A Multicenter, Randomized, Open-label, 2-arm, 2-period Crossover Trial to Investigate the Effects of Food on the Pharmacokinetics of a Single Dose of Brexpiprazole Once-weekly (QW) Formulation in Patients With Schizophrenia
Phase: PHASE1
Conditions: Schizophrenia
Sponsor: Otsuka Pharmaceutical Co., Ltd.

 
 
CLINICAL STUDY PROTOCOL 
 
 
 
A multicenter, randomized, open-label, 2-arm, 2-period crossover trial to investigate the 
effects of food on the pharmacokinetics of a single dose of brexpiprazole once-weekly 
(QW) formulation in patients with schizophrenia 
 
A food effects trial of the pharmacokinetics of brexpiprazole once-weekly (QW) 
formulation in patients with schizophrenia 
 
 
 
 
NCT Number: NCT06036108 
Protocol No. 331-102-00151 
Version Date: 29 Aug 2024 (Version 1.0) 

Otsuka Pharmaceutical Co., Ltd.
Investigational Medicinal Product
Brexpiprazole (OPC-34712)
REVISED CLINICAL PROTOCOL
A multicenter, randomized, open-label, 2-arm, 2-period crossover trial to investigate the 
effects of food on the pharmacokinetics of a single dose of brexpiprazole once-weekly 
(QW) formulation in patients with schizophrenia
A food effects trial of the pharmacokinetics of brexpiprazole once-weekly (QW) 
formulation in patients with schizophrenia
Protocol No. 331-102-00151
CONFIDENTIAL  PROPRIETARY INFORMATION
Clinical Development Phase:
1
Sponsor:
Otsuka Pharmaceutical Co., Ltd.
Immediately Reportable Event: 
Office of Pharmacovigilance Operations,
Department of Pharmacovigilance
Amendment 1 Approval:
29 Aug 2024
(English Translation: 25 Sep 2024)
Approval (Japanese Original):
07 Jun 2023
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Table of Contents
Table of Contents ..........................................................................................2
List of In-text Tables.....................................................................................8
List of In-text Figures ...................................................................................9
List of Abbreviations...................................................................................10
1
Protocol Summary..............................................................................12
1.1
Synopsis ............................................................................................................12
1.2
Schema ..............................................................................................................23
1.3
Schedule of Assessments ..................................................................................25
1.3.1
General Inpatient Procedures..........................................................................30
1.3.2
Schedule of Assessments................................................................................30
1.3.2.1
Screening Period .........................................................................................30
1.3.2.2
IMP Administration Period: Period 1 Baseline Examination .....................32
1.3.2.3
IMP Administration Period: Period 1 Postdose ..........................................33
1.3.2.4
IMP Administration Period: Period 2 Baseline Examination .....................33
1.3.2.5
IMP Administration Period: Period 2 Postdose ..........................................33
1.3.2.6
Withdrawal..................................................................................................33
1.3.2.7
Follow-up Examination...............................................................................34
2
Introduction........................................................................................34
2.1
Trial Rationale...................................................................................................34
2.2
Background .......................................................................................................35
2.2.1
Treatment of Schizophrenia............................................................................35
2.2.2
Development History of Brexpiprazole..........................................................36
2.2.2.1
Nonclinical Data .........................................................................................37
2.2.2.2
Clinical Data ...............................................................................................38
2.3
Known and Potential Risks and Benefits ..........................................................46
3
Objectives and Endpoints..................................................................47
4
Trial Design.........................................................................................48
4.1
Type/Design of Trial .........................................................................................48
4.2
Scientific Rationale for Trial Design.................................................................49
4.3
Dosing Rationale...............................................................................................51
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4.3.1
Period 1 and Period 2......................................................................................51
4.4
Start and End-of-Trial Definitions ....................................................................53
4.5
Definition of Completed Subjects.....................................................................54
5
Trial Population..................................................................................54
5.1
Subject Selection and Numbering.....................................................................54
5.2
Eligibility Criteria .............................................................................................54
5.2.1
Inclusion Criteria ............................................................................................54
5.2.2
Exclusion Criteria...........................................................................................56
5.3
Lifestyle Considerations....................................................................................59
5.3.1
Meals and Dietary Restrictions.......................................................................59
5.3.2
Alcohol ...........................................................................................................61
5.3.3
Activity ...........................................................................................................61
5.4
Screen Failures ..................................................................................................61
6
Trial Treatments ................................................................................62
6.1
Investigational Medicinal Product Administration and Predosing....................62
6.1.1
Predosing Product...........................................................................................62
6.1.2
Investigational Medicinal Product..................................................................63
6.1.3
Medical Devices .............................................................................................64
6.2
Management of Investigational Medicinal Product ..........................................64
6.2.1
Packaging and Labeling..................................................................................64
6.2.2
Storage............................................................................................................64
6.2.3
Accountability.................................................................................................65
6.2.4
Returns and Destruction .................................................................................65
6.2.5
Reporting of Product Quality Complaints......................................................65
6.2.5.1
Eliciting and Reporting Product Quality Complaints .................................65
6.2.5.2
Information Required for Reporting Product Quality Complaints .............66
6.2.5.3
Return Process When Any Product Quality Complaint Is Received..........66
6.2.5.4
Assessment/Evaluation ...............................................................................66
6.2.6
Investigational Medicinal Product Reserve Sample Requirements................66
6.3
Measures to Minimize/Avoid Bias....................................................................66
6.4
Subject Compliance...........................................................................................67
6.5
Concomitant Medications or Therapies ............................................................67
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6.5.1
Prohibited Concomitant Medications or Therapies........................................67
6.5.2
Restricted Concomitant Medications or Therapies.........................................68
6.5.3
Rescue Medications........................................................................................69
6.6
Intervention after the End of the Trial...............................................................69
7
Stopping Rules, Withdrawal Criteria, and Procedures..................69
7.1
Entire Trial or Treatment...................................................................................69
7.2
Individual Site Discontinuation.........................................................................69
7.3
Individual Subject Discontinuation...................................................................70
7.3.1
Treatment Interruption....................................................................................70
7.3.2
Treatment Discontinuation .............................................................................70
7.3.3
Documenting Reasons for Treatment Interruption or Discontinuation ..........70
7.3.4
Withdrawal of Consent or Assent...................................................................71
7.3.5
Procedures to Encourage Continued Trial Participation ................................72
7.4
Definition of Subjects Lost to Follow-up..........................................................73
8
Trial Procedures.................................................................................73
8.1
Efficacy Assessments........................................................................................73
8.2
Pharmacokinetic Assessments...........................................................................73
8.2.1
Pharmacokinetic Plasma Samples ..................................................................73
8.3
Pharmacodynamic Assessments........................................................................74
8.4
Pharmacogenomic Assessments........................................................................74
8.4.1
Pharmacogenomic Samples............................................................................75
8.5
Biomarker Assessments ....................................................................................75
8.6
Future Biospecimen Research Samples ............................................................75
8.7
Safety Assessments ...........................................................................................78
8.7.1
Clinical Laboratory Assessments ...................................................................78
8.7.1.1
Hematology, Blood chemistry, Urinalysis, and Thyroid Function Test .....78
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8.7.1.2
Pregnancy Test (For Females of Child-bearing Potential)..........................79
8.7.2
Physical Examination .....................................................................................80
8.7.3
Vital Signs ......................................................................................................80
8.7.4
Electrocardiogram...........................................................................................81
8.7.5
Columbia-Suicide Severity Rating Scale........................................................82
8.7.6
Other Safety Variables....................................................................................83
8.7.6.1
Body Weight ...............................................................................................83
8.7.6.2
Drug-Induced Extrapyramidal Symptoms Scale.........................................83
8.7.6.3
Alcohol Breath Test ....................................................................................84
8.7.6.4
Urine Drug Screening .................................................................................84
8.8
Adverse Events..................................................................................................85
8.8.1
Definitions ......................................................................................................85
8.8.2
Eliciting and Reporting Adverse Events.........................................................87
8.8.3
Immediately Reportable Events......................................................................88
8.8.4
Medical Device Incidents (Including Malfunctions)......................................89
8.8.5
Adverse Events of Special Interest.................................................................89
8.8.6
Potential Serious Hepatotoxicity ....................................................................89
8.8.7
Procedure for Breaking the Blind...................................................................89
8.8.8
Follow-up of Adverse Events.........................................................................89
8.8.8.1
Follow-up of Nonserious Adverse Events ..................................................89
8.8.8.2
Follow-up of Immediately Reportable Events............................................89
8.8.8.3
Follow-up and Reporting of Immediately Reportable Events 
Occurring after Last Scheduled Contact .....................................................90
8.9
Treatment of Overdose......................................................................................90
8.10
Subject Assessment Recording .........................................................................90
8.11
Other Assessments ............................................................................................90
8.11.1
Height .............................................................................................................90
8.11.2
Clinical Global Impression - Severity of Illness.............................................91
8.11.3
Clinical Global Impression - Global Improvement ........................................91
8.11.4
Bowel-movement Investigation......................................................................91
9
Statistical Considerations ..................................................................92
9.1
Sample Size.......................................................................................................92
9.2
Datasets for Analysis.........................................................................................93
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9.2.1
Food Effect Analysis Set ................................................................................93
9.2.2
Safety Analysis Set.........................................................................................93
9.3
Handling of Missing Data for Primary Endpoint Analysis...............................93
9.4
Statistical Analyses ...........................................................................................93
9.4.1
Efficacy Analyses...........................................................................................93
9.4.2
Safety Analysis...............................................................................................93
9.4.2.1
Adverse Events ...........................................................................................93
9.4.2.2
Clinical Laboratory Data.............................................................................94
9.4.2.3
Physical Examination and Vital Signs........................................................94
9.4.2.4
Electrocardiogram Data ..............................................................................94
9.4.2.5
Columbia-Suicide Severity Rating Scale....................................................95
9.4.2.6
Other Safety Data........................................................................................95
9.4.3
Other Analyses................................................................................................95
9.4.3.1
Analysis of Demographic and Baseline Characteristics .............................95
9.4.3.2
Pharmacokinetic Analysis...........................................................................95
9.4.3.3
Pharmacodynamic Analysis........................................................................97
9.4.3.4
Pharmacokinetic/Pharmacodynamic Analysis............................................97
9.4.3.5
Pharmacogenomic Analysis........................................................................97
9.4.3.6
Exploratory Endpoint Analysis...................................................................97
9.5
Interim Analysis and Adaptive Design .............................................................97
9.5.1
Data Monitoring Committee...........................................................................97
10
Supporting Documentation and Operational Considerations .......98
10.1
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations.............98
10.1.1
Ethics and Responsibility ...............................................................................98
10.1.2
Informed Consent ...........................................................................................98
10.1.3
Confidentiality................................................................................................99
10.1.4
Quality Control and Quality Assurance..........................................................99
10.1.4.1
Monitoring ..................................................................................................99
10.1.4.2
Auditing ....................................................................................................100
10.1.5
Protocol Deviations ......................................................................................100
10.1.6
Records Management ...................................................................................100
10.1.6.1
Source Documents ....................................................................................100
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10.1.6.2
Data Collection .........................................................................................101
10.1.6.3
File Management at the Trial Site.............................................................102
10.1.6.4
Records Retention at the Trial Site ...........................................................102
10.1.6.5
Publication Authorship Requirements ......................................................102
10.2
Appendix 2: Clinical Laboratory Tests ...........................................................104
10.3
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information......................................................................................................105
10.5
Appendix 5: Sample Menus of High-fat Meals...............................................111
10.6
Appendix 6: Protocol Amendments ................................................................112
10.6.1
Protocol Amendment(s)/Administrative Change(s) .....................................112
11
References .........................................................................................114
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List of In-text Tables
Table 1.3-1
Schedule of Assessments...............................................................25
Table 1.3-2
Acceptable Windows.....................................................................30
................39
Table 3-1
Trial Objectives and Endpoints .....................................................47
Table 10.2-1
Clinical Laboratory Assessments ................................................104
Table 10.5-1
Sample High-fat Menus...............................................................111
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List of In-text Figures
Figure 1.2-1
Trial Design Schematic..................................................................23
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List of Abbreviations
Abbreviation
Definition
5-HT1A
5-hydroxytryptamine 1A
5-HT2A
5-hydroxytryptamine 2A
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC_%Extrap
percentage of AUC due to extrapolation from tlast to infinity [(AUC∞ 
− AUCt)/AUC∞ × 100]
AUC
area under the concentration-time curve from time zero to infinity
AUC
area under the concentration-time curve during a dosing interval () at 
steady-state
AUCt
area under the concentration-time curve calculated to the last 
observable concentration at time t 
BMI
body mass index
CGI-I
Clinical Global Impression - Global Improvement
CGI-S
Clinical Global Impression - Severity of Illness
CL/F
apparent clearance of drug from plasma after extravascular 
administration
Cmax
maximum (peak) plasma concentration of the drug 
CPK
creatine phosphokinase
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP2D6
cytochrome P450 2D6
CYP3A4
cytochrome P450 3A4
DIEPSS
Drug Induced Extra-Pyramidal Symptoms Scale 
DNA
deoxyribonucleic acid 
DSM-5®
Diagnostic and Statistical Manual of Mental Disorders Fifth Edition 
EDC
electronic data capture 
EDTA
ethylenediaminetetraacetic acid 
EM
extensive metabolizer 
FBR
Future Biospecimen Research 
FDA
(United States) Food and Drug Administration 
FT4
free thyroxine
GCP
Good Clinical Practice
IB
investigator brochure
ICH
The International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
ICMJE
International Committee of Medical Journal Editors
IM
intermediate metabolizer
IRE
immediately reportable event 
IWRS
interactive web response system
LSMD
least square mean difference 
λz
apparent terminal-phase disposition rate constant (first-order) 
OD
orally disintegrating
OROS
osmotic-controlled release oral delivery system
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Abbreviation
Definition
PANSS
Positive and Negative Syndrome Scale
PM
poor metabolizer
PQC
product quality complaint
QTc
corrected QT interval
QTcI
individually corrected QT interval
QTcF
QT interval corrected for heart rate using Fridericia’s formula
QW
quaque (once) weekly
t1/2,z
terminal-phase elimination half life
TEAE
treatment-emergent adverse event 
tlast
time of last measurable (positive) concentration 
tmax
time to maximum plasma concentration
TSH
thyroid-stimulating hormone
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1
Protocol Summary
1.1
Synopsis
Name of Sponsor: Otsuka Pharmaceutical Co., Ltd.
Name of Investigational Medicinal Product: Brexpiprazole (OPC-34712)
Protocol No.: 331-102-00151
Protocol Title:
A multicenter, randomized, open-label, 2-arm, 2-period crossover trial to investigate the 
effects of food on the pharmacokinetics of a single dose of brexpiprazole once-weekly 
(QW) formulation in patients with schizophrenia
Protocol Lay Person Short Title:
A food effects trial of the pharmacokinetics of brexpiprazole once-weekly (QW) 
formulation in patients with schizophrenia
Clinical Phase/Trial Type: 
Phase 1/clinical pharmacology trial
Planned Treatment/Indication: 
Schizophrenia
Trial Rationale:
Brexpiprazole conventional tablets, a once-daily oral formulation, has demonstrated 
efficacy and safety in the treatment of schizophrenia in clinical trials in subjects with 
schizophrenia conducted in Japan, the US, and Europe and is approved in Japan and 
overseas as a treatment for schizophrenia. In the treatment of schizophrenia, maintenance 
of drug compliance is thought to be instrumental in alleviating symptoms and achieving 
favorable outcomes; however, in comparison with other chronic diseases, schizophrenia 
is generally associated with poor drug adherence due mainly to lack of consciousness of 
disease and cognitive impairment. Long-acting drugs have been introduced into clinical 
practice as a measure to improve patient adherence to medication, but currently the only 
commercially available long-acting antipsychotics are all injectable formulations, thus 
reflecting an unmet medical need for more easy-to-use long-acting antipsychotics. Otsuka 
is now developing a once-weekly (QW) formulation, utilizing the same less invasive 
route of administration as conventional brexpiprazole, namely the oral route, but with a 
different formulation to enable reduced dosing frequency.
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Otsuka has conducted clinical pharmacology trials to investigate the pharmacokinetics 
(PK), tolerability, and safety of the brexpiprazole QW formulation administered as single 
and multiple oral doses in Japanese patients with schizophrenia and confirmed the 
tolerability and safety of the drug. Based on the PK results, Otsuka has made dose 
selection and is currently conducting a phase 3 confirmatory trial to investigate the 
efficacy and safety of the brexpiprazole QW formulation in patients with acute 
schizophrenia.
According to “Clinical Pharmacokinetic Studies of Pharmaceuticals” (Evaluation and 
Licensing Division, Pharmaceutical and Medical Safety Bureau [PMSB/ELD] 
Notification No. 796, dated 01 Jun 2001), “Drug Interaction Guidelines for Drug 
Development and Proper Informatics,” (Pharmaceutical Evaluation Division, 
Pharmaceutical Safety and Environmental Health Bureau [PSEHB/PED] Notification No. 
0723-6, dated 23 Jul 2018), and “Guidelines for Design and Evaluation of Sustained-
Release (Oral) Preparations” (Notification. No. 5 of the First Evaluation and Registration 
Division, PAB dated 11 Mar 1988), there is a requirement to investigate the effects of 
food on the final drug product, and therefore it was decided to evaluate food effects in 
this trial. Additionally, the design of this trial was made with reference to various 
guidance and guidelines, and tests and endpoints are items that are commonly performed.
Based on the above, the conduct of the planned trial based on this protocol is judged to be 
scientifically and ethically appropriate.
Objectives and Endpoints:
To investigate the effect of food on the PK of a single dose of brexpiprazole QW 
formulation at 48 mg in patients with schizophrenia and to confirm safety under those 
conditions.
Objectives
Endpoints
Primary objective:
To investigate the effect of food on PK of 
a single dose of brexpiprazole QW 
formulation at 48 mg in patients with 
schizophrenia
Primary pharmacokinetic endpoint:
Geometric mean ratio and two-sided 90% confidence 
interval of Cmax, AUC∞, and AUCt of brexpiprazole in 
plasma after administration in a fed state versus 
administration in a fasting state
Secondary pharmacokinetic endpoints:

Plasma concentrations of brexpiprazole and 
metabolite 

Pharmacokinetic parameters of brexpiprazole and 
metabolite 
in plasma
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Objectives
Endpoints
Secondary objective:
To confirm safety of the brexpiprazole QW 
formulation in patients with schizophrenia 
Safety endpoints:

Adverse events (AEs)

Clinical laboratory tests

Vital signs (body temperature, blood pressure, and 
pulse rate)

Physical examination findings

Body weight

Body mass index (BMI)

12-Lead electrocardiography (ECG)

Drug Induced Extrapyramidal Symptoms Scale 
(DIEPSS)

Columbia-Suicide Severity Rating Scale (C-SSRS)
Other endpoints:

Clinical Global Impression-Severity of Illness (CGI-
S)

Clinical Global Impression - Global Improvement 
(CGI-I) 

Bowel-movement investigation
Trial Design:
Multicenter, randomized, open-label, 2-arm, 2-period crossover trial
Trial Population:
Patients at least 18 years of age and below the age of 65 with a diagnosis of 
schizophrenia based on the diagnostic criteria proposed in the Diagnostic and Statistical 
Manual of Mental Disorders Fifth Edition (DSM-5®)
Inclusion/Exclusion Criteria:
Inclusion Criteria
Subjects are required to meet the following inclusion criteria at the specified assessment 
time points:
1) Patients at least 18 years of age and below the age of 65 at the time of informed 
consent
2) Patients with a diagnosis of schizophrenia based on DSM-5® at the time of 
informed consent
3) Patients who are able to be hospitalized for the protocol-defined hospitalization 
period
4) Patients with a body mass index [BMI = body weight (kg)/height (m)2] of 
18.5 kg/m2 or higher and lower than 35.0 kg/m2 at screening
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5) Patients who provide written informed consent before commencement of any 
trial-related procedures and whom the investigator judges to be capable of 
following all the conditions of this trial
6) Patients who, in the judgment of the investigator, have stable psychotic symptoms 
maintained by administration of an antipsychotic within the dosing range 
indicated below, before commencement of investigational medicinal product 
(IMP) administration
[Upper limit of dose and regimen]

Antipsychotic medication comprising no more than 2 active components, and

A daily dose equivalent to ≤ 600 mg/day of chlorpromazine
* If multiple antipsychotics are taken in the same day, this is to be the 
combined equivalent dose.
However, this does not include administration of antipsychotic medication at 
doses equivalent to less than 100 mg/day of chlorpromazine, which are not 
expected to have any antipsychotic effect.
7) Patients who are able to finish the high-fat meal specified in this protocol within 
20 minutes
Exclusion Criteria
Subjects will be excluded if they meet any of the following exclusion criteria at the 
specified assessment time points:
<Regarding medical history and complications>
1) Patients with a concurrent mental disorder besides schizophrenia who are judged 
by the investigator to be unsuitable for participation in the trial 
2) Patients who have met the DSM-5® diagnostic criteria for substance-related or 
addictive disorder, including alcohol and benzodiazepines but excluding caffeine 
and tobacco, within 180 days before commencement of IMP administration
3) Patients with a positive drug test at screening 
However, patients who tested positive for a drug other than cocaine may be 
included if their condition is not diagnosed as any substance-related or addictive 
disorder, according to the DSM-5® diagnostic criteria.
4) Patients who fall under any of the following criteria regarding suicidal ideation 
and suicidal behavior

Patients who answered “yes” to Question 4 “Active Suicidal Ideation with 
Some Intent to Act, without Specific Plan” or Question 5 “Active Suicidal 
Ideation with Specific Plan and Intent” regarding C-SSRS suicidal ideation at 
screening (for the past 6 months) or at the Period 1 baseline examination 
(since the last assessment)

Patients who exhibited suicidal behavior on C-SSRS at screening (for the past 
2 years) or at the Period 1 baseline examination (since the last assessment)

Patients who present a serious risk of suicide based on the judgment of the 
investigator
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5) Patients who have previously undergone gastrointestinal surgery that could affect 
PK evaluation
6) Patients who have undergone major surgery or blood transfusion or who have 
made a blood donation (whole blood or blood plasma) within 30 days before the 
acquisition of informed consent
7) Patients who have a clinically significant neurological, hepatic, renal, metabolic, 
hematological, immunological, cardiovascular, pulmonary, or gastrointestinal 
disorder.
Medical conditions that are minor or well-controlled may be considered 
acceptable if the condition does not interfere with safety and PK assessments.
8) Patients with any of the following laboratory or ECG values at screening 
(according to the results from the central laboratory or the central ECG 
laboratory)
Platelets:  75000/mm3(/μL)
Hemoglobin: ≤ 9 g/dL
Neutrophils, absolute:  ≤ 1000/mm3
Aspartate aminotransferase 
(AST): > 2 × upper limit of 
normal (ULN)
Alanine aminotransferase (ALT): > 2 × ULN
Creatine phosphokinase (CPK): 
> 3 × ULN
Creatinine:  2 mg/dL
QT interval corrected for heart 
rate using Fridericia’s formula 
(QTcF): > 450 milliseconds
9) Patients who fall under any of the following criteria at screening

Inadequately controlled hypertension (supine or sitting diastolic blood 
pressure of > 95 mmHg)

Symptomatic hypotension

Orthostatic hypotension, defined as a decrease of ≥ 30 mmHg in systolic 
blood pressure or a decrease of ≥ 20 mmHg in diastolic blood pressure after 
standing for at least 3 minutes compared with the supine values prior to 
standing
10) Patients meeting any of the following criteria

Patients with type 1 diabetes mellitus or patients with type 2 diabetes mellitus 
being treated with insulin

Patients with type 2 diabetes mellitus who have not been maintained on a 
stable regimen of anti-diabetic medication(s) or undergone diet/exercise 
therapy for at least 28 days prior to screening

Patients meeting either of the following criteria for poor blood glucose control 
at screening

Glycosylated hemoglobin (HbA1c) of ≥ 7.0% according to the global 
standard value

Fasting blood glucose level of ≥ 126 mg/dL or nonfasting blood glucose 
level of ≥ 200 mg/dL
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11) Patients with a complication of hypothyroidism or hyperthyroidism (except in 
cases where the condition has been kept stable for at least 90 days at the time of 
screening through drug therapy) or patients who show abnormal values for 
thyroid-stimulating hormone (TSH) and free thyroxin (FT4) in at screening
12) Patients with a complication of ischemic heart disease, myocardial infarction, or 
congestive heart failure (whether controlled or uncontrolled), or with a history of 
angioplasty, stenting, or coronary artery bypass surgery
13) Patients with a history or complication of epilepsy or seizures, except for 
childhood febrile seizures, post-traumatic seizures, alcohol withdrawal seizures, 
etc
14) Patients with a history or a complication of neuroleptic malignant syndrome
15) Patients with a history or a complication of paralytic ileus
16) Patients with a history or a complication of water intoxication
17) Patients with a history or a complication of rhabdomyolysis
18) Patients with a history or a complication of pulmonary embolism
<Prohibited concomitant medications/therapies>
19) Patients who are using clozapine at the time of informed consent
20) Patients who fail to meet the specified requisite washout periods for the prohibited 
concomitant drugs and foods (see Section 5.3 and Section 6.5.1) before 
commencement of IMP administration, or patients who are anticipated to take any 
of the prohibited drugs or foods during the trial
21) Patients whose clinical symptoms have worsened to the point where use of 
prohibited concomitant therapy or medication is required during the washout 
period for prior medication
<Allergies or drug reactions>
22) Patients who have allergy or hypersensitivity to brexpiprazole conventional tablet, 
orally disintegrating tablet (OD tablet), or brexpiprazole QW formulation, or 
patients for whom there are known safety concerns 
23) Patients to whom brexpiprazole is contraindicated in the package insert

Patients with coma

Patients under marked influence of CNS depressants such as barbiturates or 
anesthetics

Patients receiving adrenaline
24) Patients with a history of allergy to more than one medication
<Pregnancy>
25) Females who are breast-feeding and/or who have a positive pregnancy test result 
prior to receiving IMP
26) Sexually active males or females of childbearing potential (FOCBP), or their 
partners, who do not agree to practice 2 different approved methods of birth 
control or remain fully abstinent (periodic abstinence [eg, calendar, ovulation, 
symptothermal, and postovulation methods] or withdrawal are not acceptable 
methods of contraception) during the trial and for 28 days after the last dose of 
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IMP. If employing birth control, 2 of the following approved methods must be 
used: [vasectomy, tubal ligation, intrauterine device, birth control pill, or condom 
(all of which are approved or certified in Japan)]. A definition of childbearing 
potential can be found in Section 10.3.
<Others>
27) Patients who are involuntarily hospitalized under the Mental Health and Welfare 
Law of Japan, or prisoners
28)
.
29) Patients whose cytochrome P450 2D6 (CYP2D6) phenotype is judged to be either 
poor metabolizers (PM) or Unknown based on the results of CYP2D6 genetic 
testing at screening 
30) Patients judged by the investigator to be unsuitable for participation in the trial
31) Patients with a history of unexplained loss of consciousness
Trial Site(s):
Approximately 25 sites in Japan
Trial Intervention(s), Dose, Dosage Regimen, Treatment Duration, Formulation, 
Mode of Administration:
[Screening period]
Only brexpiprazole-naive subjects will be administered the following to verify that they 
have no acute hypersensitivity to brexpiprazole. Brexpiprazole conventional tablet and 
OD tablet used in this administration are classified as drugs used in the clinical trial other 
than the IMP (predosing products).
1) Predosing products: Brexpiprazole conventional tablet (1 mg), OD tablet (0.5 mg 
or 1 mg)
2) Dose and regimen
Brexpiprazole-naive subjects will undergo and complete oral administration of 
brexpiprazole conventional tablet 1 mg (1 mg × 1 tablet) or OD tablet 1 mg (1 mg 
× 1 tablet or 0.5 mg × 2 tablets) for 2 consecutive days no later than 20 days prior 
to commencement of brexpiprazole QW formulation administration in Period 1.
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[IMP administration period (Period 1 and Period 2)]
Subjects who meet all of the inclusion criteria and do not fall under any of the exclusion 
criteria will be randomized at a 1:1 ratio to either the fasting-state-administration-first 
group or the fed-state-administration-first group on the day before administration of the 
IMP in Period 1 (or on the day of IMP administration if preparation of the high-fat meal 
is completed in time) and will receive the IMP in Period 1 and Period 2 as follows. To the 
extent possible, the IMP will be administered at approximately the same time of day in 
both Period 1 and Period 2. 
Administration of IMP should be performed at least 
48 hours after symptoms of diarrhea have disappeared. For administration in the fed state 
in Period 1 or Period 2, if the high-fat meal cannot be eaten completely during the period 
specified in Section 5.3.1, the date of IMP administration may be postponed once only, 
after consultation with the subject.
1) IMP: brexpiprazole QW formulation 24 mg tablet
2) Dose and regimen
Fasting-state-administration-first group 
In Period 1, a single oral dose of two 24 mg tablets of brexpiprazole QW 
formulation (48 mg as brexpiprazole) will be administered with approximately 
150 mL of water following at least 10 hours of fasting. In Period 2, following at 
least 10 hours of fasting, the subject will consume a high-fat meal within 20 
minutes, after which a single oral dose of two 24 mg tablets of brexpiprazole QW 
formulation (48 mg as brexpiprazole) will be administered with approximately 
150 mL of water within 10 minutes of finishing the meal.
Fed-state-administration-first group
In Period 1, following at least 10 hours of fasting, the subject will consume a 
high-fat meal within 20 minutes, after which a single oral dose of two 24 mg 
tablets of brexpiprazole QW formulation (48 mg as brexpiprazole) will be 
administered with approximately 150 mL of water within 10 minutes of finishing 
the meal. In Period 2, a single oral dose of two 24 mg tablets of brexpiprazole 
QW formulation (48 mg as brexpiprazole) will be administered with 
approximately 150 mL of water following at least 10 hours of fasting.
Trial Assessments:
Assessments for Efficacy: None
Assessments for Safety: Adverse event (AE), clinical laboratory tests, vital signs, 
physical examination findings, body weight, 12-lead ECG, DIEPSS, C-SSRS
Assessments for Pharmacokinetics: Plasma drug concentration
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Other: Height, CGI-S, CGI-I, bowel-movement investigation, CYP2D6 genetic testing, 
deoxyribonucleic acid (DNA) storage (optional)
Data Monitoring Committee: No
Statistical Methods:
Analysis of primary efficacy endpoint
The natural log-transformed Cmax, AUC∞, and AUCt of brexpiprazole in plasma will be 
analyzed using a linear mixed-effects model with group (fasting-state-administration-first 
group or fed-state-administration-first group), meal condition (fasting or fed), and period 
(Period 1, Period 2) as fixed effects, and within-group subjects as a random effect, and 
the differences in means of natural log-transformed values between meal conditions (fed-
state administration − fasting-state administration) and their two-sided 90% confidence 
intervals will be calculated. The differences in the mean natural log-transformed values 
(fed-state administration − fasting-state administration) and their two-sided 90% 
confidence intervals will be inverse-transformed to calculate the ratio of geometric mean 
values (fed-state administration/fasting-state administration) and two-sided 90% 
confidence interval.
Sample size
The sample size was set as a sufficient number required to achieve a two-sided 90% 
confidence interval of the geometric mean ratios of Cmax, AUC∞, and AUCt following 
administration in the fed state versus the fasting state within a range of 0.8 to 1.25 under 
the assumption of absence of any food effects on the brexpiprazole QW formulation.
 
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Trial Duration:
Each subject in this trial is expected to participate in the following periods of the trial:

Screening period: Up to 42 days

IMP administration period: 57 days (including washout period and follow-up period)
The trial start is defined as the date the first subject signs their informed consent form. 
Overall, the trial duration from signing of the first informed consent form to the final 
subject assessment is expected to be 1 year and 7 months.
Known and Potential Risks and Benefits:
 
 
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Based on the above, it was considered that there are no major safety concerns regarding 
administration of a single dose of brexpiprazole QW formulation at 48 mg in either a 
fasting or fed state, and the risk is considered to be manageable by observing the subjects 
under hospitalization and exercising careful consideration of safety during the first week 
after administration of the IMP.
Since this trial is a clinical-pharmacology trial to investigate the effect of food on the PK 
of a single dose of brexpiprazole QW formulation at 48 mg in patients with 
schizophrenia, no benefit to subjects is expected.
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1.2
Schema
Figure 1.2-1
Trial Design Schematic
aBrexpiprazole-naive subjects will undergo and complete oral administration of brexpiprazole conventional tablet 1 mg (1 mg × 1 tablet) or OD tablet 1 mg 
(1 mg × 1 tablet or 0.5 mg × 2 tablets) for 2 consecutive days no later than 20 days prior to commencement of brexpiprazole QW formulation 
administration in Period 1, to verify that they have no allergic reaction or hypersensitivity.
b
. 
c
dThe meal will be a high-fat meal (approximately 900 kcal or more containing approximately 35% or more lipid content). For administration after a meal in 
Period 1 or Period 2, if the high-fat meal cannot be eaten completely during the period specified in Section 5.3.1, the date of IMP administration may be 
   Single administration
Single administration
Randomization
  Day −42
   Day −20
Day −1
 Day 8            Day 14
Day 28
Day 1
Day 8
Day 14
Either hospitalization
or outpatient visits
Either hospitalization
or outpatient visits
Either hospitalization
or outpatient visits
Hospitalization:
From Day −1 to Day 8
Hospitalization:
From Day −1 to Day 8
Patients with
schizophrenia
Fasting-state-
administration-
first group
QW formulation 48 mg
fasting-state administration
QW formulation 48 mg
        fed-state administration
d
Fed-state-
administration-
first group
QW formulation 48 mg
        fed-state administration
d
QW formulation 48 mg
fasting-state administration
Screening Examination
Day 1
Day 29
Period 1
b
Washout Period
Period 2
c
Follow-up Period
Screening Period
a
Predose
Examination
IMP Administration Period
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postponed once only. The date of IMP administration in Period 1 can be adjusted within a period of 42 days from the start date of screening and, with the 
date of IMP administration in Period 1 counted as Day 1, the date of IMP administration in Period 2 can be adjusted between Day 30 and Day 36. 
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1.3
Schedule of Assessments
The schedule of assessments is shown in Table 1.3-1. 
Table 1.3-1
Schedule of Assessments
IMP Administration Period
Screening 
Period
Period 1 
Baseline 
Examination
Period 1 (Administration of QW Formulation 48 mg in a Fasting 
or Fed State)
Day (per treatment period)
From −42
−1
1
2
3
4
6
8
11
14
Hours predose/postdose
—
−24
−2
0
3
9
24
36
48
72
120
168
240
312
Informed consenta
×
Informed consent for blood sampling 
for DNA storage (optional)
×
Inclusion/exclusion criteria
×
×
Demographic data (including height)
×
Subject registration
×
×
Predosingb
×
IMP administration
×c
Blood sampling for CYP2D6 genetic 
testingd
×
Blood sampling for DNA storage 
(optional)f
×
Blood sampling for plasma drug 
concentration measurement
×
×
×
×
×
×
×
×
×
×
×
Clinical lab testsg
×
×h
×
×
×
   TSH, FT4
×
   Urine drug screening
×
×
   Alcohol breath testi
×
×
   Pregnancy test (FOCBP only)j
×
×
×
Physical examination
×
×
×
×
×
×
×
×
×
×
×
×
Washoute
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Table 1.3-1
Schedule of Assessments
IMP Administration Period
Screening 
Period
Period 1 
Baseline 
Examination
Period 1 (Administration of QW Formulation 48 mg in a Fasting 
or Fed State)
Day (per treatment period)
From −42
−1
1
2
3
4
6
8
11
14
Hours predose/postdose
—
−24
−2
0
3
9
24
36
48
72
120
168
240
312
Vital signs (body temperature, pulse 
rate, blood pressure)k
×
×
×
×
×
×
×
×
Body weight
×
×
×
×
12-Lead ECGk
×
×l
×
×
×
×
×
DIEPSS
×
×
×
×
C-SSRS
×
×
×
×
×
×
×
×
×
CGI-S
×
×
×
CGI-I
×
×
Adverse events
Concomitant medications/therapies
Washoute
Bowel-movement investigationm
Hospitalization period
Outpatient visits 
permitted
Hospitalization
Outpatient visits 
permitted
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Table 1.3-1
Schedule of Assessments
IMP Administration Period
Period 2 
Baseline 
Examination
Period 2 (Administration of QW Formulation 48 mg in a 
Fasting or Fed State)
Follow-up 
Examination
Day (per treatment period)
−1
1
2
3
4
6
8
11
14
Hours predose/postdose
−24
−2
0
3
9
24
36
48
72
120
168
240
312
Examination 
at 
Withdrawaln
28 days after last 
dose of IMP
Informed consenta
Informed consent for blood sampling 
for DNA storage (optional)
Inclusion/exclusion criteria
Demographic data (including height)
Subject registration
×
×
×
Predosingb
IMP administration
×c
Blood sampling for CYP2D6 genetic 
testingd
Blood sampling for DNA storage 
(optional)f
Blood sampling for plasma drug 
concentration measurement
×
×
×
×
×
×
×
×
×
×
×
×
Clinical lab testsg
×
×
×
×
×
   TSH, FT4
   Urine drug screening
×
   Alcohol breath testi
×
   Pregnancy test (FOCBP only)j
×
×
×
Physical examination
×
×
×
×
×
×
×
×
×
×
×
×
×
Vital signs (body temperature, pulse 
rate, blood pressure)k
×
×
×
×
×
×
×
×
Body weight
×
×
×
×
12-Lead ECGk
×
×
×
×
×
×
×
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Table 1.3-1
Schedule of Assessments
IMP Administration Period
Period 2 
Baseline 
Examination
Period 2 (Administration of QW Formulation 48 mg in a 
Fasting or Fed State)
Follow-up 
Examination
Day (per treatment period)
−1
1
2
3
4
6
8
11
14
Hours predose/postdose
−24
−2
0
3
9
24
36
48
72
120
168
240
312
Examination 
at 
Withdrawaln
28 days after last 
dose of IMP
DIEPSS
×
×
×
×
×
×
C-SSRS
×
×
×
×
×
×
×
×
×
CGI-S
×
×
×
×
CGI-I
×
×
×
Adverse events
Concomitant medications/therapies
Bowel-movement investigationm
Hospitalization period
Hospitalization
Outpatient visits permitted
aBefore any trial-related tests or treatments, written informed consent will be obtained from subjects themselves (and from their legal representatives in the 
case of subjects who are hospitalized for reasons of medical protection) prior to the screening examination. 
bBrexpiprazole-naive subjects will undergo and complete oral administration of brexpiprazole conventional tablet 1 mg (1 mg × 1 tablet) or OD tablet 1 mg 
(1 mg × 1 tablet or 0.5 mg × 2 tablets) for 2 consecutive days no later than 20 days prior to commencement of brexpiprazole QW formulation 
administration in Period 1.
cFor fasting-state administration, IMP will be administered with approximately 150 mL of water following at least 10 hours of fasting. For administration in 
the fed state, following at least 10 hours of fasting, the subject will consume a high-fat meal within 20 minutes, after which IMP will be administered with 
approximately 150 mL of water within 10 minutes of finishing the meal. To the extent possible, the IMP will be administered at approximately the same 
time of day in both Period 1 and Period 2. 
Administration of IMP should be performed at least 48 hours after symptoms of diarrhea 
have disappeared. For administration in the fed state in Period 1 or Period 2, if the high-fat meal cannot be eaten completely during the period specified in 
Section 5.3.1, the date of IMP administration may be postponed once only. The date of IMP administration in Period 1 can be adjusted within a period of 
42 days from the start date of screening and, with the date of IMP administration in Period 1 counted as Day 1, the date of IMP administration in Period 2 
can be adjusted between Day 30 and Day 36. 
dSamples collected will be delivered to the central laboratory no later than 16 working days (excluding Saturdays, Sundays, and public holidays) before the 
scheduled date of administration of the IMP. Given that approximately 16 working days are required to obtain evaluation results, the schedule of IMP 
administration, etc, will be adjusted.
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e
fA blood sample should preferably be collected at the Period 1 baseline examination, but may be collected at any time during the trial. If repeat blood 
sampling is necessary, a blood sample will be collected at any feasible time during the trial.
gClinical laboratory tests comprise hematology, blood chemistry, and urinalysis. Blood sampling should be performed after at least 8 hours of fasting, to the 
extent possible. 
hIt is not necessary to perform this examination if fasting blood sampling was performed at screening (after at least 8 hours of fasting) and IMP administration 
is started within 14 days after screening examination.
iPerformed before any other examinations. If the test result is positive, then whether the trial can be continued without any problems will be determined, and 
only after a repeat alcohol breath test is negative will the other examinations be performed. 
jIf a urine test is positive, then a serum test will be performed.
kIf performed on the same day as blood collection, performing vital sign measurement and 12-lead ECG immediately after blood collection should be avoided 
and they should be performed prior to blood collection if at all possible.
lIt is not necessary to perform this examination if IMP administration is started within 14 days after screening examination.
mFrom Day −3 to Day 8 of Period 1 and Period 2, subjects will keep a record of the date and time of bowel movements (with multiple entries if there are 
multiple bowel movements) and the condition of the stool.
nPerformed only when withdrawal occurs during the period from administration of the IMP to completion of the Day 14 examination in Period 1 and Period 2. 
If the subject refuses to undergo the examination at the time of withdrawal or if the investigator decides that the examination cannot be performed due to an 
emergency or for other reasons, only feasible observations and tests will be performed.
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Table 1.3-2
Acceptable Windows
Standard Examination Time Point
Acceptable Windows for All Observations, Tests, and 
Assessments
Predose
Blood sampling for plasma drug concentration measurement, 
physical examination, vital signs: within 2 hours predose
Other: within 24 hours predose
3 hours postdose
±30 minutes
9 hours postdose
±30 minutes
12-lead ECG only: ±60 minutes
24, 36, 48, 72, and 120 hours postdose
±2 hours
168 hours postdose
±4 hours
240 and 312 hours postdose
±24 hours
Follow-up examination
+7 days at maximum
1.3.1
General Inpatient Procedures
Subjects will remain in either a seated or half-seated position for the first 4 hours 
following IMP administration except during brief periods where protocol-related 
procedures need to be performed. In addition, to prevent self-induced emesis resulting in 
loss of the oral dose, the subject’s restroom visits must be supervised and should be brief 
(< 10 minutes). Following the 4-hour postdose period, the subjects will be allowed to 
ambulate, but should not exercise strenuously.
1.3.2
Schedule of Assessments
1.3.2.1
Screening Period
Prior to any trial-related procedures, the investigator will explain information on the 
procedure and characteristics of the trial to subjects, obtain their written informed consent 
(as well as the consent of their parent/legal guardian if subjects are hospitalized for 
reasons of medical protection), and record the following subject information in the source 
documents and electronic case report form (eCRF). Subjects from whom informed 
consent has been obtained will also be registered in the interactive web response system 
(IWRS).

Date of informed consent

Subject identifier (ID)

Previous subject ID, if the subject was rescreened

Date of informed consent for DNA storage (optional)*
*Informed consent will be obtained before blood sampling for DNA storage (optional).
After informed consent is obtained, the following observations, tests, and assessments 
will be performed as screening procedures, and will be recorded together with the date of 
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conduct in the source documents and eCRF. Subjects’ eligibility to participate in the trial 
will be assessed. A screening examination will be performed within 42 days before IMP 
administration. The IMP does not necessarily have to be administered within 42 days 
after acquisition of informed consent.
[Items]

Result of eligibility assessment

Demographics (date of investigation, date of birth, sex at birth, possibility of 
pregnancy, race, ethnicity, country [Japan])

Date of initial diagnosis of schizophrenia

Complications (at the time of informed consent)

Medical and surgical histories (within 2 years before informed consent; however, all 
histories relating to inclusion/exclusion criteria should be obtained)

Height and body weight

Urine drug screening

Alcohol breath test (Performed before any other examinations. If the test result is 
positive, then whether the trial can be continued without any problems will be 
determined, and only after a repeat alcohol breath test is negative will the other 
examinations be performed.)

Pregnancy test (Only for female subjects of childbearing potential. If a urine test is 
positive, then a serum test will be performed.)

Clinical laboratory tests (including TSH and FT4 only at screening)

Blood sampling for CYP2D6 genetic testing (Samples collected will be delivered to 
the central laboratory no later than 16 working days [excluding Saturdays, Sundays, 
and public holidays] before the scheduled date of administration of the IMP. Given 
that approximately 16 working days are required to obtain evaluation results, the 
schedule of IMP administration, etc, will be adjusted.)

Physical examination

Vital signs (body temperature, pulse rate, and blood pressure) (If vital signs are 
measured on the same day as blood collection, measurement immediately after blood 
collection should be avoided and measurement should be carried out prior to blood 
collection if at all possible. Pulse rate and blood pressure will be measured in the 
supine position [performed first], sitting position, and standing position after each 
position is maintained for at least 3 minutes [blood pressure and pulse rate 
measurements in the supine and standing positions will take place only at screening].)

12-Lead ECG (If performed on the same day as blood collection, performing 12-lead 
ECG immediately after blood collection should be avoided and it should be 
performed prior to blood collection if at all possible.)

C-SSRS

AEs
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
Concomitant medications/therapies (all prior medications/therapies administered from 
30 days prior to informed consent)

Administration status of predosing product
Brexpiprazole-naive subjects will undergo and complete oral administration of 
brexpiprazole conventional tablet 1 mg (1 mg × 1 tablet) or OD tablet 1 mg (1 mg × 1 
tablet or 0.5 mg × 2 tablets) for 2 consecutive days no later than 20 days prior to 
commencement of brexpiprazole QW formulation administration in Period 1 to verify 
that they have no acute hypersensitivity to brexpiprazole.
1.3.2.2
IMP Administration Period: Period 1 Baseline Examination
The investigator will perform the observations, tests, and assessments indicated in 
Table 1.3-1, determine subject eligibility, and register subjects in IWRS. Subjects judged 
to be eligible will be randomized to either the fasting-state-administration-first group or 
the fed-state-administration-first group on the day before administration of the IMP (or 
on the day of IMP administration if preparation of the high-fat meal is completed in time) 
and will receive the IMP in either a fasting or fed state. 
The date of IMP 
administration can be adjusted within a period of 42 days from the start date of screening, 
and administration of IMP should be performed at least 48 hours after symptoms of 
diarrhea have disappeared. If IMP administration is postponed, the observations, tests, 
and assessments for Day −1 and Day 1 shown in Table 1.3-1 will be repeated before 
administration of the IMP (although blood sampling for DNA storage does not need to be 
repeated). The starting date of hospitalization, the results of eligibility assessment, the 
date of randomization, the outcome of randomization (fasting-state-administration-first 
group or fed-state-administration-first group), and the results of observations, tests, and 
assessments will be recorded together with the date of conduct in the source documents 
and eCRF. From 3 days before IMP administration (Day −3) to 7 days after IMP 
administration (Day 8), subjects will keep a record of the date and time of bowel 
movements (with multiple entries if there are multiple bowel movements) and the 
condition of the stool. If IMP administration cannot be adjusted within a period of 42 
days from the start date of screening and has to be discontinued, re-screening and re-
randomization of the subject are possible. In such a case, the subject must once again 
provide written informed consent and be assigned a new subject ID prior to the screening 
examination.
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1.3.2.3
IMP Administration Period: Period 1 Postdose
The investigator will perform the observations, tests, and assessments shown in 
Table 1.3-1 and will record them together with the date of conduct in the source 
documents and eCRF.
1.3.2.4
IMP Administration Period: Period 2 Baseline Examination
The investigator will perform the observations, tests, and assessments shown in 
Table 1.3-1, and will record them together with the date of conduct and the starting date 
of hospitalization in the source documents and eCRF. The investigator will also 
determine the appropriateness of transitioning to IMP administration in Period 2 and will 
register subjects in IWRS. If administration is performed in the fasting state in Period 1, 
then administration will be performed in the fed state in Period 2. If administration is 
performed in the fed state in Period 1, then administration will be performed in the 
fasting state in Period 2. 
If IMP 
administration is postponed, the observations, tests, and assessments for Day −1 and 
Day 1 shown in Table 1.3-1 will be repeated before administration of the IMP. From 3 
days before IMP administration (Day −3) to 7 days after IMP administration (Day 8), 
subjects will keep a record of the date and time of bowel movements (with multiple 
entries if there are multiple bowel movements) and the condition of the stool.
1.3.2.5
IMP Administration Period: Period 2 Postdose
The investigator will perform the observations, tests, and assessments shown in 
Table 1.3-1 and will record them together with the date of conduct in the source 
documents and eCRF.
1.3.2.6
Withdrawal
When withdrawal occurs during the period from administration of the IMP to completion 
of the Day 14 examination in Period 1 and Period 2, the investigator will perform the 
observations, tests, and assessments shown in Table 1.3-1 as soon as possible after a 
decision is made to withdraw the subject, ideally on the day of withdrawal, and will 
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record them together with the date of conduct in the source documents and eCRF. If the 
subject refuses to undergo the examination at the time of withdrawal or if the investigator 
decides that the examination cannot be performed due to an emergency or for other 
reasons, only feasible observations and tests will be performed. Subjects who withdraw 
during the period from administration of the IMP in Period 1 to completion of the Day 14 
examination in Period 2 will be registered in IWRS.
1.3.2.7
Follow-up Examination
The investigator will perform the observations, tests, and assessments shown in 
Table 1.3-1 at 28 days (acceptable window: +7 days) after the date of the last dose of 
IMP and will record them together with the date of conduct in the source documents and 
eCRF, and will also record those subjects who completed the follow-up examination in 
the IWRS.
2
Introduction
Brexpiprazole is a chemical entity that works through a combination of partial agonist 
activity at dopamine D2 receptors and serotonin 1A (5-HT1A) receptors and antagonist 
activity at serotonin 2A (5-HT2A) receptors.1 The brexpiprazole once-weekly (QW) 
formulation is a once-weekly oral formulation and is currently under development as a 
treatment for schizophrenia.
Please refer to the brexpiprazole (OPC-34712) Investigator’s Brochure (IB) for more 
detailed information.
2.1
Trial Rationale
Brexpiprazole conventional tablets, a once-daily oral formulation, has demonstrated 
efficacy and safety in the treatment of schizophrenia in clinical trials in subjects with 
schizophrenia conducted in Japan, the US, and Europe and is approved in Japan and 
overseas as a treatment for schizophrenia. In the treatment of schizophrenia, maintenance 
of drug compliance is thought to be instrumental in alleviating symptoms and achieving 
favorable outcomes; however, in comparison with other chronic diseases, schizophrenia 
is generally associated with poor drug adherence due mainly to lack of consciousness of 
disease and cognitive impairment. Long-acting drugs have been introduced into clinical 
practice as a measure to improve patient adherence to medication, but currently the only 
commercially available long-acting antipsychotics are all injectable formulations, thus 
reflecting an unmet medical need for more easy-to-use long-acting antipsychotics. Otsuka 
is now developing a once-weekly (QW) formulation, utilizing the same less invasive 
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route of administration as conventional brexpiprazole, namely the oral route, but with a 
different formulation to enable reduced dosing frequency.
Otsuka has conducted clinical pharmacology trials to investigate the pharmacokinetics 
(PK), tolerability, and safety of the brexpiprazole QW formulation administered as single 
and multiple oral doses in Japanese patients with schizophrenia and confirmed the 
tolerability and safety of the drug. Based on the PK results, Otsuka has made dose 
selection and is currently conducting a phase 3 confirmatory trial to investigate the 
efficacy and safety of the brexpiprazole QW formulation in patients with acute 
schizophrenia.
According to “Clinical Pharmacokinetic Studies of Pharmaceuticals” (Evaluation and 
Licensing Division, Pharmaceutical and Medical Safety Bureau [PMSB/ELD] 
Notification No. 796, dated 01 Jun 2001), “Drug Interaction Guidelines for Drug 
Development and Proper Informatics,” (Pharmaceutical Evaluation Division, 
Pharmaceutical Safety and Environmental Health Bureau [PSEHB/PED] Notification No. 
0723-6, dated 23 Jul 2018), and “Guidelines for Design and Evaluation of Sustained-
Release (Oral) Preparations” (Notification. No. 5 of the First Evaluation and Registration 
Division, PAB dated 11 Mar 1988), there is a requirement to investigate the effects of 
food on the final drug product, and therefore it was decided to evaluate food effects in 
this trial. Additionally, the design of this trial was made with reference to various 
guidance and guidelines,2,3,4 and tests and endpoints are items that are commonly 
performed.
Based on the above, the conduct of the planned trial based on this protocol is judged to be 
scientifically and ethically appropriate.
2.2
Background
2.2.1
Treatment of Schizophrenia
Schizophrenia is a condition primarily characterized by positive symptoms such as 
hallucinations and delusions and negative symptoms such as apathy, lack of spontaneity, 
and social withdrawal, and is likely to have a chronic course. The prevalence of 
schizophrenia in the world is reported to be around 0.5%, though this percentage varies 
depending on the country.5,6 In the acute phase characterized by hallucinations, 
delusions, and psychomotor agitation, impulsive behaviors and positive symptoms should 
be controlled, while in the maintenance phase, it is vital to prevent recurrence/relapse of 
symptoms, maintain the alleviated condition, and improve cognitive function or at least 
not impair cognitive function in the course of treatment. It is recommended that 
pharmacotherapy should be performed as the mainstay of treatment in the acute phase, 
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should be continued for at least 6 months in the recovery phase, in which patients are 
recovering from acute psychotic conditions,7 and should be further continued for at least 
1 year, and perhaps permanently, in the maintenance phase.7,8 In either treatment phase, 
it has been noted that absence of medication is associated with the persistence of 
symptoms9,10 and an increase in the incidence of relapse and risks of hospitalization and 
suicide.11 Continuous treatment for an appropriate period is considered to contribute to 
the alleviation of symptoms as well as to good outcomes by preventing recurrence/relapse 
from occurring.9 However, in comparison with other chronic diseases, schizophrenia is 
generally associated with poor drug adherence due mainly to lack of consciousness of 
disease and cognitive impairment on the part of patients.7,8,9,12
As a measure to improve patient adherence to medication, long-acting drugs have been 
introduced into clinical practice. However, it is known that long-acting drugs are 
associated with the risk of causing injection site reactions (pain, swelling, itching, and 
induration), which are adverse reactions not caused by oral medications, as well as the 
risk of exacerbating or prolonging symptoms even after treatment discontinuation due to 
adverse reactions, because long-acting drugs remain in the body for a prolonged period 
instead of being rapidly excreted after administration.13 Some patients resist receiving 
injectable drugs out of fear of injection site reactions or injections themselves.13 Under 
these circumstances, it may be considered that there is an expectation for the 
development of long-acting formulations that are easier to use and contribute to 
continuation of treatment.
2.2.2
Development History of Brexpiprazole
Brexpiprazole is a new chemical entity discovered by Otsuka Pharmaceutical Co., Ltd. 
(hereinafter referred to as “Otsuka”) that works through a combination of partial agonist 
activity at dopamine D2 receptors and 5-HT1A receptors and antagonist activity at 
5-HT2A receptors.1
Brexpiprazole was studied in clinical trials in the United States (US) and Europe and was 
first granted marketing approval in the US in July 2015 as treatment for schizophrenia 
and an adjunctive therapy to antidepressants for the treatment of major depressive 
disorder. Further development of this drug for other psychiatric disorders is now ongoing 
in the US. Brexpiprazole was also proven to be effective and safe in clinical trials in 
Japanese patients with schizophrenia and was granted marketing approval in Japan in 
January 2018. The drug is currently undergoing further development for other psychiatric 
conditions.
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The approved regimen for brexpiprazole in Japan and other countries is once-daily oral 
administration. As stated above, maintenance of drug compliance is considered 
instrumental in alleviating symptoms and achieving favorable outcomes in the treatment 
of schizophrenia, but currently the only commercially available long-acting 
antipsychotics are all injectable formulations. With the goal of improving the current 
status of pharmacotherapy for schizophrenia, Otsuka is developing an oral brexpiprazole 
once-weekly formulation (hereinafter referred to as “QW formulation”) that can reduce 
the dosing frequency with the same “less invasive” route of administration as the existing 
brexpiprazole.
Otsuka has conducted clinical pharmacology trials to investigate the pharmacokinetics 
(PK), tolerability, and safety of the brexpiprazole QW formulation administered as single 
and multiple oral doses in Japanese patients with schizophrenia, and has made dose 
selection based on the PK results and confirmed the tolerability and safety of the drug. 
Accordingly, the brexpiprazole QW formulation is currently undergoing further 
development.
The results of nonclinical and clinical studies related to this drug are summarized below.
2.2.2.1
Nonclinical Data
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2.2.2.2
Clinical Data
Please refer to the brexpiprazole IB for further information.
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.
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2.3
Known and Potential Risks and Benefits
 
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Since this trial is a clinical-pharmacology trial to investigate the effect of food on the PK 
of a single dose of brexpiprazole QW formulation at 48 mg in patients with 
schizophrenia, no benefit to subjects is expected.
Further information on brexpiprazole and information regarding adverse reactions are 
presented in the IB. Trial sites will receive updated versions of the IB, when available, 
and trial sites should refer to the most current version as needed.
3
Objectives and Endpoints
To investigate the effect of food on the PK of a single dose of brexpiprazole QW 
formulation at 48 mg in patients with schizophrenia and to confirm safety under those 
conditions.
Table 3-1
Trial Objectives and Endpoints
Objectives
Endpoints
Primary objective:
To investigate the effect of food on PK 
of a single dose of brexpiprazole QW 
formulation at 48 mg in patients with 
schizophrenia
Primary pharmacokinetic endpoint:
Geometric mean ratio and two-sided 90% confidence interval 
of Cmax, AUC∞, and AUCt of brexpiprazole in plasma after 
administration in a fed state versus administration in a fasting 
state
Secondary pharmacokinetic endpoints:

Plasma concentrations of brexpiprazole and metabolite 

Pharmacokinetic parameters of brexpiprazole and 
metabolite 
in plasma
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Table 3-1
Trial Objectives and Endpoints
Objectives
Endpoints
Secondary objective:
To confirm safety of the brexpiprazole 
QW formulation in patients with 
schizophrenia
Safety endpoints:

AEs

Clinical laboratory tests

Vital signs (body temperature, blood pressure, and pulse 
rate)

Physical examination findings

Body weight

BMI

12-Lead ECG

DIEPSS

C-SSRS
Other endpoints:

CGI-S

CGI-I

Bowel-movement investigation
BMI = body mass index; CGI-I = Clinical Global Impression - Global Improvement; CGI-S = Clinical 
Global Impression-Severity of Illness; C-SSRS = Columbia-Suicide Severity Rating Scale; 
DIEPSS = Drug Induced Extrapyramidal Symptoms Scale.
Section 9.4 describes the statistical analysis of the endpoints.
4
Trial Design
4.1
Type/Design of Trial
The trial design schematic is shown in Figure 1.2-1 and the schedule of assessments is 
shown in Table 1.3-1.
This is a multicenter, randomized, open-label, 2-arm, 2-period crossover trial to 
investigate the effects of food on the PK of brexpiprazole QW formulation in patients 
with a diagnosis of schizophrenia (295.90) based on DSM-5®. The trial consists of 2 
periods, namely, the screening period and the IMP administration period (including 
washout period and follow-up period). The IMP administration period comprises Period 1 
and Period 2 to investigate the effects of food on the PK of brexpiprazole QW 
formulation 48 mg, in which a single oral dose of brexpiprazole QW formulation will be 
administered at 48 mg in a fasting state or within 10 minutes of finishing a high-fat meal 
employing a 2-arm, 2-period crossover design. The sample size necessary for the trial 
assessment is a total of 36 subjects as trial completers.
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4.2
Scientific Rationale for Trial Design
 
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4.3
Dosing Rationale
4.3.1
Period 1 and Period 2
A single oral dose of brexpiprazole QW formulation at 48 mg will be administered with 
approximately 150 mL of water in a fasting state (following at least 10 hours of fasting) 
or within 10 minutes after the completion of a high-fat meal consumed over 20 minutes 
or less following at least 10 hours of fasting.
[Rationale]
Dosing regimen is based on a commonly adopted dosing regimen for the evaluation of 
food effects with reference to the Guidelines for Bioequivalence Studies on Generic 
Drugs3 and the FDA’s guidance on food effect assessment.2 A high-fat meal, which is 
considered to have more pronounced food effects, is the type of meal selected.
The dosing unit of the brexpiprazole QW formulation is a 24 mg tablet. With reference to 
the FDA’s guidance on food effect assessment,2 this trial will use 48 mg. This dose, 
which is assumed will be the clinically recommended dose of the brexpiprazole QW 
formulation and which is used in phase 3 trials, is the dose at which the PK of 
brexpiprazole is likely to be more susceptible to food effects than the 24 mg dose. 
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4.4
Start and End-of-Trial Definitions
The trial start is defined as the first visit of the first subject, which is the date the first 
subject signs their informed consent form (ICF). The end-of-trial date is defined as the 
last date of contact, or the date of final contact attempt as recorded on the post-treatment 
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follow-up electronic case report form (eCRF) page for the last subject completing or 
withdrawing from the trial.
4.5
Definition of Completed Subjects
The treatment period is defined as the time period during which subjects are evaluated for 
primary and/or secondary objectives of the trial. 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 complete Day 14 blood sampling for plasma drug 
concentration measurement in Period 2 will be defined as trial completers.
5
Trial Population
Patients at least 18 years of age and below the age of 65 with a diagnosis of 
schizophrenia based on the diagnostic criteria proposed in the DSM-5®
5.1
Subject Selection and Numbering
5.2
Eligibility Criteria
Exceptions for eligibility criteria will not be permitted during the trial, neither by the 
investigator nor by the medical monitor.
5.2.1
Inclusion Criteria
Subjects are required to meet the following inclusion criteria at the specified assessment 
time points:
1) Patients at least 18 years of age and below the age of 65 at the time of informed 
consent
2) Patients with a diagnosis of schizophrenia based on DSM-5® at the time of 
informed consent
3) Patients who are able to be hospitalized for the protocol-defined hospitalization 
period
4) Patients with a body mass index [BMI = body weight (kg)/height (m)2] of 
18.5 kg/m2 or higher and lower than 35.0 kg/m2 at screening
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5) Patients who provide written informed consent before commencement of any 
trial-related procedures and whom the investigator judges to be capable of 
following all the conditions of this trial
6) Patients who, in the judgment of the investigator, have stable psychotic symptoms 
maintained by administration of an antipsychotic within the dosing range 
indicated below, before commencement of IMP administration
[Upper limit of dose and regimen]

Antipsychotic medication comprising no more than 2 active components, and

A daily dose equivalent to ≤ 600 mg/day of chlorpromazine
* If multiple antipsychotics are taken in the same day, this is to be the 
combined equivalent dose.
However, this does not include administration of antipsychotic medication at 
doses equivalent to less than 100 mg/day of chlorpromazine, which are not 
expected to have any antipsychotic effect.
7) Patients who are able to finish the high-fat meal specified in this protocol within 
20 minutes
[Rationale for Inclusion Criteria]
1) The age range is based on epidemiological data on the age of onset and 
prevalence of schizophrenia. An age of 18 years was set as the lower limit 
because individuals of this age can take responsibility for their own health and 
drug therapy as adults and are competent for informed consent. An age of less 
than 65 years was set as the upper limit so as to exclude the elderly for their safety 
and because they are more likely to suffer complications, which may have an 
effect on the safety evaluation. The upper limit of age is also based on the 
guideline, Studies in Support of Special Populations: Geriatrics (PAB/NDD 
Notification No. 104, dated 02 Dec 1993), in which the elderly are defined as 
individuals aged 65 years or older.
2) This criterion was set to identify patients with schizophrenia.
3) This criterion was set in consideration of the effects on PK assessment and subject 
safety.
4) This criterion was set to minimize interindividual PK variations due to obesity. 
Since this trial is conducted in patients, the upper limit for obesity or adiposity 
was set at BMI < 35.0 kg/m2 based on the criteria proposed by the Japan Society 
for the Study of Obesity.
5) This criterion was set for ethical reasons.
6) This criterion was set in consideration of subject safety.
7) This criterion was set because this trial is designed to evaluate food effect on PK 
and meal conditions need to be uniform for appropriate assessment.
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5.2.2
Exclusion Criteria
Subjects will be excluded if they meet any of the following exclusion criteria at the 
specified assessment time points:
<Regarding medical history and complications>
1) Patients with a concurrent mental disorder besides schizophrenia who are judged 
by the investigator to be unsuitable for participation in the trial
2) Patients who have met the DSM-5® diagnostic criteria for substance-related or 
addictive disorder, including alcohol and benzodiazepines but excluding caffeine 
and tobacco, within 180 days before commencement of IMP administration
3) Patients with a positive drug test at screening
However, patients who tested positive for a drug other than cocaine may be 
included if their condition is not diagnosed as any substance-related or addictive 
disorder, according to the DSM-5® diagnostic criteria.
4) Patients who fall under any of the following criteria regarding suicidal ideation 
and suicidal behavior

Patients who answered “yes” to Question 4 “Active Suicidal Ideation with 
Some Intent to Act, without Specific Plan” or Question 5 “Active Suicidal 
Ideation with Specific Plan and Intent” regarding C-SSRS suicidal ideation at 
screening (for the past 6 months) or at the Period 1 baseline examination 
(since the last assessment)

Patients who exhibited suicidal behavior on C-SSRS at screening (for the past 
2 years) or at the Period 1 baseline examination (since the last assessment)

Patients who present a serious risk of suicide based on the judgment of the 
investigator
5) Patients who have previously undergone gastrointestinal surgery that could affect 
PK evaluation
6) Patients who have undergone major surgery or blood transfusion or who have 
made a blood donation (whole blood or blood plasma) within 30 days before the 
acquisition of informed consent
7) Patients who have a clinically significant neurological, hepatic, renal, metabolic, 
hematological, immunological, cardiovascular, pulmonary, or gastrointestinal 
disorder.
Medical conditions that are minor or well-controlled may be considered 
acceptable if the condition does not interfere with safety and PK assessments.
8) Patients with any of the following laboratory or ECG values at screening 
(according to the results from the central laboratory or the central ECG 
laboratory)
Platelets:  75000/mm3(/μL)
Hemoglobin: ≤ 9 g/dL
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Neutrophils, absolute: ≤ 1000/mm3
Aspartate aminotransferase 
(AST): > 2 × upper limit of 
normal (ULN)
Alanine aminotransferase (ALT): > 2 × ULN
CPK: > 3 × ULN
Creatinine:  2 mg/dL
QT interval corrected for heart 
rate using Fridericia’s formula 
(QTcF): > 450 milliseconds
9) Patients who fall under any of the following criteria at screening

Inadequately controlled hypertension (supine or sitting diastolic blood 
pressure of > 95 mmHg)

Symptomatic hypotension

Orthostatic hypotension, defined as a decrease of ≥ 30 mmHg in systolic 
blood pressure or a decrease of ≥ 20 mmHg in diastolic blood pressure after 
standing for at least 3 minutes compared with the supine values prior to 
standing
10) Patients meeting any of the following criteria

Patients with type 1 diabetes mellitus or patients with type 2 diabetes mellitus 
being treated with insulin

Patients with type 2 diabetes mellitus who have not been maintained on a 
stable regimen of anti-diabetic medication(s) or undergone diet/exercise 
therapy for at least 28 days prior to screening

Patients meeting either of the following criteria for poor blood glucose control 
at screening

Glycosylated hemoglobin (HbA1c) of ≥ 7.0% according to the global 
standard value

fasting blood glucose level of ≥ 126 mg/dL or nonfasting blood glucose 
level of ≥ 200 mg/dL
11) Patients with a complication of hypothyroidism or hyperthyroidism (except in 
cases where the condition has been kept stable for at least 90 days at the time of 
screening through drug therapy) or patients who show abnormal values for 
thyroid-stimulating hormone (TSH) and free thyroxin (FT4) in at screening
12) Patients with a complication of ischemic heart disease, myocardial infarction, or 
congestive heart failure (whether controlled or uncontrolled), or with a history of 
angioplasty, stenting, or coronary artery bypass surgery
13) Patients with a history or complication of epilepsy or seizures, except for 
childhood febrile seizures, post-traumatic seizures, alcohol withdrawal seizures, 
etc
14) Patients with a history or a complication of neuroleptic malignant syndrome
15) Patients with a history or a complication of paralytic ileus
16) Patients with a history or a complication of water intoxication
17) Patients with a history or a complication of rhabdomyolysis
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18) Patients with a history or a complication of pulmonary embolism
<Prohibited concomitant medications/therapies>
19) Patients who are using clozapine at the time of informed consent
20) Patients who fail to meet the specified requisite washout periods for the prohibited 
concomitant drugs and foods (see Section 5.3 and Section 6.5.1) before 
commencement of IMP administration, or patients who are anticipated to take any 
of the prohibited drugs or foods during the trial
21) Patients whose clinical symptoms have worsened to the point where use of 
prohibited concomitant therapy or medication is required during the washout 
period for prior medication
<Allergies or drug reactions>
22) Patients who have allergy or hypersensitivity to brexpiprazole conventional tablet, 
OD tablet, or brexpiprazole QW formulation, or patients for whom there are 
known safety concerns
23) Patients to whom brexpiprazole is contraindicated in the package insert

Patients with coma

Patients under marked influence of CNS depressants such as barbiturates or 
anesthetics

Patients receiving adrenaline
24) Patients with a history of allergy to more than one medication
<Pregnancy>
25) Females who are breast-feeding and/or who have a positive pregnancy test result 
prior to receiving IMP
26) Sexually active males or females of childbearing potential (FOCBP), or their 
partners, who do not agree to practice 2 different approved methods of birth 
control or remain fully abstinent (periodic abstinence [eg, calendar, ovulation, 
symptothermal, and postovulation methods] or withdrawal are not acceptable 
methods of contraception) during the trial and for 28 days after the last dose of 
IMP. If employing birth control, 2 of the following approved methods must be 
used: [vasectomy, tubal ligation, intrauterine device, birth control pill, or condom 
(all of which are approved or certified in Japan)]. A definition of childbearing 
potential can be found in Section 10.3.
<Others>
27) Patients who are involuntarily hospitalized under the Mental Health and Welfare 
Law of Japan, or prisoners
28)
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29) Patients whose CYP2D6 phenotype is judged to be either PM or Unknown based 
on the results of CYP2D6 genetic testing at screening
30) Patients judged by the investigator to be unsuitable for participation in the trial
31) Patients with a history of unexplained loss of consciousness
[Rationale for Exclusion Criteria]
1) though 4), 7) through 19), 21) through 27), and 29): These criteria were set based on 
safety considerations.
5) This criterion was set to ensure appropriate PK assessment.
6), 20), 28), and 30): These criteria were set to ensure appropriate PK assessment and in 
consideration of safety.
31) This criterion is specified to exclude patients who, although they have not received a 
diagnosis such as ventricular tachycardia or ventricular fibrillation, nevertheless have the 
potential risk of sudden death.
Subjects must agree to the restrictions specified in Section 5.3 and Section 6.5.1.
5.3
Lifestyle Considerations
The following lifestyle considerations apply for the trial:

Meals and diets

Alcohol

Activity
5.3.1
Meals and Dietary Restrictions
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5.3.2
Alcohol
5.3.3
Activity
5.4
Screen Failures
A screen failure is a subject from whom informed consent is obtained and is documented 
in writing (ie, subject signs an ICF), but who is not randomized. All AEs must be 
reported after subject informed consent has been obtained, including screening failures 
due to AEs, irrespective of administration of drugs used in the clinical trial.
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If the subject meets the definition of a screen failure in this trial, the following 
information will be recorded in the source documents and eCRF:

Date of informed consent

Date of screening examination

Demographics (date of investigation, date of birth, sex at birth, race, ethnicity, 
country [Japan])

Result of eligibility assessment

Administration status of predosing product

Screen failure date

Reason for screen failure

AEs
Subjects excluded for positive drug/alcohol screen or for CYP2D6 PM or Unknown 
phenotype are not eligible to be rescreened. However, subjects excluded for other reasons 
may be rescreened at any time if the exclusion characteristic has changed. If a 
reexamination can be performed within the acceptable window of the screening period, it 
will not be necessary to obtain reconsent and only the tests relevant to changed 
characteristic will be performed. If a reexamination cannot be performed within the 
acceptable window of the screening period, new written consent must be obtained and a 
new subject ID assigned prior to screening examination.
6
Trial Treatments
6.1
Investigational Medicinal Product Administration and Predosing
The drugs used in the clinical trial are indicated below. Please refer to the most current 
version of the brexpiprazole IB for further information.
Drugs used in the clinical trial other than the IMP (predosing products): Brexpiprazole 
conventional tablet (1 mg) or OD tablet (0.5 mg or 1 mg)
IMP: brexpiprazole QW formulation 24 mg tablet
6.1.1
Predosing Product
The predosing method is indicated below.
Screening period
Only brexpiprazole-naive subjects will be administered the following to verify that they 
have no acute hypersensitivity to brexpiprazole. Regarding the status of predosing, 
whether or not predosing is performed, the type of brexpiprazole tablet (conventional 
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tablet or OD tablet), the start and end dates of predosing, and the dose per day (mg) will 
be recorded in the source documents and eCRF.
1) Predosing products: Brexpiprazole conventional tablet (1 mg) or OD tablet 
(0.5 mg or 1 mg)
2) Dose and regimen
Brexpiprazole-naive subjects will undergo and complete oral administration of 
brexpiprazole conventional tablet 1 mg (1 mg × 1 tablet) or OD tablet 1 mg (1 mg 
× 1 tablet or 0.5 mg × 2 tablets) for 2 consecutive days no later than 20 days prior 
to commencement of brexpiprazole QW formulation administration in Period 1.
6.1.2
Investigational Medicinal Product
The IMP administration method is indicated below. Please refer to Section 4.1 for the 
administration method and treatment duration for each period and each treatment group. 
Regarding the status of trial treatment, the date and time of IMP administration and the 
dose (the number of tablets taken) will be recorded in the source documents and eCRF. 
The status of meal consumption will also be recorded in the source documents and eCRF 
(see Section 5.3.1).
1) IMP: brexpiprazole QW formulation 24 mg tablet
2) Dose and regimen
Period 1 and Period 2
Subjects who meet all of the inclusion criteria and do not fall under any of the exclusion 
criteria will be randomized at a 1:1 ratio to either the fasting-state-administration-first 
group or the fed-state-administration-first group on the day before administration of the 
IMP in Period 1 (or on the day of IMP administration if preparation of the high-fat meal 
is completed in time) and will receive the IMP in Period 1 and Period 2 as follows. To the 
extent possible, the IMP will be administered at approximately the same time of day in 
both Period 1 and Period 2. 
For administration in the fed state 
in Period 1 or Period 2, if the high-fat meal cannot be eaten completely during the period 
specified in Section 5.3.1, the date of IMP administration may be postponed once only, 
after consultation with the subject.
1) Fasting-state-administration-first group
In Period 1, a single oral dose of two 24 mg tablets of brexpiprazole QW 
formulation (48 mg as brexpiprazole) will be administered with approximately 
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150 mL of water following at least 10 hours of fasting. In Period 2, following at 
least 10 hours of fasting, the subject will consume a high-fat meal within 20 
minutes, after which a single oral dose of two 24 mg tablets of brexpiprazole QW 
formulation (48 mg as brexpiprazole) will be administered with approximately 
150 mL of water within 10 minutes of finishing the meal.
2) Fed-state-administration-first group
In Period 1, following at least 10 hours of fasting, the subject will consume a 
high-fat meal within 20 minutes, after which a single oral dose of two 24 mg 
tablets of brexpiprazole QW formulation (48 mg as brexpiprazole) will be 
administered with approximately 150 mL of water within 10 minutes of finishing 
the meal. In Period 2, a single oral dose of two 24 mg tablets of brexpiprazole 
QW formulation (48 mg as brexpiprazole) will be administered with 
approximately 150 mL of water following at least 10 hours of fasting.
6.1.3
Medical Devices
Not applicable.
6.2
Management of Investigational Medicinal Product
For full details on IMP management, please refer to the brexpiprazole IB and separate 
manual. The predosing products (brexpiprazole conventional tablets 1 mg or OD tablets 
0.5 mg or 1 mg) stored at the trial site will be used for predosing. They will not be 
provided by the sponsor for the purpose of predosing.
6.2.1
Packaging and Labeling
The IMP will be provided by the sponsor or designated agent to the IMP manager. 
6.2.2
Storage
The IMP will be stored in a securely locked cabinet or enclosure. Access will be limited 
to the IMP manager.
The IMP will be stored according to the conditions indicated on the IMP label.
The trial site staff will maintain a temperature log in the IMP storage area to record the 
temperature.
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6.2.3
Accountability
The IMP manager must maintain an inventory record of IMP received, dispensed, 
administered, and returned. The IMP manager may not provide IMP to any subject not 
participating in this trial.
The drugs used in the clinical trial other than the IMP that are not supplied by the sponsor 
and that are used from those stored at the trial site should be managed according to the 
site-specific procedures for handling, storage, and dispensing.
6.2.4
Returns and Destruction
Upon completion or termination of the trial, unused IMP and partially used IMP must be 
returned to the sponsor or a designated agent. All IMP returned to the sponsor must be 
accompanied by the appropriate documentation and be clearly identified by protocol 
number and trial site number on the outermost shipping container. Returned supplies 
should be in the original containers. The assigned trial monitor will facilitate the return of 
used IMP containers, unused IMP, and partially used IMP.
6.2.5
Reporting of Product Quality Complaints
A Product Quality Complaint (PQC) is any written, electronic, or oral communication 
provided by a healthcare professional, consumer, clinical trial subject, medical 
representative, regulatory agency, partner, or other third party that alleges deficiencies 
related to the identity, quality, durability, reliability, safety, effectiveness, or performance 
of a Medical Device or Medicinal Product or a falsified, tampered, or diverted product 
after it is released for distribution to a clinical trial. 
Examples include, but are not limited to, communications involving:

Failure/malfunction of a medicinal product to meet any of its specifications

Incorrect or missing labeling

Packaging issues (eg, damaged, dirty, crushed, missing product)

Blister defects (eg, missing, empty blisters)

Product defect (eg, odor, chipped, broken, embossing illegible)

Loss or theft of product
6.2.5.1
Eliciting and Reporting Product Quality Complaints
The investigator or designee must record all PQCs identified through any means from the 
receipt of the IMP from the sponsor or sponsor’s designee, through and including 
reconciliation and up to destruction, including subject dosing. The investigator or 
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designee must notify the sponsor or sponsor’s designee of the information indicated in 
Section 6.2.5.2 by e-mail (address: 
) immediately after 
becoming aware of any PQC.
Identification of a PQC by the subject should be reported to the site investigator, who 
should then follow the reporting mechanism above.
6.2.5.2
Information Required for Reporting Product Quality Complaints

Description of complaint

Reporter identification (eg, subject, investigator, site, etc.)

Reporter contact information (eg, address, phone number, e-mail address)

ID of material (product/compound name, kit number)

Clinical protocol reference (number and/or trial name)

Dosage form/strength (if known)

Pictures of complaint sample (if available)

Availability of complaint sample for return
6.2.5.3
Return Process When Any Product Quality Complaint Is 
Received
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 return instructions 
as needed.
It must be documented in the site accountability record that the complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation.
6.2.5.4
Assessment/Evaluation
Assessment and evaluation of PQCs will be handled by the sponsor.
6.2.6
Investigational Medicinal Product Reserve Sample Requirements
Not applicable.
6.3
Measures to Minimize/Avoid Bias
Since the primary endpoint in this trial is based on plasma drug concentrations, bias does 
not arise from not implementing blinding.
This trial will be conducted in a randomized, open-label, 2-arm, 2-period crossover 
fashion. Subjects who meet all of the inclusion criteria and do not fall under any of the 
exclusion criteria will be randomized at a 1:1 ratio to either the fasting-state-
administration-first group or the fed-state-administration-first group on the day before 
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administration of the IMP in Period 1 (or on the day of IMP administration if preparation 
of the high-fat meal is completed in time).
6.4
Subject Compliance
Subjects will be placed under the supervision of the investigator. The investigator will 
instruct subjects to:
1) Comply with the specified dose and regimen when taking the predosing product 
and IMP,
2) Adhere to the specified schedule during the trial,
3) Observe the lifestyle restrictions during the trial (see Section 5.3),
4) Cooperate in bowel-movement investigation from 3 days before IMP 
administration (Day −3) until 7 days postdose (Day 8) in Period 1 and Period 2,
5) Not take any prohibited concomitant medications (see Section 6.5.1), 
6) Not receive any prohibited concomitant therapies (see Section 6.5.1), and
7) Not disclose any information obtained through participation in the trial to any 
third party.
For subjects who meet the criteria specified in Section 7, the required measures must be 
taken.
6.5
Concomitant Medications or Therapies
The investigator will record all medications (prescription medications, over-the-counter 
medications, herbal remedies, etc) and therapies taken by the subject from 30 days prior 
to signing of informed consent through the last scheduled contact in the source 
documents and eCRF. The investigator will record all medications and therapies taken by 
the subject for treatment of an AE or which caused an AE until the end of the trial 
(defined as the last date of contact or date of final contact attempt) in the source 
documents and eCRF.
For concomitant medications, the following will be recorded in the source documents and 
eCRF: medication, indication, dose, frequency, route, start date and end date. For 
concomitant therapy, the following will be recorded in the source documents and eCRF: 
therapy, indication, start date and end date.
6.5.1
Prohibited Concomitant Medications or Therapies
The use of the following medications is prohibited from the specified date and time 
through the last scheduled contact:
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The use of the following medications is prohibited from the specified date and time until 
completion of Day 14 examination in Period 2 or withdrawal examination:
The use of the following non-drug therapy is prohibited from the day of informed consent 
until completion of Day 14 examination or withdrawal examination in Period 2:
6.5.2
Restricted Concomitant Medications or Therapies
The use of the following medications is restricted from the day of IMP administration in 
Period 1 until completion of Day 14 examination in Period 2 or withdrawal examination, 
except for prohibited concomitant medications:

Antipsychotics other than brexpiprazole
The use of other antipsychotics at a steady dose and regimen is permitted. The dose or 
frequency may be reduced at the discretion of the investigator in response to 
symptom improvement or maintenance or from a safety perspective. As-needed use is 
not allowed.
The upper limit of dose and regimen of antipsychotics are as follows:

Antipsychotic medication comprising no more than 2 active components, and

A daily dose equivalent to ≤ 600 mg/day of chlorpromazine

If multiple antipsychotics are taken in the same day, this is to be the combined 
equivalent dose.

Chlorpromazine equivalent doses are based on Equivalent Conversion Table 
for Antipsychotics, as specified separately.
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However, this does not include administration of antipsychotic medication at doses 
equivalent to less than 100 mg/day of chlorpromazine, which are not expected to have 
any antipsychotic effect.

Antiparkinsonian drugs and valbenazine
The use of these medications is permitted only when extrapyramidal symptoms are 
present and such use is necessary in the opinion of the investigator. The dose and 
regimen must comply with the instructions in the package insert, and dosing within 
12 hours before Drug Induced Extrapyramidal Symptoms Scale (DIEPSS) assessment 
must be avoided. Prophylactic use is not allowed. Therefore, in subjects who are 
using antiparkinsonian drugs or valbenazine at the time of informed consent, even if 
they are without a history of extrapyramidal symptoms related to the concomitant 
medications, use of these medications must be suspended by the day of IMP 
administration.
Before new use or dose increase of such medications, extrapyramidal symptoms will 
be assessed by DIEPSS.

Beta-blockers
The use of β-blockers will be permitted only for the treatment of nonpsychiatric 
complications (eg, cardiovascular disorders) and only if the dose and regimen remain 
unchanged from before participation in the trial.
6.5.3
Rescue Medications
Not applicable.
6.6
Intervention after the End of the Trial
Not applicable.
7
Stopping Rules, Withdrawal Criteria, and Procedures
7.1
Entire Trial or Treatment
If the sponsor terminates or suspends the trial for any reason, prompt notification will be 
given to the head of the trial site and regulatory authorities in accordance with regulatory 
requirements.
7.2
Individual Site Discontinuation
Individual trial site participation may be discontinued by the sponsor, the investigator, or 
the IRB/IEC/EC if judged to be necessary for medical, safety, regulatory, ethical, or other 
reasons consistent with applicable laws, regulations, and Good Clinical Practice (GCP). 
The head of the trial site will notify the sponsor promptly if the investigator or the 
IRB/IEC/EC at the site discontinues participation in the trial.
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7.3
Individual Subject Discontinuation
7.3.1
Treatment Interruption
Not applicable.
7.3.2
Treatment Discontinuation
After treatment assignment, IMP administration may be discontinued for a variety of 
reasons. Treatment discontinuations may be initiated by a subject who is not satisfied 
with treatment or may become medically necessary due to AEs, required treatment with a 
disallowed medication or therapy, or other issues, as determined by the investigator. 
However, each investigator must comprehensively review the circumstances and offer the 
subject options for continued treatment to the degree possible as described in 
Section 7.3.5.
7.3.3
Documenting Reasons for Treatment Interruption or 
Discontinuation
A subject may discontinue the IMP for the reasons listed below. Only one reason for 
discontinuation (the main reason) and the date of discontinuation will be recorded in the 
source documents and eCRF. Any AE related to treatment discontinuation must always 
be regarded as the reason for the discontinuation.

Adverse event

Death

Continuing IMP places the subject at undue risk as determined by the investigator

Safety concern that is possibly, probably, or likely related to IMP

SAE

Exacerbation or progression of the underlying disease

Subject decides to discontinue because of annoyance or discomfort due to a 
nonserious AE which is not otherwise determined to be an undue hazard

Subject vomits within 12 hours after IMP administration

Subject shows allergic reaction or hypersensitivity to brexpiprazole

Other potentially IMP-related safety concerns or AEs

Occurrence of major protocol deviation

Failure to meet the inclusion/exclusion criteria (however, treatment 
discontinuation based on assessment of the results of clinical laboratory tests and 
central ECG assessment in Period 1 baseline examination is not considered a 
protocol deviation)

Randomized by mistake
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
Subject uses, or it is considered that the subject needs to use, any prohibited 
concomitant medication or therapy

Noncompliance with IMP administration

Failure to take the specified number of IMP tablets on the day of IMP 
administration

Protocol-specific withdrawal criterion met

Prior to IMP administration in Period 1 and Period 2, the subject is unable to 
finish the prescribed high-fat meal within 30 minutes after starting to eat and also 
fails to complete IMP administration after finishing eating within 30 minutes after 
starting to eat (however, the date of IMP administration may be postponed once 
only, after consultation with the subject)

Subjects with a positive drug screen for cocaine, or subjects with a positive drug 
screen for any other drug who are dependent on the drug or are unlikely to 
overcome their drug dependency in the opinion of the investigator

Subjects with a positive alcohol breath test who are dependent on alcohol or are 
unlikely to overcome their alcohol dependency in the opinion of the investigator

Lost to follow-up

Investigator’s decision (other than AE)

Pregnancy (see Section 10.3)

Trial site terminated by sponsor

Trial terminated by sponsor

Request by the subject’s parent/legal guardian to discontinue treatment (including 
consent withdrawal by the subject’s parent/legal guardian)

Request by the subject to discontinue treatment (including consent withdrawal by the 
subject)

Other
If the subject discontinues IMP due to an AE, the investigator, or other trial personnel, 
will make every effort to follow the event until it has resolved or stabilized. Follow-up 
procedures in Section 7.3.2 must be followed.
7.3.4
Withdrawal of Consent or Assent
Each subject has the right to withdraw their consent from further participation in the trial 
at any time without prejudice. Subjects can withdraw consent for use of data which has 
not previously been anonymously transferred into trial data sets collected as part of the 
trial and can only withdraw consent for future participation. The investigator can also 
discontinue a subject’s participation in the trial at any time if medically necessary. Unless 
the subject provides their written withdrawal of consent or there is other written 
documentation by the investigator confirming the subject’s verbal intent to completely 
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withdraw from the trial, subjects should be followed for all protocol-specified evaluations 
and assessments, if possible.
Complete withdrawal of consent requires a subject’s refusal of ALL of the following 
methods of follow-up:

Participation in all follow-up procedures specified in the protocol (whether in-clinic, 
by telephone, or by a home visit).

Participation in a subset of protocol-specified follow-up procedures (by a frequency 
schedule and method, as agreed by subject and trial site staff).

Contact of the subject by trial personnel, even if only by telephone, to assess current 
medical condition, and obtain necessary medical or laboratory reports relevant to the 
trial’s objectives.

Contact of alternative person(s) who have been designated in source records as being 
available to discuss the subject’s medical condition, even if only by telephone, mail, 
or e-mail (eg, family, spouse, partner, legal representative, friend, neighbor, or 
physician).

Access to medical information from alternative sources (eg, hospital/clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, social media sources).
Withdrawal of consent is a critical trial event and, therefore, should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent. 
The reasons for a subject’s intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial. 
A subject may initially express their desire to discontinue IMP administration, which is 
not equivalent to a complete withdrawal of consent for further participation (see 
Section 7.3.2). A subject may, however, indicate that further trial participation is creating 
a burden on their work, school, or social schedule. Therefore, the investigator should 
follow the procedures outlined in Section 7.3.3 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 methods of follow-up are considered to have completely withdrawn their 
consent to participate in the trial.
Details on the withdrawal of consent from the optional Future Biospecimen Research 
(FBR) substudy are provided in the ICF for FBR.
7.3.5
Procedures to Encourage Continued Trial Participation
In all cases of impending IMP discontinuation or consent withdrawal, investigators will 
be instructed to meet and discuss (without undue coercion) with the subject their options 
of continuing in the trial, preferably on therapy. The investigator should ensure 
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understanding and documentation of the reasons for the subject’s desire to withdraw 
consent.
7.4
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted during the trial period, who do not have a known 
reason for discontinuation (eg, withdrew consent or AE), and for whom a survival status 
at the end of the trial cannot be determined will be classified as “lost to follow-up.” 
Survival status can be determined from a variety of sources, either by obtaining 
acceptable documentation for death (ie, death certificate, medical records, public records, 
statement by a family member or primary care physician) or acceptable documentation 
for life (ie, direct contact with the subject, medical records, successful telephone contact 
with the subject, statement by a family member or primary care physician, or public 
records).
The site will make 3 documented attempts to contact the subject by telephone and in the 
event the site is unable to reach the subject by telephone, the site will attempt to contact 
the subject via certified mail or an alternative similar method, where appropriate, before 
assigning a “lost to follow-up” status.
If the subject was classified as “lost to follow-up,” “Were you able to contact the 
subject?,” “Date of contact/Date of final contact attempt,” and “Contact method” will be 
recorded in the source documents and eCRF.
8
Trial Procedures
The assessments to be conducted during the trial are summarized in Table 1.3-1.
8.1
Efficacy Assessments
Not applicable.
8.2
Pharmacokinetic Assessments
Blood samples for plasma drug concentration measurement will be collected at the time 
points described in the schedule of assessments (Table 1.3-1).
8.2.1
Pharmacokinetic Plasma Samples
1) Time Points for Blood Sampling
Blood samples for drug concentration measurement will be collected at the time 
points described in the schedule of assessments (Table 1.3-1). The acceptable window 
for blood sampling time points should follow Table 1.3-2. Whether or not a blood 
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sample is collected and the date and time of blood sampling will be recorded in the 
source documents and the eCRF.
2) Blood Sampling and Measurement Methods
Blood samples (2 mL) will be collected in vacutainers containing heparin and 
processed into plasma to determine the concentrations of brexpiprazole and 
metabolite 
by validated high performance liquid chromatography-tandem 
mass spectrometry. Metabolites that are not identified in the protocol may also be 
analyzed, if needed. In addition, blood samples for drug concentration measurement 
may be used for the investigation of a bioanalytical method, if needed.
All plasma samples will be shipped to the bioanalytical laboratory. The bioanalytical 
laboratory will submit an electronic file containing the final data to the sponsor. 
Therefore, there is no need to record the results of measurements in the source 
documents and the eCRF.
Details of the sample collection, handling, and shipping methods are provided in 
separately prepared procedures.
3) Rationale for Time Points for Blood Sampling
8.3
Pharmacodynamic Assessments
Not applicable.
8.4
Pharmacogenomic Assessments
Cytochrome P450 2D6 genetic testing is mandatory.
[Rationale for pharmacogenomic assessment]
Cytochrome P450 3A4 and CYP2D6 are involved in the metabolism of brexpiprazole, 
and CYP2D6 is known to have multiple genotypes with different enzyme activities. 
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Therefore, in this trial it has been decided to investigate CYP2D6 genotypes which are 
involved in the PK variability of brexpiprazole. Cytochrome P450 2D6 genetic testing 
will be performed as part of screening to exclude from the trial subjects with reduced or 
unknown CYP2D6 activity (see Section 4.3.1).
8.4.1
Pharmacogenomic Samples
Blood samples for CYP2D6 genetic testing will be collected at the time points described 
in the schedule of assessments (Table 1.3-1). Whether or not sample collection is 
performed and the date of blood sampling will be recorded in the source documents and 
the eCRF.
Blood samples (2 mL) will be collected in vacutainers containing 
ethylenediaminetetraacetic acid (EDTA). Genomic DNA will be extracted from a whole 
blood sample and used to determine genotypes and related phenotypes for CYP2D6. The 
method used to determine these genotypes may also generate genotype data for additional 
genes related to absorption, distribution, metabolism, and excretion. Phenotyping of these 
additional genes is not currently planned but may be considered in the future. If so, the 
phenotyping data may be included in a PK analysis to be reported separately.
All pharmacogenomic (PGx) samples will be shipped to the PGx laboratory. The PGx 
laboratory will perform PGx analyses and submit the results of phenotype determination 
to the sponsor and investigator. After dating and signing the clinical laboratory test 
report, the investigator will record the results of phenotype determination in the source 
documents and eCRF. The analysis results will be disclosed to subjects by the 
investigator only at their request.
The PGx laboratory will submit an electronic file containing the final data to the sponsor.
Details of the sample collection, handling, and shipping methods are provided in 
separately prepared procedures.
8.5
Biomarker Assessments
Not applicable.
8.6
Future Biospecimen Research Samples
.
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8.7
Safety Assessments
Details pertaining to the definitions, collection, reporting, and follow-up of AEs are 
described in Section 8.8. Each safety assessment will be performed at the time points 
described in the schedule of assessments (Table 1.3-1).
8.7.1
Clinical Laboratory Assessments
8.7.1.1
Hematology, Blood chemistry, Urinalysis, and Thyroid Function 
Test
Clinical laboratory samples will be collected to perform the clinical laboratory 
assessments described in Section 10.2. The total volume of blood to be collected during 
the trial will be documented in the ICF.
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Refer to Section 8.7.6 for urine drug screening and alcohol breath test.
1) Timing
Refer to Table 1.3-1.
Blood sampling should be performed after at least 8 hours of fasting, to the extent 
possible.
2) Test Items
Refer to Section 10.2.
3) Methods
Clinical laboratory tests for the items listed in the table in Section 10.2 will be 
performed at specified time points using test kits supplied by the central laboratory. 
The central laboratory will analyze the samples and report the analysis results as 
needed to the investigator for review. The investigator will then date and sign the 
clinical laboratory test report to make it an official document. Whether or not blood 
and urine samples are collected, the date and time of blood sampling and the date and 
time of urine sampling, and whether or not the subject has fasted for at least 8 hours 
will be recorded in the source documents and the eCRF. As the results of clinical 
laboratory tests are reported directly from the central laboratory to the sponsor as an 
electronic file, they do not need to be recorded in the source documents or the eCRF. 
For the procedures for the collection, handling, and shipment of samples, the 
separately prepared procedures should be followed.
8.7.1.2
Pregnancy Test (For Females of Child-bearing Potential)
1) Timing
Refer to Table 1.3-1.
2) Test Items
Pregnancy test (human chorionic gonadotropin [hCG] in urine)
3) Methods
A urine pregnancy test will be performed at the specified time points on FOCBPs (all 
women excluding sterile and postmenopausal women). If a urine test is positive, then 
a serum test will be performed. Whether or not a urine sample is collected for urine 
pregnancy test, the date and time of urine sampling and the test result, and if a serum 
pregnancy test is performed, whether or not a blood sample is collected and the date 
and time of blood sampling will be recorded in the source documents and the eCRF. 
A serum pregnancy test will be performed by the central laboratory selected by the 
sponsor. For the correct procedures for the collection, handling, and shipment of 
samples, separate procedures will be prepared and provided prior to the start of the 
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trial. The central laboratory will report the results of tests to the investigator, who will 
review the results of tests and date and sign the clinical laboratory test report to make 
it an official document. As the results of serum tests will be reported directly from the 
central laboratory to the sponsor as an electronic file, they do not need to be recorded 
in the source documents or the eCRF.
For FOCBPs, a pregnancy test will be performed before initiation of any trial 
procedure and the test result must be obtained before the first dose of IMP.
A sterile woman is defined as a woman who successfully underwent a reproductive 
sterilization procedure (hysterectomy and bilateral ovariectomy). A postmenopausal 
woman is defined as a woman who has been amenorrheic for at least 12 months 
without any medical cause.
8.7.2
Physical Examination
1) Timing
Refer to Table 1.3-1.
2) Test Items
Head, eye, ear, nose, and throat, chest, abdomen, limb, nerves, and skin mucosa
3) Methods
The investigator will perform a physical examination of the subject and record 
findings in the source documents. At screening, whether or not examination is 
performed and the date, time, and results of examination will be recorded in the 
eCRF. Thereafter, whether or not examination is performed and the date and time of 
examination will be recorded in the eCRF. As far as possible, the same assessor will 
perform assessment of the same subject throughout the trial period.
8.7.3
Vital Signs
Subjects should be monitored for potentially clinically significant vital signs values.
1) Timing
Refer to Table 1.3-1.
Measurement immediately after blood collection should be avoided (measurement 
prior to blood collection if at all possible)
2) Test Items
Body temperature, systolic and diastolic blood pressure (in supine, sitting, and 
standing positions), and pulse rate (in supine, sitting, and standing positions)
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3) Methods
Body temperature will be measured in increments of 0.1°C, and whether or not 
measurement is performed, the date and time of measurement, and the measurement 
results will be recorded in the source documents and eCRF.
Blood pressure and pulse rate measurement at screening will be performed in the 
supine position followed by the sitting and standing positions. Measurement in each 
position will be performed after that position has been maintained for at least 3 
minutes and whether or not measurement is performed, posture at measurement, the 
date and time of measurement, and the measurement results will be recorded in the 
source documents and eCRF. At time points other than screening, vital signs will be 
measured only in the sitting position after that position has been maintained for at 
least 3 minutes, and whether or not vital signs are measured, posture at measurement, 
the date and time of measurement, and the measurement results will be recorded in 
the source documents and the eCRF. In the event that the subject complains of 
symptoms suggestive of orthostatic hypotension before assessment at any time point 
after the Period 1 baseline examination, vital signs will also be measured in the 
supine and standing positions, in the order of supine, sitting, and standing positions, 
as done at screening, wherever possible.
8.7.4
Electrocardiogram
Subjects should be monitored for potentially clinically significant ECG results.
1) Timing
Refer to Table 1.3-1.
Measurement immediately after blood collection should be avoided (measurement 
prior to blood collection if at all possible)
2) Methods
ECG will be recorded with the subject in a supine position and having been at rest for 
at least 5 minutes. The 12-lead electrocardiograph provided by the central ECG 
laboratory will be used to record ECGs. Measurement results for heart rate, RR 
interval, PR interval, QRS interval, QT interval, and QTc interval (QTcF) will be 
analyzed at the central ECG laboratory. The investigator will confirm the results of 
analysis reported by the central ECG laboratory and date and sign the analysis result 
report to make it an official document. The investigator will make a judgment by 
referring to the analysis result report sent from the central ECG laboratory and record 
whether or not measurement is performed and the date and time of measurement, 
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normal/abnormal judgment, and any abnormal findings in the source documents and 
eCRF.
ECG results for this trial will be analyzed at the central ECG laboratory. As the 
results of analysis are reported directly from the central ECG laboratory to the 
sponsor as an electronic file, they do not need to be recorded in the source documents 
or the eCRF.
8.7.5
Columbia-Suicide Severity Rating Scale
1) Timing
Refer to Table 1.3-1.
2) Methods
The investigator or designated person will perform the C-SSRS assessment at the 
scheduled time points. The C-SSRS assesses the occurrence, severity, and frequency 
of suicidal ideation/behavior during the assessment period. This assessment consists 
of the “Baseline/Screening Version,” which assesses the history of suicide-related 
events and suicidal ideation in the lifetime and within the last 24 months, and the 
“Since Last Visit Version,” which focuses on suicidality since the last assessment in 
the trial. The “Baseline/Screening Version” will be used at screening and the “Since 
Last Visit” will be used at subsequent time points for C-SSRS assessment. Whether 
or not assessment is performed and the date and time of assessment, and the 
assessment results will be recorded in the source documents and the eCRF. As far as 
possible, the same assessor will perform assessment of the same subject throughout 
the trial period.
The presence of suicidal ideation 1 to 2 will be assessed with “yes” or “no,” and if the 
answer to 2 is “yes,” suicidal ideation 3 to 5 will be assessed. If the answer to suicidal 
ideation 1 or 2 is “yes,” the intensity of ideation will also be rated. Intensity of 
ideation will be rated on a 5-point scale for frequency and duration and a 6-point 
scale for controllability, deterrents, and reasons for ideation.
The following suicidal behavior will also be assessed with “yes” or “no,” and if the 
answer is “yes,” details will be assessed, and the total numbers of each suicide 
attempt will be recorded.
If there is an actual attempt, actual lethality/physical damage will be rated on a 6-
point scale, and if actual lethality/physical damage is 0, potential lethality will be 
rated on a 3-point scale.
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Suicidal ideation:
1. Wish to be dead
2. Non-specific active suicidal thoughts
3. Active suicidal ideation with any methods (not plan) without intent to act
4. Active suicidal ideation with some intent to act, without specific plan
5. Active suicidal ideation with specific plan and intent
Suicidal behavior:
Actual attempt, non-suicidal self-injurious behavior, interrupted attempt
Aborted attempt, preparatory acts or behavior, suicidal behavior, suicide (only for 
“Since Last Visit Version”)
8.7.6
Other Safety Variables
8.7.6.1
Body Weight
1) Timing
Refer to Table 1.3-1.
Before eating if at all possible, and preferably at approximately the same time of day 
each time.
2) Methods
Body weight should be measured using the same scales and the standard 
measurement method (the subject should wear his/her usual clothes but without 
shoes) throughout the course of the trial. Weight will be measured in 0.1 kg 
increments. For a weight measured to the second or further decimal place, the number 
will be rounded off to the first decimal place. Whether or not measurement is 
performed and the date and time of measurement, and the measurement results will be 
recorded in the source documents and the eCRF.
8.7.6.2
Drug-Induced Extrapyramidal Symptoms Scale
1) Timing
Refer to Table 1.3-1.
2) Methods
The investigator will use DIEPSS to assess the following 9 items related to 
extrapyramidal symptoms on a 5-point scale (0: none, normal, 1: minimal, 
questionable, 2: mild, 3: moderate, 4: severe). Whether or not assessment is 
performed and the date and time of assessment, and the assessment results will be 
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recorded in the source documents and the eCRF. As far as possible, the same assessor 
will perform assessment of the same subject throughout the trial period.
1. Gait
2. Bradykinesia
3. Sialorrhea
4. Muscle rigidity
5. Tremor
6. Akathisia
7. Dystonia
8. Dyskinesia
9. Overall severity
8.7.6.3
Alcohol Breath Test
1) Timing
Refer to Table 1.3-1.
An alcohol breath test will be performed before any other examinations scheduled for 
the visit. If the test result is positive, then whether the trial can be continued without 
any problems will be determined, and only after a repeat alcohol breath test is 
negative will the other examinations be performed.
2) Methods
An alcohol breath test will be performed using a device provided by the sponsor. 
Whether or not examination is performed, the date and time of assessment, and 
assessment result will be recorded in the source documents and the eCRF.
If the test result is positive, then whether the trial can be continued without any 
problems will be determined, and only after a repeat alcohol breath test is negative 
will the other examinations be performed. For subjects with a positive alcohol breath 
test who are dependent on alcohol or are unlikely to overcome their alcohol 
dependency in the opinion of the investigator, trial treatment will be discontinued.
8.7.6.4
Urine Drug Screening
1) Timing
Refer to Table 1.3-1.
2) Methods
Drug screening data for the following items will be collected using the test kits 
provided by the central laboratory. Whether or not urine sampling is performed, the 
date and time of urine sampling, and result of assessment will be recorded in the 
source documents and the eCRF. For subjects with a positive drug screen for cocaine, 
or subjects with a positive drug screen for any other drug who are dependent on the 
drug or are unlikely to overcome their drug dependency in the opinion of the 
investigator, trial treatment will be discontinued.

Amphetamines

Barbiturates

Benzodiazepines
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
Cannabinoids

Cocaine

Marijuana

Opiates

Phencyclidine
8.8
Adverse Events
8.8.1
Definitions
An AE is defined as any untoward medical occurrence in a clinical trial subject 
administered a drug used in the clinical trial and which does not necessarily have a causal 
relationship with this treatment. In this trial, any untoward medical occurrence in a 
subject not administered a drug used in the clinical trial is also deemed as an AE. 
Adverse events would not include information recorded as medical history at screening 
for pre-planned procedures for which the underlying condition was known and no 
worsening occurred. An adverse reaction is any untoward and unintended response to a 
drug used in the clinical trial, related to any dose administered.
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
drug used in the clinical trial caused the AE.
There are adverse reactions to drugs used in the clinical trial specified in the GCP and 
adverse reactions to the IMP as an endpoint in this trial. This section describes the 
definition of the former. 
Treatment-emergent AEs (TEAEs) are defined as AEs with an onset date on or after the 
start of open-label IMP administration. In more detail, TEAEs are all AEs which started 
after the start of open-label IMP administration; or if the event was continuous from the 
start of IMP administration and has worsened thereafter.
For the purposes of this trial, AEs in the screening period will be assessed by comparing 
against the subject’s condition at the time of informed consent, AEs in Period 1 will be 
assessed by comparing against the subject’s condition at the start of IMP administration 
in Period 1, and AEs in Period 2 will be assessed by comparing against the subject’s 
condition at the start of IMP administration in Period 2.
An SAE includes any event that results in any of the following outcomes:

Death
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
Life-threatening; ie, the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred. It does not include an event 
that, had it occurred in a more severe form, might have caused death.

Persistent or significant incapacity/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. Note that hospitalization is 
an outcome of some event, and, therefore, the reason for the hospitalization 
should be reported whenever possible. In the event the reason is not known, 
the event of hospitalization should still be reported as an SAE.

Hospitalizations or prolonged hospitalizations for social admissions (ie, those 
required for reasons of convenience or other nonmedical need) are not 
considered SAEs.

Prescheduled hospitalization to address a condition that has existed prior to 
the signing of the ICF should not be considered an SAE.

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.
Adverse Events of Special Interest (AESIs): A noteworthy event for the particular 
product/IMP or class of products that a sponsor may wish to monitor carefully. All AESIs 
are to be reported as immediately reportable events (IREs). No AESIs have been 
identified for the IMP to be administered during this trial.
Immediately Reportable Event (IRE):

Any SAE.

Any AE related to occupational exposure (eg, an investigator getting a skin rash 
after exposure to a medication). Non-subject AEs would not be recorded on the 
eCRF form but must be reported on an IRE form, etc, and submitted to the 
sponsor.

Potential serious hepatotoxicity (see Section 8.8.6). 

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 and the 
Pregnancy Surveillance Form(s) to the sponsor. This includes pregnancy of the 
subject or the partner of the subject. Pregnancy will only be documented on the 
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AE eCRF if the pregnancy occurs in a female subject and there is an abnormality 
or complication (see Section 10.3).
Clinical Laboratory Test Value Changes: It is the investigator’s responsibility to review 
the results of laboratory tests for each individual subject as they become available. This 
review will be documented by the investigator’s dated signature on the laboratory report. 
The investigator may repeat the laboratory test or request additional tests to verify the 
results of the original laboratory tests. If this laboratory value is considered medically 
relevant (ie, clinically significant) by the investigator (subject is symptomatic, requiring 
corrective treatment or further evaluation), or if the laboratory value leads to 
discontinuation, and/or fulfills a seriousness criterion, this is considered an AE.
Severity: Adverse events will be graded on a 3-point scale and reported as indicated in 
the eCRF. The severity of an adverse experience is defined as follows:
1 = Mild:
Discomfort noticed, but no disruption to daily activity.
2 = Moderate:
Discomfort sufficient to reduce or affect normal daily activity.
3 = Severe:
Inability to work or perform normal daily activity.
Causality to IMP or other drugs used in the clinical trial: Assessment of causal 
relationship of an AE to the use of the IMP or other drugs used in the clinical trial is 
defined as follows:
Related: 
There is a reasonable possibility of a temporal and causal 
relationship between the IMP or other drugs used in the clinical trial 
and the AE.
Not Related:
There is no temporal or causal relationship between the IMP or 
other drugs used in the clinical trial and the AE.
8.8.2
Eliciting and Reporting Adverse Events
The investigator will regularly assess subjects for the occurrence of AEs. To avoid bias in 
eliciting AEs, subjects should be asked the nonleading question: “How have you felt 
since your last visit?” All AEs (serious and nonserious) reported by the subject must be 
recorded on the source documents and the eCRF provided by the sponsor. Adverse event 
collection will begin after a subject signs the ICF, and will continue until the follow-up 
period. All AEs must be reported after subject informed consent has been obtained, 
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including screening failures due to AEs, irrespective of administration of drugs used in 
the clinical trial.
Medical terminology should be used for AE reporting. Adverse events should be reported 
as a single unifying diagnosis whenever possible or, in the absence of a unifying 
diagnosis, as individual signs or symptoms.
Exacerbation or disease progression should be reported as an AE only if there are 
unusual or severe clinical features that were not present, or experienced earlier, or not 
expected based on the course of the condition.
Medical or surgical procedures (eg, endoscopy, appendectomy) should not be reported 
as AEs; however, the condition that led to the procedure may be reported as an AE.
If a reported AE worsens in its severity or seriousness, it should be reported as a new AE 
in the source documents and eCRF.
In addition, the sponsor must be notified immediately by e-mail in principle of any IREs 
according to the procedure outlined below, in Section 8.8.3. Special attention should be 
paid to recording hospitalization and concomitant medications.
The AE, start date and time, end date (end date and time for diarrhea, vomiting, and 
constipation), seriousness, severity, relationship to trial treatment (causality), action taken 
with trial treatment, and outcome will be recorded in the source documents and the eCRF. 
Causality and measures taken regarding drug administration will be assessed and 
recorded for all drugs used in the clinical trial. When SAEs are reported using an IRE 
form, etc, causality and action taken regarding drug administration will be assessed for 
drugs used in the clinical trial other than the IMP as done for the IMP and will be 
recorded in the source documents.
For subjects who are suspected to have COVID-19 during the trial, the investigator will 
check their antigen test results and take appropriate measures (eg, trial discontinuation) as 
necessary in consideration of their safety. If a positive COVID-19 test is confirmed, this 
will be reported as an AE in the source documents and eCRF.
8.8.3
Immediately Reportable Events
The investigator must immediately report (within 24 hours), using an IRE form, etc, after 
he/she or site personnel become aware of any IRE (SAE, AE related to occupational 
exposure, AESI, potential serious hepatotoxicity, or confirmed pregnancy), by e-mail in 
principle to the sponsor or designee using the contact information on the cover page of 
this protocol (please note that the IRE form is NOT the AE eCRF). Patient confidentiality 
must be protected and contact information such as name, address, phone number or any 
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other protected health information as determined by applicable local regulation must be 
redacted when forwarding Safety Information and supporting documentation. Details 
regarding the follow-up of IREs are included in Section 8.8.8.2.
8.8.4
Medical Device Incidents (Including Malfunctions)
Not applicable.
8.8.5
Adverse Events of Special Interest
Not applicable.
8.8.6
Potential Serious Hepatotoxicity
For a subject who experiences an elevation in AST or ALT that is  3 times the ULN, a 
total bilirubin level should also be evaluated. If the total bilirubin is  2 times the ULN, 
complete an IRE form, etc, with all values listed and also report as an AE in the source 
documents and eCRF.
8.8.7
Procedure for Breaking the Blind
This trial does not use blinding procedures.
8.8.8
Follow-up of Adverse Events
8.8.8.1
Follow-up of Nonserious Adverse Events
Nonserious AEs that are identified at any time during the trial must be recorded on the 
source documents and AE eCRF with the current status (ongoing or resolved/recovered) 
noted. All nonserious events (that are not IREs) that are ongoing at the last scheduled 
contact will be recorded as ongoing in the source documents and eCRF. For any AE 
having been identified throughout the trial, during analysis, additional relevant medical 
history information may be requested by the sponsor to further ascertain causality 
(including, but not limited to, information such as risk-related behavior, family history, 
and occupation).
8.8.8.2
Follow-up of Immediately Reportable Events
This trial requires that subjects be actively monitored for IREs until the last scheduled 
contact.
Immediately reportable events that are identified or ongoing at the last scheduled 
contact must be recorded as such on the source documents, the AE eCRF page, and the 
IRE form, etc. If updated information (eg, resolved status) on IRE status becomes 
available after a subject’s last scheduled contact (up to last in-clinic visit for the entire 
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trial), this must be reported to the sponsor and recorded on the AE eCRF page and the 
IRE form, according to the appropriate reporting procedures described in Section 8.8.3. 
It is expected that the investigator will provide or arrange appropriate supportive care for 
the subject and will provide prompt updates on the subject’s status to the sponsor. The 
investigator will follow IREs until:

the events are resolved,

the events have stabilized,

the subject is lost to follow-up, or

the subject has died.
Resolution means that the subject has returned to the state of health observed at the start 
of IMP administration and stabilized means that the investigator does not expect any 
further improvement or worsening of the subject’s condition. The investigator will 
continue to report any significant follow-up information to the sponsor up to the point the 
event has resolved or stabilized, or the subject is lost to follow-up, or has died.
Refer to Section 10.3 for additional information regarding the follow-up period for 
subjects that become pregnant or for pregnant partners of male subjects. 
8.8.8.3
Follow-up and Reporting of Immediately Reportable Events 
Occurring after Last Scheduled Contact
Any new IREs reported to the investigator which occur after the last scheduled contact 
and are determined by the investigator to be reasonably associated with the drugs used in 
the clinical trial, should be reported to the sponsor according to the procedures outlined in 
Section 8.8.3. This may include IREs that are captured on follow-up telephone contact or 
at any other time point after the defined trial period and continue to report any significant 
follow-up information should continue to be reported to the sponsor until the events are 
resolved or stabilized, or the subject is lost to follow-up or has died.
8.9
Treatment of Overdose
For treatment of overdoses, please refer to the IB section for overdose.
8.10
Subject Assessment Recording
Not applicable.
8.11
Other Assessments
8.11.1
Height
1) Timing
Refer to Table 1.3-1.
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2) Methods
Height will be measured in increments of 0.1 cm by the standard measurement 
method (the subject should wear his/her usual clothes but without shoes). For a height 
measured to the second or further decimal place, the number will be rounded off to 
the first decimal place. Whether or not measurement is performed and the date and 
results of measurements will be recorded in the source documents and the eCRF.
8.11.2
Clinical Global Impression - Severity of Illness
1) Timing
Refer to Table 1.3-1.
2) Methods
The investigator will assess the severity of schizophrenia on the following 8-point 
scale using the Clinical Global Impression-Severity of Illness (CGI-S). Whether or 
not assessment is performed and the date and time of assessment, and the assessment 
results will be recorded in the source documents and the eCRF.
0. Not assessed
1. Normal, not ill at all
2. Borderline mentally ill 3. Mildly ill 
4. Moderately ill
5. Markedly ill
6. Severely ill
7. Among the most extremely ill patients
8.11.3
Clinical Global Impression - Global Improvement
1) Timing
Refer to Table 1.3-1.
2) Methods
The investigator will assess the improvement of schizophrenia on the following 8-
point scale using the Clinical Global Impression - Global Improvement (CGI-I). 
Within each period, improvement will be assessed by comparing the subject’s 
condition after IMP administration or at withdrawal with that at the start of that 
period. Whether or not assessment is performed and the date and time of assessment, 
and the assessment results will be recorded in the source documents and the eCRF.
0. Not assessed
1. Very much improved
2. Much improved   
3. Minimally improved
4. No change
5. Minimally worse   
6. Much worse
7. Very much worse
8.11.4
Bowel-movement Investigation
1) Timing
Refer to Table 1.3-1.
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2) Methods
From Day −3 through Day 8 of Period 1 and Period 2, subjects will keep a record of 
the date and time of bowel movements (with multiple entries if there are multiple 
bowel movements) and the condition of the stool (hard, normal, soft, muddy to 
watery). With the subject’s records used as the source documents, the date and time 
of bowel movement and the condition of the stool will be recorded in the eCRF.
9
Statistical Considerations
9.1
Sample Size
 
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9.2
Datasets for Analysis
9.2.1
Food Effect Analysis Set
The food effect analysis set includes all subjects for whom Cmax, AUC∞ or AUCt could 
be calculated throughout Period 1 and Period 2.
9.2.2
Safety Analysis Set
The safety analysis set includes all subjects who were administered at least one dose of 
IMP.
9.3
Handling of Missing Data for Primary Endpoint Analysis
No imputation procedures will be applied for missing data.
9.4
Statistical Analyses
9.4.1
Efficacy Analyses
Not applicable.
9.4.2
Safety Analysis
The safety analysis set will be used for analysis by meal condition. The baseline value 
will be the last measurement prior to IMP administration in each period.
9.4.2.1
Adverse Events
All AEs will be coded by system organ class and Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term. The incidence of the following events will be 
summarized. A TEAE in each period is defined as a TEAE that occurs after IMP 
administration in each period up to before IMP administration in the next period (if the 
IMP is to be administered in the next period).

TEAEs

TEAEs by severity

TEAEs with an outcome of death

Serious TEAEs
Similarly, IMP-related TEAEs will also be summarized.
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9.4.2.2
Clinical Laboratory Data
For each quantitative laboratory parameter, descriptive statistics of actual measurements 
and changes from baseline at each time point will be calculated.
For each quantitative laboratory parameter, measured values 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 ranges 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.
The number and proportion of subjects in whom any measurement after IMP 
administration in each period up to before IMP administration in the next period (if the 
IMP is to be administered in the next period) meets the criteria for potentially clinically 
significant laboratory test values will be determined.
9.4.2.3
Physical Examination and Vital Signs
Listings of physical examination findings will be provided.
For each vital sign parameter, descriptive statistics of actual measurements and changes 
from baseline at each time point will be calculated.
The number and proportion of subjects in whom any measurement after IMP 
administration in each period up to before IMP administration in the next period (if the 
IMP is to be administered in the next period) meets the criteria for potentially clinically 
significant vital signs will be determined.
9.4.2.4
Electrocardiogram Data
For each ECG parameter, descriptive statistics of actual measurements and changes from 
baseline at each time point will be calculated.
A shift table from baseline for normal/abnormal judgment on ECG in each period will be 
produced.
The numbers and proportions of subjects with actual measurements of QTcF interval of 
> 450 milliseconds, > 480 milliseconds, and > 500 milliseconds after IMP administration 
in each period up to before IMP administration in the next period (if the IMP is to be 
administered in the next period) will be determined. The numbers and proportions of 
subjects with changes from baseline of > 30 milliseconds and > 60 milliseconds will be 
determined.
The number and proportion of subjects in whom any measurement after IMP 
administration in each period up to before IMP administration in the next period (if the 
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IMP is to be administered in the next period) meets the criteria for potentially clinically 
significant ECG values will be determined.
9.4.2.5
Columbia-Suicide Severity Rating Scale
The number and proportion of subjects with each C-SSRS item (suicidality, suicidal 
ideation, suicidal behavior, completed suicide, emergence of suicidal ideation, emergence 
of serious suicidal ideation, worsening of suicidal ideation, and emergence of suicidal 
behavior) at each time point will be determined.
9.4.2.6
Other Safety Data
9.4.2.6.1
Body Weight and Body Mass Index
For body weight and BMI, descriptive statistics of actual measurements and changes 
from baseline at each time point will be calculated.
The number and proportion of subjects in whom any measurement after IMP 
administration in each period up to before IMP administration in the next period (if the 
IMP is to be administered in the next period) meets the criteria for potentially clinically 
significant body weight will be determined. 
9.4.2.6.2
Drug Induced Extrapyramidal Symptoms Scale
For the DIEPSS total score (total of scores for items 1 through 8) and a score for each 
DIEPSS item, descriptive statistics of actual measurements and changes from baseline at 
each time point will be calculated.
9.4.3
Other Analyses
9.4.3.1
Analysis of Demographic and Baseline Characteristics
Descriptive statistics or the frequency distribution of demographic and other baseline 
characteristics will be determined overall and for each group in each analysis set.
9.4.3.2
Pharmacokinetic Analysis
Pharmacokinetic parameters will be calculated in subjects who received at least one dose 
of the brexpiprazole QW formulation and had at least one plasma drug concentration 
measurement. The analyses described in Section 9.4.3.2.1 2) and Section 9.4.3.2.2 2) will 
be performed on the food effect analysis set.
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9.4.3.2.1
Analysis of Primary Efficacy Endpoint
1) Endpoint
Geometric mean ratio and two-sided 90% confidence interval of Cmax, AUC∞, and 
AUCt of brexpiprazole in plasma after administration in a fed state versus 
administration in a fasting state
2) Statistical Methods
The natural log-transformed Cmax, AUC∞, and AUCt of brexpiprazole in plasma will 
be analyzed using a linear mixed-effects model with group (fasting-state-
administration-first group or fed-state-administration-first group), meal condition 
(fasting or fed), and period (Period 1, Period 2) as fixed effects, and within-group 
subjects as a random effect, and the differences in means of natural log-transformed 
values between meal conditions (fed-state administration − fasting-state 
administration) and their two-sided 90% confidence intervals will be calculated. The 
differences in the mean natural log-transformed values (fed-state administration − 
fasting-state administration) and their two-sided 90% confidence intervals will be 
inverse-transformed to calculate the ratio of geometric mean values (fed-state 
administration/fasting-state administration) and two-sided 90% confidence interval.
9.4.3.2.2
Analyses of Secondary Pharmacokinetic Endpoints
1) Endpoints
a) Plasma concentrations of brexpiprazole and metabolite 
b) Cmax, AUC∞, AUCt, tmax, t1/2,z, CL/F,a CL/F/BW,a tlast, AUC_%Extrap, and 
z of brexpiprazole and metabolite 
in plasma
aFor brexpiprazole only
c) Ratios of the AUC (AUC∞ and AUCt) of metabolite 
to that of 
brexpiprazole
2) Statistical Methods
Descriptive statistics will be calculated as described below. However, if more than 
half of the subjects in an analysis set are excluded from summarization due to missing 
values, not calculable, or rejected data, descriptive statistics to be calculated for that 
parameter will include only the number of subjects in the analysis set and the number 
of subjects tabulated.
a) Plasma drug concentration

For 1) a), descriptive statistics will be calculated at each blood sampling 
time point excluding the withdrawal time point by meal condition and 
compound.
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
The descriptive statistics to be calculated will include the number of 
subjects in the analysis set, the number of subjects tabulated, arithmetic 
mean, standard deviation, coefficient of variation, minimum, median, and 
maximum.
b) Plasma PK parameters (except for z)

For 1) b), descriptive statistics will be calculated by meal condition and 
compound.

For 1) c), descriptive statistics will be calculated by meal condition.

The descriptive statistics to be calculated will include the number of 
subjects in the analysis set, the number of subjects tabulated, arithmetic 
mean, standard deviation, coefficient of variation, geometric mean, 
minimum, median, and maximum. However, descriptive statistics to be 
calculated for tmax and tlast will be the number of subjects in the analysis 
set, the number of subjects tabulated, minimum, median, and maximum.
9.4.3.3
Pharmacodynamic Analysis
No pharmacodynamic (PD) analysis is planned.
9.4.3.4
Pharmacokinetic/Pharmacodynamic Analysis
No PK/PD analysis is planned.
9.4.3.5
Pharmacogenomic Analysis
Listings of data on CYP2D6 phenotypes will be provided. The frequency distribution will 
be determined as described in Section 9.4.3.1.
9.4.3.6
Exploratory Endpoint Analysis
9.5
Interim Analysis and Adaptive Design
No interim analysis or adaptive design is applicable.
9.5.1
Data Monitoring Committee
Not applicable.
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10
Supporting Documentation and Operational Considerations
10.1
Appendix 1: Regulatory, Ethical, and Trial Oversight 
Considerations
10.1.1
Ethics and Responsibility
This trial must be conducted in compliance with the protocol, applicable ICH GCP 
guidance, international ethical principles derived from the Declaration of Helsinki and 
Council for International Organizations of Medical Science (CIOMS) guidelines, and 
applicable local laws and regulations. Each trial site will seek approval by an IRB 
according to regional requirements, 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 the eCRF, IRE, and any safety information, 
the investigator and trial site staff will take measures to ensure adequate care in 
protecting subject privacy. To this end, a subject ID will be used to identify each subject.
Financial aspects, subject insurance, and the publication policy for the trial will be 
documented in the agreement between the sponsor and the trial site.
10.1.2
Informed Consent
Informed consent will be freely obtained from all subjects (or their guardian or legally 
acceptable representative, as applicable for local laws). The ICF will be approved by the 
same IRB that approves this protocol. If a potential subject is under hospitalization for 
medical care and protection, written informed consent must also be obtained from his or 
her parent/legal guardian, as specified by local laws.
Each ICF will comply with the ICH GCP Guidelines, and local regulatory requirements.
Investigators may discuss trial availability and the possibility for entry with a potential 
subject without first obtaining consent. However, informed consent must be obtained and 
documented before initiation of any procedures that are performed solely for the purpose 
of determining eligibility for this trial, including withdrawal from current medication(s).
Potential subjects are free to refuse entry into the trial, or withdraw from the trial at any 
time, without justification, and there will be no consequences to their further care.
Once appropriate essential information has been provided and fully explained in 
layman’s language to the subject by the investigator (or a qualified designee), and it has 
been documented that the subject has had the opportunity to ask questions and have those 
questions answered, the IRB-approved paper ICF will be signed and dated by both the 
subject and the person obtaining consent (investigator or designee). The subject will 
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receive a copy of the signed ICF; the original shall be kept on file by the investigator. 
Subjects may be asked to sign additional ICFs if the protocol is amended and the changes 
to the protocol result in additional information that needs to be provided to the subjects, 
so that they can make a knowledgeable and voluntary decision on continued trial 
participation. Female partners of male subjects who become pregnant during the course 
of the trial may be asked to sign additional ICFs in order to collect additional information 
regarding the nonsubject partner and fetus.
For PGx assessment, informed consent will be obtained as part of the main trial. 
Pharmacogenomic assessment is mandatory for trial participation, and subjects who do 
not consent to PGx assessment cannot participate in the trial.
If blood samples for FBR are to be collected, a similar consent process to that for the 
main trial is to be followed using a separate ICF. Consent must be obtained before the 
blood samples can be collected. Blood sampling for FBR is optional, and refusal to 
provide blood samples for FBR will not affect participation in the main trial.
10.1.3
Confidentiality
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission. Subject confidentiality requirements of the region(s) where the trial is 
conducted will be met. However, authorized regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy the records, 
consistent with local requirements. All IMP, subject bodily fluids, and/or other materials 
collected shall be used solely in accordance with this protocol, unless otherwise agreed to 
in writing by the sponsor.
Subjects will be identified only by unique subject ID in the eCRF. 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.
10.1.4
Quality Control and Quality Assurance
The sponsor will implement the trial-related quality management activities in accordance 
with ICH GCP guidance and standard operating procedures.
10.1.4.1
Monitoring
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, the applicable ICH GCP guidance, and applicable 
regulatory requirements and local laws. As part of a concerted effort to fulfill these 
obligations (maintain current personal knowledge of the progress of the trial), the 
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sponsor’s monitors will visit the site during the trial, as well as communicate frequently 
via telephone, e-mail, and written communications. In addition, all investigators and trial 
site personnel (including those in charge of blood sampling for clinical laboratory tests) 
will undergo initial and ongoing training for this particular trial, and this training will be 
clearly documented.
10.1.4.2
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, site operations, delegation of authority and training, and a 
review of the eCRF with source documents, as applicable. The investigator will agree to 
cooperate and participate with audits.
Regulatory authorities may inspect the investigator site during or after the trial. The 
investigator will cooperate with such inspections and will contact the sponsor 
immediately if such an inspection occurs.
10.1.5
Protocol Deviations
In the event of a significant deviation from the protocol due to an emergency, accident, or 
mistake (eg, violation of informed consent process, IMP dispensing or subject dosing 
error, treatment assignment error, subject enrolled in violation of eligibility criteria or 
concomitant medication criteria), the investigator or designee will contact the sponsor or 
designee at the earliest possible time by telephone or via e-mail. The investigator and 
sponsor (or designee) will come as quickly as possible to a joint decision regarding the 
subject’s continuation in the trial. This decision will be documented by the investigator 
and the sponsor (or designee) and reviewed by the site monitor.
Any major protocol deviation will be recorded in the source documents and eCRF along 
with the start date and details of the deviation.
10.1.6
Records Management
10.1.6.1
Source Documents
Source documents are defined as records of the results of original observations and 
activities of a clinical investigation. Source documents will include but are not limited to 
medical records, electronic data, logs, and recorded data from automated instruments or 
applications. All source documents pertaining to this trial (except for those related to drug 
concentration measurement, PGx assessment, and FBR) will be maintained by the trial 
sites and made available for direct inspection by authorized persons.
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Investigator(s)/institution(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. Documents related to drug concentration 
measurement, PGx assessment, and FBR (eg, original reports, measurement data, etc) 
will be retained by the bioanalytical laboratory, PGx laboratory, and biorepository 
/laboratory related to FBR, respectively. In all cases, subject confidentiality must be 
maintained in accordance with local regulatory requirements.
10.1.6.2
Data Collection
During each subject’s visit to the site, an investigator or their designee participating in the 
trial will record information to document all significant observations. At a minimum, 
these notes will contain:

Documentation of the informed consent process, including any revised consents;

Documentation of the investigator’s decision to enroll the subject into the trial, the 
review of all inclusion/exclusion criteria prior to IMP administration, and 
confirmation of the subject’s actual participation in the trial;

Documentation of baseline and demographic characteristics (eg, age, sex, race, 
ethnicity, etc);

The date of the visit and the corresponding Visit or Day in the trial schedule;

General subject status remarks, including any significant medical findings. The 
severity, frequency, duration, action taken, and outcome of any AEs and the 
investigator’s assessment of relationship to IMP or other drugs used in the clinical 
trial must also be recorded;

Any changes in concomitant medications or dosages;

A general reference to the procedures completed, including dosing and IMP 
compliance;

The signature (or initials) and date of the investigator (or designee) who made an 
entry in the medical record.
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.
Information from medical records and other source documents will be entered by 
investigative site personnel onto eCRFs in the sponsor’s electronic data capture (EDC) 
system that is 21 CFR Part 11 compliant. Changes to the data will be captured by an 
automatic audit trail in the EDC system.
Electronic data not entered on eCRF, such as data received from central laboratories and 
central ECG readers, will be reconciled using key data fields by the sponsor or the CRO 
with the eCRF data to ensure consistency.
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10.1.6.3
File Management at the Trial Site
The head of the trial site will ensure that the trial site file is maintained in accordance 
with ICH guidance and as required by applicable local regulations. The trial site will take 
measures to prevent accidental or premature destruction of these documents.
10.1.6.4
Records Retention at the Trial Site
The trial site will retain all the trial-related documents and records for the longest of the 
following 3 periods. 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.

A period of at least 2 years after the date on which approval to market the drug is 
obtained. 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, a period of at least 3 years after receipt of such 
notification.

A period of at least 3 years after discontinuation or completion of the trial.

A period of FBR sample storage.
The trial site must not dispose of any records relevant to this trial without either (1) 
written permission from the sponsor or (2) provision of 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 
this trial including any data clarification forms received from the sponsor. Such 
documentation is subject to inspection by the sponsor and relevant regulatory authorities.
10.1.6.5
Publication Authorship Requirements
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 
criteria (http://www.icmje.org/recommendations). According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met:
1) Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors.
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Investigators or other trial subjects 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 subjects consent to such acknowledgement in any 
publications resulting from its conduct.
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10.2
Appendix 2: Clinical Laboratory Tests
The tests detailed in Table 10.2-1 will be performed.
Table 10.2-1
Clinical Laboratory Assessments
Hematology:
Hemoglobin
Hematocrit
RBC count
WBC count (absolute and differential)
Platelets
Urinalysis:
Occult blood
Glucose
Microscopic analysis, WBC/RBC counts per high 
powered field
pH
Protein
Ketone body
Specific gravity
Blood chemistry:
ALP
ALT
AST
Albumin
Total bilirubin
BUN
Uric acid
Serum electrolytes (Na, K, Cl, Ca, Mg, P, 
bicarbonate)
Cholesterol (total cholesterol, LDL cholesterol, 
and HDL cholesterol) 
Creatinine
γ-GTP
Glucose
LDH
Total protein
Triglyceride
CPK
Prolactin 
HbA1c
Insulin
Thyroid function test (at screening only):
TSH and FT4
Additional tests:
Urine (or serum) pregnancy test for females of 
childbearing potential
Urine drug screening (amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, 
marijuana, opiates, and phencyclidine)
Alcohol breath test
ALP = alkaline phosphatase; BUN = blood urea nitrogen; HDL = high-density lipoprotein; LDH = 
lactate dehydrogenase; LDL = low-density lipoprotein; RBC = red blood cell; WBC = white blood 
cell; γ-GTP = Gamma-glutamyl transpeptidase.
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10.3
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information
Females of childbearing potential (FOCBP) are females whose menstruation has started 
and who are not documented as sterile (eg, have had a bilateral oophorectomy, or 
hysterectomy, or who are postmenopausal). Postmenopausal is defined as being 
amenorrheic for at least 12 months without any medical cause. Females of non-
childbearing potential do not meet the definition of FOCBP.
For males and FOCBP, or their partners, who are sexually active, there must be a 
documented agreement that the subject and their partner will take effective measures (ie, 
2 different approved methods of birth control) to prevent pregnancy during the course of 
the trial and for 28 days after the last administration of drugs used in the clinical trial. 
Unless the subject or their partner is sterile (ie, females who have had a bilateral 
oophorectomy, have had a hysterectomy, or have been postmenopausal for at least 
12 consecutive months; or males who have had a bilateral orchiectomy) or remains 
abstinent during the trial and for 28 days after the last administration of drugs used in the 
clinical trial, 2 of the following approved methods of birth control must be used: 
vasectomy, tubal ligation, intrauterine device, birth control pill, condom (all of which are 
approved in Japan). Any single method of birth control, including vasectomy and tubal 
ligation, may fail, leading to pregnancy. The contraceptive method will be documented in 
the source document. Subjects must also agree not to donate sperm or eggs from trial 
screening through 28 days after the last administration of drugs used in the clinical trial.
Before enrolling males and females in this clinical trial, investigators must review the 
following information about trial participation as part of the ICF process. The topics 
should generally include:

General information

ICF

Pregnancy prevention information

Drug interactions with hormonal contraceptives

Contraceptives in current use

Follow-up of a reported pregnancy
Before trial enrollment, males and FOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy. Subjects must sign the ICF confirming that the above-mentioned risk factors 
and the consequences were discussed.
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A urine or serum pregnancy test for hCG will be performed at screening on all FOCBP. If 
a urine test is performed and is positive, the investigator will follow-up with a 
confirmatory serum test.
During the trial, all FOCBP should be instructed to contact the investigator immediately 
if they suspect they might be pregnant (eg, missed or late menstrual cycle). Male subjects 
must be instructed to contact the investigator immediately, during the trial, if their partner 
suspects that they might be pregnant (eg, missed or late menstrual cycle).
If a subject is suspected to be pregnant before she receives the drugs used in the clinical 
trial, the drug must be withheld until the results of pregnancy tests are available. If the 
pregnancy is confirmed, the subject must not receive the drugs used in the clinical trial 
and must not be enrolled in the trial. If pregnancy is suspected while the subject is taking 
the drugs used in the clinical trial, the drugs 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 drugs used in the clinical trial 
will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for subject safety) and the subject will be withdrawn from the trial. Exceptions 
to trial discontinuation may be considered for life-threatening conditions only after 
consultations with the IRE contact (see the title page of this protocol for contact 
information).
The investigator must immediately notify the sponsor (within 24 hours) of any pregnancy 
associated with IMP exposure during the trial and for at least 28 days after the last dose 
of drugs used in the clinical trial, and record the event on the IRE form, etc, and forward 
it to the sponsor. The sponsor will forward the Pregnancy Surveillance Form(s) to the 
investigator for monitoring the outcome of the pregnancy.
Protocol required procedures for trial discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated. In addition, the 
investigator must report to the sponsor, on the Pregnancy Surveillance Form(s), follow-
up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome. Infants will be followed for a minimum of 6 months from the date of birth.
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.
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10.5
Appendix 5: Sample Menus of High-fat Meals
Breakfast served before fed-state IMP administration must meet the requirements 
specified in Section 5.3.1. Sample high-fat menus are shown in Table 10.5-1. 
Table 10.5-1
Sample High-fat Menus
Meal Components
Amount of Intake
Vacuum-packed white rice 
200 g (1 pack)
Retort pouch curry 
1 pouch
Package of milk
200 mL (1 pack)
Sample 1
Canned Spam
100 g (approximately half of 1 
can)
Vacuum-packed white rice
180 g (1 pack)
Retort pouch beef stew
1 pouch
Retort-packed ham
140 g (1 pack)
Sample 2
Water
150 mL
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10.6
Appendix 6: Protocol Amendments
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval 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 “non-substantial” amendments, investigators will wait for IRB 
approval 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 the 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 agencies within local applicable timelines as required.
When the IRB, investigators, and/or the sponsor conclude that the protocol amendment 
substantially alters the trial design and/or increases the potential risk to the subject, the 
currently approved written ICF will require similar modification. In such cases, after 
approval 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.
10.6.1
Protocol Amendment(s)/Administrative Change(s)
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11
References
1
Akazawa H. In vitro receptor binding profiles of OPC-34712 for human dopamine 
D2, serotonin 5-HT2A, and adrenaline alpha1A receptors. Otsuka Study No. 025637, 
Otsuka Report No. 020442, 2007.
2
Assessing the Effects of Food on Drugs in INDs and NDAs — Clinical 
Pharmacology Considerations, Guidance for Industry, U.S. Department of Health and 
Human Services, Food and Drug Administration, Center for Drug Evaluation and 
Research (CDER); June 2022.
3
Ministry of Health Labour and Welfare. Partial Revision of the Guidelines for 
Bioequivalence Studies of Generic Products. PSEHB/PED Notification No. 0319-1. 
2020.
4
Ministry of Health Labour and Welfare. Guidelines for Pharmacokinetic Drug 
Interaction for Drug Development and Proper Information Provision. PSEHB/PED 
Notification No. 0723-(4). 2018.
5
Messias EL, Chen CY, Eaton WW. Epidemiology of schizophrenia: Review of 
findings and myths. Psychiatr Clin North Am. 2007;30:323-38.
6
McGrath J, Saha S, Chant D, Welham J. Schizophrenia: a concise overview of 
incidence, prevalence, and mortality. Epidemiol Rev. 2008;30:67-76.
7
Sato M, Niwa S, Inoue S, eds. Council of Psychiatric Study Course Supervisors, eds-
in-chief. Treatment Guidelines for Schizophrenia. 2nd ed. Tokyo. Igaku-Shoin: 2008.
8
Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, et al. World 
Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological 
treatment of schizophrenia – a short version for primary care. Int J Psychiatry Clin 
Pract. 2017;21:82-90.
9
Barnes TR, Drake R, Paton C, Cooper SJ, Deakin B, Ferrier IN, et al. Evidence-based 
guidelines for the pharmacological treatment of schizophrenia: updated 
recommendations from the British Association for Psychopharmacology. J 
Psychopharmacol. 2020;34:3-78.
10 Haddad PM, Brain C, Scott J. Nonadherence with antipsychotic medication in 
schizophrenia: challenges and management strategies. Patient Relat Outcome Meas. 
2014;5:43-62.
11 Leucht S, Heres S. Epidemiology, clinical consequences, and psychosocial treatment 
of nonadherence in schizophrenia. J Clin Psychiatry. 2006;67:3-8.
12 Japanese Society of Neuropsychopharmacology, ed. Guideline for Pharmacological 
Therapy of Schizophrenia. Tokyo. Igaku-Shoin;2016.
13 Hatano M, Kamei H, Iwata N. The role of long-acting injection in schizophrenia 
treatment and future challenges. Drug Delivery System. 2016;31(3):186-93.
14
15
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16
17
18
19
 
20
21
22
23
24
25 Regarding Clinical Studies Utilizing Pharmacogenomics. PFSB/ELD Notification 
No. 0930007; 2008.
26 Guidelines on Genomic Sampling and Management of Genomic Data. PSEHB/PED 
Notification No. 0118-1; 2018.
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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 medicinal product, brexpiprazole (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 eCRF by me and my staff will be 
utilized by the sponsor in various ways, such as for submission to governmental regulatory authorities 
and/or in combination with clinical data gathered from other research sites, whenever applicable. I 
agree to allow sponsor and designee monitors and auditors full access to all medical records at the 
research facility for subjects screened or enrolled in the trial.
I agree to await IRB approval before implementation of any substantial amendments to this protocol. 
If, however, I do not comply with the protocol to avoid an immediate hazard to subjects, I will 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 experiences in accordance with the 
terms of the sponsor’s Clinical Trial Agreement and the relevant regional regulation(s) and 
guideline(s). I further agree to provide all required information regarding financial certification or 
disclosure to the sponsor for all investigators and 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 
results on an individual basis may occur, and I consent to be acknowledged in any such cooperative 
publications that result.
____________________________
_______________________________________
Principal Investigator Print Name
Trial Site Print Name
__________________________
____________________
Signature
Date
The sponsor signed this agreement electronically. The page of electronic signature is attached to this 
agreement.
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