial 
needs to be titrated from a lower dose. Therefore, for all subjects in the current trial, the 
starting dose will be 0.5 mg, the same level as in Trial 331-102-00088, and the dose will 
be increased to 1 mg after 1 week (after evaluation at Week 1 [Day 8]) and to 2 mg after 
2 weeks (after evaluation at Week 2 [Day 15]). In view of the fact that in clinical settings, 
pharmacotherapy for agitation is administered with caution due to the risk of AEs,17 


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maintaining the dose at 1 mg instead of increasing it to 2 mg after 2 weeks (after 
evaluation at Week 2 [Day 15]) will be permitted when dose increase to 2 mg is 
considered difficult for safety reasons. After Week 2 (Day 15), dose adjustment to either 
1 or 2 mg will be permitted if the investigator or subinvestigator finds it necessary based 
on the subject’s condition. 
The regimen is oral administration once daily as in Trial 331-102-00088. 
3.2.3 
Rationale for Duration of Treatment 
Given that the Practice Guideline for Dementia 2017 states17 that atypical antipsychotics 
“should not be continued without a compelling reason even if their efficacy is recognized, 
and appropriate dose reduction or temporary cessation in response to symptom 
improvement should be considered to reduce the incidence of adverse drug reactions,” it 
is considered that brexpiprazole will not be used for long-term maintenance therapy after 
improvement of symptoms. Therefore, brexpiprazole does not fall under the group of 
drugs that need to be evaluated for long-term administration as specified in “Regarding 
the Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-
Term Treatment of Non-Life-Threatening Conditions” (Yakushin Notification No. 592 
dated 24 May 1995). In real-world clinical settings, however, a certain proportion of 
patients with dementia of the Alzheimer’s type seems to have no other choice but to stay 
on antipsychotics for more than 10 weeks, the treatment period used in Trial 331-102-
00088. According to “Medical fee claim results for antipsychotics prescribed to patients 
with Alzheimer’s disease during the 3 years between January 2015 and December 2017” 
generated by the MDV Analyzer system (Medical Data Vision Co., Ltd.), the prescription 
duration is 180 days or less for 85.2% of patients receiving typical antipsychotics. With 
all the above considered, Otsuka has decided to evaluate in this trial the safety of 
brexpiprazole when administered for more than 10 weeks, with a maximum of 24 weeks, 
in subjects who have completed the treatment period of Trial 331-102-00088. 
3.3 
Trial Population 
3.3.1 
Number of Subjects and Trial Population 
A total of 157 male and female patients with agitation associated with dementia of the 
Alzheimer’s type who have completed the treatment period of Trial 331-102-00088 and 
whose condition can be observed by a caregiver in at least 4 days per week for 4 hours or 
more a day. 


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3.3.2 
Subject Number Assignment 
 
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 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) Guideline23 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 


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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 
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). 
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, along with their caregivers, 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 have completed the 10-week treatment period of Trial 331-102-00088, as well as 
all observations, tests, and assessments at Week 10. 
3 
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. 
4 
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). 
 
[Rationale for inclusion criteria] 
1 This criterion is specified for ethical considerations. 
2 This criterion is specified to identify the patients suitable for this trial. 
3 and 4 These criteria are specified for the appropriate assessment of the safety of 
brexpiprazole. 
 


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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 experienced SAEs that were judged to be related to the IMP by the investigator or 
subinvestigator in Trial 331-102-00088. 
2 
Patients who experienced episodes of delirium during Trial 331-102-00088. 
3 
Patients who had clinically significant nervous, hepatic, renal, metabolic, immunological, 
hematological, cardiovascular, pulmonary, or digestive abnormalities during Trial 331-102-
00088. 
4 
Patients with psychological symptoms or behavioral problems clearly due to other diseases or a 
drug substance. 
5 
Patients who had a stroke, transient ischemic attack, or pulmonary embolism during Trial 331-
102-00088. 
6 
Patients who had heart failure of New York Heart Association Class III or higher during Trial 
331-102-00088. 
7 
Patients who received pharmacological therapy for arrhythmia or ischemic heart disease during 
Trial 331-102-00088, not including patients for whom the investigator or subinvestigator judges 
pharmacological therapy to be the primary prevention of ischemic heart disease. 
8 
Patients whose QTcF values (based on central laboratory or mechanical reading) at Week 10 of 
Trial 331-102-00088 meet the criteria below. If mechanically read QTcF values meet the 
criteria, 2 ECG examinations should be additionally performed, and at least 1 of these 2 
measurements must meet the criteria. 
 
Men: ≥ 450 msec; women: ≥ 470 msec 
9 
Patients with the following abnormal laboratory test values at Week 10 of Trial 331-102-00088 
(assessed on the basis of the results from the central or local 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 
10 
Patients who required insulin treatment during Trial 331-102-00088. 
11 
Patients whose laboratory test results at evaluation at Week 10 of Trial 331-102-00088 meet 
either of the following criteria for poor blood glucose control (assessed on the basis of the 
results from the central or local 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 
12 
Patients who had neuroleptic malignant syndrome, tardive dyskinesia, paralytic ileus, or 
rhabdomyolysis during Trial 331-102-00088. 
13 
Patients who had convulsive disorders (eg, epilepsy) in Trial 331-102-00088, not including 
patients with febrile seizure, post-traumatic seizure, or alcohol withdrawal seizure. 
14 
Patients who are unable to take oral medication due to severe dysphagia. 


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Table 3.4.3-1 
Exclusion Criteria 
15 
Patients whose Sheehan Suicidality Tracking Scale (S-STS) score in Trial 331-102-00088 
meets 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 
16 
Patients whose body weight at evaluation at Week 10 of Trial 331-102-00088 was < 30 kg. 
17 
Patients whose body weight had fallen by ≥ 7% at Week 10 from baseline in Trial 331-102-
00088. 
18 
Patients who were confirmed to meet the following contraindications in the package insert of 
REXULTI® during Trial 331-102-00088: 
 
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® 
19 
Patients who are bedridden and require assistance for excretion, eating, and changing clothes 
20 
Women who had a positive pregnancy test result at Week 10 of Trial 331-102-00088 (women 
of childbearing potential only) 
21 
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. 
22 
Patients who otherwise were judged by the investigator or subinvestigator to be unsuitable for 
extended treatment with brexpiprazole. 
 
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. 
[Rationale for the exclusion criteria] 
1 to 19 These criteria are specified in view of safety. 
20, 21 These criteria are specified in consideration of safety, as the safety of 
brexpiprazole during pregnancy or while breastfeeding has not yet been established. 
22 This criterion is specified for the appropriate assessment of safety and efficacy. 
 
3.5 
Requirements for Caregivers 
A caregiver who meets the following criteria will be designated as the main caregiver in 
the trial: 


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 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, until 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. 
If the main caregiver is unable to respond to queries, a substitute caregiver is allowed to 
respond to queries on the trial evaluation items. A substitute caregiver should be able to 
obtain basic 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. Patient information required for evaluations should be 
collected until the end of follow-up observation period, which is 28 days after the 
completion or discontinuation of IMP administration. Queries at the end of follow-up 
observation period will be answered not only by the main caregiver but also by caregivers 
who are in charge of the patient’s care and able to provide the patient information 
required for evaluations. 
In the event that replacement of the main caregiver is required during the trial period due 
to a change in the patient care environment or for other reasons, a caregiver who is able 
to provide the patient information required for evaluations in response to queries 
regarding the trial evaluation items will be selected as the new main caregiver. The new 
main caregiver must also be able to observe the patient’s condition in at least 4 days per 
week for 4 hours or more a day. 
3.6 
Endpoints 
3.6.1 
Safety Endpoints 
 Adverse events 
 Physical examinations 
 Laboratory tests 
 Vital signs 
 Body weight 


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 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) 
 
3.6.2 
Efficacy endpoints 
 CMAI total score 
 Clinical Global Impression–Severity of Illness (CGI-S) 
 Clinical Global Impression–Global Improvement (CGI-I) 
 
 
 
 
 
 
 
3.6.3 
Other Endpoints 
 Alzheimer's Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) 
 Mini-Mental State Examination (MMSE) 
 
3.7 
Measures to Minimize/Avoid Bias 
This is an uncontrolled trial. 
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. 
 


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Table 3.8-1 
Schedule of Assessments 
Item 
Screening Period 
Treatment Period 
Follow-up 
Period 
Baseline evaluationa 
Week 1 
(Day 8) 
Week 2 
(Day 15) 
Week 4 
 (Day 29) 
Week 6 
(Day 43) 
Week 8 
 (Day 57) 
Week 10 
(Day 71) 
Week 12 
(Day 85) 
Week 14 
(Day 99) 
At  
discontinu- 
ation 
28 days after  
completion/ 
discontinuation 
Informed consent 
From Week 4 of 
Trial 331-102-00088 
 
 
 
 
 
 
 
 
 
Subject background 
information 
● 
 
 
 
 
 
 
 
 
 
Environment investigation 
 
 
Subject diary 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
● 
 
 
 
 
 
 
 
 
 
Compliance status 
 
● 
● 
● 
● 
● 
● 
● 
● 
 
Safety endpoints 
 
Adverse events 
 
Confirmation of 
medications and therapies 
 
Height 
△ 
 
 
 
 
 
 
 
 
 
Body weight 
△ 
 
 
 
● 
 
 
 
● 
 
Physical examination 
△ 
● 
● 
● 
● 
● 
● 
● 
● 
 
Laboratory tests 
△ 
 
 
● 
 
 
● 
 
● 
 
Vital signs 
△ 
● 
● 
● 
● 
● 
● 
● 
● 
 
12-lead ECG 
△ 
 
● 
● 
 
 
● 
 
● 
 
Pregnancy testb 
△ 
 
 
 
 
 
 
 
● 
 
DIEPSS 
△ 
● 
● 
● 
● 
 
● 
 
● 
● 
AIMS 
△ 
 
 
 
 
 
 
 
● 
● 
BARS 
△ 
 
 
 
 
 
 
 
● 
● 
S-STS 
△ 
 
 
● 
 
 
 
 
● 
 


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Table 3.8-1 
Schedule of Assessments 
Item 
Screening Period 
Treatment Period 
Follow-up 
Period 
Baseline evaluationa 
Week 1 
(Day 8) 
Week 2 
(Day 15) 
Week 4 
 (Day 29) 
Week 6 
(Day 43) 
Week 8 
 (Day 57) 
Week 10 
(Day 71) 
Week 12 
(Day 85) 
Week 14 
(Day 99) 
At  
discontinu- 
ation 
28 days after  
completion/ 
discontinuation 
Efficacy endpoints 
 
CMAI 
△ 
 
 
● 
 
 
 
 
● 
 
CGI-S 
△ 
 
● 
● 
● 
 
● 
 
● 
 
CGI-I 
 
 
● 
● 
● 
 
● 
 
● 
 
 
△ 
 
 
● 
 
 
 
 
● 
 
 
△ 
 
 
● 
 
 
 
 
● 
 
Other endpoints 
 
ADCS-ADL 
△ 
 
 
 
 
 
 
 
● 
● 
MMSE 
△ 
 
 
 
 
 
 
 
● 
● 
The date of starting IMP administration is designated as Day 1. IMP administration will begin no later than 10 days after the date of evaluation at Week 10 of 
Trial 331-102-00088. 
△ The results of evaluation at Week 10 of Trial 331-102-00088 will be used except for height, for which the data obtained at screening of Trial 331-102-
00088 will be used. 
aThe date of evaluation at Week 10 of Trial 331-102-00088 will be the date of baseline evaluation in this trial. 
bPregnancy test (human chorionic gonadotropin [HCG] test) will be performed for WOCBP only. If urinary test is positive, serum test will be performed. 
c
 
d
 
 


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Table 3.8-2 
Allowable Time Windows for Evaluations, Tests, and 
Observations 
Test Point 
Base Date 
Allowable Time Window From 
the Base Date 
Baseline evaluation date 
(at evaluation at Week 10 of Trial 
331-102-00088) 
Baseline evaluation date 
Day −9 to 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 74 
Week 12 
Day 85 
Day 82 to Day 88 
Week 14 
Day 99 
Day 96 to Day 106 
Follow-up period 
28 days after the final 
administration of IMP 
23 to 35 days after the final 
administration of IMP 
The date of starting IMP administration is designated as Day 1, and the day before initiation of IMP 
treatment is designated as Day −1. 
 
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 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 Safety Assessments to Section 3.8.4 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 
Date of Informed Consent 
The investigator or subinvestigator will obtain informed consent from prospective 
subjects (or their legally acceptable representatives) between the date of evaluation at 
Week 4 and the date of evaluation at Week 10 (both dates inclusive) of Trial 331-102-
00088. The investigator or subinvestigator will also explain the details of the trial to the 
caregivers of prospective subjects by using explanatory materials designed for caregivers 
and obtain their written informed consent to cooperate in the trial. Following the 
provision of informed consent, the subject will be assigned the same subject ID as in 


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Trial 331-102-00088 and will be registered in the IWRS. The investigator or 
subinvestigator will record the following information. 
 Subject ID 
 Date of informed consent by the subject (or their legally acceptable representatives) 
and caregivers 
 
3.8.1.2 
Day of Baseline Assessment 
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 review the observations, tests, and assessments performed in Trial 331-102-00088 
and record the following: 
 Date of visit 
 Subject background information 
 Sex, date of birth, race, ethnicity, and trial countrya 
 Possibility of getting pregnant in women of childbearing potential (WOCBP) (see 
Section 5.5 Pregnancy) (if there is no childbearing potential, record the reason)a 
 Diagnosis of dementia of the Alzheimer’s type (diagnostic criteria of 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])a 
 Timepoint of onset of dementia of the Alzheimer’s typea 
 Timepoint of diagnosis of dementia of the Alzheimer’s typea 
 Timepoint of onset of agitation associated with dementia of the Alzheimer’s typea 
 Complicationsa 
 Medical historya 
 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) 
 Confirmation of eligibility 
 Prior use of antipsychotics (yes or no)a 
 Heighta 
aThe screening results of Trial 331-102-00088 will be used. 
 


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The investigator or subinvestigator will start administration of the IMP to subjects who 
are judged to be eligible and for whom registration in the IWRS has been completed. The 
investigator or subinvestigator will provide subjects with the IMP needed for the period 
up until the next assessment and give them instructions to bring any unused IMPs with 
them to the next assessment. 
3.8.1.3 
Environment Investigation (Day of Baseline Evaluation to Week 
14 [Day 99]) 
If there are any changes to the subject's environment from the time of registration, the 
investigator or subinvestigator will record the following. 
 Date of change 
 Medical care category (inpatient or outpatient; if outpatient, institutionalized or care 
at home) 
 Type of caregiver (hospital staff, care facility staff, family, or other) 
 
3.8.1.4 
Seven Days After Administration (Week 1 [Day 8]) to 98 Days 
After Administration (Week 14 [Day 99]) 
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. 
On each assessment day, the investigator or subinvestigator will provide subjects with the 
IMP needed for the period up until the next assessment and give them instructions to 
bring any unused IMPs with them to the next assessment. At visits 14 days after 
administration (Week 2 [Day 15]) and 84 days after administration (Week 12 [Day 85]), 
the investigator or subinvestigator will provide caregivers with a subject diary and give 
them instructions to complete the diary for 14 days before CMAI assessment and bring it 
with them to the next visit. 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). 
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. 


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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. 
3.8.2 
Safety Assessments 
Evaluation points for each item are shown in Table 3.8-1. 
3.8.2.1 
Adverse Events 
Refer to Section 5 Reporting of Adverse Events. 
3.8.2.2 
Clinical Laboratory Assessments 
In this trial, the clinical laboratory tests shown in Table 3.8.2.2-1 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 or local laboratory. If laboratory test values determined at the local laboratory are 
used for verification of subject eligibility, it must first be verified that quality control has 
been performed. If any of the test results provided by the central laboratory at a later date 
falls under the exclusion criteria, the subject will be withdrawn from the trial. For 
appropriate procedures for the collection, handling, and shipment of samples analyzed at 
the central laboratory, 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. 


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Table 3.8.2.2-1 
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) 
 
Endocrinology: 
Serum prolactin 
Insulin 
 
3.8.2.3 
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 baseline evaluation, all the physical findings obtained on the evaluation day will be 
recorded in the source document and CRF. In subsequent evaluations, only information 
on whether an observation was made or not and the 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. 
3.8.2.4 
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. The results, date and time 
of measurement will be recorded in the source document and CRF. If the subject 
complained of symptoms of orthostatic hypotension before evaluation, measurement 
should also be performed in the supine and standing positions, in so far as possible, in the 
order of the supine, sitting, and standing positions. 


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3.8.2.5 
Body Weight 
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 
(increments: 0.1 kg). 
3.8.2.6 
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. The subject’s 
eligibility will be determined on the basis of their centrally or mechanically read QTcF 
values. If eligibility judgment is based on the results of centrally read QTcF values, those 
subjects whose values at Week 10 of Trial 331-102-00088 meet the criteria (≥ 450 msec 
for men, ≥ 470 msec for women) will be excluded from the trial. If eligibility judgment is 
based on the results of mechanically read QTcF values, those subjects whose values at 
Week 10 of Trial 331-102-00088 meet the criteria (≥ 450 msec for men, ≥ 470 msec for 
women) will undergo 2 additional ECG examinations, and those with at least 1 of the 2 
QTcF measurements meeting the criteria will be excluded from the trial. If QTcF results 
provided by the central ECG laboratory at a later date fall under the discontinuation 
criteria, the subject will be withdrawn from the trial. In triplicate ECG examinations, a 
subject will be withdrawn from the trial if at least 2 of 3 QTcF measurements meet the 
discontinuation criteria. ECG examinations will be performed at appropriate intervals 
after the subject’s resting state is confirmed. 
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 


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laboratory to the sponsor as an electronic file, they do not need to be recorded in the 
source documents or the CRF. 
3.8.2.7 
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 Week 10 of Trial 
331-102-00088 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. 
3.8.2.8 
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. 
3.8.2.8.1 
Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) 
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 information regarding the 
subject's condition after the previous assessment. 
Nine items related to extrapyramidal symptoms: 
Gait, bradykinesia, sialorrhea, muscle rigidity, tremor, akathisia, dystonia, dyskinesia, 
and overall severity 
3.8.2.8.2 
Abnormal Involuntary Movement Scale (AIMS) 
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). 


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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” 
3.8.2.8.3 
Barnes Akathisia Rating Scale (BARS) 
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. 
3.8.2.8.4 
Sheehan Suicidality Tracking Scale (S-STS) 
By using S-STS, the investigator or subinvestigator will assess suicidal attempt and 
behavior during the period since the previous visit on the basis of 22 question items. 
3.8.3 
Efficacy Assessments 
The rater for each of the assessment items should refer to Section 3.8.8 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. 
3.8.3.1 
Cohen-Mansfield Agitation Inventory (CMAI) 
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 


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destroying property,” “performing repetitious mannerisms,” “making verbal sexual 
advances,” “making physical sexual advances,” and “general restlessness” 
3.8.3.2 
Clinical Global Impression–Severity of Illness (CGI-S) 
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. 
3.8.3.3 
Clinical Global Impression–Global Improvement (CGI-I) 
The rater will assess (by time point evaluation in comparison with the date of baseline 
evaluation of this trial) improvement of agitation associated with dementia of the 
Alzheimer’s type on an 8-point scale using the CGI-I. 
3.8.3.4 
 
 
 
 
 
3.8.3.5 
 


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. 
3.8.4 
Other Endpoints 
The rater for each of the assessment items should refer to Section 3.8.8 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. 
3.8.4.1 
Alzheimer's Disease Cooperative Study–Activities of Daily 
Living (ADCS-ADL) 
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 date. 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. 
3.8.4.2 
Mini-Mental State Examination (MMSE) 
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” 
3.8.5 
Concomitant Medications and Therapies 
The investigator or subinvestigator will investigate medications and therapies 
administered during the trial. 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. 


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3.8.6 
End of Trial 
The end-of-trial date is defined as the date of last visit or contact, or the date of final 
contact attempt as recorded on the follow-up page of the CRF prepared for the last 
subject completing or withdrawing from the trial. 
3.8.7 
Independent Data Monitoring Committee (IDMC) 
In order to avoid exposing subjects to any potential risks (including the risk of death) 
during the trial period and to ensure the safe conduct of the trial, the IDMC established in 
Trial 331-102-00088 will monitor the current trial (331-102-00184) as well. The IDMC 
will meet either regularly as specified in the protocol of Trial 331-102-00088 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. 
3.8.8 
Raters 
Table 3.8.8-1 shows persons who are authorized to evaluate each evaluation scale. While 
the CMAI, 
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. 
Evaluations using the CMAI, CGI-S, CGI-I, 
, DIEPSS, 
AIMS, BARS, S-STS, ADCS-ADL, and MMSE will be conducted by raters who have 
been trained for this trial. 
The investigator or subinvestigator will check how evaluations are being conducted and 
their content after receiving training for the trial. 
Table 3.8.8-1 
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 
○ 
 
 
 
 


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Table 3.8.8-1 
Raters of Evaluation Scales 
 
Investigator or 
Subinvestigator 
Clinical Psychologist 
(Including Clinical 
Psychological 
Technologist) 
Occupational 
Therapist 
Speech-
language-
Hearing 
Therapist 
Nurse 
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 
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. 
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 


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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 dose of brexpiprazole needs to be reduced to lower than 1 mg due to the 
occurrence of an AE. 
 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 is judged to be in 
need of prohibited drugs. 
 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 
 After initiation of IMP treatment, any of the following external test results at 
Week 10 of Trial 331-102-00088 are obtained: 
 QTcF on the basis of ECG results from the central ECG laboratory is 
≥ 450 msec in men or ≥ 470 msec in women (in triplicate ECG examinations, 
at least 2 measurements meet the criteria). 


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 Results from the central laboratory: 
 Platelet count: ≤ 75,000/mm3 
 Hemoglobin: ≤ 9 g/dL 
 Neutrophil count: ≤ 1000/mm3 
 AST and ALT: > 2 times ULN 
 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 
 HbA1c (NGSP): ≥ 8.0% 
 Fasting blood glucose level of ≥ 126 mg/dL or nonfasting blood glucose 
level of ≥ 200 mg/dL 
 
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. 


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 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 
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 who has given informed consent to participate in the trial 
and has signed the informed consent form, but who was not enrolled. 
For screen failures, the following information will be recorded in the CRF: 
 Subject ID 
 Date of informed consent 
 Date of visit 


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 Subject demographics (date of investigation, date of birth, sex, race, ethnicity, and 
country where trial is performed; all of these data are derived from the screening 
results of Trial 331-102-00088.) 
 Results of eligibility criteria assessment 
 Date of assessment as screen failure 
 Reason for screening failure 
 
3.11 
Definition of Completed Subjects 
The treatment period is defined as the time period during which subjects are evaluated for 
safety and efficacy (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 14 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-trial date 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 
The investigator or subinvestigator will appropriately instruct subjects and caregivers to 
comply with the protocol-defined provisions. 


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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, subject enrolled in violation of eligibility criteria or concomitant medication 
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 brexpiprazole are prohibited from the date of 
evaluation at Week 10 of Trial 331-102-00088 until completion of 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 
Remarks 
Antipsychotics 
 
 
Clozapine 
Brexpiprazole is prohibited until completion of 
follow-up observation 
 
Sustained release injections 
 
 
Brexpiprazole 
 
 
Other antipsychotics 
 
Antidepressants 
 
Mood stabilizers 
 
Psychostimulants 
 
Narcotic analgesics for agitation 
 
Yokukansan and other herbal medicines and 
supplements for treatment of BPSD 
 
Adrenaline 
 
Antiepileptic drugs 
 
Antiparkinson drugs 
 
Varenicline 
 
Benzodiazepines 
 
Belsomra 
 
Lemborexant 
 
Drugs (β-blockers) for extrapyramidal symptoms 
If administration is necessary due to AEs that occur 
after IMP administration, use will be permitted in 
accordance with the stipulations for restricted drugs. 


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Table 4.1-1 
Prohibited Medications 
Drug Type 
Remarks 
CYP2D6 inhibitors, CYP3A4 inhibitors and 
inducersa 
 
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 is permitted under the prescribed restrictions from 
completion of evaluation at Week 10 of Trial 331-102-00088 until completion of 
examinations scheduled at the completion or discontinuation of IMP administration. 
Table 4.2-1 
Restricted Medications 
Drug Type 
Restriction 
Antidementia 
drugs 
The continued use of these drugs from Trial 331-102-00088 is permitted if the dose and 
regimen have not been changed. 
Narcotic 
analgesics 
If not used for agitation (eg, pain control, tooth extraction), the use of these drugs is 
permitted. 
β-Blockers 
 
Treatment of complications (eg, cardiovascular diseases) other than psychiatric 
diseases 
The continued use of these drugs from Trial 331-102-00088 is permitted if the dose 
and regimen have not been changed. (Discontinuation or dose reduction is permitted 
only when these actions are necessary due to AEs caused by β-blockers or 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. 


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Table 4.2-1 
Restricted Medications 
Drug Type 
Restriction 
Hypnotics 
 
Ultra-short-acting nonbenzodiazepine hypnotics (zolpidem, zopiclone, eszopiclone), 
ramelteon 
The continued use of these drugs from Trial 331-102-00088 is permitted if the dose 
and regimen have not been changed. (Discontinuation and dose reduction are 
permitted only when these actions are necessary due to AEs caused by hypnotics or 
after remission of symptoms of insomnia.) 
 
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. 
 
4.3 
Other Restrictions 
is prohibited from completion of evaluation at 
Week 10 of Trial 331-102-00088 until completion of examinations scheduled at the 
completion or discontinuation of IMP administration. 
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 events recorded as 
complications at screening of Trial 331-102-00088 for which the underlying condition 
was known and no worsening occurred during this trial. In addition, events that were 
recorded as AEs before evaluation at Week 10 of Trial 331-102-00088 and did not 
worsen during this trial (331-102-00184) will not be deemed to be AEs in this trial. 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. 
 


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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 
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, 


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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. 
 
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 after evaluation at Week 10 of Trial 331-102-00088 until the end-of-trial date. 
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. 


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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 
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 


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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 
 
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 evaluation at Week 10 of Trial 331-102-00088. 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 initiation of IMP treatment, 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 


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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. 
5.6 
Procedure for Breaking the Blind 
Not applicable. 
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 


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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 
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 
This trial aims to include 100 completers of brexpiprazole treatment in Trial 331-102-
00088 as subjects who will continue to receive brexpiprazole for more than 10 weeks. 
Since patients are assigned to the 1 mg group, the 2 mg group, or the placebo group at a 
ratio of 3:4:4 in Trial 331-102-00088, the target sample size for this trial (331-102-
00184) has been determined to be 157 subjects, taking into account some of them have 
received placebo in the previous trial. 
6.2 
Datasets for Analysis 
Analyses in this trial will be performed for each of the following groups unless otherwise 
specified: 


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 Rollover subjects from the brexpiprazole group in Trial 331-102-00088 
 Rollover subjects from the placebo group in Trial 331-102-00088 
 All subjects (rollover subjects from the brexpiprazole group + rollover subjects from 
the placebo group) 
 
6.2.1 
Efficacy Analysis Set 
The efficacy analysis set will comprise subjects who 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 treatment. 
6.2.2 
Safety Analysis Set 
The safety analysis set will comprise subjects who have received at least 1 dose of the 
IMP. 
6.3 
Handling of Missing Data 
For analyses at the final assessment, the last observation carried forward (LOCF) method 
(in which missing Week 14 data are imputed by the data which were observed after 
initiation of IMP treatment and obtained immediately before Week 14) will also be used. 
6.4 
Efficacy Endpoint Analyses 
Efficacy analyses will be performed on the efficacy analysis set. Baseline is defined as 
the last data obtained prior to initiation of IMP treatment in this trial. 
 CMAI total score 
 CGI-S 
 CGI-I 
 
 
 
 
 
 
 
For endpoints other than CGI-I, descriptive statistics of actual measurements and changes 
from baseline at each time point and the final assessment (Week 14 LOCF) will be 
calculated. For CGI-I, descriptive statistics of actual measurements at each time point and 
the final assessment (Week 14 LOCF) will be calculated. 


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. 
6.4.1 
Interim Analysis 
In this trial, safety will also be evaluated by the IDMC, when approximately 25%, 50%, 
and 75% of the target number of subjects in the preceding Trial 331-102-0008 have 
completed or discontinued the trial. Additional evaluation by the IDMC may be 
performed depending on the status of subject enrollment into the current trial (331-102-
00184). 
6.5 
Analysis of Demographic and Baseline Characteristics 
Descriptive statistics or frequency distribution of demographics and other baseline 
characteristics will be determined for each analysis set. 
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 this trial. 
6.6.1 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The incidences of the following events will be summarized 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 leading to IMP dose reduction 
 
TEAEs potentially causally related to the IMP will also be summarized in the same 
manner. 


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6.6.2 
Clinical Laboratory Data 
For each quantitative laboratory parameter, descriptive statistics of actual measurements 
and changes from baseline at each time point and the final assessment (Week 14 LOCF) 
will be calculated. 
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 qualitative laboratory parameter, a shift table from baseline will be produced. 
Numbers and proportions of subjects with clinically significant changes in laboratory test 
values will be determined. 
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 and the final assessment (Week 14 LOCF) will be 
calculated. 
Numbers and proportions of subjects with clinically significant changes in vital signs will 
be determined. 
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 and the 
final assessment (Week 14 LOCF) will be calculated. 
A shift table from baseline for normal/abnormal 12-lead ECG will be produced. 
The numbers and proportions of subjects with actual measurements of corrected QT 
interval (QTcF, QTcB, and QTcN) at each time point and the final assessment (Week 14 
LOCF) of > 450 msec, > 480 msec, and > 500 msec will be determined. Numbers and 
proportions of subjects with changes from baseline of > 30 msec and > 60 msec will be 
determined. 
Numbers and proportions of subjects with clinically significant changes in ECG 
parameters will be determined. 


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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 and the final assessment (Week 14 LOCF) will be 
calculated. 
Numbers and proportions of subjects with results meeting the criteria for clinically 
significant changes will be determined. 
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 and the final assessment 
(Week 14 LOCF) will be calculated. 
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 and the final assessment (Week 14 LOCF) will be calculated. 
6.7 
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 this trial. 
 ADCS-ADL 
 MMSE 
 
For ADCS-ADL total score and MMSE total score, descriptive statistics of actual 
measurements and changes from baseline at each time point and the final assessment 
(Week 14 LOCF) will be calculated. 
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 
. Each 
used in the dosing period will be 


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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 original 
. 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 
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) 


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 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. (E-mail address: 
) 
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. 
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. 


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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 investigator or subinvestigator (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 
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 


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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 document 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 two 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. 
 
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. 


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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 


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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: 


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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. 


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9 
D’Onofrio 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. Alzheimers 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 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. 


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23 International Conference on Harmonisation. Guideline For Good Clinical 
Practice:E6(R1). Geneva, Switzerland: International Conference on Harmonisation; 
1996. 
 
 


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Appendix 1 
Protocol Amendments/Administrative Changes 
 
Amendment: Number: 1 
Issue Date: 
01 Oct 2018 
PURPOSE: 
 
BACKGROUND: 
. 
MODIFICATIONS TO PROTOCOL: 
Sectional Revisions: 
Location 
Before Change 
After Change 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ADDITIONAL RISK TO THE SUBJECT 
. 
 
 


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Amendment:  Number: 2 
Issue Date: 
05 Mar 2020 
 
PURPOSE: 
 
 
BACKGROUND: 
 
 
MODIFICATIONS TO PROTOCOL: 
Sectional Revisions: 
Location 
Before Change 
After Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Location 
Before Change 
After Change 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADDITIONAL RISK TO THE SUBJECT 
 
 
 


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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 
. 
 
 
 


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Agreement 
I, the undersigned principal investigator, have read and understand the protocol 
(including the Investigator's Brochure) and agree that it contains all the ethical, legal and 
scientific information necessary to conduct this trial in accordance with the principles of 
Good Clinical Practices and as described herein and in the sponsor's (or designee's) 
Clinical Trial Agreement. 
I will provide copies of the protocol to all physicians, nurses, and other professional 
personnel to whom I delegate trial responsibilities. I will discuss the protocol with them 
to ensure that they are sufficiently informed regarding the investigational new drug, 
OPC-34712, the concurrent medications, the efficacy and safety parameters and the 
conduct of the trial in general. I am aware that this protocol must be approved by the 
Institutional Review Board (IRB) 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 


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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. 

SAP_001.pdf: 
 
 
STATISTICAL  ANALYSIS  PLAN 
 
 
 
A multicenter, uncontrolled, open-label trial to evaluate the safety of extended treatment  
with brexpiprazole (OPC-34712) in patients with agitation associated with dementia of  
the Alzheimer’s type 
 
 
 
 
NCT Number: NCT03724942 
Protocol No. 331-102-00184 
Version Date: 04 Feb 2022 (Version 1.0) 


Statistical Analysis Plan 
1 of 28 
Version: 1.0 Date: 04/02/2022 
 
Otsuka Pharmaceutical Co., Ltd. 
 
 
Investigational New Drug Brexpiprazole (OPC-34712) 
 
 
 
 
 
Protocol No. 331-102-00184 
 
 
 
A multicenter, uncontrolled, open-label trial to evaluate the safety of extended treatment 
with brexpiprazole (OPC-34712) in patients with agitation associated with dementia of 
the Alzheimer’s type 
 
Statistical Analysis Plan 
 
Version: 1.0 
Date: 04 Feb 2022 
Protocol Version 4 Date: 03 Feb 2021 
 
 
 
 
 
 
 
 
 
 
 
Confidential 
May not be used, divulged, published, or otherwise disclosed without the prior written 
consent of Otsuka Pharmaceutical Co., Ltd 


Protocol 331-102-00184 
 
Statistical Analysis Plan 
2 of 28 
Version: 1.0 Date: 04/02/2022 
Table of Contents 
Table of Contents ........................................................................................... 2 
List of Appendices.......................................................................................... 4 
List of Abbreviations and Definition of Terms ........................................... 5 
1 
Introduction .........................................................................................................6 
2 
Trial Objectives ...................................................................................................6 
3 
Trial Design .........................................................................................................6 
3.1 
Type/Design of Trial .........................................................................................6 
3.2 
Trial Treatments ................................................................................................7 
3.3 
Trial Population ................................................................................................8 
3.4 
Trial Visit Window ...........................................................................................8 
3.5 
Handling of Endpoints ......................................................................................9 
3.5.1 
Cohen-Mansfield Agitation Inventory (CMAI) ............................................9 
3.5.2 
Clinical Global Impression - Severity of Illness (CGI-S) .............................9 
3.5.3 
Clinical Global Impression - Improvement (CGI-I) .....................................9 
3.5.4 
 
 ................................................................9 
3.5.5 
 
 
 .....................................................................10 
3.5.6 
Drug Induced Extra-Pyramidal Symptoms Scale (DIEPSS) ......................10 
3.5.7 
Abnormal Involuntary Movement Scale (AIMS) .......................................10 
3.5.8 
Sheehan Suicidality Tracking Scale (S-STS) ..............................................10 
3.5.9 
Alzheimer’s Disease Cooperative Study - Activities of Daily Living 
(ADCS-ADL) ..............................................................................................10 
3.5.10 
Mini-Mental State Examination (MMSE) ..................................................10 
4 
Sample Size .......................................................................................................10 
5 
Statistical Analysis Datasets ..............................................................................11 
5.1 
Efficacy Analysis Set ......................................................................................11 
5.2 
Safety Analysis Set .........................................................................................11 
5.3 
Handling of Missing Data ...............................................................................11 
6 
Primary and Secondary Outcome Variables .....................................................11 
7 
Disposition and Demographic Analysis ............................................................11 


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7.1 
Subject Disposition .........................................................................................11 
7.2 
Demographic and Baseline Characteristics ....................................................12 
7.3 
Baseline Disease Evaluation ...........................................................................12 
7.4 
Treatment Compliance ....................................................................................12 
7.5 
Prior and Concomitant Medications ...............................................................12 
7.6 
Protocol Deviations ........................................................................................13 
8 
Efficacy Analysis ..............................................................................................13 
8.1 
Subgroup Analyses .........................................................................................14 
9 
Safety Analyses .................................................................................................14 
9.1 
Extent of Exposure .........................................................................................14 
9.2 
Adverse Events ...............................................................................................14 
9.2.1 
Adverse Events of Interest ..........................................................................15 
9.2.2 
Subgroup Analysis of Adverse Events ........................................................15 
9.3 
Clinical Laboratory Data ................................................................................16 
9.4 
Vital Sign Data ...............................................................................................17 
9.5 
Physical Examination Data .............................................................................17 
9.6 
Electrocardiogram Data ..................................................................................17 
9.7 
Other Safety Data ...........................................................................................18 
9.7.1 
Body Weight and BMI ................................................................................18 
9.7.2 
DIEPSS, AIMS, and BARS ........................................................................18 
9.7.3 
S-STS ..........................................................................................................18 
10 
Pharmacokinetic Analyses ................................................................................19 
11 
Pharmacodynamic Analyses..............................................................................19 
12 
Pharmacogenomic Analyses..............................................................................19 
13 
Analysis of Other Endpoints .............................................................................19 
14 
Interim Analysis ................................................................................................19 
15 
Changes in the Planned Analyses ......................................................................19 
16 
References .........................................................................................................20 
 


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Version: 1.0 Date: 04/02/2022 
List of Appendices 
Appendix 1 
Criteria for Identifying Vital Signs and Weight of Potential 
Clinical Relevance ........................................................................ 21 
Appendix 2 
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance ........................................................................ 22 
Appendix 3 
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance ........................................................................ 23 
Appendix 4 
List of Summary Tables ................................................................ 24 
Appendix 5 
List of Subject Data Listings......................................................... 28 


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Version: 1.0 Date: 04/02/2022 
List of Abbreviations and Definition of Terms 
Abbreviation 
Definition 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study - Activities of Daily Living 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BARS 
Barnes Akathisia Rating Scale 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CGI-I 
Clinical Global Impression - Global Improvement 
CGI-S 
Clinical Global Impression - Severity of Illness 
CMAI 
Cohen-Mansfield Agitation Inventory 
CPK 
Creatine phosphokinase 
DIEPSS 
Drug Induced Extra-Pyramidal Symptoms Scale 
FAS 
Full analysis set 
HDL 
High-density lipoprotein 
IDMC 
Independent data monitoring committee 
LDH 
Lactate (lactic acid) dehydrogenase 
LDL 
Low-density lipoprotein 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMSE 
Mini-Mental State Examination 
 
 
 
 
 
 
 
 
 
 
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 
S-STS 
Sheehan Suicidality Tracking Scale 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limits of normal 


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1 
Introduction 
This statistical analysis plan documents in detail the statistical analysis methods planned 
for the clinical study report of Trial 331-102-00184. 
2 
Trial Objectives 
The objective of the trial is to evaluate the safety of brexpiprazole 1 or 2 mg administered 
for 14 weeks in patients with agitation associated with dementia of Alzheimer’s type who 
have completed the treatment period of a double-blind trial (Trial 331-102-00088), and to 
explore the efficacy of extended treatment with brexpiprazole. 
3 
Trial Design 
3.1 
Type/Design of Trial 
This is a multicenter, uncontrolled, open-label 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 prospective subjects 
(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 main caregivers using the 
explanatory materials and informed consent form (ICF) and obtain written consent for 
participation in the trial from the prospective subjects (or their legally acceptable 
representatives) and caregivers during Trial 331-102-00088 between the dates of 
evaluation at Week 4 and Week 10. The investigator or subinvestigator will assess the 
eligibility of subjects to participate in the trial based on observations, tests, and 
investigations performed during the treatment period of Trial 331-102-00088. All 
subjects judged to be eligible based on the results of observations, tests, and 
investigations in Trial 331-102-00088 will skip the follow-up observation of Trial 331-
102-00088 and be rolled over into the treatment period of this trial (331-102-00184). 
Subjects will receive brexpiprazole for 14 weeks, starting at 0.5 mg, followed by dose 
titration, and then at either 1 or 2 mg, according to Section 3.2 Trial Treatments, and will 
undergo periodic observation, tests, and investigations to assess efficacy and safety. 
Investigational medicinal product (IMP) administration will begin no later than 10 days 


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after the date of evaluation at Week 10 of Trial 331-102-00088. 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 for each subject is from completion of evaluation at Week 10 of Trial 
331-102-00088 to the end of follow-up observation. 
 
Figure 3.1-1 
Trial Design 
Double-blind trial = Trial 331-102-00088, Extension trial = Trial 331-102-00184, Brex = brexpiprazole,  
BL = baseline 
 
3.2 
Trial Treatments 
Brexpiprazole will be administered orally as one tablet once a day for 14 weeks. 
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. The 
IMP doses are shown in Table 3.2-1. IMP administration will be initiated at 0.5 mg and 
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). If the investigator or subinvestigator judges that dose 
increase to 2 mg is difficult for safety reasons based on the subject’s condition after 
evaluation at Week 2 (Day 15), the dose may be maintained at 1 mg (see Section 3.2 1) 
Dose Maintenance at 1 mg). From Week 2 (Day 15), the dose may be reduced or 
increased to 1 or 2 mg if the investigator or subinvestigator decides that dose adjustment 
is necessary (see Section 3.2 2) Dose Change). In cases where dose reduction to lower 
than 1 mg is required, the trial should be discontinued. 
 
Trial  331-102-00088
Informed consent
Follow-up
period
Day 28
Trial 331-102-00184
Screening period
Treatment period
Dose adjustment as appropriate
1 week
Brex: 1 or 2 mg
1 week
Brex: 1 mg
Brex: 0.5 mg
up to 10 days
Double-blind trial
Week 10
(BL of extension trial)
Double-blind trial 
Week 4
Start of IMP 
administration
(Day 1)
Week 1
(Day 8)
Week 2
(Day 15)
Week 14
(Day 99)


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Table 3.2-1 
Doses of IMP 
Day 1-7 
Day 8-14 
Day 15-98 
0.5 mg 
1 mg 
1 mg or 2 mg 
 
1) Dose Maintenance at 1 mg 
If the investigator or subinvestigator decides that dose increase to 2 mg is difficult 
due to the occurrence of an adverse event (AE) identified from the evaluation at 
Week 2 (Day 15), the dose will be maintained at 1 mg. The AE for which this 
judgement was made will be recorded in the case report form (CRF). 
2) Dose Change 
If the investigator or subinvestigator decides that dose adjustment is necessary 
based on the subject’s condition, the dose will be reduced or increased to 1 or 
2 mg. 
If the investigator or subinvestigator decides that the current dose is not 
sufficiently effective, the dose will be increased to 2 mg. If either of the following 
cases applies, the dose will be reduced to 1 mg and the reason for dose reduction 
will be recorded in the CRF. In the event that both of the following cases apply, 
the AE should be recorded as the reason for dose reduction. When the occurrence 
of an AE necessitates dose reduction, enter “dose reduction” in the CRF as the 
action taken for the AE in relation to IMP administration. 
The dose may be reduced to 1 mg in the following cases: 
 Dose reduction is necessary because an AE has occurred. 
 Dose reduction is necessary because symptoms have improved. 
 
3.3 
Trial Population 
A total of 157 male and female patients with agitation associated with dementia of the 
Alzheimer’s type who have completed the treatment period of Trial 331-102-00088 and 
whose condition can be observed by a caregiver in at least 4 days per week for 4 hours or 
more a day. 
3.4 
Trial Visit Window 
For all endpoints, acceptable windows for analysis are specified, and analysis should take 
place at the analysis time points regardless of time points recorded on the case report 
form. 
Acceptable windows for analysis are shown in Table 3.4-1. Day 1 is defined as the day 
when treatment with the IMP begins. If multiple data exist within an acceptable window, 
the last data within the window will be used in analysis. Data obtained 7 days or later 
after the final dosing will be excluded from the analysis. 
 


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Table 3.4-1 
Acceptable Windows for Analysis 
Week 
Target Day 
Trial Day Interval 
Baseline 
1 
- 1 
Week 1 
8 
2 - 11 
Week 2 
15 
12 - 22 
Week 4 
29 
23 - 36 
Week 6 
43 
37 - 50 
Week 8 
57 
51 - 64 
Week 10 
71 
65 - 78 
Week 12 
85 
79 - 92 
Week 14 
99 
93 - 113 
 
3.5 
Handling of Endpoints 
3.5.1 
Cohen-Mansfield Agitation Inventory (CMAI) 
The CMAI total score will be the sum of scores for 29 CMAI items. 
The CMAI Aggressive Behavior score will be the sum of scores for CMAI Items 3, 4, 7, 
8, 9, 10, 11, 13, 14, 15, 21, and 25. 
The CMAI Physically Non-aggressive Behavior score will be the sum of scores for 
CMAI Items 1, 2, 16, 22, 26, and 29. 
The CMAI Verbally Agitated Behavior score will be the sum of scores for CMAI Items 
5, 6, 18, and 19. 
3.5.2 
Clinical Global Impression - Severity of Illness (CGI-S) 
“0. Not assessed” will be handled as missing data. 
3.5.3 
Clinical Global Impression - Improvement (CGI-I) 
“0. Not assessed” will be handled as missing data. 
3.5.4 
 
 
 
 


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3.5.5 
 
 
 
3.5.6 
Drug Induced Extra-Pyramidal Symptoms Scale (DIEPSS) 
The DIEPSS total score will be the sum of scores for DIEPSS items 1 through 8. 
3.5.7 
Abnormal Involuntary Movement Scale (AIMS) 
The AIMS total score will be the sum of scores for AIMS items 1 through 7. 
3.5.8 
Sheehan Suicidality Tracking Scale (S-STS) 
The S-STS total score will be the sum of scores for Item 1a, Items 2 through 11, highest 
of Item 12 or any row of Item 16, highest of Item 14 or any row of Item 15, Item 17, and 
Item 20. 
The S-STS suicidal ideation subscale score will be the sum of scores for Items 2 through 
11. 
The S-STS suicidal behavior subscale score will be the sum of scores for Item 1a, highest 
of Item 12 or any row of Item 16, highest of Item 14 or any row of Item 15, Item 17, and 
Item 20. 
3.5.9 
Alzheimer’s Disease Cooperative Study - Activities of Daily 
Living (ADCS-ADL) 
The ADCS-ADL total score will be the sum of scores for ADCS-ADL Items 1 through 
19. 
3.5.10 
Mini-Mental State Examination (MMSE) 
The MMSE total score will be the sum of scores for MMSE Items 1 through 30. 
4 
Sample Size 
This trial aims to include 100 completers of brexpiprazole treatment in Trial 331-102-
00088 as subjects who will continue to receive brexpiprazole for more than 10 weeks. 
Since patients are assigned to the 1 mg group, the 2 mg group, or the placebo group at a 
ratio of 3:4:4 in Trial 331-102-00088, the target sample size for this trial (331-102-


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00184) has been determined to be 157 subjects, taking into account some of them have 
received placebo in the previous trial. 
5 
Statistical Analysis Datasets 
Analyses in this trial will be performed for each of the following groups unless otherwise 
specified: 
 Rollover subjects from the brexpiprazole group in Trial 331-102-00088 
 Rollover subjects from the placebo group in Trial 331-102-00088 
 All subjects (rollover subjects from the brexpiprazole group + rollover subjects from 
the placebo group) 
5.1 
Efficacy Analysis Set 
The efficacy analysis set will comprise subjects who 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 treatment. 
5.2 
Safety Analysis Set 
The safety analysis set will comprise subjects who have received at least 1 dose of the 
IMP. 
5.3 
Handling of Missing Data 
For analyses at the final assessment, the last observation carried forward (LOCF) method 
(in which missing Week 14 data are imputed by the data which were observed after 
initiation of IMP treatment and obtained immediately before Week 14) will also be used. 
6 
Primary and Secondary Outcome Variables 
Neither primary nor secondary outcome variables are planned. 
7 
Disposition and Demographic Analysis 
7.1 
Subject Disposition 
Numbers and proportions of subjects from whom informed consent was obtained, those 
who received trial treatment, those who completed the trial, those who discontinued the 
trial, those who discontinued the trial by reason for discontinuation, and those included in 
each analysis set will be summarized. 


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7.2 
Demographic and Baseline Characteristics 
Descriptive statistics (mean, standard deviation, minimum, median, and maximum; 
hereinafter the same applies) of age, height,a baseline body weight, and baseline body 
mass index (BMI), and frequency distribution of age category (< 80, ≥ 80) (< 65, ≥ 65 to 
< 75, ≥ 75), sex,a race,a ethnicity,a country where trial is conducted,a complications,a 
medical history,a and dose used in the previous trial will be determined in each analysis 
set. 
aData obtained at screening in Trial 331-102-00088 will be used. 
 
7.3 
Baseline Disease Evaluation 
Descriptive statistics of the duration of dementia of the Alzheimer’s type,a duration of 
agitation associated with dementia of the Alzheimer’s type,a 
CGI-S, CMAI (total score, subscale scores), 
MMSE total score, and ADCS-ADL total score, and frequency distribution of medical 
care category,b prior use of antipsychotics (yes or no),a type of caregiver,b and 
concomitant use of antidementia drugs (yes or no). 
aData obtained at screening in Trial 331-102-00088 will be used. 
bData obtained at the start of the present trial will be used. 
 
The duration of dementia of the Alzheimer’s type and the duration of agitation associated 
with dementia of the Alzheimer’s type will be calculated using the following formula: 
duration (months) = (date of subject demographic evaluation – date of onset + 1) / 30. 
Any unknown month or day of onset will be replaced with June or 15, respectively. 
7.4 
Treatment Compliance 
Treatment compliance (number of days when the subject actually received the 
IMP/number of days for which the IMP was prescribed) will be grouped into < 70%, 
≥ 70% to < 80%, ≥ 80% to < 90%, and ≥ 90%, and the frequency distribution will be 
determined in the efficacy analysis set. 
7.5 
Prior and Concomitant Medications 
Numbers and proportions of subjects who used medications before, during, and after the 
treatment period will be determined by drug class and preferred term of the World Health 
Organization Drug Dictionary (WHODD) version Global B3 March 2018 in the safety 
analysis set. 


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7.6 
Protocol Deviations 
Numbers and proportions of subjects with major deviations from the protocol will be 
determined for each category (IMP administration, eligibility criteria, a failure to 
discontinue the trial when the subject meets the withdrawal criteria, procedures that affect 
evaluation of the primary endpoint, use of prohibited medications, and overall) at each 
trial site in the safety analysis set. 
8 
Efficacy Analysis 
Efficacy analyses will be performed on the efficacy analysis set. Baseline is defined as 
the last data obtained prior to initiation of IMP treatment in this trial. 
 CMAI total score 
 CMAI subscales (Aggressive Behavior, Physically Non-aggressive Behavior, and 
Verbally Agitated Behavior) 
 CGI-S 
 CGI-I 
 
 
 
 
 
 
 
 
 
 
 
 
For endpoints other than CGI-I, descriptive statistics of actual measurements and changes 
from baseline at each time point and the final assessment (Week 14 LOCF) will be 
calculated. For CGI-I, descriptive statistics of actual measurements at each time point and 
the final assessment (Week 14 LOCF) will be calculated. 


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. 
8.1 
Subgroup Analyses 
No subgroup efficacy analyses will be performed. 
9 
Safety Analyses 
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 this trial. 
9.1 
Extent of Exposure 
Descriptive statistics and frequency distribution (1-7, 8-14, 15-21, 22-28, 29-35, 36-42, 
43-49, 50-56, 57-63, 64-70, 71-77, 78-84, 85-91, 92-98, > 98, and ≥ 7, ≥ 14, ≥ 28, ≥ 42, 
≥ 56, ≥ 70, ≥ 84, ≥ 98) of the duration (days) of treatment with the IMP will be 
determined. 
Descriptive statistics of the mean daily dose will be determined for each section of the 
treatment period (1-7, 8-14, 15-21, 22-28, 29-35, 36-42, 43-49, 50-56, 57-63, 64-70, 71-
77, 78-84, 85-91, 92-98, > 98) and for the entire treatment period. 
Frequency distribution of the most frequent dose will be determined for each section of 
the treatment period (1-7, 8-14, 15-21, 22-28, 29-35, 36-42, 43-49, 50-56, 57-63, 64-70, 
71-77, 78-84, 85-91, 92-98, > 98) and for the entire treatment period. Frequency 
distribution of the final dose will also be determined. 
9.2 
Adverse Events 
Adverse events will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) (Ver. 25.0). The incidences of the following events will be summarized 
according to System Organ Class (SOC) and Preferred Term (PT). If an AE occurs more 
than once in the same subject, the severest event will be used in summarization. 
 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 leading to IMP dose reduction 
 TEAEs occurring in ≥ 2% of subjects in any group 


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 TEAEs by days of initial onset (1-7, 8-14, 15-21, 22-28, 29-35, 36-42, 43-49, 50-56, 
57-63, 64-70, 71-77, 78-84, 85-91, 92-98, > 98, post-trial treatment). 
 
TEAEs potentially causally related to the IMP will also be summarized in the same 
manner. 
9.2.1 
Adverse Events of Interest 
Each AE of interest is defined in Appendix 4 in the Statistical Analysis Plan for the 
double-blind trial (331-102-00088). Numbers and proportions of subjects with the 
following AEs of interest will be summarized by SOC and PT. 
 Extrapyramidal AEs 
 Accident- and injury-related AEs 
 Cerebrovascular AEs 
 Cardiovascular AEs 
 Glucose metabolism-related AEs 
 Lipid metabolism-related AEs 
 Body weight-related AEs 
 Blood disorder-related AEs 
 Hypersensitive symptom-related AEs 
 Neuroleptic malignant syndrome-related AEs 
 Orthostatic disorder-related AEs 
 Prolactin increase-related AEs 
 QT interval prolongation-related AEs 
 Rhabdomyolysis 
 Seizure-related AEs 
 Oversedation-related AEs 
 Suicide/suicide attempt-related AEs 
 Venous thrombosis 
 Infectious pneumonia 
 
9.2.2 
Subgroup Analysis of Adverse Events 
Numbers and proportions of subjects with TEAEs will be summarized by SOC and PT in 
each of the following subgroups. Subgroups of medical care category and subgroups of 
type of caregiver will include only subjects for whom the medical care category or the 
type of caregiver remains unchanged throughout the trial. 
 Medical care category (inpatient, outpatient) 


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 Prior use of antipsychotics (yes or no) 
 Type of caregiver (hospital staff, care facility staff, family, or other) 
 Sex (male, female) 
 Age (< 80, ≥ 80) (< 65, ≥ 65 to < 75, ≥ 75) 
 Body weight (≤ median, > median) 
 BMI (≤ median, > median) 
 Impact of COVID-19 pandemic (subjects who completed/discontinued the trial before 
07 Apr 2020, subjects who completed/discontinued the trial on or after 07 Apr 2020) 
 Concomitant use of antidementia drugs (yes or no) 
 
9.3 
Clinical Laboratory Data 
For each quantitative laboratory parameter, descriptive statistics of actual measurements 
and changes from baseline at each time point and the final assessment (Week 14 LOCF) 
will be calculated. 
For each quantitative laboratory parameter, 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 qualitative laboratory parameter, a shift table from baseline will be produced. 
Numbers and proportions of subjects with laboratory test values not meeting the criteria 
for potentially clinically significant laboratory test values (Appendix 2) at baseline and 
meeting the criteria after treatment will be determined. A listing of these subjects will be 
provided. 
Numbers and proportions of subjects with postdose values of alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), and total bilirubin (TBL) meeting Hy’s Law 
criteria (ALT or AST ≥ 3 × the upper limit of normal [ULN] and TBL ≥ 2 × ULN) will 
be determined. A listing of these subjects will be provided. 
Numbers and proportions of subjects with a prolactin value not meeting the criteria of 
> 1 × ULN, > 2 × ULN, or > 3 × ULN at baseline and meeting the criteria after treatment 
will be determined by sex. A listing of these subjects will be provided. 
Numbers and proportions of subjects with postdose values of fasting low-density 
lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, 
and blood glucose meeting the criteria for changes in glucose and lipid metabolism-
related parameters (Table 9.3-1) will be determined by baseline value. A listing of these 
subjects will be provided. 


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Table 9.3-1 
Changes in Glucose and Lipid Metabolism-related 
Parameters 
LAB PARAMETER 
BASELINE 
ANYTIME POST BASELINE 
Cholesterol, Fasting 
(mg/dL) 
Normal <200 
Borderline 200-<240 
Normal/Borderline <240 
Normal <200 
Any Value 
High >=240 
High >=240 
High >=240 
Borderline/High >=200 
Increased >=40  
LDL Cholesterol, Fasting  
(mg/dL) 
Normal <100 
Borderline 100-<160 
Normal/Borderline <160 
Normal <100 
Any Value 
High >=160 
High >=160 
High >=160 
Borderline/High >=100 
Increased >=30  
HDL Cholesterol, Fasting 
(mg/dL) 
Normal >=40 
Any Value 
Low <40 
Decreased >=20 
Triglycerides, Fasting  
(mg/dL)    
Normal <150 
Normal <150 
Borderline 150-<200 
Normal/Borderline <200 
Normal/Borderline <200 
Normal <150 
Normal/Borderline/high <500 
Any Value 
High 200-<500 
Very High >=500 
High 200-<500 
High 200-<500 
Very High >=500 
Borderline/High/Very High >=150 
Very High >=500 
Increased >=50 
Glucose Fasting, Serum  
(mg/dL)    
Normal <100 
Impaired 100-<126 
Normal/Impaired <126 
Any Value 
High >=126 
High >=126 
High >=126 
Increased >=10 
 
9.4 
Vital Sign Data 
For each vital sign parameter (sitting position), descriptive statistics of actual 
measurements and changes from baseline at each time point and the final assessment 
(Week 14 LOCF) will be calculated. 
Numbers and proportions of subjects with vital signs meeting the criteria for potentially 
clinically significant vital signs (Appendix 1) will be determined. A listing of these 
subjects will be provided. 
9.5 
Physical Examination Data 
Physical examination data will be provided in a listing. 
9.6 
Electrocardiogram Data 
For heart rate, PR interval, RR interval, QRS interval, QT interval, and QT corrected for 
heart rate (QTc), descriptive statistics of actual measurements and changes from baseline 
at each time point and the final assessment (Week 14 LOCF) will be calculated. 


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A shift table from baseline for normal/abnormal 12-lead electrocardiogram (ECG) 
(evaluated at the trial site) will be produced. 
Numbers and proportions of subjects with actual measurements of QTc [QTcF, QTcB, 
QTcN = QT interval/(RR interval)0.37] not meeting the criteria of > 450 msec, 
> 480 msec, or > 500 msec at baseline and meeting the criteria after treatment will be 
determined. Numbers and proportions of subjects with changes from baseline of 
> 30 msec and > 60 msec will be determined. Numbers and proportions of subjects with 
actual measurements of > 450 msec with a % change from baseline of > 10% will be 
determined. 
Numbers and proportions of subjects with ECG results meeting the criteria for potentially 
clinically significant ECG data (Appendix 3) will be determined. A listing of these 
subjects will be provided. 
9.7 
Other Safety Data 
9.7.1 
Body Weight and BMI 
For body weight and BMI, descriptive statistics of actual measurements and changes 
from baseline at each time point and the final assessment (Week 14 LOCF) will be 
calculated. 
Numbers and proportions of subjects with results meeting the criteria for potentially 
clinically significant body weight gain or loss (Appendix 1) will be determined. Body 
weight data will also be analyzed by baseline BMI category (< 18.5, ≥ 18.5 to < 25, ≥ 25 
to < 30, ≥ 30) in a similar manner. A listing of subjects with results meeting the criteria 
for potentially clinically significant body weight gain or loss (Appendix 1) will be 
provided. 
9.7.2 
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 and the last assessment time 
point (Week 14 LOCF) and the worst postdose measurement and its change from 
baseline will be calculated. 
9.7.3 
S-STS 
For the score for each S-STS item (2 through 14), total score, suicidal ideation subscale 
score, and suicidal behavior subscale score, descriptive statistics of actual measurements 


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and changes from baseline at each time point and the final assessment (Week 14 LOCF) 
will be calculated. 
10 
Pharmacokinetic Analyses 
Not applicable. 
11 
Pharmacodynamic Analyses 
Not applicable. 
12 
Pharmacogenomic Analyses 
Not applicable. 
13 
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. 
 ADCS-ADL 
 MMSE 
 
For ADCS-ADL total score and MMSE total score, descriptive statistics of actual 
measurements and changes from baseline at each time point and the final assessment 
(Week 14 LOCF) will be calculated. 
14 
Interim Analysis 
In this trial, safety will also be evaluated by the IDMC, when approximately 25%, 50%, 
and 75% of the target number of subjects in the preceding Trial 331-102-00088 have 
completed or discontinued the trial. Additional evaluation by the IDMC may be 
performed depending on the status of subject enrollment into the current trial (331-102-
00184). 
A statistical analysis plan for interim analysis is described in a separate interim analysis 
plan. 
15 
Changes in the Planned Analyses 
 
 


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The following changes were made to categorical analyses of QTc: 
 Only subjects with postdose QTc meeting the criteria will be summarized, instead of 
summarization at all time points. 
 Only subjects with QTc not meeting the criteria at baseline and meeting the criteria 
after baseline will be summarized. 
 
16 
References 
Not applicable. 
 


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Appendix 1 
Criteria for Identifying Vital Signs and Weight of Potential 
Clinical Relevance 
 
Variable 
Criterion Valuea 
Change Relative to Baselinea 
Pulse Rate 
> 120 bpm 
< 50 bpm 
 15 bpm increase 
 15 bpm decrease 
Systolic Blood Pressure 
> 180 mmHg 
< 90 mmHg 
 20 mmHg increase 
 20 mmHg decrease 
Diastolic Blood Pressure 
> 105 mmHg 
< 50 mmHg 
 15 mmHg increase 
 15 mmHg decrease 
Weight 
- 
 7% increase 
 7% decrease 
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column. 
 


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Appendix 2 
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance 
 
Laboratory Tests 
Criteria 
Chemistry 
 
 
AST (SGOT) 
 3 x upper limit of normal (ULN) 
 
ALT (SGPT) 
 3 x ULN 
 
Alkaline phosphatase 
 3 x ULN 
 
LDH 
 3 x ULN 
 
BUN 
 30 mg/dL 
 
Creatinine 
 2.0 mg/dL 
 
Uric Acid 
 
 
 
Men 
 10.5 mg/dL 
 
 
Women 
 8.5 mg/dL 
 
Bilirubin (total) 
 2.0 mg/dL 
 
CPK 
 3 x ULN 
Endocrinology  
 
 
Prolactin 
> ULN 
Hematology 
 
 
Hematocrit 
 
 
 
Men 
 37 % and decrease of  3 percentage points from Baseline 
 
 
Women 
 32 % and decrease of  3 percentage points from Baseline 
 
Hemoglobin 
 
 
 
Men 
 11.5 g/dL 
 
 
Women 
 9.5 g/dL 
 
White blood count 
 2,800/ mm3 or  16,000/ mm3 
 
Eosinophils 
 10% 
 
Neutrophils 
 15% 
 
Absolute neutrophil count 
 1,000/ mm3 
 
Platelet count 
 75,000/ mm3 or  700,000/ mm3 
Urinalysis 
 
 
Protein 
Increase of  2 units 
 
Glucose 
Increase of  2 units 
Additional Criteria 
 
 
Chloride 
 90 mEq/L or  118 mEq/L 
 
Potassium 
 2.5 mEq/L or  6.5 mEq/L 
 
Sodium 
 126 mEq/L or  156 mEq/L 
 
Calcium 
 8.2 mg/dL or  12 mg/dL 
 
Glucose 
 
 
 
Fasting 
 100 mg/dL 
 
 
Non-Fasting 
 200 mg/dL 
 
Total Cholesterol, Fasting 
 240 mg/dL 
 
LDL Cholesterol, Fasting 
 160 mg/dL 
 
HDL Cholesterol, Fasting 
 
 
 
Men 
< 40 mg/dL 
 
 
Women 
< 50 mg/dL 
 
Triglycerides, Fasting 
 150 mg/dL 
 


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Appendix 3 
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance 
 
Variable 
Criterion Valuea 
Change Relative to Baselinea 
Heart Rate 
 120 bpm 
 50 bpm 
increase of   15 bpm 
decrease of  15 bpm 
PR 
 200 msec 
increase of   50 msec 
QRS 
 120 msec 
increase of  20 msec 
QTcF 
> 450 msec 
(males) 
> 470 msec 
(females) 
 
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column. 


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Appendix 4 
List of Summary Tables 
 
CT-1 
Subject Disposition (Enrolled Subjects) 
CT-2 
Reasons for Discontinuation (Safety Analysis Set) 
CT-3.1.1 
Demographic Characteristics (Efficacy Analysis Set) 
CT-3.1.2 
Demographic Characteristics (Safety Analysis Set) 
CT-3.2.1 
Baseline Disease Characteristics (Efficacy Analysis Set) 
CT-3.2.2 
Baseline Disease Characteristics (Safety Analysis Set) 
CT-4.1.1 
Concomitant Medications: Medications Taken Prior to Start of Study Therapy (Safety 
Analysis Set) 
CT-4.1.2 
Concomitant Medications: Medications Taken During Study Therapy (Safety Analysis 
Set) 
CT-4.1.3 
Concomitant Medications: Medications Taken Post Study Therapy (Safety Analysis Set) 
CT-4.2 
Summary of Major Protocol Deviations by Center and Type of Deviation (Safety Analysis 
Set) 
CT-5.1 
Summary of Mean Change From Baseline by Study Week in CMAI Total Score (Efficacy 
Analysis Set) 
CT-5.2 
Summary of Mean Change From Baseline by Study Week in CMAI Subscale Score 
(Efficacy Analysis Set) 
CT-5.3 
Summary of Mean Change From Baseline by Study Week in CGI-S (Efficacy Analysis 
Set) 
CT-5.4.1 
Summary of Mean CGI-I Score (Efficacy Analysis Set)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT-7.1 
Extent of Exposure (Safety Analysis Set) 
CT-7.2 
Duration of Exposure Summary (Safety Analysis Set) 
CT-7.3 
Summary of Average Daily Dose (mg) (Safety Analysis Set) 
CT-7.4 
Summary of Modal and Final Dose (Safety Analysis Set) 
CT-7.5 
Summary of Treatment Compliance (Efficacy Analysis Set) 
CT-8.1 
Adverse Events (All Causalities) (Safety Analysis Set) 


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CT-8.2.1 
Incidence of TEAEs by MedDRA System Organ Class and Preferred Term (Safety 
Analysis Set) 
CT-8.2.2 
Incidence of Drug-related TEAEs by MedDRA System Organ Class and Preferred Term 
(Safety Analysis Set) 
CT-8.3.1 
Incidence of TEAEs by MedDRA System Organ Class, Preferred Term and Severity 
(Safety Analysis Set) 
CT-8.3.2 
Incidence of Drug-related TEAEs by MedDRA System Organ Class, Preferred Term and 
Severity (Safety Analysis Set) 
CT-8.4.1 
Incidence of Deaths due to TEAEs by MedDRA System Organ Class and Preferred Term 
(Safety Analysis Set) 
CT-8.4.2 
Incidence of Deaths due to Drug-related TEAEs by MedDRA System Organ Class and 
Preferred Term (Safety Analysis Set) 
CT-8.5.1 
Incidence of Serious TEAEs by MedDRA System Organ Class and Preferred Term 
(Safety Analysis Set) 
CT-8.5.2 
Incidence of Serious Drug-related TEAEs by MedDRA System Organ Class and Preferred 
Term (Safety Analysis Set) 
CT-8.6.1 
Incidence of TEAEs Resulting in Discontinuation of IMP by MedDRA System Organ 
Class and Preferred Term (Safety Analysis Set) 
CT-8.6.2 
Incidence of Drug-related TEAEs Resulting in Discontinuation of IMP by MedDRA 
System Organ Class and Preferred Term (Safety Analysis Set) 
CT-8.7.1 
Incidence of TEAEs Resulting in Dose Reduction of IMP by MedDRA System Organ 
Class and Preferred Term (Safety Analysis Set) 
CT-8.7.2 
Incidence of Drug-related TEAEs Resulting in Dose Reduction of IMP by MedDRA 
System Organ Class and Preferred Term (Safety Analysis Set) 
CT-8.8.1 
Incidence of TEAEs of at Least 2% in Any Group by MedDRA System Organ Class and 
Preferred Term (Safety Analysis Set) 
CT-8.8.2 
Incidence of Drug-related TEAEs of at Least 2% in Any Group by MedDRA System 
Organ Class and Preferred Term (Safety Analysis Set) 
CT-8.9.1 
Incidence of TEAEs by MedDRA System Organ Class, Preferred Term and Time to First 
Onset (Safety Analysis Set) 
CT-8.9.2 
Incidence of Drug-related TEAEs by MedDRA System Organ Class, Preferred Term and 
Time to First Onset (Safety Analysis Set) 
CT-8.10.1 
Incidence of TEAEs for EPS (Safety Analysis Set) 
CT-8.10.2 
Incidence of TEAEs for Accidents and Injuries Including Fall (Safety Analysis Set) 
CT-8.10.3 
Incidence of TEAEs for Cerebrovascular Events (Safety Analysis Set) 
CT-8.10.4 
Incidence of TEAEs for Cardiovascular Events (Safety Analysis Set) 
CT-8.10.5 
Incidence of TEAEs for Effect on Glucose (Safety Analysis Set) 
CT-8.10.6 
Incidence of TEAEs for Effect on Lipids (Safety Analysis Set) 
CT-8.10.7 
Incidence of TEAEs for Effect on Weight (Safety Analysis Set) 
CT-8.10.8 
Incidence of TEAEs for Haematopoietic/Leukopenia (Safety Analysis Set) 
CT-8.10.9 
Incidence of TEAEs for Hypersensitivity (Safety Analysis Set) 
CT-8.10.10 
Incidence of TEAEs for Neuroleptic Malignant Syndrome (Safety Analysis Set) 
CT-8.10.11 
Incidence of TEAEs for Orthostatic Hypotension, Dizziness, and Syncope (Safety 
Analysis Set) 
CT-8.10.12 
Incidence of TEAEs for Effect on Prolactin (Safety Analysis Set) 
CT-8.10.13 
Incidence of TEAEs for QT Prolongation (Safety Analysis Set) 
CT-8.10.14 
Incidence of TEAEs for Rhabdomyolysis and CPK Elevation (Safety Analysis Set) 
CT-8.10.15 
Incidence of TEAEs for Seizures (Safety Analysis Set) 
CT-8.10.16 
Incidence of TEAEs for Somnolence (Safety Analysis Set) 
CT-8.10.17 
Incidence of TEAEs for Suicidality (Safety Analysis Set) 
CT-8.10.18 
Incidence of TEAEs for VTE (Thrombotic and Embolic Events) (Safety Analysis Set) 
CT-8.10.19 
Incidence of TEAEs for Infective Pneumonia (Safety Analysis Set) 


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CT-8.11.1 
Incidence of TEAEs by MedDRA System Organ Class and Preferred Term by Medical 
Care Category (Safety Analysis Set) 
CT-8.11.2 
Incidence of TEAEs by MedDRA System Organ Class and Preferred Term by Prior 
Antipsychotics (Safety Analysis Set)  
CT-8.11.3 
Incidence of TEAEs by MedDRA System Organ Class and Preferred Term by Main Care 
Giver (Safety Analysis Set) 
CT-8.11.4 
Incidence of TEAEs by MedDRA System Organ Class and Preferred Term by Gender 
(Safety Analysis Set) 
CT-8.11.5.1 
Incidence of TEAEs by MedDRA System Organ Class and Preferred Term by Age(< 80, 
>= 80) (Safety Analysis Set)  
CT-8.11.5.2 
Incidence of TEAEs by MedDRA System Organ Class and Preferred Term by Age(<65, 
>=65 - <75, >=75) (Safety Analysis Set)  
CT-8.11.6 
Incidence of TEAEs by MedDRA System Organ Class and Preferred Term by Baseline 
Weight (Safety Analysis Set) 
CT-8.11.7 
Incidence of TEAEs by MedDRA System Organ Class and Preferred Term by Baseline 
BMI (Safety Analysis Set) 
CT-8.11.8 
Incidence of TEAEs by MedDRA System Organ Class and Preferred Term by Impact of 
COVID-19 Pandemic (Safety Analysis Set) 
CT-8.11.9 
Incidence of TEAEs by MedDRA System Organ Class and Preferred Term by 
Concomitant Antidementia Drugs (Safety Analysis Set) 
CT-9.1 
Listing of Deaths (Safety Analysis Set) 
CT-9.2 
Listing of Serious Adverse Events (Safety Analysis Set) 
CT-9.3 
Listing of Discontinuation of IMP due to Adverse Events (Safety Analysis Set) 
CT-9.4 
Listing of Dose Reduction due to Adverse Events (Safety Analysis Set) 
CT-10.1.1 
Mean Change From Baseline in Clinical Laboratory Test Results - Serum Chemistry 
(Safety Analysis Set) 
CT-10.1.2 
Mean Change From Baseline in Clinical Laboratory Test Results - Hematology (Safety 
Analysis Set) 
CT-10.1.3 
Mean Change From Baseline in Clinical Laboratory Test Results - Urinalysis (Safety 
Analysis Set) 
CT-10.1.4 
Mean Change From Baseline in Clinical Laboratory Test Results - Prolactin, by Gender 
(Safety Analysis Set) 
CT-10.1.5 
Mean Change From Baseline in Clinical Laboratory Test Results - Other Tests (Safety 
Analysis Set)  
CT-10.2.1 
Shift Tables of Clinical Laboratory Test Results - Serum Chemistry (Safety Analysis Set) 
CT-10.2.2 
Shift Tables of Clinical Laboratory Test Results - Hematology (Safety Analysis Set) 
CT-10.2.3 
Shift Tables of Clinical Laboratory Test Results - Urinalysis1 (Safety Analysis Set) 
CT-10.2.4 
Shift Tables of Clinical Laboratory Test Results - Urinalysis2 (Safety Analysis Set) 
CT-10.2.5 
Shift Tables of Clinical Laboratory Test Results - Prolactin, by Gender (Safety Analysis 
Set) 
CT-10.2.6 
Shift Tables of Clinical Laboratory Test Results - Other Tests (Safety Analysis Set)  
CT-10.3.1 
Incidence of Laboratory Test Values With Potential Clinical Relevance (Safety Analysis 
Set) 
CT-10.3.2 
Listing of Laboratory Test Values With Potential Clinical Relevance by Subject (Safety 
Analysis Set) 
CT-10.4.1 
Incidence of Potential Hy's Law Cases (Safety Analysis Set) 
CT-10.4.2 
Listing of Potential Hy's Law Cases (Safety Analysis Set) 
CT-10.5.1 
Incidence of Laboratory Test Values With Potential Clinical Relevance - Prolactin (Safety 
Analysis Set) 
CT-10.5.2 
Listing of Laboratory Test Values With Potential Clinical Relevance - Prolactin (Safety 
Analysis Set) 
CT-10.6.1 
Incidence of Treatment-emergent Significant Change in Lipids (Safety Analysis Set) 
CT-10.6.2 
Listing of Treatment-emergent Significant Change in Lipids (Safety Analysis Set) 


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CT-10.7.1 
Incidence of Treatment-emergent Significant Change in Glucose (Safety Analysis Set) 
CT-10.7.2 
Listing of Treatment-emergent Significant Change in Glucose (Safety Analysis Set) 
CT-11.1 
Mean Change From Baseline in Vital Signs (Safety Analysis Set) 
CT-11.2 
Incidence of Potentially Clinically Relevant Abnormalities in Vital Signs (Safety Analysis 
Set) 
CT-11.3 
Listing of Potentially Clinically Relevant Abnormalities in Vital Signs (Safety Analysis 
Set) 
CT-11.4 
Summary of Mean Change From Baseline by Study Week in Body Weight (kg) (Safety 
Analysis Set) 
CT-11.5 
Summary of Mean Change From Baseline by Study Week in BMI (kg/m^2) (Safety 
Analysis Set) 
CT-11.6 
Incidence of Potentially Clinically Relevant Weight Gain or Loss by Baseline BMI 
(Safety Analysis Set) 
CT-12.1 
Mean Change From Baseline in ECG Results (Safety Analysis Set) 
CT-12.2 
Shift Tables of ECG (Safety Analysis Set) 
CT-12.3 
Incidence of Categorical Increases in QT Evaluations (Safety Analysis Set) 
CT-12.4 
Incidence of Potentially Clinically Relevant Abnormalities in ECG Evaluations (Safety 
Analysis Set) 
CT-12.5 
Listing of Potentially Clinically Relevant Abnormalities in ECG Evaluations (Safety 
Analysis Set) 
CT-13.1 
Summary of Mean Change From Baseline by Study Week in DIEPSS (Safety Analysis 
Set) 
CT-13.2 
Summary of Mean Change From Baseline by Study Week in AIMS Total Score and Item 
Scores 8, 9 and 10 (Safety Analysis Set) 
CT-13.3 
Summary of Mean Change From Baseline by Study Week in BARS, Global Clinical 
Assessment of Akathisia (Safety Analysis Set) 
CT-14.1 
Summary of Mean Change From Baseline by Study Week in Sheehan-STS Score (Safety 
Analysis Set) 
CT-14.2 
Summary of Mean Change From Baseline by Study Week in Sheehan-STS - Total Score 
(Safety Analysis Set) 
CT-14.3 
Summary of Mean Change From Baseline by Study Week in Sheehan-STS - Suicidal 
Ideation Subscale Score (Safety Analysis Set) 
CT-14.4 
Summary of Mean Change From Baseline by Study Week in Sheehan-STS - Suicidal 
Behavior Subscale Score (Safety Analysis Set) 
CT-15.1 
Summary of Mean Change From Baseline by Study Week in ADCS-ADL Total Score 
(Safety Analysis Set) 
CT-15.2 
Summary of Mean Change From Baseline by Study Week in MMSE Total Score (Safety 
Analysis Set) 
 


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Appendix 5 
List of Subject Data Listings 
 
AE-1 
Adverse Events (Subjects Assigned to Treatment) 
DEMOG-1 
Demographic Characteristics (Subjects Assigned to Treatment) 
DREAS-1 
Discontinued Subjects and Reason for Discontinuation (Subjects Assigned to 
Treatment) 
LAB-1 
Laboratory Test Results: Serum Chemistry (Subjects Assigned to Treatment) 
LAB-2 
Laboratory Test Results: Hematology (Subjects Assigned to Treatment) 
LAB-3 
Laboratory Test Results: Urinalysis (Subjects Assigned to Treatment) 
LAB-4 
Laboratory Test Results: Other Laboratory Tests (Subjects Assigned to Treatment) 
LAB-5 
Pregnancy Test (Subjects Assigned to Treatment) 
EFF-1 
Cohen-Mansfield Agitation Inventory (CMAI) (Subjects Assigned to Treatment) 
EFF-2 
Clinical Global Impression - Severity of Illness (CGI-S) (Subjects Assigned to 
Treatment) 
EFF-3 
Clinical Global Impression - Improvement (CGI-I) (Subjects Assigned to Treatment) 
 
 
 
 
 
PDATA-1.1 
Inclusion and Exclusion Criteria (Subjects Assigned to Treatment) 
PDATA-1.2 
Inclusion and Exclusion Criteria (Screening Failures) 
PDATA-2 
Treatment Assignment List (Subjects Assigned to Treatment) 
PDATA-3 
Study Completion Status and Reasons for Discontinuation (Subjects Assigned to 
Treatment) 
PDATA-4 
Medical History (Subjects Assigned to Treatment) 
PDATA-5 
Alzheimer’s Disease History (Subjects Assigned to Treatment) 
PDATA-6 
Patient Care (Subjects Assigned to Treatment) 
PDATA-7.1 
Prior and Concomitant Medications (Subjects Assigned to Treatment) 
PDATA-7.2 
Prior and Concomitant Therapy (Subjects Assigned to Treatment) 
PDATA-8 
Physical Examination (Subjects Assigned to Treatment) 
PDATA-9 
Vital Signs (Subjects Assigned to Treatment) 
PDATA-10 
Electrocardiogram Results (Subjects Assigned to Treatment) 
PDATA-11.1 
Sheehan-Suicidality Tracking Scale (S-STS) - Other than Q15 and Q16 (Subjects 
Assigned to Treatment) 
PDATA-11.2 
Sheehan-Suicidality Tracking Scale (S-STS) - Q15 (Subjects Assigned to Treatment) 
PDATA-11.3 
Sheehan-Suicidality Tracking Scale (S-STS) - Q16 (Subjects Assigned to Treatment) 
PDATA-12 
Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) (Subjects Assigned to 
Treatment) 
PDATA-13 
Barnes Akathisia Rating Scale (BARS) (Subjects Assigned to Treatment) 
PDATA-14 
Abnormal Involuntary Movement Scale (AIMS) (Subjects Assigned to Treatment) 
PDATA-15 
Mini-Mental State Examination (MMSE) (Subjects Assigned to Treatment) 
PDATA-16 
Alzheimer’s Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) 
(Subjects Assigned to Treatment) 
PDATA-17 
Post-treatment Follow-up (Subjects Assigned to Treatment) 
PDATA-18 
Screening Failures 
PDEV-1 
Major Protocol Deviations by Type of Deviation (Subjects Assigned to Treatment) 
SMED-1 
Study Medication Administration (Subjects Assigned to Treatment) 
SMED-2 
Study Medication Compliance (Subjects Assigned to Treatment) 
SUBEX-1 
Subjects Excluded From Analysis Set (Subjects Assigned to Treatment)