Clinical trial NCT03902574
Conditions: Healthy Adult Male
Sponsor: Otsuka Pharmaceutical Co., Ltd.
Start date: 2019-03-27; Completion date: 2019-06-18
Enrollment: 21 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To investigate the bioequivalence of brexpiprazole ODT 2 mg and brexpiprazole conventional tablet 2 mg

Detailed description:

Arms: arm 1: Brexpiprazole ODT 2mg is administered with water. arm 2: Brexpiprazole ODT 2mg is administered without water. arm 3: Brexpiprazole conventional tablet 2mg is administered with water.
Interventions: intervention 1: Brexpiprazole ODT 2mg with water intervention 2: Brexpiprazole ODT 2mg without water intervention 3: Brexpiprazole conventional tablet 2mg
Intervention descriptions: intervention 1: Brexpiprazole ODT 2mg is administered with water. intervention 2: Brexpiprazole ODT 2mg is administered without water. intervention 3: Brexpiprazole conventional tablet 2mg is administered with water.

Protocol documents:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
A Single Center, Open-label, Randomized, 3-arm, 3-way Crossover Trial to 
Investigate the Bioequivalence of Brexpiprazole (OPC-34712) Orally Disintegrating 
Tablets in Healthy Adult Males 
 
 
 
 
NCT Number: NCT03902574 
PRT NO.: 331-14-002 
Version Date: 18 January 2019 (Version 1.0) 


 
Otsuka Pharmaceutical Co., Ltd. 
 
Investigational Medicinal Product 
 
Brexpiprazole (OPC-34712) 
 
CLINICAL PROTOCOL 
 
(Translation of Japanese Original) 
 
A Single Center, Open-label, Randomized, 3-arm, 3-way Crossover Trial to Investigate 
the Bioequivalence of Brexpiprazole (OPC-34712) Orally Disintegrating Tablets in 
Healthy Adult Males 
 
Protocol No. 331-14-002 
 
CONFIDENTIAL - PROPRIETARY INFORMATION 
 
Clinical Development Phase:                        1 
 
Sponsor: 
Otsuka Pharmaceutical Co., Ltd. 
 
Immediately Reportable Event: 
Pharmacovigilance Department 
3-2-27 Otedori, Chuo-ku, Osaka 540-0021, 
Japan 
E-mail: IRE_331-14-002@otsuka.jp 
 
Issue Date: 
 
 
 
 
18 Jan 2019 
 
Protocol Version Number: 
 
 
1.0 
 
(Date of Translation:  
 
 
10 May 2019) 
 
 


 
 
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Protocol Synopsis 
 
Name of Sponsor: Otsuka Pharmaceutical Co., Ltd. 
Name of Investigational Medicinal Product: 
Brexpiprazole (OPC-34712) 
Protocol No.: 331-14-002 
 
Protocol Title: 
A single center, open-label, randomized, 3-arm, 3-way 
crossover trial to investigate the bioequivalence of 
brexpiprazole (OPC-34712) orally disintegrating tablets in 
healthy adult males 
Clinical Phase: 
Phase 1 
Treatment Indication: 
Schizophrenia 
Objective(s): 
To investigate the bioequivalence of brexpiprazole 2-mg 
orally disintegrating tablet (ODT) formulation and 
brexpiprazole 2-mg conventional tablet 
Trial Design: 
This is a single center, open-label, randomized, 3-arm, 3-way 
crossover trial. 
A 2-mg dose of brexpiprazole will be administered to each 
subject as either an ODT or a conventional tablet on Days 1, 
21, and 41 according to the randomized administration 
schedule. 
Dose 
Sequence 
Period 1 
Period 2 
Period 3 
2 mg 
1 
ODT without 
water 
Conventional 
tablet 
ODT with 
water 
2 
ODT with 
water 
ODT without 
water 
Conventional 
tablet 
3 
Conventional 
tablet 
ODT with 
water 
ODT without 
water 
Subjects will be admitted to the trial site 3 times during the 
trial (Days −1 to 8, Days 20 to 28, and Days 40 to 48) and 
will be discharged (on Days 8, 28, and 48) after completion of 
safety evaluation and pharmacokinetic (PK) blood sampling. 
Subject Population: 
A total of 21 healthy Japanese male subjects at least 20 years 
of age and below 40 years of age, will be enrolled. 
Inclusion/Exclusion 
Criteria: 
Inclusion Criteria: 
1) Healthy Japanese male subjects at least 20 years of age 
and below 40 years of age, at the time of informed 


 
 
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consent. 
2) Subjects with a body mass index (BMI: weight [kg] ÷ 
height [m]2) within the range of 18.5 to < 25.0 kg/m2 (to 
be checked also at the time of screening). 
3) Subjects capable of providing written informed consent 
prior to initiation of any trial-related procedures, and 
able, in the opinion of the investigator or 
subinvestigator, to comply with all requirements of the 
trial. 
Exclusion Criteria: 
1) Clinically significant abnormality at the time of 
screening (eg, significant deviation from reference 
ranges) or in medical history that, in the opinion of 
investigator, subinvestigator, or sponsor may place the 
subject at risk or interfere with outcome variables, 
including drug absorption, distribution, metabolism, and 
excretion. 
2) Subjects who have supine blood pressure, after resting 
for at least 3 minutes, higher than 140 mmHg or lower 
than 100 mmHg (systolic blood pressure) or higher than 
90 mmHg or lower than 50 mmHg (diastolic blood 
pressure) and who have a reduction in blood pressure 
upon standing of ≥ 20 mmHg (based on the difference 
between standing and sitting systolic blood pressure) at 
the time of screening. 
3) Subjects who have a supine pulse rate, after resting for 
at least 3 minutes, outside the range of 40 to 90 bpm at 
the time of screening. 
4) Clinically relevant electrocardiogram (ECG) findings in 
the 12-lead ECG tests performed at screening or at 
admission to the trial site in Period 1, such as 
atrioventricular block, QRS interval > 120 msec, or 
QTcF interval ≥ 450 msec. 
5) Subjects who meet any of the following for hepatitis: 


 
 
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 History of or current hepatitis B, or current hepatitis 
C. Positive test result for hepatitis B surface antigen 
(HBsAg) or hepatitis C antibodies (anti-HCV) at the 
time of screening. 
 History of or current alcoholic hepatitis or 
nonalcoholic steatohepatitis. 
6) History of or current acquired immunodeficiency 
syndrome (AIDS). Positive test result for human 
immunodeficiency virus (HIV) at the time of screening. 
7) History of serious mental disorder. 
8) History of drug or alcohol abuse within 2 years prior to 
screening. 
9) Positive alcohol test or urine drug screen for substance 
abuse at screening or at admission to trial site in each 
period. 
10) Sexually active males who cannot or will not practice 2 
different methods of birth control or remain abstinent 
during the trial and until 30 days after the final 
administration of the investigational medicinal product 
(IMP), or will not refrain from sperm donation from the 
screening visit until 30 days after the final 
administration of IMP. 
11) History of any significant drug allergy. 
12) Any history of significant bleeding or hemorrhagic 
tendency. 
13) Blood collection (blood donation, etc) exceeding 
200 mL within 30 days or 400 mL within 90 days prior 
to the first administration of IMP, or blood collection 
(blood donation, etc) exceeding 1200 mL in total within 
1 year prior to first administration of IMP. 
14) History of difficulty in donating blood 
15) Use of another investigational drug within 120 days 
prior to the first administration of IMP. 
16) Previous exposure to brexpiprazole. 


 
 
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17) Use of tobacco products or daily exposure to 
secondhand smoke within 2 months prior to screening, 
or positive urine cotinine test (urine cotinine 
concentration of > 200 ng/mL) at screening. 
18) Consumption of grapefruit, grapefruit products, Seville 
orange, Seville orange products, star fruit, or star fruit 
products within 72 hours prior to first administration of 
IMP, or consumption of alcohol within 72 hours prior to 
administration of IMP. 
19) Use of prescription, over-the-counter (OTC), or herbal 
medication, or vitamin supplements, or consumption of 
food or beverages containing St. John’s Wort within 14 
days prior to the first administration of IMP, or use of 
antibiotics within 30 days prior to the first 
administration of IMP. The sponsor may allow use only 
if the medication used is considered unlikely to impact 
PK assessment. 
20) History of major surgery of the digestive tract 
(excluding appendectomy). 
21) Occupational exposure to pesticides or organic solvents 
within 30 days prior to screening. 
22) Any subject visiting other hospitals or departments or 
planning to visit other hospitals or departments during 
the trial period. 
23) Any subject who, in the judgment of the investigator or 
subinvestigator, should not participate in the trial. 
Trial Site: 
Medical Co. LTA Hakata Clinic 


 
 
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Investigational 
Medicinal Product, 
Dose, Dosage 
Regimen, Treatment 
Duration, 
Formulation, Mode of 
Administration: 
[Investigational medicinal product: Brexpiprazole ODTs] 
Active ingredient 
(content per tablet) 
per 
dose 
Regimen 
Brexpiprazole 2 mg 
1 tablet 
With water: IMP will be 
administered with 150 mL of 
ordinary-temperature water after 
at least 10 hours of fasting. 
Without water: After at least 
10 hours of fasting, IMP will be 
allowed to disintegrate in the 
mouth (on the tongue), and will 
then be promptly swallowed with 
saliva. 
Reference Product, 
Dose, Dosage 
Regimen, Treatment 
Duration, 
Formulation, Mode of 
Administration: 
[Reference product: Brexpiprazole conventional tablets] 
Active ingredient 
(content per tablet)  
per 
dose 
Regimen 
Brexpiprazole 2 mg 1 tablet 
IMP will be administered with 
150 mL of ordinary-temperature 
water after at least 10 hours of 
fasting. 
Trial Assessments: 
[Primary endpoints] 
Cmax and AUCt of brexpiprazole 
[Secondary endpoints] 
1) Plasma concentration-time profiles of brexpiprazole 
2) Brexpiprazole AUC∞, tmax, λz, AUC_%Extrap, t1/2,z, 
CL/F, CL/F/BW, and tlast 
[Safety endpoints] 
Adverse events (AEs), clinical laboratory values, vital signs 
(body temperature, blood pressure, pulse rate, respiratory 
rate), body weight, 12-lead ECG, physical examination, and 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Statistical Methods: 
[Statistical methods for the primary endpoints] 
The Cmax and AUCt of brexpiprazole will be analyzed using 
the natural log-transformed values in a mixed effect model 
with sequence (1, 2, and 3), formulation and administration 
method (conventional tablet, ODT without water, ODT with 
water), and period (Period 1, Period 2, and Period 3) as fixed 
effects and the subjects within each sequence as a random 
effect. The 90% confidence intervals of geometric mean ratios 
for brexpiprazole Cmax and AUCt between ODT (with or 
without water) and conventional tablet will be calculated. If 
the 90% confidence intervals are within the range of 0.8 to 
1.25, the 2 formulations and administration methods will be 
judged to be bioequivalent. 
[Rationale for target sample size] 
Based on the Guideline for Bioequivalence Studies of Generic 


 
 
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Products, the sample size was calculated so that the 90% 
confidence intervals of geometric mean ratios for 
brexpiprazole Cmax and AUCt between ODT (with or without 
water) and conventional tablet would fall within the 
bioequivalence range of 0.8 to 1.25. 
In a brexpiprazole 4-mg ODT bioavailability study conducted 
in Japan (331-102-00019) and brexpiprazole bioequivalence 
studies conducted outside Japan (331-10-243 and 331-13-
209), the within-subject variance for natural log-transformed 
Cmax and AUCt values was greatest for Cmax in Trial 331-13-
209 (at 0.035). 
Assuming a geometric mean ratio of 1.0 for brexpiprazole 
Cmax between ODT (with and without water) and 
conventional tablet, and a within-subject variance of 0.035 for 
natural log-transformed Cmax, to achieve at least 90% power 
will require 6 subjects in each sequence, 18 in total. 
Considering the possibility of some subjects being excluded 
from analysis due to discontinuation, etc, the number of 
subjects was set at 7 for each sequence and 21 in total. 
Trial Duration: 
The total duration of the trial for each subject will be up to 
85 days, including the following trial periods:  
 Screening period: Days −22 to −1 
 Period 1: Days 1 to 20 (Day 1 dosing) 
 Period 2: Days 21 to 40 (Day 21 dosing) 
 Period 3: Days 41 to 60 (Day 41 dosing) 
 Follow-up period: Days 61 to 63 
Trial Duration: March 2019 to June 2019 
 
 


 
 
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Table of Contents 
Protocol Synopsis ........................................................................................... 2 
Table of Contents ........................................................................................... 8 
List of In-text Tables ................................................................................... 13 
List of In-text Figures .................................................................................. 14 
List of Appendices........................................................................................ 15 
List of Abbreviations and Definitions of Terms ....................................... 16 
1 
Introduction ........................................................................................ 18 
1.1 
Nonclinical Data ................................................................................................19 
1.2 
Clinical Data ......................................................................................................19 
1.2.1 
Phase 1 Single-dose Trial in Healthy Adult Subjects (Japanese Study 
331-07-002) ....................................................................................................19 
1.2.2 
BA Study of ODTs and Conventional Tablets in Healthy Adult Subjects 
(Japanese Study 331-102-00019) ...................................................................20 
1.2.3 
QT/QTc Study in schizophrenia patients (US Study 331-10-242) .................21 
1.3 
Pharmacokinetics...............................................................................................21 
1.4 
Risks and Benefits .............................................................................................22 
2 
Trial Rationale and Objectives.......................................................... 22 
2.1 
Trial Rationale ...................................................................................................22 
2.2 
Dosing Rationale ...............................................................................................23 
2.2.1 
Regimen ..........................................................................................................23 
2.2.2 
Dose ................................................................................................................23 
2.3 
Trial Objectives .................................................................................................23 
3 
Trial Design ......................................................................................... 24 
3.1 
Type/Design of Trial .........................................................................................24 
3.2 
Trial Treatments ................................................................................................26 
3.2.1 
Investigational Medicinal Product ..................................................................26 
3.2.1.1 
Brexpiprazole ODTs (Investigational Medicinal Product) .........................26 
3.2.1.2 
Brexpiprazole Conventional Tablets ...........................................................26 
3.2.2 
Treatment Period ............................................................................................26 
3.3 
Trial Population .................................................................................................27 


 
 
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3.3.1 
Number of Subjects and Description of Population .......................................27 
3.3.2 
Assignment of Subject Identification Number ...............................................27 
3.4 
Eligibility Criteria..............................................................................................27 
3.4.1 
Informed Consent ...........................................................................................27 
3.4.2 
Inclusion Criteria ............................................................................................28 
3.4.3 
Exclusion Criteria ...........................................................................................29 
3.5 
Endpoints ...........................................................................................................30 
3.5.1 
Primary Endpoints ..........................................................................................30 
3.5.2 
Secondary Endpoints ......................................................................................31 
3.5.3 
Safety Endpoints .............................................................................................31 
3.6 
Measures to Minimize/Avoid Bias ....................................................................31 
3.7 
Trial Procedures ................................................................................................31 
3.7.1 
General Inpatient Procedures ..........................................................................34 
3.7.2 
Dietary Requirements .....................................................................................34 
3.7.3 
Schedule of Assessments ................................................................................34 
3.7.4 
Safety Assessments .........................................................................................42 
3.7.4.1 
Adverse Events............................................................................................42 
3.7.4.2 
Clinical Laboratory Assessments ................................................................42 
3.7.4.3 
Physical Examination and Vital Sign Assessments ....................................43 
3.7.4.4 
Electrocardiogram Assessments..................................................................44 
3.7.4.5 
Body Weight ...............................................................................................45 
3.7.4.6 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................45 
3.7.5 
Pharmacokinetic Assessments ........................................................................45 
3.7.5.1 
Pharmacokinetic Plasma Samples ...............................................................45 
3.7.6 
End of Trial .....................................................................................................46 
3.8 
Stopping Rules, Withdrawal Criteria, and Procedures ......................................46 
3.8.1 
Entire Trial ......................................................................................................46 
3.8.2 
Individual Site .................................................................................................46 
3.8.3 
Individual Subject Discontinuation ................................................................46 
3.8.3.1 
Treatment Discontinuation ..........................................................................46 
3.8.3.2 
Documenting Reasons for Discontinuation ................................................47 
3.8.3.3 
Withdrawal of Consent ...............................................................................47 


 
 
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3.9 
Screen Failures ..................................................................................................48 
3.10 
Definition of Completed Subjects .....................................................................48 
3.11 
Definition of Subjects Lost to Follow-up ..........................................................48 
3.12 
Subject Compliance ...........................................................................................49 
3.13 
Protocol Deviations ...........................................................................................49 
4 
Restrictions .......................................................................................... 49 
4.1 
Prohibited Medications......................................................................................49 
4.2 
Other Restrictions ..............................................................................................50 
5 
Reporting of Adverse Events ............................................................. 50 
5.1 
Definitions .........................................................................................................50 
5.2 
Eliciting and Reporting Adverse Events ...........................................................52 
5.3 
Immediately Reportable Events ........................................................................53 
5.4 
Potential Serious Hepatotoxicity .......................................................................53 
5.5 
Pregnancy ..........................................................................................................53 
5.6 
Procedure for Breaking the Blind ......................................................................55 
5.7 
Follow-up of Adverse Events ............................................................................55 
5.7.1 
Follow-up of Nonserious Adverse Events ......................................................55 
5.7.2 
Follow-up of Serious Adverse Events and Immediately Reportable 
Events .............................................................................................................55 
5.7.3 
Follow-up and Reporting of Serious Adverse Events and Immediately 
Reportable Events Occurring After Last Scheduled Contact .........................56 
6 
Pharmacokinetic Analysis .................................................................. 56 
6.1 
Pharmacokinetic Methods .................................................................................56 
6.1.1 
Primary Endpoints ..........................................................................................56 
6.1.2 
Secondary Endpoints ......................................................................................56 
6.1.3 
Datasets for Analysis ......................................................................................56 
6.1.4 
Analysis Methods ...........................................................................................56 
6.2 
Pharmacodynamic Methods ..............................................................................56 
6.3 
Pharmacokinetic/Pharmacodynamic Methods ..................................................56 
6.4 
Pharmacogenomic Methods ..............................................................................57 
7 
Statistical Analysis .............................................................................. 57 
7.1 
Determination of Sample Size ...........................................................................57 


 
 
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7.2 
Datasets for Analysis .........................................................................................57 
7.2.1 
Bioequivalence Analysis Set ..........................................................................57 
7.2.2 
Safety Population ............................................................................................57 
7.3 
Handling of Missing Data .................................................................................57 
7.4 
Primary Endpoint Analyses ...............................................................................58 
7.5 
Analysis of Demographic and Baseline Characteristics....................................58 
7.6 
Safety Analysis ..................................................................................................58 
7.6.1 
Adverse Events ...............................................................................................58 
7.6.2 
Clinical Laboratory Data ................................................................................59 
7.6.3 
Physical Examination and Vital Signs Data ...................................................59 
7.6.4 
Electrocardiogram Data ..................................................................................59 
7.6.5 
Other Safety Data ...........................................................................................59 
7.6.5.1 
Body Weight ...............................................................................................59 
7.6.5.2 
The Columbia-Suicide Severity Rating Scale .............................................59 
7.7 
Judgement for Conduct of Add-on Subject Study.............................................60 
7.8 
Pharmacodynamic Analysis ..............................................................................60 
8 
Management of Investigational Medicinal Product ........................ 60 
8.1 
Packaging and Labeling ....................................................................................60 
8.2 
Storage ...............................................................................................................60 
8.3 
Accountability ...................................................................................................61 
8.4 
Returns and Destruction ....................................................................................61 
8.5 
Reporting of Product Quality Complaints .........................................................61 
8.5.1 
Eliciting and Reporting Product Quality Complaints .....................................62 
8.5.2 
Information Required for Reporting Product Quality Complaints .................62 
8.5.3 
Return Process for Product Quality Complaints .............................................62 
8.5.4 
Assessment/Evaluation ...................................................................................62 
9 
Records Management ......................................................................... 63 
9.1 
Source Documents .............................................................................................63 
9.2 
Data Collection ..................................................................................................63 
9.3 
File Management at the Trial Site .....................................................................64 
9.4 
Record Retention at the Trial Site .....................................................................64 


 
 
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Quality Control and Quality Assurance ........................................... 65 
10.1 
Monitoring .........................................................................................................65 
10.2 
Auditing .............................................................................................................65 
10.3 
Protocol Deviations ...........................................................................................65 
11 
Ethics and Responsibility ................................................................... 66 
12 
Confidentiality .................................................................................... 66 
13 
Amendment Policy .............................................................................. 67 
14 
Publication Authorship Requirements ............................................. 67 
15 
References ............................................................................................ 68 
 
 


 
 
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List of In-text Tables 
Table 3.4.2-1 
Inclusion Criteria .......................................................................... 28 
Table 3.4.3-1 
Exclusion Criteria ......................................................................... 29 
Table 3.7-1 
Schedule of Assessments .............................................................. 32 
Table 3.7.3-1 
Trial Days and Activities .............................................................. 35 
Table 3.7.4.2-1 
Clinical Laboratory Assessments .................................................. 43 
 


 
 
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List of In-text Figures 
Figure 3.1-1 
Trial Design .................................................................................. 25 
 


 
 
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List of Appendices 
Appendix 1 
Baseline Columbia-Suicide Severity Rating Scale ....................... 70 
Appendix 2 
Since Last Visit Columbia-Suicide Severity Rating Scale ........... 74 
 


 
 
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List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
5-HT1A 
5-Hydroxytryptamine 1A 
5-HT2A 
5-Hydroxytryptamine 2A 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC24h 
Area under the concentration-time curve from time zero to 24 hours 
AUC∞ 
Area under the concentration-time curve from time zero to infinity 
AUCt 
Area under the concentration-time curve calculated to the last 
observable concentration at time t 
AUC_%Extrap 
Percentage of AUC due to extrapolation from tlast to infinity 
[(AUC∞ - AUCt) / AUC∞ × 100] 
BA 
Bioavailability 
BE 
Bioequivalence 
BMI 
Body mass index 
bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
CIOMS 
Council for International Organizations of Medical Science 
CL/F 
Apparent clearance of drug from plasma after extravascular 
administration 
CL/F/BW 
CL/F normalized in body weight 
Cmax 
Maximum (peak) plasma concentration of the drug 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP2D6 
Cytochrome P450 2D6 
CYP3A4 
Cytochrome P450 3A4 
D2 
Dopamine D2 
EDC 
Electronic data capture 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IRB 
Institutional review board 
IRE 
Immediately reportable event 
λz 
Apparent terminal-phase disposition rate constant (first-order) 
LDH 
Lactic dehydrogenase 
LSMD 
Least square mean difference 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 


 
 
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Abbreviation 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
OD 
Orally disintegrating 
OTC 
Over-the-counter 
PANSS 
Positive and Negative Syndrome Scale 
PQC 
Product quality complaint 
QTc 
Corrected QT interval 
QTcB 
QT interval corrected for heart rate by Bazett’s formula 
QTcF 
QT interval corrected for heart rate by Fridericia’s formula 
QTcI 
Individually corrected QT interval 
RBC 
Red blood cell count 
SAE 
Serious adverse event 
t1/2,z 
Terminal-phase elimination half-life 
TEAE 
Treatment-emergent adverse event 
tlast 
Time of last measurable [positive] concentration 
tmax 
Time to maximum (peak) plasma concentration 
WBC 
White blood cell count 
 
 
 


 
 
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1 
Introduction 
Brexpiprazole (OPC-34712) is a new compound synthesized by Otsuka Pharmaceutical 
Co., Ltd. that exhibits partial agonistic action against serotonin 5-hydroxytryptamine 1A 
(5-HT1A) receptors,1 antagonistic action against serotonin 5-hydroxytryptamine 2A 
(5-HT2A) receptors,2 and partial agonistic action against dopamine D2 (D2) receptors.2 
Compared with aripiprazole, brexpiprazole has the optimized intrinsic activity against D2 
receptors and enhanced actions on the serotonergic system. Therefore, a reduction in 
adverse drug reactions including akathisia and insomnia, and improvement of positive 
symptoms, negative symptoms, and cognitive impairment, which were problems 
associated with aripiprazole treatment, are expected. 
In the US, brexpiprazole received manufacturing and marketing approval as monotherapy 
for schizophrenia and as an adjunctive therapy to antidepressants for the treatment of 
major depressive disorder in July 2015. Brexpiprazole is currently being developed for 
treating other mental disorders. In Japan, brexpiprazole has undergone a placebo-
controlled double-blind trial (331-10-002) and a long-term study (331-10-003) in 
schizophrenia patients, received manufacturing and marketing approval in January 2018, 
and has been available for clinical use as monotherapy for schizophrenia since April of 
the same year. Clinical investigations of brexpiprazole as an adjunctive therapy for major 
depressive disorder and as a treatment for agitation associated with dementia of the 
Alzheimer’s type are currently ongoing. 
In the treatment of mental disorders such as schizophrenia, it is important that the patient 
continue to take antipsychotic medication; however, among patients who require such 
treatment are those who suffer from dysphagia or for whom it is not possible to take 
medication in a hard form such as a tablet when their condition is critical, while there are 
others who are unable to comprehend the need for treatment due to lack of knowledge of 
their disease or cognitive dysfunction, resulting in decreased adherence or a tendency to 
refuse to take their medication. For these reasons, orally disintegrating tablets (ODTs) 
that can be taken without water are being developed so that the treatment method that 
best suits a patient’s condition can be selected. This will enable a more appropriate 
response to the needs that are seen in clinical practice and will widen the selection of 
treatments available. 


 
 
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1.1 
Nonclinical Data 
Data from preclinical studies have shown that brexpiprazole has high binding affinity for 
D2 receptors,2 5-HT1A receptors,1 and 5-HT2A receptors2 and also has partial agonistic 
action against dopamine D2 receptors and serotonin 5-HT1A receptors and antagonistic 
action against serotonin 5-HT2A receptors, suggesting that the drug has a favorable 
profile as an antipsychotic treatment. 
For detailed information regarding relevant data from preclinical animal studies, 
including Pharmacokinetics (PK) and toxicology studies, refer to the current version of 
the investigator’s brochure. 
1.2 
Clinical Data 
No clinical trials of the brexpiprazole ODTs used in the present trial have been conducted. 
As reference, the results of a single-dose trial of conventional tablets and a bioavailability 
(BA) study using ODTs with a different formulation/manufacturing method in healthy 
adult Japanese subjects, and the results of a QT/QTc study in schizophrenia patients in 
the US are outlined below. For detailed information, refer to the current version of the 
investigator’s brochure. 
1.2.1 
Phase 1 Single-dose Trial in Healthy Adult Subjects (Japanese 
Study 331-07-002) 
A single rising dose trial of brexpiprazole (0.2, 0.5, 1, 2, 4, 6, 10, 15, 20, and 30 mg) was 
conducted in healthy adult male subjects. An adverse event (AE; blood pressure 
decreased) that occurred in the 6 mg group was assessed as an AE meeting the criteria for 
stopping dose escalation, resulting in dose discontinuation at a dose of 6 mg. A total of 10 
subjects were included in each of the dose groups: 8 subjects in the brexpiprazole group 
(6 subjects in the 4 mg group) and 2 subjects in the placebo group. 
The Cmax, AUC∞, and AUCt of brexpiprazole at single doses of brexpiprazole (0.2 to 
6 mg) increased dose-proportionally. The result of regression analysis showed that AUC∞ 
was also dose-proportional. The mean cumulative urinary excretion of brexpiprazole at 
168 hours postdose was less than 0.4%; the contribution of renal excretion was minimal. 
The incidence of AEs was 26.1% (12/46 subjects) in the brexpiprazole group. Adverse 
events that occurred in 2 or more subjects were nausea (10.9%, 5/46 subjects), dizziness 
(8.7%, 4/46 subjects), and blood triglycerides increased and somnolence (4.3% each, 


 
 
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2/46 subjects). All AEs were mild or moderate in severity, and no serious adverse events 
(SAEs) were observed. In this study, the maximum tolerated dose was 4 mg. 
1.2.2 
BA Study of ODTs and Conventional Tablets in Healthy Adult 
Subjects (Japanese Study 331-102-00019) 
A randomized, 3-arm, 3-way crossover trial to evaluate the BA of a brexpiprazole 4-mg 
ODT formulation relative to the 4-mg conventional tablet was conducted in 18 healthy 
adult male subjects. A total of 17 subjects received brexpiprazole 4-mg conventional 
tablet, 18 subjects received brexpiprazole 4-mg ODT without water, and 16 subjects 
received brexpiprazole 4-mg ODT with water. 
Mean plasma brexpiprazole concentration peaked at 6 hours after administration of 
conventional tablet, at 5 hours after administration of ODT without water, and at 4 hours 
after administration of ODT with water, and declined gradually thereafter. The Cmax 
following administration of conventional tablet, administration of ODT without water, 
and administration of ODT with water was 46.1 ± 10.8 ng/mL (mean ± standard 
deviation, same hereafter), 44.9 ± 13.8 ng/mL, and 47.4 ± 10.0 ng/mL, respectively, 
AUCt was 2590 ± 1210 ng·h/mL, 2680 ± 1150 ng·h/mL, and 2750 ± 1380 ng·h/mL, 
respectively, and AUC∞ was 2770 ± 1460 ng·h/mL, 2830 ± 1270 ng·h/mL, and 
2920 ± 1630 ng·h/mL, respectively. The geometric mean ratios for Cmax, AUCt, and 
AUC∞, between administration of ODT without water and administration of conventional 
tablet were 0.9790, 1.0049, and 0.9965, respectively, and their 90% confidence intervals 
were 0.8842–1.0840, 0.9549–1.0575, and 0.9454–1.0505, respectively. The geometric 
mean ratios for Cmax, AUCt, and AUC∞, between administration of ODT with water and 
administration of conventional tablet were 1.0241, 1.0386, and 1.0369, respectively, and 
their 90% confidence intervals were 0.9231–1.1363, 0.9858–1.0942, and 0.9825–1.0943, 
respectively. 
The incidence of AEs was 52.9% following administration of conventional tablet, 38.9% 
following administration of ODT without water, and 50.0% following administration of 
ODT with water. The AEs included orthostatic hypotension (7 events) and nausea 
(4 events) following administration of conventional tablet; nausea (5 events), orthostatic 
hypotension (3 events), vomiting (1 event), and headache (1 event) following 
administration of ODT without water; and nausea (4 events), orthostatic hypotension 
(4 events), vomiting (1 event), blood creatine phosphokinase increased (1 event), and 
dizziness (1 event) following administration of ODT with water. All AEs were mild or 
moderate in severity, and no SAEs were observed. 


 
 
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1.2.3 
QT/QTc Study in schizophrenia patients (US Study 331-10-242) 
A total of 205 patients with schizophrenia or schizoaffective disorder received 4 mg or 
12 mg brexpiprazole, placebo, or moxifloxacin once daily for 11 days. The 12 mg group 
consisted of 67 subjects. 
For a primary endpoint of time-matched QTcI change from baseline corrected for placebo 
on Day 11 following brexpiprazole treatment, no QTcI prolongation was observed at 
either dose of 4 mg or 12 mg. 
An event of worsening of schizoaffective disorder was reported as an SAE in the 
brexpiprazole 4 mg/day group and assessed as not related to the study drug. Adverse 
events leading to discontinuation occurred in 3 subjects in the 4 mg/day group, including 
vomiting, dermatitis contact, and orthostatic hypotension (1.4%, 1/70 subjects) and 7 
subjects in the 12 mg/day group, including dizziness and extrapyramidal disorder (3.0%, 
2/67 subjects), akathisia, psychotic disorder, and joint stiffness (1.5%, 1/67 subjects). Of 
these, orthostatic hypotension (1 subject) in the 4 mg/day group, and extrapyramidal 
disorder (2 subjects), dizziness (2 subjects), joint stiffness (1 subject), and akathisia 
(1 subject) in the 12 mg/day group were assessed as related to the study drug. 
1.3 
Pharmacokinetics 
Data from clinical trials in healthy adult subjects conducted in the US indicate that 
brexpiprazole has linear PKs in the steady state when administered as single oral doses of 
0.2 to 8 mg or repeated oral doses of 0.5 to 2 mg. The terminal-phase elimination half-life 
(t1/2,z) of brexpiprazole following single oral doses of 0.2 to 8 mg was 48.3 to 80.8 hours 
and the median tmax was 2 to 6 hours.3 Investigation of the median Cmax, AUCt, AUC∞, 
and tmax values of brexpiprazole following single administration after a high-fat meal 
showed no food effects on the rate or extent of absorption.4 The Cmax and AUCt values 
observed in repeated oral administration of brexpiprazole to healthy adult subjects at 
doses of 0.5 to 2 mg showed that the cumulative coefficient was almost four-fold.5 Data 
from a drug interaction trial indicate that brexpiprazole is metabolized by CYP3A4 and 
CYP2D6 isozymes.6 
Data from a clinical trial in healthy adult Japanese subjects indicate that brexpiprazole 
has linear PKs following single oral doses of 0.2 to 6 mg. The t1/2,z of brexpiprazole was 
43.9 to 66.6 hours, and the median tmax was 3 to 7 hours.7 Brexpiprazole also showed 
linear PKs in the steady state with repeated oral administration at doses of 1, 4, and 6 mg 


 
 
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in Japanese patients with schizophrenia. Brexpiprazole reached steady state on Day 10, 
and the cumulative coefficient was 2.5 to 5.5, based on Cmax and AUC24h.8 
1.4 
Risks and Benefits 
Non-Japanese phase 1 trials using brexpiprazole conventional tablets indicated that 
brexpiprazole had good safety and tolerability when administered to healthy adult 
subjects at single doses of 0.2 to 6 mg and at a repeated dose of 2 mg/day.3,5,9 Repeated-
dose trials conducted in the US indicate that brexpiprazole had good tolerability when 
administered to patients with schizophrenia or schizoaffective disorder at doses of up to 
12 mg/day.10 In addition, a phase 1 single-dose trial conducted in Japan indicated good 
tolerability at doses of up to 4 mg/day in healthy adult subjects,7 and a phase 1 repeated-
dose trial indicated good tolerability at doses of up to 6 mg/day in schizophrenia 
patients.8 
If this trial is conducted within the dose range for which tolerability has been 
demonstrated in trials conducted to date and, as a result, ODTs become available in 
clinical practice, this will broaden the selection of available drug formulations, leading to 
improved adherence. 
For detailed information regarding brexpiprazole and possible risks and adverse reactions, 
refer to the current version of the investigator’s brochure. 
2 
Trial Rationale and Objectives 
2.1 
Trial Rationale 
Brexpiprazole tablets received manufacturing and marketing approval for treatment of 
schizophrenia in Japan in January 2018, and have been available for clinical use since 
April of the same year. 
Because ODTs can be taken without water, they provide an easy-to-use option for 
patients with dysphagia and patients who are unable to take medication in a hard form 
such as a tablet when their condition is critical. The marketing of the ODT formulation in 
addition to the conventional tablet is considered to be extremely significant as it will 
provide patients with a choice of formulations to match their various circumstances, 
thereby leading to improved treatment adherence. 
The results of a phase 1 single-dose trial in healthy adult Japanese subjects (331-07-002) 
have demonstrated the tolerability of single doses up to 4 mg, and therefore it will be 
possible to ensure subject safety by conducting this clinical trial with a dose of 2 mg. It is 


 
 
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considered appropriate to conduct this trial to investigate the bioequivalence of the ODTs 
in accordance with the Guideline for Bioequivalence Studies of Generic Products11 
(hereinafter “BE Guideline”). 
2.2 
Dosing Rationale 
2.2.1 
Regimen 
According to the Guideline for Bioequivalence Studies for Formulation Changes of Oral 
Solid Dosage Forms Q&A (Attachment 3),12 a bioequivalence study conducted when 
applying for approval of dosage forms different from conventional tablets, from the 
characteristics of ODT formulation, should be basically conducted as a bioequivalence 
study of “conventional tablets administered with water” and “proposed formulation 
administered without water,” and a bioequivalence study of “conventional tablets 
administered with water” and “proposed formulation administered with water,” and 
therefore administration both with and without water was decided. In addition, according 
to the BE Guideline,11 study drugs should be taken, as a rule, with a certain amount of 
water, between 100 to 200 mL (typically 150 mL) after fasting for at least 10 hours, and 
it was therefore decided that the amount of water for administration of investigational 
medicinal products (IMPs) would be 150 mL. 
2.2.2 
Dose 
According to the BE Guideline,11 one dose unit or clinical usual dose should generally be 
employed. Including the starting dose, a single dose unit of the approved dose of 
Brexpiprazole in Japan is either 1 mg or 2 mg; however, in the Guideline for 
Bioequivalence Studies for Different Strengths of Oral Solid Dosage Forms (Attachment 
2),13 it states that if there are several dose formulations of the original drug product, in 
principle, the high-dose formula of the original drug product should be used as the 
standard formulation for the conduct of a bioequivalence study. 
Based on the above, it was decided to perform single oral administrations of ODTs and 
conventional tablet at 2 mg. 
2.3 
Trial Objectives 
The purpose of the present trial is to investigate the bioequivalence of brexpiprazole ODT 
2 mg and brexpiprazole conventional tablet 2 mg. 


 
 
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3 
Trial Design 
3.1 
Type/Design of Trial 
This is a single center, open-label, randomized, 3-arm, 3-way crossover trial in 21 healthy 
adult male subjects. Subjects will be hospitalized to the trial site 3 times during the trial 
(Days −1 to 8, Days 20 to 28, and Days 40 to 48) and will be discharged at the end of 
each period of hospitalization (on Days 8, 28, and 48) after completion of safety 
evaluation and blood collection for pharmacokinetic assessment. 
A 2-mg dose of brexpiprazole will be administered to each subject as either an ODT or a 
conventional tablet on Days 1, 21, and 41, and ODT will be administered either with 
water or without water, according to the randomized administration schedule. 
Subjects randomized to Sequence 1 will receive an ODT without water on Day 1, a 
conventional tablet on Day 21, and an ODT with water on Day 41. 
Subjects randomized to Sequence 2 will receive an ODT with water on Day 1, an ODT 
without water on Day 21, and a conventional tablet on Day 41. 
Subjects randomized to Sequence 3 will receive a conventional tablet on Day 1, an ODT 
with water on Day 21, and an ODT without water on Day 41. 
The trial design schematic is shown in Figure 3.1-1. 


 
 
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Brex = brexpiprazole; ODT = orally disintegrating tablet 
Figure 3.1-1 
Trial Design 
 
Period 1
Period 2
Period 3
Follow-up
Period
(Days 1 to 20)
(Days 21 to 40)
(Days 41 to 60)
Day 1: Dosing
Day 21: Dosing
Day 41: Dosing
Sequence 1
Brex ODT
without water
Brex conventional tablet
Brex ODT
with water
Sequence 2
Brex ODT
with water
Brex ODT
without water
Brex conventional tablet
Sequence 3
Brex conventional tablet
Brex ODT
with water
Brex ODT
without water
Screening Period
(Days −22 to −1)
Population:
Healthy
adult males
21 eligible
subjects
(7 subjects per
sequence)
Visit
(Days 10, 12, 14)
Visit
(Days 30, 32, 34)
Visit
(Days 50, 52, 54)
Screening 
(Days −22 to −2)
Hospitalization
(Admission to trial 
site on Day −1)
Hospitalization
(Days −1 to 8)
Hospitalization
(Days 20 to 28)
Hospitalization
(Days 40 to 48)
Follow-up
(Days 61 to 63)


 
 
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3.2 
Trial Treatments 
3.2.1 
Investigational Medicinal Product 
3.2.1.1 
Brexpiprazole ODTs (Investigational Medicinal Product) 
Subjects will receive one 2-mg brexpiprazole ODT with or without 150 mL of ordinary-
temperature water. When administered without water, the subject will be instructed to 
place the tablet directly on the tongue and keep it there until it disintegrates completely 
before swallowing. Compliance will be ensured by a mouth check. 
All doses will be administered after fasting for at least 10 hours and no food will be 
allowed until 4 hours postdose. Except as part of the dosing procedure, water will be 
restricted from 1 hour prior to dosing until 2 hours postdose. 
3.2.1.2 
Brexpiprazole Conventional Tablets 
Subjects will receive one 2-mg brexpiprazole conventional tablet with 150 mL of 
ordinary-temperature water. Compliance will be ensured by a mouth check. The IMP will 
be administered after fasting for at least 10 hours and no food will be allowed until 
4 hours postdose. Except as part of the dosing procedure, water will be restricted from 
1 hour prior to dosing until 2 hours postdose. 
3.2.2 
Treatment Period 
After single oral administration of the Period 1 IMP, there will be a washout period of 
20 days, after which subjects will receive single oral administration of the Period 2 IMP 
(a different combination of drug formulation and administration method than that of 
Period 1). After single oral administration of the Period 2 IMP, there will be another 
washout period of 20 days, after which subjects will receive single oral administration of 
the Period 3 IMP (a different combination of drug formulation and administration method 
than those of Period 1 and Period 2). 
[Rationale for treatment period] 
According to the BE Guideline,11 studies should be conducted based on single dosing, as 
a rule. 
[Rationale for washout period] 
From the results of a Japanese single-dose trial (331-07-002), the mean elimination half-
life of brexpiprazole was 66.6 hours in the 4 mg treatment group, for which the 
elimination half-life was longest. According to the BE Guideline, “Washout periods 


 
 
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should usually be more than 5 times the elimination half-life of the unchanged active 
ingredient or active metabolites to be measured.” This suggests that the washout period 
should be more than 333 hours (more than 14 days), which is 5 times the elimination 
half-life. The results of the Japanese bioequivalence study (331-10-005) showed that the 
blood drug concentration prior to the dosing for Period 2 after a washout period of 
20 days was less than 5% of Cmax in all subjects, and therefore the washout period 
following trial drug administration is set to be 20 days. 
3.3 
Trial Population 
3.3.1 
Number of Subjects and Description of Population 
A total of 21 healthy male subjects at least 20 years of age and below 40 years of age, 
will be enrolled. 
Any subjects scheduled for IMP administration who withdraw their consent or are judged 
to be unable to receive the IMP before the first administration will be replaced by reserve 
subjects, without re-randomization of treatment allocations. 
There will be no addition or replacement of subjects if any subjects withdraw from the 
trial after the first randomized administration. 
3.3.2 
Assignment of Subject Identification Number 
Subjects who provided written informed consent will be given a unique subject 
identification number (site number [3 digits] + subject number [S + 5 digits]). Site 
number will be assigned by the sponsor. Subject numbers will be assigned as site serial 
numbers, in the order informed consent is obtained, beginning with S00001. 
3.4 
Eligibility Criteria 
3.4.1 
Informed Consent 
Informed consent will be freely obtained from all subjects. The informed consent form 
(ICF) will be approved by the same institutional review board (IRB) that approves this 
protocol. 
Each ICF will comply with the International Council for Harmonisation (ICH) Good 
Clinical Practice (GCP) Guideline14 and local regulatory requirements. 
The investigator or subinvestigator 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 prior to initiation of any procedures that are performed 


 
 
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solely for the purpose of determining eligibility for research, 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 subinvestigator, the IRB approved 
written ICF will be signed and dated by both the subject and the person obtaining consent 
(investigator or subinvestigator). If a study collaborator has provided a supplemental 
explanation, the IRB approved written ICF will also be signed and dated by the study 
collaborator. The subject will receive a copy of the signed ICF; the original shall be kept 
on file by the investigator or subinvestigator. 
Subjects may be asked to sign additional ICFs if the protocol is amended and the changes 
to the protocol result in additional information that needs to be provided to the subjects, 
so that they can make a knowledgeable and voluntary decision on trial participation. 
3.4.2 
Inclusion Criteria 
Subjects are required to meet the inclusion criteria in Table 3.4.2-1. 
Table 3.4.2-1 
Inclusion Criteria 
1. 
Healthy Japanese male subjects at least 20 years of age and below 40 years of age, at the time of 
informed consent. 
2. 
Subjects with a body mass index (BMI: weight [kg] ÷ height [m]2) within the range of 18.5 to 
< 25.0 kg/m2 (to be checked also at the time of screening). 
3. 
Subjects capable of providing written informed consent prior to initiation of any trial-related 
procedures, and able, in the opinion of the investigator or subinvestigator, to comply with all 
requirements of the trial. 
 
[Rationale] 
1. 
The lower age limit is the age at which subjects are capable of taking responsibility for providing 
informed consent as legal adults, and the upper age limit is set because subjects older than 40 years 
are more likely to have complications and their metabolism may differ from that of younger subjects. 
The subject population is restricted to males to eliminate the need to consider the possibility of 
pregnancy or the effects of menstruation. 
2. 
Specified to reduce the inter-individual variability in pharmacokinetics due to obesity. 
3. 
Specified to ensure that subjects are capable of providing informed consent and to allow the 
investigator or subinvestigator to judge whether subjects are able to comply with the protocol. 
 


 
 
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3.4.3 
Exclusion Criteria 
Subjects will be excluded if they meet any of the exclusion criteria in Table 3.4.3-1. 
Table 3.4.3-1 
Exclusion Criteria 
1. 
Clinically significant abnormality at the time of screening (eg, significant deviation from reference 
ranges) or in medical history that, in the opinion of investigator, subinvestigator, or sponsor may 
place the subject at risk or interfere with outcome variables, including drug absorption, 
distribution, metabolism, and excretion. 
This includes, but is not limited to, history of or concurrent cardiac, hepatic, renal, neurologic, 
gastrointestinal, respiratory, hematologic, and immunologic disease. 
2. 
Subjects who have supine blood pressure, after resting for at least 3 minutes, higher than 
140 mmHg or lower than 100 mmHg (systolic blood pressure) or higher than 90 mmHg or lower 
than 50 mmHg (diastolic blood pressure) and who have a reduction in blood pressure upon 
standing of ≥ 20 mmHg (based on the difference between standing and sitting systolic blood 
pressure) at the time of screening. 
3. 
Subjects who have a supine pulse rate, after resting for at least 3 minutes, outside the range of 40 to 
90 bpm at the time of screening. 
4. 
Clinically relevant electrocardiogram (ECG) findings in the 12-lead ECG tests performed at 
screening or at admission to the trial site in Period 1, such as atrioventricular block, QRS interval 
> 120 msec, or QTcF interval ≥ 450 msec. 
5. 
Subjects who meet any of the following for hepatitis: 
 
History of or current hepatitis B, or current hepatitis C. Positive test result for hepatitis B 
surface antigen (HBsAg) or hepatitis C antibodies (anti-HCV) at the time of screening. 
 
History of or current alcoholic hepatitis or nonalcoholic steatohepatitis. 
6. 
History of or current acquired immunodeficiency syndrome (AIDS). Positive test result for human 
immunodeficiency virus (HIV) at the time of screening. 
7. 
History of serious mental disorder. 
8. 
History of drug or alcohol abuse within 2 years prior to screening. 
9. 
Positive alcohol test or urine drug screen for substance abuse at screening or at admission to trial 
site in each period. 
10. 
Sexually active males who cannot or will not practice 2 different methods of birth control or 
remain abstinent during the trial and until 30 days after the final administration of the IMP, or will 
not refrain from sperm donation from the screening visit until 30 days after the final administration 
of IMP. 
If employing birth control, 2 of the following methods must be used: vasectomy, tubal ligation, 
vaginal diaphragm, intrauterine device, oral contraceptive, or condom containing sponge with 
spermicide. 
11. 
History of any significant drug allergy. 
12. 
Any history of significant bleeding or hemorrhagic tendency. 
13. 
Blood collection (blood donation, etc) exceeding 200 mL within 30 days or 400 mL within 90 days 
prior to the first administration of IMP, or blood collection (blood donation, etc) exceeding 
1200 mL in total within 1 year prior to first administration of IMP. 
14. 
History of difficulty in donating blood. 
15. 
Use of another investigational drug within 120 days prior to the first administration of IMP. 
16. 
Previous exposure to brexpiprazole. 
17. 
Use of tobacco products or daily exposure to secondhand smoke within 2 months prior to 
screening, or positive urine cotinine test (urine cotinine concentration of > 200 ng/mL) at 
screening. 


 
 
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Table 3.4.3-1 
Exclusion Criteria 
18. 
Consumption of grapefruit, grapefruit products, Seville orange, Seville orange products, star fruit, 
or star fruit products within 72 hours prior to first administration of IMP, or consumption of 
alcohol within 72 hours prior to administration of IMP. 
19. 
Use of prescription, over-the-counter (OTC), or herbal medication, or vitamin supplements, or 
consumption of food or beverages containing St. John’s Wort within 14 days prior to the first 
administration of IMP, or use of antibiotics within 30 days prior to the first administration of IMP. 
The sponsor may allow use only if the medication used is considered unlikely to impact PK 
assessment. 
20. 
History of major surgery of the digestive tract (excluding appendectomy). 
21. 
Occupational exposure to pesticides or organic solvents within 30 days prior to screening. 
22. 
Any subject visiting other hospitals or departments or planning to visit other hospitals or 
departments during the trial period. 
23. 
Any subject who, in the judgment of the investigator or subinvestigator, should not participate in 
the trial. 
QTcF = QT interval corrected for heart rate by Fridericia’s formula 
 
[Rationale] 
1 to 4 
Specified to confirm that subjects are healthy. 
5 to 9 
Specified because such subjects cannot be considered healthy. 
10 
Specified to ensure the safety of subjects and their partners. 
11 to 15 
This criterion was set to ensure the safety of subjects. 
(13: Specified in reference to the criteria for blood donation of the New Blood Program 
Advisory Committee. 15: Specified in reference to “Criteria for Period of Suspending 
Participation in Clinical Studies” of the Japan Association of Contract Institutes for Clinical 
Trials.) 
16 
This criterion was set to ensure the safety of subjects and to avoid possible effects of 
previous exposure to brexpiprazole on PK and safety assessments. 
17 
Specified to confirm that subjects are healthy. 
18 to 20 
Specified to avoid possible effects on PK. 
21 
Specified to avoid possible effects on PK due to exposure to any substances known to 
stimulate hepatic microsomal enzymes. 
22 
This criterion was set to ensure the safety of subjects. 
23 
Specified to allow the investigator or subinvestigator to make judgments on subjects’ 
eligibility, taking subjects’ compliance into account. 
 
Re-entry of subjects who fail a screening examination will not be permitted. If the 
investigator or subinvestigator judges that a clinical laboratory test or other test should be 
repeated, a record is to be kept according to the procedures of the trial site. 
3.5 
Endpoints 
3.5.1 
Primary Endpoints 
Cmax and AUCt of brexpiprazole 


 
 
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3.5.2 
Secondary Endpoints 
1) Plasma concentration-time profiles of brexpiprazole 
2) Brexpiprazole AUC∞, tmax, λz, AUC_%Extrap, t1/2,z, CL/F, CL/F/BW, and tlast 
 
3.5.3 
Safety Endpoints 
Adverse events, clinical laboratory values, vital signs (body temperature, blood pressure, 
pulse rate, respiratory rate), body weight, 12-lead ECG, physical examination, and 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
3.6 
Measures to Minimize/Avoid Bias 
The primary endpoints of the present trial are based on plasma drug concentrations, not 
producing bias without blinding, and therefore this trial will be conducted as an open-
label, randomized, 3-arm, 3-way crossover study. 
3.7 
Trial Procedures 
Participation in this trial will be for a total of up to 85 days, including the screening 
period, 3 periods of hospitalization and outpatient visits, and the follow-up period. 
Subjects will provide consent and be screened between Days −22 and −2 prior to dosing. 
Subjects who meet the inclusion criteria and do not fulfill any of the exclusion criteria 
will be admitted to the trial site on Day −1. Subjects will receive the IMP on Day 1. The 
washout period following trial drug administration will be 20 days. Subjects will remain 
hospitalized for 1 week from the day after IMP administration, during which they will 
undergo observation and examination. Subjects will be discharged on Day 8 after 
completion of safety evaluation and PK blood sampling. After discharge, subjects will 
return to the trial site 3 times for examinations and observations on an outpatient basis. 
For hospitalization in Period 2 and Period 3, subjects will again be hospitalized on the 
day before IMP administration (on Days 20 and 40), and will undergo IMP 
administration and observation and examination as with hospitalization in Period 1. The 
post-treatment follow-up will be performed by trial site visit or telephone between 20 and 
22 days after the final IMP administration (between Days 61 and 63). If an AE is 
suspected as a result of information obtained in a telephone call, the subject will be asked 
to come to the trial site for further confirmation. 
Subjects who discontinue participation should complete the same assessments as are 
performed at discharge. 
Trial assessment time points are summarized in Table 3.7-1. 


 
 
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Table 3.7-1 
Schedule of Assessments 
 
Screen
-ing
Admission
IMP Administration
Discharge
Visit
At Discon
-tinuation
Follow-upa
Day of Conduct
Day −22 to
−2
Day −1, 20, 40
Day 1, 21, 41
Day 2, 22,
42
Day 3, 23,
43
Day 4, 24,
44
Day 5, 25,
45
Day 6, 26,
46
Day 7, 27,
47
Day 8, 28, 48
Day 10, 12, 14,
30, 32, 34,
50, 52, 54
Day 61 to 63
Informed consent
X
Inclusion/exclusion criteria
X
X
Subject background
X
Medical history
X
Hepatitis and HIV screen
X
Alcohol test and urine drug screen
X
X
Urine cotinine test
X
Admission to trial site:
Admission
X
Meals
Dinner (followed by
fasting from approx
22:00 on Day −1)
Lunch (4 h postdose) and dinner
Discharge
X
IMP Administration:
Randomization
Predose on Day 1
Sequenceb                                         Sequence 1:
Day 1, 41: Brex ODT 2 mg
Day 21: Brex conventional tablet 2 mg
Sequence 2: 
Day 1, 21: Brex ODT 2 mg
Day 41:  Brex conventional tablet 2 mg
  Sequence 3: 
Day 1: Brex conventional tablet 2 mg
Day 21, 41: Brex ODT 2 mg
Record of concomitant drugs and therapies
Safety:
Adverse events
Height
X
Weight
X
X
X
X
Physical examination
X
X
X
Day 14, 34, 54
X
Vital signsc
X
X
Predose and 2, 6, 12 h postdose
24 h
postdose
72 h
postdose
120 h
postdose
168 h postdose
216, 264, 312 h
postdose
X
12-lead ECGd
X
X
(3 consecutive
measurements)
2, 6 h postdose
24 h
postdose
72 h
postdose
168 h postdose
X
Clinical laboratory testse
(Including prolactin concentration)
C-SSRS
Baseline
version
Performed predose using since-last-visit
version
Since-last-visit
version
Since-last-
visit version
Pharmacokinetics:
PK blood sampling
Predose and 1, 2, 3, 4, 5, 6, 8, 12 h
postdose
16, 24 h
postdose
48 h
postdose
72 h
postdose
96 h
postdose
120 h
postdose
144 h
postdose
168 h postdose
216, 264, 312 h
postdose
X
X
X
Predose
X
X
Ongoing
Period 1: Days 1 to 20, Period 2: Days 21 to 40, Period 3: Days 41 to 60
Postdose Hospitalization Periods
Breakfast, lunch, dinner
Ongoing


 
 
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Brex = brexpiprazole; C-SSRS = Columbia-Suicide Severity Rating Scale; HIV = human immunodeficiency virus; ODT = orally disintegrating tablet 
a The post-treatment follow-up will be performed by trial site visit or telephone between 20 and 22 days after the final IMP administration. 
b ODT will be administered with and without water in the following sequences. Sequence 1: Administered without water on Day 1 and with 150 mL of 
ordinary-temperature water on Day 41. Sequence 2: Administered with 150 mL of ordinary-temperature water on Day 1 and without water on Day 21. 
Sequence 3: Administered with 150 mL of ordinary-temperature water on Day 21 and without water on Day 41. 
c Blood pressure and pulse rate will be taken with the subject in the supine (performed first), sitting, and standing positions after remaining for at least 
3 minutes in each position. Sitting and standing blood pressure and pulse rate will be measured only at screening. Body temperature and respiratory rate 
will be measured with the subject in the supine position. 
d Twelve-lead ECG will be performed after the subject has been supine and at rest for at least 10 minutes. Three consecutive ECG measurements will be taken 
upon admission in each period and the mean value of those three measurements will be used as the baseline data for each period respectively. 
e Measurement of prolactin concentration at admission (Days −1, 20, and 40) is not required. 
 


 
 
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3.7.1 
General Inpatient Procedures 
On Days 1, 21, and 41, the IMP will be administered after subjects have fasted for at least 
10 hours (from approximately 22:00 the day before dosing) and no food will be allowed 
for 4 hours postdose. Except as part of the dosing procedure, water will be restricted from 
1 hour prior to dosing until 2 hours postdose. 
Subjects will be instructed to remain either seated or in a semi-recumbent position for the 
first 4 hours following dosing except during brief periods when protocol-related 
procedures are performed. Restroom visits must be supervised during the 4 hours 
postdose and should be brief (< 10 minutes). In addition, during the 4-hour period post 
oral dosing, the subject’s toilet use must be supervised to prevent self-induced emesis 
resulting in loss of the oral dose. 
Following the 4-hour postdose period, the subjects will be allowed to ambulate, but will 
be instructed not to exercise strenuously. 
3.7.2 
Dietary Requirements 
 From 14 days before the first IMP administration until completion of blood sampling 
at 312 hours postdose on Day 54 
Consumption of food or beverages containing St. John’s Wort is prohibited. 
 From 72 hours before the first IMP administration until completion of blood sampling 
at 312 hours postdose on Day 54 
Consumption of grapefruit, grapefruit products, Seville oranges, Seville orange 
products, star fruit, or star fruit products is prohibited. 
 From 72 hours before each administration until discharge at the end of each 
hospitalization period 
Consumption of alcohol is prohibited. 
 During hospitalization 
Consumption of food or beverages containing methylxanthines (such as caffeinated 
coffee, caffeinated tea, caffeinated soda, and chocolate) is prohibited. 
 
3.7.3 
Schedule of Assessments 
Trial days and activities are summarized in Table 3.7.3-1. 
 


 
 
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Table 3.7.3-1 
Trial Days and Activities 
Screening (Days −22 to −2) 
 
Written informed consent 
 
Confirmation of the inclusion and exclusion criteria 
 
Subject background survey (date of birth, sex, race, ethnicity, current symptoms, medical history, drinking habit, smoking habit) 
 
Physical examination 
 
Vital signs (body temperature, blood pressure, pulse rate, respiratory rate) 
 
Blood pressure and pulse rate will be taken with the subject in the supine (performed first), sitting, and standing positions after remaining for at least 
3 minutes in each position (sitting and standing blood pressure and pulse rate will be measured only at screening). 
 
Body temperature and respiratory rate will be taken with the subject in the supine position. 
 
The difference between standing and sitting systolic blood pressure will also be measured. 
 
Measurement of height, body weight, and BMI  
 
Height will be measured to the nearest 0.1 cm. 
 
Body weight will be measured in the fasting state. 
 
BMI will be calculated based on the body weight and height at screening, by rounding down to the first decimal place. 
 
Clinical laboratory tests (hematology, biochemistry, urinalysis) 
 
Prolactin concentration test 
 
Alcohol test, urine drug screen, urinary cotinine test 
 
Human immunodeficiency virus (HIV) screen, and hepatitis B surface antigen (HBsAg) and hepatitis C antibodies (anti-HCV) screens 
 
12-lead ECG 
 
The ECG will be performed after the subject has rested in the supine position for at least 10 minutes. 
 
Columbia-Suicide Severity Rating Scale (C-SSRS) (use of baseline version) 
 
Confirmation of concomitant medications and therapies 
 
Identification/assessment of AEs 


 
 
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Table 3.7.3-1 
Trial Days and Activities 
Admission (Days −1, 20, and 40) 
 
Subjects will be admitted to the trial site. 
 
Reconfirmation of the inclusion and exclusion criteria (Note: HIV and hepatitis tests and BMI measurement do not need to be reperformed) 
 
Physical examination 
 
Vital signs (body temperature, blood pressure, pulse rate, respiratory rate) 
 
Blood pressure and pulse rate will be taken after the subject has rested in the supine position for at least 3 minutes. 
 
Body temperature and respiratory rate will be taken with the subject in the supine position. 
 
Body weight 
 
Clinical laboratory tests (hematology, biochemistry, urinalysis) 
 
Alcohol test, urine drug screen 
 
12-lead ECG 
 
The ECG will be performed after the subject has rested in the supine position for at least 10 minutes. 
 
The mean value of three consecutive ECG measurements taken upon admission in each period will be used as the baseline data for each period 
respectively. 
 
Confirmation of concomitant medications and therapies 
 
Identification/assessment of AEs 
 
Meals will be provided as follows: dinner, followed by fasting from approximately 22:00. 


 
 
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Table 3.7.3-1 
Trial Days and Activities 
IMP Administration (Days 1, 21, and 41) 
 
Eligible subjects will be randomized before IMP administration on Day 1. 
 
If replacement of any subject occurs before the first administration of IMP, a reserve subject will receive the IMP treatment allocated to the dropout subject, 
without re-randomization of treatment allocations. Subjects who do not receive the IMP treatment will be discharged from the trial site. 
 
Subjects randomized to Sequence 1 will receive one ODT without water on Day 1, one conventional tablet with 150 mL of ordinary-temperature water on 
Day 21, and one ODT with 150 mL of ordinary-temperature water on Day 41. 
 
Subjects randomized to Sequence 2 will receive one ODT with 150 mL of ordinary-temperature water on Day 1, one ODT without water on Day 21, and one 
conventional tablet with 150 mL of ordinary-temperature water on Day 41. 
 
Subjects randomized to Sequence 3 will receive one conventional tablet with 150 mL of ordinary-temperature water on Day 1, one ODT with 150 mL of 
ordinary-temperature water on Day 21, and one ODT without water on Day 41. 
 
The IMP will be administered after fasting for at least 10 hours. 
 
No food will be allowed for 4 hours postdose. Except as part of the dosing procedure, water will be restricted from 1 hour prior to dosing until 2 hours 
postdose. 
 
Vital signs (body temperature, blood pressure, pulse rate, respiratory rate): predose (within 120 minutes prior to dosing) and 2, 6, and 12 hours postdose. 
 
Blood pressure and pulse rate will be taken after the subject has rested in the supine position for at least 3 minutes. 
 
Body temperature and respiratory rate will be taken with the subject in the supine position. 
 
Except at predose, vital signs should be measured within 60 minutes prior to the designated time and prior to PK blood collection. 
 
Clinical laboratory tests (hematology, biochemistry, urinalysis): predose 
 
Prolactin concentration test: predose 
 
Blood sampling for PK assessments: predose (within 120 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 8, and 12 hours postdose. 
 
Except at predose, if a sample cannot be taken at the designated time, a window of ± 3 minutes is acceptable for each blood collection. 
 
12-lead ECG: 2 and 6 hours postdose 
 
The ECG will be performed after the subject has rested in the supine position for at least 10 minutes. 
 
ECGs should be performed within 60 minutes prior to the designated time and prior to PK blood collection. 
 
C-SSRS (use of since-last-visit version): predose 
 
Confirmation of concomitant medications and therapies 
 
Identification/assessment of AEs 
 
Meals will be provided as follows: lunch and dinner. 


 
 
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Table 3.7.3-1 
Trial Days and Activities 
Postdose Hospitalization Period (Days 2 to 7, Days 22 to 27, and Days 42 to 47) 
 
Vital signs (body temperature, blood pressure, pulse rate, respiratory rate): 24, 72, and 120 hours postdosea 
 
Blood pressure and pulse rate will be taken after the subject has rested in the supine position for at least 3 minutes. 
 
Body temperature and respiratory rate will be taken with the subject in the supine position. 
 
Vital signs should be measured within 60 minutes prior to the designated time and prior to PK blood collection. 
 
Blood sampling for PK assessments: 16, 24, 48, 72, 96, 120, and 144 hours postdosea 
 
If a sample cannot be taken at the designated time, a window of ± 3 minutes is acceptable for each blood collection. 
 
12-lead ECG: 24 and 72 hours postdose 
 
The ECG will be performed after the subject has rested in the supine position for at least 10 minutes. 
 
ECGs should be performed within 60 minutes prior to the designated time and prior to PK blood collection. 
 
Confirmation of concomitant medications and therapies 
 
Identification/assessment of AEs 
 
Meals will be provided as follows: breakfast, lunch, and dinner. 


 
 
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Table 3.7.3-1 
Trial Days and Activities 
Discharge (Days 8, 28, and 48) 
 
Physical examination 
 
Vital signs (body temperature, blood pressure, pulse rate, respiratory rate): 168 hours postdose 
 
Blood pressure and pulse rate will be taken after the subject has rested in the supine position for at least 3 minutes. 
 
Body temperature and respiratory rate will be taken with the subject in the supine position. 
 
Vital signs should be measured within 60 minutes prior to the designated time and prior to PK blood collection. 
 
Body weight 
 
Clinical laboratory tests (hematology, biochemistry, urinalysis) 
 
Prolactin concentration test 
 
Blood sampling for PK assessments: 168 hours postdose 
 
If a sample cannot be taken at the designated time, a window of ± 3 minutes is acceptable for each blood collection. 
 
12-lead ECG: 168 hours postdose 
 
The ECG will be performed after the subject has rested in the supine position for at least 10 minutes. 
 
ECGs should be performed within 60 minutes prior to the designated time and prior to PK blood collection. 
 
C-SSRS (use of since-last-visit version) 
 
Confirmation of concomitant medications and therapies 
 
Identification/assessment of AEs 
 
Subjects will be discharged. 


 
 
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Table 3.7.3-1 
Trial Days and Activities 
Outpatient Visits (Days 10, 12, 14, 30, 32, 34, 50, 52, and 54) 
 
Subjects will visit the trial site. 
 
Physical examination: on the third visit day of each period (Days 14, 34, and 54) 
 
Vital signs (body temperature, blood pressure, pulse rate, respiratory rate): 216, 264, and 312 hours postdosea 
 
Blood pressure and pulse rate will be taken after the subject has rested in the supine position for at least 3 minutes. 
 
Body temperature and respiratory rate will be taken with the subject in the supine position. 
 
Vital signs should be measured within 60 minutes prior to the designated time and prior to the PK blood sample being taken; however, a window of 
± 5 hours is acceptable. 
 
Blood sampling for PK assessments: 216, 264, and 312 hours postdosea 
 
If a sample cannot be taken at the designated time, a window of ± 5 hours is acceptable for the blood collection. 
 
Confirmation of concomitant medications and therapies 
 
Identification/assessment of AEs 


 
 
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Table 3.7.3-1 
Trial Days and Activities 
Discontinuation 
 
Physical examination 
 
Vital signs (body temperature, blood pressure, pulse rate, respiratory rate) 
 
Blood pressure and pulse rate will be taken after the subject has rested in the supine position for at least 3 minutes. 
 
Body temperature and respiratory rate will be taken with the subject in the supine position. 
 
Vital signs should be measured prior to PK blood collection. 
 
Body weight 
 
Clinical laboratory tests (hematology, biochemistry, urinalysis) 
 
Prolactin concentration test 
 
Blood sampling for PK assessments 
 
12-lead ECG 
 
The ECG will be performed after the subject has rested in the supine position for at least 10 minutes. 
 
ECGs should be performed prior to PK blood collection. 
 
C-SSRS (use of since-last-visit version) 
 
Confirmation of concomitant medications and therapies 
 
Identification/assessment of AEs 
Follow-up (Days 61 to 63) 
 
Conducted by trial site visit or telephone. 
 
Confirmation of concomitant medications and therapies 
 
Identification/assessment of AEs 
 
If an AE is suspected as a result of information obtained in a telephone call, the subject will be asked to come to the trial site for further confirmation. 
a Refer to Table 3.7-1 for conduct days. 


 
 
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3.7.4 
Safety Assessments 
3.7.4.1 
Adverse Events 
Refer to Section 5 Reporting of Adverse Events for the methods and timing for assessing, 
recording, and analyzing AEs. This trial is a crossover study, and AEs in each period will 
be assessed based on a comparison with the subject’s status before the IMP 
administration in the respective periods. 
3.7.4.2 
Clinical Laboratory Assessments 
The data from the clinical laboratory assessments listed in Table 3.7.4.2-1 will be 
collected on the measurement days specified in the schedule of assessments (Table 3.7-1), 
and processed according to the procedures specified by the clinical chemistry laboratory. 
The volume of blood collected will be 10 mL per sampling for hematology and serum 
biochemistry, 3 mL per sampling for human immunodeficiency virus (HIV), hepatitis B 
surface antigen (HBsAg), and hepatitis C antibodies (anti-HCV), and 3 mL per sampling 
for prolactin concentration. The date and time of each blood and urine collection will be 
recorded in the case report form (CRF). 


 
 
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Table 3.7.4.2-1 
Clinical Laboratory Assessments 
Hematology: 
WBC count with differential 
RBC count 
Hematocrit 
Hemoglobin 
MCV 
MCHC 
Platelet Count 
 
Additional Tests: 
HIV 
HBsAg 
anti-HCV 
Prolactin 
Serum Chemistry: 
ALT 
Albumin 
ALP 
AST 
Total Bilirubin 
BUN 
Calcium 
Chloride 
Total Cholesterol 
Creatinine 
Creatinine Phosphokinase 
GGGT 
Glucose 
LDH 
Inorganic Phosphorus 
Potassium 
Total Protein 
Sodium 
Uric acid 
Triglycerides 
Urinalysis: 
Color 
Appearance 
Bilirubin 
Glucose 
Ketones 
Leukocyte Esterase 
Nitrites 
Occult blood 
Protein 
Urobilinogen 
pH 
Microscopic analysis of RBC/WBC (per high 
powered field) 
Drug Screen (all items in urine except where noted): 
Amphetamines 
Barbiturates 
Benzodiazepines 
Cannabinoids 
Cocaine 
Opiates 
Phencyclidine 
 
Alcohol Test (breath or urine) 
 
Urinary Cotinine Test 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; anti-HCV = hepatitis C antibodies; 
AST = aspartate aminotransferase; BUN = blood urea nitrogen; GGGT = gamma glutamyl 
transferase; HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; 
LDH = lactic dehydrogenase; MCHC = mean corpuscular hemoglobin concentration; MCV = mean 
corpuscular volume; RBC = red blood cell; WBC = white blood cell. 
 
3.7.4.3 
Physical Examination and Vital Sign Assessments 
A complete medical history will be taken at the screening visit. A physical examination 
will be performed in accordance with Section 3.7.3 Schedule of Assessments of this 
protocol. The physical examination will include an evaluation of the following body 
systems: head, ears, eyes, nose, and throat; thorax; abdomen; urogenital; extremities; 
neurological; and skin and mucosae. Whenever possible, all physical examinations for 
individual subjects should be performed by the same physician (investigator or 


 
 
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subinvestigator) throughout the trial. The date and result of assessment will be recorded 
in the CRF. Assessments for each period will be made in comparison with the physical 
condition at the time of admission in each period. 
Vital signs (including body temperature, blood pressure, pulse rate, and respiratory rate) 
will be performed and documented according to Section 3.7.3 Schedule of Assessments 
of this protocol. Blood pressure and pulse rate will be measured in the order of supine, 
sitting, and standing after each position has been maintained for at least 3 minutes. If the 
blood pressure or pulse rate at screening is within the range of exclusion criteria but is not 
deemed clinically relevant, a total of 3 readings will be taken 10 minutes apart. The 
subject will be included in the trial if 2 out of 3 readings are outside the range of 
exclusion criteria. Sitting and standing blood pressure and pulse rate will be measured 
only at screening, and the difference between standing and sitting systolic blood pressure 
will be calculated. Body temperature and respiratory rate will be taken with the subject in 
the supine position. Body temperature will be recorded up to the first decimal place on 
the CRF. If body temperature is measured to the second decimal place or less, the second 
decimal place will be rounded. Vital signs will be obtained prior to PK blood collection at 
the nominal time points, where applicable. Measurement date and time, and measurement 
result will be recorded in the source document and CRF. 
3.7.4.4 
Electrocardiogram Assessments 
ECGs will be recorded according to the schedule outlined in Section 3.7.3 Schedule of 
Assessments of this protocol. ECGs will be obtained prior to PK blood collections at 
either nominal time point, where applicable. Twelve-lead ECGs will be recorded with the 
subject supine and at rest (for at least 10 minutes), and the original ECG output recording 
will be retained in the medical record or principal investigator file. The central ECG 
laboratory will collect and analyze ECG data, and measure heart rate, PR interval, RR 
interval, QRS interval, QT interval, and QTc (QTcF, QTcB). Three consecutive ECG 
measurements will be taken upon admission in each period and the mean value of those 
three measurements will be used as the baseline data for each period respectively. The 
analysis results will be reported to the investigator or subinvestigator. The investigator or 
subinvestigator will review the analysis results from the central ECG laboratory, and add 
their signature and the date of confirmation. The investigator or subinvestigator will 
determine if a result is normal or abnormal with reference to the analysis results provided 
by the central ECG laboratory and record measurement date and time, assessment result, 
and findings in the source documents and CRF. 


 
 
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Analysis results will be directly reported from the central ECG laboratory to the sponsor 
with the electronic file, and therefore recording in the source documents and CRFs is 
unnecessary. 
3.7.4.5 
Body Weight 
Body weight will be measured in tenths of a kilogram using the same weight scale 
throughout the trial in accordance with Section 3.7.3 Schedule of Assessments of this 
protocol. Measurement date and time, and the measurement result will be recorded in the 
source documents and CRF. 
3.7.4.6 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The Columbia-Suicide Severity Rating Scale (C-SSRS) will be administered in 
accordance with Section 3.7.3 Schedule of Assessments of this protocol. The C-SSRS 
captures the occurrence, severity, and frequency of suicide related thoughts and behaviors 
during the assessment period. This scale consists of a baseline version that is designed to 
assess of the history of suicide-related events and suicidal ideation that the subject has 
had at any time in the past, and a since-last-visit version that focuses on any suicidal 
tendencies that might have arisen since the last assessment. Assessment at screening will 
be performed using the baseline version, and assessment after that will be performed 
using the since-last-visit version. A copy of the baseline version of the C-SSRS is 
presented in Appendix 1, and a copy of the since-last-visit version is presented in 
Appendix 2. The date and result of assessment will be recorded in the source documents 
and CRF. 
3.7.5 
Pharmacokinetic Assessments 
3.7.5.1 
Pharmacokinetic Plasma Samples 
At each time point shown in Table 3.7-1, a 3-mL blood sample will be collected, and 
plasma concentrations of brexpiprazole will be measured by a validated high-
performance liquid chromatography with tandem mass spectrometry method. Additional 
metabolites that are not identified in the protocol may also be analyzed if new 
information becomes available. Plasma samples may be used for examination of analysis 
methods as needed. 
The results of drug concentration measurement will be retained by the bioanalytical 
laboratory, and the electronic file will be submitted to the sponsor. While recording the 
measurement results in the source documents and CRFs is unnecessary, the date and time 
of blood sampling will be recorded in the source documents and CRF. 


 
 
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The samples will be shipped to the bioanalytical laboratory, and backup samples will be 
stored at the trial site and shipped to the bioanalytical laboratory as needed. Detailed 
handling and shipping instructions are provided in the procedures that have been prepared 
separately. 
3.7.6 
End of Trial 
The end of trial date is defined as the last date of contact or the date of the final contact 
attempt from the post-treatment follow-up CRF page for the last subject completing or 
withdrawing from the trial. 
3.8 
Stopping Rules, Withdrawal Criteria, and Procedures 
3.8.1 
Entire Trial 
If the sponsor prematurely terminates or suspends the trial for safety or unanticipated 
other reasons, prompt notification will be given to the head of the trial site and regulatory 
authorities in accordance with regulatory requirements. 
3.8.2 
Individual Site 
The sponsor, investigator, or the IRB has the right to terminate the participation of a 
particular trial site, if necessary, due to lack of subject enrollment, noncompliance with 
the protocol, or if judged to be necessary for medical, safety, regulatory, ethical, or other 
reasons consistent with applicable laws, regulations, and GCP. The head of the trial site 
will notify the sponsor promptly if the trial is terminated by the investigator or the IRB at 
the trial site. 
3.8.3 
Individual Subject Discontinuation 
3.8.3.1 
Treatment Discontinuation 
After the first dose of IMP, a subject may stop treatment permanently for a variety of 
reasons. Treatment discontinuations may be initiated by a subject or may become 
medically necessary due to AEs, required treatment with a disallowed medication or 
therapy, or other reasons, as determined by the investigator or subinvestigator. If a 
subject discontinues treatment, their participation in the trial will be discontinued. 
Discontinued subjects should be encouraged to complete all early termination (ET) and 
follow-up assessments with ET assessments conducted as soon as possible after the 
subject is withdrawn. 


 
 
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3.8.3.2 
Documenting Reasons for Discontinuation 
All subjects have the right to withdraw, and the investigator or subinvestigator can 
discontinue a subject’s participation in the trial at any time if medically necessary. In 
addition, subjects meeting the following criteria must be withdrawn from the trial (only 
one reason for discontinuation [the main reason] can be recorded in the CRF): 
 AEs 
 Subject decides to discontinue because of annoyance or discomfort due to a 
nonserious AE which is not otherwise determined to be an undue hazard 
 Continuing IMP places the subject at undue risk as determined by the investigator 
or subinvestigator (eg, a safety concern that is possibly, probably, or likely related 
to IMP) 
 SAE 
 Other potentially IMP-related safety concerns or AEs 
 Death 
 Lost to follow-up 
 Investigator’s or subinvestigator’s decision (other than AE) 
 Pregnancy (see Section 5.5 Pregnancy) 
 Protocol deviation (other than non-compliance with IMP) 
 A subject was considered to have not met the inclusion criteria or have met the 
exclusion criteria. 
 A prohibited concomitant medication was administered or judged to be necessary. 
 Termination of all or part of the trial by the sponsor 
 Withdrawal of consent by subject (if confirmed not related to an AE) 
 Other 
 
If the subject discontinues IMP due to an AE, the investigator or subinvestigator, or other 
trial personnel, will make every effort to follow the event until the event is resolved or 
stabilized, or the subject is lost to follow-up or has died. Follow-up procedures in 
Section 5.7 must be followed. Subjects may be replaced, if withdrawals occur, as 
described in Section 3.3.1.  
3.8.3.3 
Withdrawal of Consent 
All subjects have the right to withdraw their consent from further participation in the trial 
at any time without prejudice. Subjects cannot withdraw consent for use of data already 
collected as part of the trial, but only for future participation. 


 
 
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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 understood, documented, and 
managed to protect the rights of the subject and the integrity of the trial. 
Subjects who withdraw, should be encouraged to complete all ET and follow-up 
assessments with ET assessments conducted as soon as possible after the subject is 
withdrawn. 
3.9 
Screen Failures 
A screen failure subject is one from whom informed consent is obtained and is 
documented (ie, subject signs an ICF), but who is withdrawn from this study before being 
randomized. 
For any subject to whom screen failure applies, the following items will be recorded in 
the CRF: 
 Subject identification number 
 Date of informed consent 
 Date of visit (date of screening examination) 
 Subject background survey (date of survey, date of birth, sex, race, ethnicity) 
 Assessment result for eligibility criteria 
 Date of assessment of screen failure 
 Reason for assessment of screen failure 
 
3.10 
Definition of Completed Subjects 
The treatment period is defined as the time period during which subjects are evaluated for 
trial objectives irrespective of whether or not the subject actually consumes all doses of 
IMP. Subjects who are evaluated at the last scheduled visit during the trial period will be 
defined as trial completers. For purposes of this trial, subjects who complete Day 54 will 
be defined as trial completers. 
3.11 
Definition of Subjects Lost to Follow-up 
Subjects with whom contact is lost during the trial period and subjects who do not have a 
known reason for discontinuation (eg, withdrew consent or AE, etc.) will be classified as 
lost to follow-up. 
The investigator or subinvestigator, or designee will make 3 documented attempts to 
contact the subject by telephone and in the event the site is unable to reach the subject by 


 
 
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telephone, the investigator or subinvestigator, or designee will attempt to contact the 
subject via certified mail or an alternative similar method where appropriate, before 
assigning a “lost to follow-up” status. When a subject is lost to follow-up, 
presence/absence of contact with the subject, date of contact, and contact method will be 
recorded in the CRF. 
3.12 
Subject Compliance 
The date and time of each trial drug administration, dosage form, and use or non-use of 
water when taking medication will be recorded in the source documents and CRF. 
Information regarding any missed or inappropriately administered doses will also be 
documented in the source document and in the CRF. 
3.13 
Protocol Deviations 
In the event of a major deviation from the protocol due to an emergency, accident, or 
mistake (eg, IMP dispensing or subject dosing error or violation of concomitant 
medication criteria), the investigator or subinvestigator, or designee will contact the 
sponsor at the earliest possible time by telephone. The investigator or subinvestigator, 
medical expert, and sponsor will come to a joint decision as quickly as possible regarding 
the subject’s continuation in the trial. If the decision reached is to allow the subject to 
continue in the trial, this must be documented by the investigator or subinvestigator, and 
the sponsor, and approved by the medical expert. All deviations from the written protocol 
should be recorded in the source documents by the investigator or subinvestigator. If a 
significant deviation occurs, the date of occurrence of significant deviation and its 
summary should be recorded in the CRF. 
4 
Restrictions 
4.1 
Prohibited Medications 
No medications other than planned IMP may be taken during the trial. 
 From 14 days before the first IMP administration until completion of follow-up 
Prescription medications, OTC medications, herbal medication, vitamin supplements 
 From 30 days before the first IMP administration until completion of follow-up 
Antibiotics 
Exceptions to the above may be allowed only in cases where the sponsor judges that 
administration of the drug is unlikely to influence the pharmacokinetics of brexpiprazole. 
Exceptions must be discussed with the sponsor on a case-by-case basis and reasons 
documented. 


 
 
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4.2 
Other Restrictions 
The following will be prohibited during the specified period. 
 From 14 days before the first IMP administration until completion of blood sampling 
on Day 54 (312 hours postdose in Period 3) 
Food or beverages containing St. John’s Wort 
 From 72 hours before the first IMP administration until completion of blood sampling 
on Day 54 (312 hours postdose in Period 3) 
Grapefruit, grapefruit products, Seville oranges, Seville orange products, star fruit, or 
star fruit products 
 From 72 hours before each administration until discharge at the end of each 
hospitalization period 
Alcohol 
 During hospitalization 
Food or beverages containing methylxanthines (such as caffeinated coffee, 
caffeinated tea, caffeinated soda, and chocolate) 
 From 2 months before screening until completion of follow-up 
Smoking 
 From the time of informed consent until completion of follow-up 
Blood donation 
 
5 
Reporting of Adverse Events 
5.1 
Definitions 
An AE is defined as any untoward medical occurrence in a clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. Adverse events would not include information recorded 
as current symptoms at screening for preplanned procedures for which the underlying 
condition was known and no worsening occurred. 
An adverse reaction is any untoward and unintended response to an IMP related to any 
dose administered. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE.  


 
 
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An SAE includes any event that results in any of the following outcomes: 
 Death 
 Life-threatening; ie, the subject was, in the opinion of the investigator or 
subinvestigator, at immediate risk of death from the event as it occurred. It does not 
include an event that, had it occurred in a more severe form, might have caused death. 
 Persistent or significant incapacity/disability 
 Requires inpatient hospitalization or prolongs hospitalization 
 Hospitalization itself should not be reported as a serious treatment-emergent 
adverse event (TEAE); whenever possible the reason for the hospitalization 
should be reported. 
 Hospitalizations or prolonged hospitalizations for social admissions (ie, those 
required for reasons of convenience or other nonmedical need) are not considered 
serious TEAEs. 
 Congenital anomaly/birth defect. 
 Other medically significant events that, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above, eg, allergic bronchospasm requiring 
intensive treatment in an emergency room or home, blood dyscrasias or convulsions 
that do not result in hospitalization, or the development of drug dependency or drug 
abuse. 
 
Nonserious AEs are all AEs that do not meet the criteria for a “serious” AE. 
Immediately Reportable Event (IRE): 
 Any SAE 
 Any AE related to occupational exposure. 
 Potential serious hepatotoxicity (see Section 5.4 Potential Serious Hepatotoxicity). 
 Pregnancy. Although normal pregnancy is not an AE, it will mandate IMP 
discontinuation and must be reported on an IRE form to the sponsor. Pregnancy will 
only be documented on the AE CRF if there is a complication or abnormality in the 
newborn. The above includes pregnancy occurring in female partners of male subject. 
 
Clinical Laboratory Assessment Value Changes: It is the investigator’s or 
subinvestigator’s responsibility to review the results of all laboratory tests as they become 
available. This review will be documented by the investigator’s or subinvestigator’s dated 
signature on the laboratory report. For each abnormal laboratory test result, the 
investigator or subinvestigator needs to ascertain if this is an abnormal (ie, clinically 
relevant) change from baseline in each period for that individual subject. This 


 
 
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determination, however, does not necessarily need to be made the first time an abnormal 
value is observed. The investigator or subinvestigator may repeat the laboratory test or 
request additional tests to verify the results of the original laboratory tests. If this 
laboratory value is considered clinically relevant by the investigator or subinvestigator 
(eg, subject is symptomatic, requiring corrective treatment or further evaluation), or if the 
laboratory value leads to discontinuation, or fulfills a seriousness criterion, this is 
considered an AE. 
Severity: Adverse events will be graded on a 3-point scale. 
1 = Mild: 
Discomfort noticed, but no disruption to daily activity. 
2 = Moderate: Discomfort sufficient to reduce or affect normal daily activity. 
3 = Severe: 
Inability to work or perform normal daily activity. 
 
IMP Causality: Assessment of causal relationship of an AE to the use of IMP: 
Related:  
There is a reasonable possibility of a temporal and causal 
relationship between the IMP and the AE. 
Not Related: 
There is no temporal or reasonable relationship between the IMP and 
the AE. 
 
5.2 
Eliciting and Reporting Adverse Events 
The investigator or subinvestigator will assess subjects for the occurrence of AEs. For 
this trial, information on AEs will be followed until the end of the trial as specified in 
Section 3.7.6. To avoid bias in eliciting AEs, subjects should be asked the non-leading 
question: “How are you feeling?” All AEs (serious and nonserious) reported by the 
subject must be recorded in the source documents and CRFs provided by the sponsor. 
The source documents and CRF are to include event name, date and time of onset 
(recording of time of day is necessary for vomiting and wherever possible for other AEs), 
date of recovery, seriousness, severity, IMP causality, action taken regarding IMP 
administration, and outcome. All AE and SAE collections are to begin after a subject has 
signed the ICF and will continue until the last scheduled contact. 
Use medical terminology in AE reporting. Adverse events should be reported as a single 
unifying diagnosis whenever possible or, in the absence of a unifying diagnosis, as 
individual signs or symptoms. Exacerbation or disease progression should be reported as 


 
 
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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. 
If there is any change in the severity or seriousness of an AE that has been reported, the 
AE must be reported as a new AE in the CRF. 
In addition, the sponsor must be notified immediately by e-mail, as a rule, of any IREs 
according to the procedure outlined below in Section 5.3 Immediately Reportable Events. 
Special attention should be paid to recording hospitalization and concomitant medications 
5.3 
Immediately Reportable Events 
The investigator or subinvestigator, or designee must report any SAE, any AE related to 
occupational exposure, potential serious hepatotoxicity, or confirmed pregnancy, by e-
mail to the sponsor, immediately after either the investigator or subinvestigator become 
aware of the event. An IRE form or other form should be completed and sent by e-mail, 
in principle, to the sponsor using the contact information on the title page of this protocol. 
(Please note that the IRE form is a specific form provided by the sponsor and is NOT the 
AE CRF.) 
Subjects experiencing SAEs or IREs should be followed clinically as described in 
Section 5.7.2. It is expected that the investigator or subinvestigator will provide or 
arrange appropriate supportive care for the subject and will provide prompt updates on 
the subject’s status to the sponsor. 
5.4 
Potential Serious Hepatotoxicity 
For a subject who experiences an elevation in aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) that is ≥ 3 times the upper limit of normal (ULN), a total 
bilirubin level should also be evaluated. If the total bilirubin is ≥ 2 times the ULN, 
complete an IRE form or other form with all values listed and also report as an AE on the 
CRF. 
5.5 
Pregnancy 
Women of childbearing potential are women whose menstruation has started and who are 
not documented as sterile (eg, have had a bilateral oophorectomy, or hysterectomy, or 
who have been postmenopausal for at least 12 months). 
For sexually active subjects with partners who are women of childbearing potential, there 
must be a documented agreement that the subject and their partner will take effective 
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prevent pregnancy during the course of the trial and for 30 days after the last dose of IMP. 
Unless the subject or subject’s partner is sterile (ie, women who have had a bilateral 
oophorectomy, have had a hysterectomy, or have been postmenopausal for at least 
12 consecutive months; or men who have had a bilateral orchidectomy) or remains 
abstinent during the trial and for 30 days after the last dose of IMP, 2 of the following 
approved methods of birth control must be used: vasectomy, tubal ligation, intrauterine 
device, birth control pills, condom with spermicide, or occlusive cap (vaginal diaphragm 
or cervical/vault cap) with spermicide. Any single method of birth control, including 
vasectomy and tubal ligation, may fail, leading to pregnancy. The contraceptive method 
will be documented in the CRF. Male subjects must also agree not to donate sperm from 
trial screening through 30 days after the last dose of IMP. 
Before enrolling subjects in this clinical trial, investigators or subinvestigators must 
review the below information about trial participation as part of the ICF process. The 
topics should generally include: 
 General information 
 Informed consent form 
 Pregnancy prevention information 
 Contraceptives in current use 
 Follow-up of a reported pregnancy 
 
Before trial enrollment, subjects 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. 
During the trial, all subjects should be instructed to contact the investigator or 
subinvestigator immediately if they suspect their partners might be pregnant (eg, missed 
or late menstrual cycle). 
The investigator or subinvestigator must immediately notify the sponsor of any 
pregnancy associated with IMP exposure during the trial and for 30 days after the last 
dose of IMP, and record the event on the IRE form and forward it to the sponsor. The 
sponsor will forward the Pregnancy Surveillance Form(s) to the investigator or 
subinvestigator for monitoring the outcome of the pregnancy. 
Protocol required procedures for trial discontinuation and follow-up must be performed 
on the subject. Other appropriate pregnancy follow-up procedures for a subject’s partner 


 
 
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should be considered if indicated. In addition, the investigator or subinvestigator 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. 
5.6 
Procedure for Breaking the Blind 
Not applicable for this open-label trial. 
5.7 
Follow-up of Adverse Events 
5.7.1 
Follow-up of Nonserious Adverse Events 
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE CRF with the current status (ongoing or resolved/recovered) noted. All nonserious 
events (excluding IREs) that are ongoing at the last scheduled contact will be recorded as 
ongoing on the CRF. For any AE having been identified throughout the trial, during data 
analysis, additional relevant medical history information may be requested by the sponsor 
to further ascertain causality (including, but not limited to, information such as risk-
related behavior, family history and occupation). The follow-up information after the last 
scheduled contact will be recorded in the subject’s medical record. 
5.7.2 
Follow-up of Serious Adverse Events and Immediately 
Reportable Events 
This trial requires that subjects be actively monitored for SAEs and IREs until the last 
scheduled contact as specified in Section 3.7.6. 
Serious AEs and IREs that are identified or ongoing at the last scheduled contact must be 
recorded on the AE CRF page. Any new information (eg, Resolved) related to the SAE or 
IRE obtained from the last scheduled contact of the subject until the last scheduled 
contact of the last subject in the entire trial must be reported to the sponsor with the IRE 
form and so on, and the information must be recorded on the AE CRF page. The 
investigator or subinvestigator must follow SAEs and IREs until the events have resolved 
or are stabilized, or the subject is lost to follow-up or has died, and report any significant 
follow-up information to the sponsor with the IRE form and so on. Resolution means the 
subject has returned to the baseline state of health and stabilized means that the 
investigator or subinvestigator does not expect any further improvement or worsening of 
the subject’s condition. 


 
 
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5.7.3 
Follow-up and Reporting of Serious Adverse Events and 
Immediately Reportable Events Occurring After Last Scheduled 
Contact 
Any new SAEs or IREs reported to the investigator or subinvestigator, which occur after 
the last scheduled contact and are determined by the investigator or subinvestigator to be 
reasonably associated with the use of the IMP, should be reported to the sponsor. This 
may include SAEs or IREs that are captured on follow-up telephone contact or at any 
other time point after the defined trial period. The investigator or subinvestigator should 
follow SAEs or IREs identified after the last scheduled contact and continue to report any 
significant follow-up information to the sponsor with the IRE form and so on until the 
events have resolved or are stabilized, or the subject is lost to follow-up or has died. 
6 
Pharmacokinetic Analysis 
6.1 
Pharmacokinetic Methods 
6.1.1 
Primary Endpoints 
Cmax and AUCt of brexpiprazole 
6.1.2 
Secondary Endpoints 
1) Plasma concentration-time profiles of brexpiprazole 
2) Brexpiprazole AUC∞, tmax, λz, AUC_%Extrap, t1/2,z, CL/F, CL/F/BW, and tlast 
 
6.1.3 
Datasets for Analysis 
The bioequivalence analysis set is defined as the analysis dataset (see Section 7.2.1). 
6.1.4 
Analysis Methods 
The PK parameters of brexpiprazole (Cmax, AUCt, AUC∞, tmax, t1/2,z, λz, tlast, CL/F, 
CL/F/BW, AUC_%Extrap) will be calculated through a noncompartmental PK analysis. 
The plasma concentrations and estimated PK parameters will be presented with 
descriptive statistics by formulation and administration method. 
6.2 
Pharmacodynamic Methods 
No pharmacodynamic parameters will be evaluated for this trial. 
6.3 
Pharmacokinetic/Pharmacodynamic Methods 
No pharmacokinetic or pharmacodynamic-related analyses are scheduled for this trial. 


 
 
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6.4 
Pharmacogenomic Methods 
No pharmacogenomic-related analyses are scheduled for this trial. 
7 
Statistical Analysis 
The definition of analysis sets and analysis method by endpoint are summarized below. 
The analysis plan will be described in detail in the Statistical Analysis Plan separately. 
The Statistical Analysis Plan is to be determined before data lock. 
7.1 
Determination of Sample Size 
Based on the BE Guideline, the sample size was calculated so that the 90% confidence 
intervals of geometric mean ratios for brexpiprazole Cmax and AUCt between ODT (with 
or without water) and conventional tablet would fall within the bioequivalence range of 
0.8 to 1.25. 
In a brexpiprazole 4-mg ODT BA study conducted in Japan (331-102-00019) and 
brexpiprazole bioequivalence studies conducted outside Japan (331-10-243 and 
331-13-209), the within-subject variance for natural log-transformed Cmax and AUCt 
values was greatest for Cmax in Trial 331-13-209 (at 0.035). 
Assuming a geometric mean ratio of 1.0 for brexpiprazole Cmax between ODT (with and 
without water) and conventional tablet, and a within-subject variance of 0.035 for natural 
log-transformed Cmax, to achieve at least 90% power will require 6 subjects in each 
sequence, 18 in total. Considering the possibility of some subjects being excluded from 
analysis due to discontinuation, etc, the number of subjects was set as 7 for each 
sequence and 21 in total. 
7.2 
Datasets for Analysis 
7.2.1 
Bioequivalence Analysis Set 
All subjects who provided Cmax or AUCt through Period 1, Period 2, and Period 3 
7.2.2 
Safety Population 
All subjects who received at least one dose of IMP 
7.3 
Handling of Missing Data 
There will be no imputation for missing data. 


 
 
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7.4 
Primary Endpoint Analyses 
The following analysis will be performed on the bioequivalence analysis set: 
The Cmax and AUCt of brexpiprazole will be analyzed using the natural log-transformed 
values in a mixed effect model with sequence (1, 2, and 3), formulation and 
administration method (conventional tablet, ODT without water, ODT with water), and 
period (Period 1, Period 2, and Period 3) as fixed effects and the subjects within each 
sequence as a random effect. The 90% confidence intervals of geometric mean ratios for 
brexpiprazole Cmax and AUCt between ODT (with or without water) and conventional 
tablet will be calculated. If the 90% confidence intervals are within the range of 0.8 to 
1.25, the 2 formulations and administration methods will be judged to be bioequivalent. 
If an add-on subject study is conducted, bioequivalence will be assessed on the same 
basis from the result of combining the initial study and the add-on subject study by 
including study as a fixed effect in the above mixed effect model. 
If there are any subjects who had no evaluable parameters through Period 1, Period 2, and 
Period 3, analysis in which those subjects are included will be performed. 
The Kenward–Roger method will be used to estimate the degrees of freedom in the 
mixed effect model analysis. 
7.5 
Analysis of Demographic and Baseline Characteristics 
For age, height, weight (screening period), BMI, and medical history and current 
symptoms, the frequency distribution or descriptive statistics will be presented overall 
and by sequence for the bioequivalence analysis set and safety analysis set. 
7.6 
Safety Analysis 
Safety analysis will be conducted upon the safety analysis set for each formulation and 
administration method. Baseline is defined as the last measurement immediately before 
each dosing. 
7.6.1 
Adverse Events 
Medical Dictionary for Regulatory Activities (MedDRA) will be used to code AEs. The 
incidence of the following events will be summarized by system organ class and 
preferred term. 
 TEAEs 
 TEAEs by severity 


 
 
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 TEAEs with an outcome of death 
 Serious TEAEs 
 TEAEs leading to discontinuation of the IMP 
TEAEs potentially causally related to the IMP will also be summarized in the same way. 
7.6.2 
Clinical Laboratory Data 
For each clinical laboratory parameter except for qualitative urinalysis, the descriptive 
statistics of measured values and of changes from baseline will be calculated by time 
point. For qualitative parameters of clinical laboratory urinalysis, shift tables versus 
baseline at each time point will be produced. For the clinical laboratory parameters 
except for qualitative urinalysis, measured values will be classified as Within Reference 
Range, Lower Than Reference Range, and More Than Reference Range, using the 
reference range of the trial site, and shift tables versus baseline at each time point will be 
produced. 
7.6.3 
Physical Examination and Vital Signs Data 
For physical examination, listing of physical findings will be presented by each subject. 
For each vital sign, the descriptive statistics of measured values and of changes from 
baseline will be presented by time point. 
7.6.4 
Electrocardiogram Data 
For each 12-lead ECG parameter, the descriptive statistics of measured values and of 
changes from baseline will be calculated by time point. For 12-lead ECG assessment of 
normality/abnormality, shift tables versus baseline at each time point will be produced. 
For QTcF and QTcB, categorical analysis of measured values and of changes from 
baseline at each time point will be performed to calculate the number and percentage of 
subjects. 
7.6.5 
Other Safety Data 
7.6.5.1 
Body Weight 
For body weight, the descriptive statistics of measured values and of changes from 
baseline will be presented. 
7.6.5.2 
The Columbia-Suicide Severity Rating Scale 
C-SSRS data for individual subjects will be listed. 


 
 
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7.7 
Judgement for Conduct of Add-on Subject Study 
If bioequivalence cannot be demonstrated in the initial study because of an insufficient 
number of subjects, an add-on subject study can be performed in accordance with this 
protocol. 
The add-on subject study will be performed using not less than half the number of 
subjects in the initial study. No add-on subject study will be performed in the following 
cases: 
1) If the results of the initial study show that the point estimates of the geometric 
mean ratios for AUCt and Cmax between ODT and conventional tablet do not fall 
within the range of 0.8 to 1.25, and 
2) If the required number of subjects for the add-on subject study estimated from the 
results of the initial study is considered to be a sample size that is ethically or 
scientifically infeasible. 
7.8 
Pharmacodynamic Analysis 
No pharmacodynamic-related analyses are scheduled for this trial. 
8 
Management of Investigational Medicinal Product 
2-mg brexpiprazole ODT is the test formulation provided as the IMP, and 2-mg 
brexpiprazole conventional tablet is provided as the reference product. 
For the detailed management of the IMP and reference product, see the investigator’s 
brochure and clinical operation manual. 
8.1 
Packaging and Labeling 
The IMP and reference product will be provided to the IMP manager by the sponsor or 
designated agent. The IMP will be provided in bottles. Each IMP bottle used will be 
labeled to clearly disclose the statement “For clinical trial use only,” as well as the trial 
number, IMP name, amount, lot number, expiry date, storage, and sponsor’s name and 
address. The reference product will be provided in commercial product packaging. 
8.2 
Storage 
The IMP and reference product will be stored in a securely locked cabinet or enclosure. 
Access will be limited to the IMP manager. The IMP manager may not provide IMP or 
reference product to any subject not participating in this protocol. 
The IMP and reference product will be stored at room temperature. 


 
 
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The trial site staff will maintain a temperature log in the drug storage area recording the 
temperature at least once each working day. 
8.3 
Accountability 
The IMP manager must maintain an inventory record of IMP and reference product 
received, dispensed, administered, and returned. 
8.4 
Returns and Destruction 
Upon completion or termination of the trial, all containers of used IMP and reference 
product, and all unused and partially used IMP and reference product must be returned to 
the sponsor or a designated agent. 
All IMP and reference products returned to the sponsor must be accompanied by the 
appropriate documentation and be clearly identified by protocol number with trial site 
number on the outermost shipping container. Returned supplies of IMP and reference 
product should be in the original containers. The assigned trial monitor will facilitate the 
return of containers of used IMP and reference product, and unused or partially used IMP 
and reference product. 
8.5 
Reporting of Product Quality Complaints 
A Product Quality Complaint (PQC) is any written, electronic, or verbal communication 
by a healthcare professional, consumer, subject, medical representative, Competent 
Authority, regulatory agency, partner, affiliate, or other third party that alleges 
deficiencies or dissatisfaction related to identity, quality, labeling, packaging, reliability, 
safety, durability, tampering, counterfeiting, theft, effectiveness, or performance of an 
IMP, reference product, or medical device after it is released for distribution. Examples 
include, but are not limited to, communications involving: 
 Failure/malfunction of a product to meet any of its specifications 
 Incorrect or missing labeling 
 Packaging issues (eg, damaged, dirty, crushed, missing product) 
 Blister defects (eg, missing, empty blisters) 
 Bottle defects (eg, under/over-fill, no safety seal) 
 Product defects (eg, odor, chipped, broken, embossing illegible) 
 Loss or theft of product 
 


 
 
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8.5.1 
Eliciting and Reporting Product Quality Complaints 
The investigator or subinvestigator, or designee must record all PQCs identified through 
any means from the receipt of the IMP and reference product from the sponsor, or 
sponsor’s designee, through subject dosing, up to product return, including reconciliation. 
The investigator or subinvestigator, or designee must notify the sponsor (or sponsor’s 
designee) of the items in Section 8.5.2 Information Required for Reporting Product 
Quality Complaints by e-mail (e-mail address of the transmission destination: 
PQC_331-14-002@otsuka.jp) immediately after of becoming aware of the PQC. 
Identification of a PQC by the subject should be reported to the investigator or 
subinvestigator who should then follow one of the reporting mechanisms below. 
8.5.2 
Information Required for Reporting Product Quality Complaints 
The following information is required for reporting purposes: 
 Description of complaint 
 Reporter identification (eg, subject, investigator or subinvestigator, site information, 
etc) 
 Reporter contact information (eg, address, phone number, e-mail address) 
 ID of material (product/compound name, lot number) 
 Clinical protocol reference (number and trial name) 
 Dosage form/strength (if known) 
 Pictures (if available) 
 Complaint sample availability for return 
 
8.5.3 
Return Process for Product Quality Complaints 
Indicate during the report of the PQC if the complaint sample is available for return. The 
sponsor will provide instructions for complaint sample return, when applicable. 
It must be documented in the site accountability record that a complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation. 
8.5.4 
Assessment/Evaluation 
Assessment and evaluation of PQCs will be handled by the sponsor. 


 
 
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9 
Records Management 
9.1 
Source Documents 
Source documents are defined as the results of original observations and activities of a 
clinical investigation. Source documents will include, but are not limited to, progress 
notes, electronic data, screening logs, and recorded data from automated instruments. All 
source documents pertaining to this trial will be maintained by the trial site and made 
available for direct inspection by authorized persons. 
Investigator(s)/trial site(s) will permit trial-related monitoring, audits, IRB review, and 
regulatory inspection(s) by providing direct access to source data/documents by 
authorized persons as defined in the ICF. Materials concerning drug concentration 
measurement, including the original of the report and measurement data, will be 
maintained by the bioanalytical laboratory. In all cases, subject confidentiality must be 
maintained in accordance with local regulatory requirements. 
9.2 
Data Collection 
During each subject’s visit to the trial site, the investigator or subinvestigator will record 
progress notes to document all significant observations. At a minimum, these notes will 
contain: 
 Documentation of the informed consent process, including any revised consents; 
 Documentation of the investigator’s or subinvestigator’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; 
 The date of the visit and the corresponding visit or day in the trial schedule; 
 General subject status remarks, including any significant medical findings. The 
severity, frequency, duration, action taken, and outcome of any AEs and the 
investigator’s or subinvestigator’s assessment of relationship to IMP must also be 
recorded; 
 Any changes in concomitant medications or dosages; 
 A general reference to the procedures completed;  
 The signature (or initials) and date of all investigators or subinvestigators (or 
designee) who made an entry in the progress notes. 
 
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as 
described above. 


 
 
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Any changes to information in the trial progress notes or other source documents will be 
initialed and dated on the day the change is made by a trial site staff member authorized 
to make the change. Changes will be made by crossing out the erroneous data, and clearly 
entering the correct data (eg, wrong data right data). If the reason for the change is not 
apparent, a brief explanation for the change will be provided in the source document by 
the investigator or subinvestigator. If electronic data systems are being utilized, a full 
audit trail of changes must be maintained. 
Information from the trial progress notes, the results for clinical laboratory tests, and 
other source documents will be entered by trial site personnel directly onto eCRFs in the 
sponsor’s electronic data capture (EDC) system. Changes to the data will be captured by 
an automatic audit trail. 
9.3 
File Management at the Trial Site 
The head of the trial site will ensure that the trial site file is maintained in accordance 
with Section 8 of the ICH GCP Guideline E6 and as required by applicable local 
regulations. The trial site file will include all source documentation as well as completed 
CRF data for all subjects screened or enrolled at the trial site. The trial site will take 
measures to ensure confidentiality and prevent accidental or premature destruction of 
these documents. 
9.4 
Record Retention at the Trial Site 
The trial site will retain all the trial-related documents and records for one of the two 
periods of time indicated below, whichever is longer. 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. 
 The date 2 years after the date of manufacturing and marketing approval. 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, the date 3 years after receipt of such notification. 
 The date 3 years after termination or completion of the trial. 
The trial site must not dispose of any records relevant to this trial without either (1) 
written permission from the sponsor or (2) providing an opportunity for the sponsor to 
collect such records. The trial site shall take responsibility for maintaining adequate and 
accurate electronic or hard copy source documents of all observations and data generated 
during this trial. Such documentation is subject to inspection by the sponsor and relevant 
regulatory agencies. 


 
 
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10 
Quality Control and Quality Assurance 
10.1 
Monitoring 
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, ICH E6 GCP: Consolidated Guidance, and 
applicable regulatory requirements and local laws. As part of a concerted effort to fulfill 
these obligations (maintain current personal knowledge of the progress of the trial), the 
sponsor’s (or sponsor designee’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, subinvestigators, and trial site staff will undergo initial and ongoing 
training for this particular trial, and this training will be clearly documented. 
10.2 
Auditing 
The sponsor’s (or designee’s) Quality Assurance Unit (or representative) may conduct 
trial site audits. Audits will include, but are not limited to, IMP supply, presence of 
required documents, the informed consent process, and comparison of CRFs with source 
documents. The investigator agrees to participate with audits. 
Regulatory authorities may inspect the trial site during or after the trial. The investigator 
will cooperate with such inspections and will contact the sponsor immediately if such an 
inspection occurs. 
10.3 
Protocol Deviations 
Due to the complexity of clinical trial protocols and despite training and preventive 
efforts, deviations from the written protocol may occur and potentially result in harm to 
subjects, biased or inaccurate results, and possible rejection of all or part of the trial data. 
Per the ICH E3 guidance on the structure and content of clinical study reports, 
Section 10.2, protocol deviations should be summarized by site and grouped into 
different categories such as: 
 those who entered the study even though they did not satisfy the entry criteria 
 those who developed withdrawal criteria during the study but were not withdrawn 
 those for whom there were major IMP dosing errors that may compromise subject 
safety or PK assessments. 
 those who received an excluded concomitant treatment during the course of the trial 
 
Otsuka categorizes clinical protocol deviations as major versus minor. A major deviation 
is an intentional or accidental action or omission in a trial conduct that could potentially 


 
 
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have a negative impact on the integrity of the trial’s primary scientific objectives or has a 
significant potential to have a negative impact on the safety or efficacy assessments of 
any trial subject. Major deviations are those that might significantly affect the 
completeness, accuracy, or reliability of the trial data or that might significantly affect a 
subject’s rights, safety, or well-being. 
A minor deviation is an intentional or accidental action or omission during trial conduct 
in which the protocol is not strictly followed, but which has inconsequential impact on 
the integrity of the trial as a whole or the safety or efficacy analyses of an individual 
subject. 
All protocol deviations will be categorized as major or minor according to the above 
definitions and only major deviations will be summarized in the clinical study report. 
If the same protocol deviation occurs for multiple subjects, it must be recorded separately 
for each subject. 
The investigator or subinvestigator is expected to document potential protocol deviations 
as well as their medical assessment regarding continuation of the subject(s) due to the 
protocol deviation. 
11 
Ethics and Responsibility 
This trial must be conducted in compliance with the protocol, ICH GCP Guideline (E6), 
international ethical principles derived from the Declaration of Helsinki and Council for 
International Organizations of Medical Science (CIOMS) guidelines, and applicable local 
laws and regulations. The trial site(s) will seek approval/favorable opinion 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 CRFs, the investigator, subinvestigator, and 
their staff will take measures to ensure adequate care in protecting subject privacy. To 
this end, a subject number or subject identification number will be used to identify each 
subject. 
Financial aspects, subject insurance, and publication policy for the trial will be 
documented in the agreement between the sponsor and the trial site. 
12 
Confidentiality 
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 


 
 
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written permission. Subject confidentiality requirements of the region(s) where the trial is 
conducted will be met. However, authorized regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy the records, 
consistent with local requirements. All IMPs, subject bodily fluids, and other materials 
collected shall be used solely in accordance with this protocol, unless otherwise agreed to 
in writing by the sponsor. 
Subjects will be identified only by unique subject identifiers in CRFs. If further subject 
identification is required, subjects’ full names may be made known to a regulatory 
agency or other authorized officials if necessary, subject to local regulations. 
13 
Amendment Policy 
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval/favorable opinion by the IRB. Any permanent 
change to the protocol, whether an overall change or a change for specific trial site(s), 
must be handled as a protocol amendment. Any amendment will be written by the 
sponsor. Each amendment will be submitted to the IRB, as required by local regulations. 
Except for “administrative” or “nonsubstantial” amendments, investigators or 
subinvestigator will wait for IRB approval/favorable opinion of the amended protocol 
before implementing the change(s). Administrative amendments are defined as having no 
effect on the safety of subjects, conduct or management of the trial, trial design, or the 
quality or safety of IMP(s) used in the trial. However, a protocol change intended to 
eliminate an apparent immediate hazard to subjects should be implemented immediately, 
followed by IRB notification within local applicable timelines. The sponsor will submit 
protocol amendments to the applicable regulatory agency within local applicable 
timelines. 
When the IRB, investigators, or the sponsor conclude that the protocol amendment 
substantially alters the trial design or increases the potential risk to the subject, the 
currently approved written ICF will require similar modification. In such cases, after 
approval/favorable opinion of the new ICF by the IRB, repeat written informed consent 
will be obtained from subjects enrolled in the trial before expecting continued 
participation and before the amendment-specified changes in the trial are implemented. 
14 
Publication Authorship Requirements 
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 


 
 
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criteria (http://www.icmje.org/recommendations). According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met: 
1) Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND 
2) Drafting the work or revising it critically for important intellectual content; AND 
3) Final approval of the version to be published; AND 
4) Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved. 
 
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors. 
Investigators or other trial participants who do not qualify for authorship may be 
acknowledged in publications resulting from the trial. By agreeing to participate in the 
trial, investigators or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct. 
15 
References 
1 
Koprivica V. In vitro binding and functional characteristics of OPC-34712 at a clone 
of the human serotonin 5-HT1A receptor. Otsuka Study No. 026010, Otsuka Report 
No. 020193, 2007. 
2 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. 
3 
Mallikaarjun S. A phase 1, randomized, double-blind, placebo-controlled study to 
assess the tolerability, safety, and pharmacokinetics of ascending single oral doses of 
OPC-34712 in healthy subjects. Otsuka Clinical Study Report for Protocol 331-07-
201, issued 07 Dec 2009. 
4 
Youakim JM. An open-label, randomized, two-way crossover trial of the effect of a 
high-fat meal on the pharmacokinetics of OPC-34712 in healthy subjects. Otsuka 
Clinical Study Report for Protocol 331-10-246, issued 10 Oct 2012. 
5 
Skuban A. A phase 1, open-label, multiple-dose, parallel-group study to assess the 
pharmacokinetics and safety of oral OPC-34712 in healthy subjects. Otsuka Clinical 
Study Report for Protocol 331-08-206, issued 19 Feb 2010. 
6 
Mallikaarjun S. A pilot study to assess the potential for cytochrome P450-mediated 
and P-glycoprotein-mediated drug interactions with OPC-34712 in healthy subjects. 
Otsuka Clinical Study Report for Protocol 331-08-207, issued 18 Mar 2010. 


 
 
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7 
Otsuka Pharmaceutical Co, Ltd. A randomized, double-blind, placebo-controlled, 
single-dose trial of OPC-34712 in healthy adult male subjects. Final Study Report for 
Protocol 331-07-002, issued 15 Oct 2009. 
8 
Otsuka Pharmaceutical Co, Ltd. A repeated-dose trial of OPC-34712 in patients with 
schizophrenia. Final Study Report for Protocol 331-10-001, issued 08 Jun 2011. 
9 
Skuban A. A phase 1, open-label, positron emission tomography (PET) study in 
healthy subjects following a single oral dose of OPC-34712. Otsuka Clinical Study 
Report for Protocol 331-07-202, issued 06 Apr 2010. 
10 Skuban A. A phase 1, multi-center, randomized, double-blind, comparator-controlled 
study to assess the tolerability, safety, efficacy, and pharmacokinetics of ascending 
multiple oral doses of OPC-34712 in adult subjects with a diagnosis of schizophrenia 
or schizoaffective disorder. Otsuka Clinical Study Report for Protocol 331-08-205, 
issued 15 Mar 2010. 
11 Guideline for Bioequivalence Studies of Generic Products (PFSB/ELD Notification 
No. 0229-10 dated 29 Feb 2012). 
12 Guideline for Bioequivalence Studies for Formulation Changes of Oral Solid Dosage 
Forms Q&A (Attachment 3) (Office Communication dated 29 Feb 2012). 
13 Guideline for Bioequivalence Studies for Different Strengths of Oral Solid Dosage 
Forms (Attachment 2) (Office Communication dated 29 Feb 2012). 
14 International Council for Harmonisation (ICH) [homepage on the Internet]. E6(R2): 
Good Clinical Practice: Integrated Addendum to ICH E6(R1) [finalized 2016 
November; cited 2018 Nov 9]. Available from: 
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/
E6/E6_R2__Step_4_2016_1109.pdf. 
 
 
 


 
 
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Appendix 1 
Baseline Columbia-Suicide Severity Rating Scale 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Baseline 
Version 1/14/09 
 
 Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; 
Fisher, P.; Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J.  
 
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. 
The questions contained in the Columbia-Suicide Severity Rating Scale are suggested probes. 
Ultimately, the determination of the presence of suicidal ideation or behavior depends on the 
judgment of the individual administering the scale. 
 
Definitions of behavioral suicidal events in this scale are based on those used in The 
Columbia Suicide History Form, developed by John Mann, MD and Maria Oquendo, 
MD, Conte Center for the Neuroscience of Mental Disorders (CCNMD), New York State 
Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., Halberstam 
B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. 
In M.B. First [Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 
1051 Riverside Drive, New York, New York, 10032; inquiries and training requirements contact 
posnerk@nyspi.columbia.edu  
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 


 
 
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SUICIDAL IDEATION 
Ask questions 1 and 2. If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 
2 is “yes”, ask questions 3, 4 and 5. If the answer to question 1 and/or 2 is “yes”, complete “Intensity of 
Ideation” section below. 
 
Lifetime:  
Time He/She 
Felt Most 
Suicidal 
1.  Wish to be Dead  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
 
If yes, describe: 
 
Yes       No 
□    □ 
2.  Non-Specific Active Suicidal Thoughts 
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of 
ways to kill oneself/associated methods, intent, or plan.  
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
Yes      No 
 □    □ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific 
plan with time, place or method details worked out (e.g., thought of method to kill self but not a specific plan). Includes person who 
would say, “I thought about taking an overdose but I never made a specific plan as to when, where or how I would actually do it…and I 
would never go through with it.” 
Have you been thinking about how you might do this? 
 
If yes, describe: 
 
Yes      No 
 □    □ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the 
thoughts but I definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them?  
 
If yes, describe: 
 
Yes       No 
 □    □ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
   
If yes, describe: 
 
Yes      No 
 □    □ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being 
the least severe and 5 being the most severe). Ask about time he/she was feeling the most suicidal.  
                                             
Most Severe Ideation:             _____                      _________________________________________________ 
                                               
                                                                                                           Type # (1-5)                                         Description of Ideation 
Most 
Severe 
Frequency 
How many times have you had these thoughts?  
(1) Less than once a week    (2) Once a week   (3) 2-5 times in week    (4) Daily or almost daily    (5) Many times each day 
 
____ 
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time 
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts                                                      (4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty                                     (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty                                    (0) Does not attempt to control thoughts 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die 
or acting on thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you  
(2) Deterrents probably stopped you                                                    (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you                                             (0) Does not apply 
____ 


 
 
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SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
 
Lifetime  
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill 
oneself. Intent does not have to be 100%. If there is any intent/desire to die associated with the act, then it can be considered an actual 
suicide attempt. There does not have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while 
gun is in mouth but gun is broken so no injury results, this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For 
example, a highly lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from 
window of a high floor/story). Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be 
inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better,
get sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
Yes      No 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes    No 
□   □ 
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt 
would have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this becomes an attempt rather than an 
interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from 
pulling trigger. Once they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and 
taken down from ledge. Hanging: Person has noose around neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you 
before you actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
Total # of 
interrupted 
 
______ 
 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-
destructive behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by 
something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything? 
If yes, describe: 
 
 
Yes      No 
□   □ 
 
Total # of 
aborted 
 
______ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself? Was it to end the pain or 
stop the way you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or 
was it to get attention, revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others       (4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others                     living with the pain or how you were feeling) 
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t go on  
       and to end/stop the pain.                                                                        living with the pain or how you were feeling) 
                                                                                                                 (0) Does not apply 
 
 
 
 
____ 


 
 
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Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as 
assembling a specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing 
a suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, 
getting a gun, giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
Yes      No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 
Answer for Actual Attempts Only 
Most Recent  
Attempt 
Date: 
Most Lethal        
Attempt 
Date: 
Initial/First  
Attempt 
Date: 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat 
responsive; second-degree burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., 
comatose with reflexes intact; third-degree burns less than 20% of body; extensive blood loss but can 
recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without 
reflexes; third-degree burns over 20% of body; extensive blood loss with unstable vital signs; major 
damage to a vital area). 
5.  Death 
 
Enter Code 
 
 
 
______ 
 
 
 
Enter Code 
 
 
 
______ 
 
 
 
Enter Code 
 
 
 
______ 
 
 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual 
medical damage, had potential for very serious lethality: put gun in mouth and pulled the trigger but gun 
fails to fire so no medical damage; laying on train tracks with oncoming train but pulled away before run 
over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care  
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
 
 


 
 
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Appendix 2 
Since Last Visit Columbia-Suicide Severity Rating Scale 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Since Last Visit 
Version 1/14/09 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; 
Fisher, P.; Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J.  
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. 
The questions contained in the Columbia-Suicide Severity Rating Scale are suggested probes. 
Ultimately, the determination of the presence of suicidal ideation or behavior depends on the 
judgment of the individual administering the scale. 
 
Definitions of behavioral suicidal events in this scale are based on those used in The 
Columbia Suicide History Form, developed by John Mann, MD and Maria Oquendo, 
MD, Conte Center for the Neuroscience of Mental Disorders (CCNMD), New York State 
Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., Halberstam 
B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. 
In M.B. First [Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 
1051 Riverside Drive, New York, New York, 10032; inquiries and training requirements contact 
posnerk@nyspi.columbia.edu 
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 


 
 
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SUICIDAL IDEATION 
Ask questions 1 and 2. If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 
2 is “yes”, ask questions 3, 4 and 5. If the answer to question 1 and/or 2 is “yes”, complete “Intensity of 
Ideation” section below. 
Since Last 
Visit 
1.  Wish to be Dead 
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up? 
 
If yes, describe: 
 
 Yes 
No 
 
 
 
2.  Non-Specific Active Suicidal Thoughts 
General non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of 
ways to kill oneself/associated methods, intent, or plan during the assessment period. 
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
 Yes 
No 
 
 
 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific 
plan with time, place or method details worked out (e.g., thought of method to kill self but not a specific plan). Includes person who 
would say, “I thought about taking an overdose but I never made a specific plan as to when, where or how I would actually do it…..and I 
would never go through with it”. 
Have you been thinking about how you might do this? 
 
If yes, describe: 
 
 Yes 
No 
 
 
 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the 
thoughts but I definitely will not do anything about them”. 
Have you had these thoughts and had some intention of acting on them? 
 
If yes, describe: 
 
 Yes 
No 
 
 
 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
 
If yes, describe: 
 
 Yes 
No 
 
 
 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e.,1-5 from above, with 1 being 
the least severe and 5 being the most severe). 
Most 
Severe 
Most Severe Ideation: 
 ________  
 __________________________________________________  
 
Type # (1-5) 
Description of Ideation 
Frequency 
How many times have you had these thoughts? 
____ 
 
(1) Less than once a week 
(2) Once a week 
(3) 2-5 times in week 
(4) Daily or almost daily 
(5) Many times each day 
 
Duration 
When you have the thoughts how long do they last? 
 
(1) Fleeting - few seconds or minutes 
(2) Less than 1 hour/some of the time 
(3) 1-4 hours/a lot of time 
(4) 4-8 hours/most of day 
(5) More than 8 hours/persistent or continuous 
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
 
(1) Easily able to control thoughts 
(2) Can control thoughts with little difficulty 
(3) Can control thoughts with some difficulty 
(4) Can control thoughts with a lot of difficulty 
(5) Unable to control thoughts 
(0) Does not attempt to control thoughts 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to 
die or acting on thoughts of committing suicide? 
 
(1) Deterrents definitely stopped you from attempting suicide 
(2) Deterrents probably stopped you 
(3) Uncertain that deterrents stopped you 
(4) Deterrents most likely did not stop you 
(5) Deterrents definitely did not stop you 
(0) Does not apply 
____ 


 
 
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Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself? Was it to end the pain or 
stop the way you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) 
or was it to get attention, revenge or a reaction from others? Or both? 
 
(1) Completely to get attention, revenge or a reaction from 
others 
(2) Mostly to get attention, revenge or a reaction from others 
(3) Equally to get attention, revenge or a reaction from others 
and to end/stop the pain 
(4) Mostly to end or stop the pain (you couldn’t go on living with 
the pain or how you were feeling) 
(5) Completely to end or stop the pain (you couldn’t go on living 
with the pain or how you were feeling) 
(0) Does not apply 
____ 
 
SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since Last 
Visit 
Actual Attempt: 
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to 
kill oneself. Intent does not have to be 100%. If there is any intent/desire to die associated with the act, then it can be considered an 
actual suicide attempt. There does not have to be any injury or harm, just the potential for injury or harm. If person pulls trigger 
while gun is in mouth but gun is broken so no injury results, this is considered an attempt. 
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For 
example, a highly lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping 
from window of a high floor/story). Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may 
be inferred. 
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______as a way to end your life? 
Did you want to die (even a little) when you_____? 
Were you trying to end your life when you_____? 
Or Did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel 
better, get sympathy, or get something else to happen)? (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
 Yes 
No 
 
 
 
Total # of 
Attempts 
______ 
 Yes 
No 
 
 
 
Interrupted Attempt: 
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt 
would have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this becomes an attempt rather than an 
interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from 
pulling trigger. Once they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and 
taken down from ledge. Hanging: Person has noose around neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you 
before you actually did anything? 
If yes, describe: 
 
 Yes 
No 
 
 
 
Total # of 
interrupted 
______ 
Aborted Attempt: 
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-
destructive behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped 
by something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before 
you actually did anything? 
If yes, describe: 
 Yes 
No 
 
 
 
Total # of 
aborted 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as 
assembling a specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, 
writing a suicide note). 
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, 
getting a gun, giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 Yes 
No 
 
 
 


 
 
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Protocol Version 1.0, 18 Jan 2019 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
 Yes 
No 
 
 
 
Suicide: 
 Yes 
No 
 
 
 
Answer for Actual Attempts Only 
Most Lethal 
Attempt  
Date: 
Actual Lethality/Medical Damage: 
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree burns; bleeding 
of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes intact; 
third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree burns over 
20% of body; extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
Enter Code 
______ 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had potential 
for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on train tracks with 
oncoming train but pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care 
Enter Code 
______ 
 
 


 
 
Protocol 331-14-002 
 
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Protocol Version 1.0, 18 Jan 2019 
Agreement 
I, the undersigned principal investigator, have read and understand the protocol 
(including the Investigator’s Brochure) and agree that it contains all the ethical, legal and 
scientific information necessary to conduct this trial in accordance with the principles of 
Good Clinical Practices and as described herein and in the sponsor’s (or designee’s) 
Clinical Trial Agreement. 
I will provide copies of the protocol to all physicians, nurses, and other professional 
personnel to whom I delegate trial responsibilities. I will discuss the protocol with them 
to ensure that they are sufficiently informed regarding the investigational new drug, 
brexpiprazole, the concomitant 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 brexpiprazole will be tested prior to commencement of this trial. I agree to adhere 
strictly to the attached protocol (unless amended in the manner set forth in the sponsor’s 
Clinical Trial Agreement, at which time I agree to adhere strictly to the protocol as 
amended). 
I understand that this IRB-approved protocol will be submitted to the appropriate 
regulatory authority/ies by the sponsor. I agree that clinical data entered on case report 
forms by me and my staff will be utilized by the sponsor in various ways, such as for 
submission to governmental regulatory authorities and/or in combination with clinical 
data gathered from other trial sites, whenever applicable. I agree to allow sponsor and 
designee monitors and auditors full access to all medical records at the trial site for 
subjects screened or enrolled in the trial. 
I agree to await IRB approval before implementing any amendments made to this 
protocol. If, however, there is an immediate hazard to subjects, I will implement a 
deviation or change from the protocol, and provide the information to the IRB within the 
required local applicable timelines. Administrative changes to the protocol will be 
transmitted to the IRB for informational purposes only, if required by local regulations. 
I agree to provide all subjects with informed consent forms, as required by the applicable 
regulations and by ICH guidelines. I agree to report to the sponsor any adverse events in 
accordance with the terms of the sponsor’s Clinical Trial Agreement and the relevant 
regional regulation(s) and guideline(s). I further agree to provide all required information 
regarding financial certification or disclosure to the sponsor for all investigators and 
subinvestigators in accordance with the terms of the relevant regional regulation(s). I 


 
 
Protocol 331-14-002 
 
Confidential - Proprietary Information 
79 
Protocol Version 1.0, 18 Jan 2019 
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 can occur, and I consent to be acknowledged in any such 
cooperative publications that result. 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
Principal Investigator’s Name 
 
  Name of Trial Site 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
Signature 
 
 
 
 
  Date 
 

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
A single center, open-label, randomized, 3-arm, 3-way crossover trial to investigate 
the bioequivalence of brexpiprazole (OPC-34712) orally disintegrating tablets in 
healthy adult males 
 
 
 
 
NCT Number: NCT03902574 
PRT NO.: 331-14-002 
Version Date: 02 July 2019 (Version 1.0) 


  
  
Otsuka Pharmaceutical Co., Ltd. 
 
 
Investigational New Drug Brexpiprazole (OPC-34712) 
 
 
 
 
Protocol No. 331-14-002 
 
 
 
A single center, open-label, randomized, 3-arm, 3-way crossover trial to investigate the 
bioequivalence of brexpiprazole (OPC-34712) orally disintegrating tablets in healthy 
adult males 
 
Statistical Analysis Plan 
 
Version: 1.0 
Date: July 2, 2019 
Protocol Date:  Jan 18, 2019 
 
 
 
 
 
 
Confidential 
May not be used, divulged, published, or otherwise disclosed without the prior written 
consent of Otsuka Pharmaceutical Co., Ltd. 
 


Protocol 331-14-002 
Statistical Analysis Plan                                        2 of 19 
Version Date: 07/02/2019 
 
Table of Contents 
Table of Contents ........................................................................................... 2 
List of Appendices ......................................................................................... 4 
List of Abbreviations and Definition of Terms .......................................... 5 
1 
Introduction .......................................................................................... 6 
2 
Trial Objectives .................................................................................... 6 
3 
Trial Design ........................................................................................... 6 
3.1 
Type/Design of Trial ...........................................................................................6 
3.2 
Trial Treatments ..................................................................................................8 
3.2.1 
Brexpiprazole ODTs (Investigational Medicinal Product) ...............................8 
3.2.2 
Brexpiprazole Conventional Tablets ................................................................8 
3.3 
Trial Population ...................................................................................................8 
3.4 
Trial Visit Window ..............................................................................................8 
4 
Sample Size ............................................................................................ 8 
4.1 
Judgment for Conduct of Add-on Subject Study ................................................9 
5 
Statistical Analysis Sets ........................................................................ 9 
5.1.1 
Bioequivalence Analysis Set.............................................................................9 
5.1.2 
Safety Population ..............................................................................................9 
5.1.3 
Handling of Missing Data .................................................................................9 
6 
Primary and Secondary Outcome Variables ..................................... 9 
6.1 
Primary Outcome Variables ................................................................................9 
6.2 
Secondary Outcome Variables ..........................................................................10 
7 
Disposition and Demographic Analysis............................................ 10 
7.1 
Subject Disposition ...........................................................................................10 
7.2 
Demographic and Baseline Characteristics .......................................................10 
7.3 
Treatment Compliance ......................................................................................10 
7.4 
Prior and Concomitant Medication ...................................................................10 
7.5 
Protocol Deviations ...........................................................................................10 
8 
Efficacy Analyses ................................................................................ 10 
9 
Safety Analyses ................................................................................... 11 


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9.1 
Extent of Exposure ............................................................................................11 
9.2 
Adverse Events ..................................................................................................11 
9.3 
Clinical Laboratory Data ...................................................................................11 
9.4 
Vital Sign Data ..................................................................................................12 
9.5 
Physical Examination Data................................................................................12 
9.6 
Electrocardiogram Data .....................................................................................12 
9.7 
Other Safety Data ..............................................................................................12 
9.7.1.1 
Body Weight ...............................................................................................12 
9.7.1.2 
The Columbia-Suicide Severity Rating Scale .............................................12 
10 
Pharmacokinetic Analyses ................................................................. 12 
10.1 
Statistical Analyses of Primary Pharmacokinetic Endpoints ............................12 
10.2 
Pharmacokinetic Methods .................................................................................13 
10.2.1 
Pharmacokinetic Analysis ...............................................................................13 
10.2.2 
Handling of Data .............................................................................................13 
10.2.3 
Calculation of descriptive statistics ................................................................14 
11 
Pharmacodynamic Analyses .............................................................. 14 
12 
Pharmacogenomic Analyses .............................................................. 15 
13 
Interim Analysis.................................................................................. 15 
14 
Changes in Planned Analysis ............................................................ 15 
15 
References ............................................................................................ 16 
 
 


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List of Appendices 
 
Appendix 1 
List of Summary Tables .................................................................17 
Appendix 2 
List of Subject Data Listings ..........................................................19 
 
 


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List of Abbreviations and Definition of Terms 
Abbreviation 
Definition 
AE 
Adverse event 
BE 
Bioequivalence 
BMI 
Body mass index 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
ECG 
Electrocardiogram 
IMP 
Investigational medicinal product 
LLOQ 
Lower limit of quantitation 
MedDRA 
Medical Dictionary for Regulatory Activities 
OD 
Orally disintegrating 
PK 
Pharmacokinetic 
QTc 
Corrected QT interval 
QTcB 
QT interval corrected for heart rate by Bazett’s formula 
QTcF 
QT interval corrected for heart rate by Fridericia’s formula 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
TEAE 
Treatment-emergent adverse event 
WHODD 
World Health Organization Drug Dictionary 
AUC 
Area under the concentration-time curve 
AUC∞ 
Area under the concentration-time curve from time zero to infinity 
AUCt 
Area under the concentration-time curve calculated to the last 
observable concentration at time t 
AUC_%Extrap Ratio of area under the concentration-time curve from tlast to infinity 
versus AUC∞ 
CL/F 
Apparent clearance of drug from plasma after extravascular 
administration 
CL/F/BW 
Apparent clearance of drug from plasma after extravascular 
administration per body weight 
Cmax 
Maximum (peak) plasma concentration of the drug 
λz 
Terminal elimination rate constant 
λz (Rsq) 
Goodness of fit statistic for the terminal elimination phase, adjusted for 
the number of points used in the estimation of λz 
λz (point) 
Number of points used in computing λz 
λz (upper) 
Upper limit of time for values to be included in the calculation of λz 
λz (lower) 
Lower limit on time for values to be included in the calculation of λz 
t1/2,z 
Terminal-phase elimination half-life 
tlast 
Time of the last measureable concentration 
tmax 
Time to maximum (peak) plasma concentration 
 


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1 
Introduction 
This statistical analysis plan (SAP) describes the statistical methodology and data analysis 
algorithms and conventions to be applied for statistical analysis in 331-14-002 trial. 
2 
Trial Objectives 
The purpose of the present trial is to investigate the bioequivalence of brexpiprazole ODT 
2 mg and brexpiprazole conventional tablet 2 mg. 
3 
Trial Design 
3.1 
Type/Design of Trial 
This is a single center, open-label, randomized, 3-arm, 3-way crossover trial in 21 healthy 
adult male subjects. Subjects will be hospitalized to the trial site 3 times during the trial 
(Days −1 to 8, Days 20 to 28, and Days 40 to 48) and will be discharged at the end of 
each period of hospitalization (on Days 8, 28, and 48) after completion of safety 
evaluation and blood collection for pharmacokinetic assessment. 
A 2-mg dose of brexpiprazole will be administered to each subject as either an ODT or a 
conventional tablet on Days 1, 21, and 41, and ODT will be administered either with 
water or without water, according to the randomized administration schedule. 
Subjects randomized to Sequence 1 will receive an ODT without water on Day 1, a 
conventional tablet on Day 21, and an ODT with water on Day 41. 
Subjects randomized to Sequence 2 will receive an ODT with water on Day 1, an ODT 
without water on Day 21, and a conventional tablet on Day 41. 
Subjects randomized to Sequence 3 will receive a conventional tablet on Day 1, an ODT 
with water on Day 21, and an ODT without water on Day 41. 
The trial design schematic is shown in Figure 3-1.


Period 1
Period 2
Period 3
Follow-up
Period
(Days 1 to 20)
(Days 21 to 40)
(Days 41 to 60)
Day 1: Dosing
Day 21: Dosing
Day 41: Dosing
Sequence 1
Brex ODT
without water
Brex conventional tablet
Brex ODT
with water
Sequence 2
Brex ODT
with water
Brex ODT
without water
Brex conventional tablet
Sequence 3
Brex conventional tablet
Brex ODT
with water
Brex ODT
without water
Screening Period
(Days −22 to −1)
Population:
Healthy
adult males
21 eligible
subjects
(7 subjects per
sequence)
Visit
(Days 10, 12, 14)
Visit
(Days 30, 32, 34)
Visit
(Days 50, 52, 54)
Screening 
(Days −22 to −2)
Hospitalization
(Admission to trial 
site on Day −1)
Hospitalization
(Days −1 to 8)
Hospitalization
(Days 20 to 28)
Hospitalization
(Days 40 to 48)
Follow-up
(Days 61 to 63)
 
Brex = brexpiprazole; ODT = orally disintegrating tablet 
Figure 3-1 
Trial Design 
 


3.2 
Trial Treatments 
3.2.1 
Brexpiprazole ODTs (Investigational Medicinal Product) 
Subjects will receive one 2-mg brexpiprazole ODT with or without 150 mL of ordinary-
temperature water. When administered without water, the subject will be instructed to 
place the tablet directly on the tongue and keep it there until it disintegrates completely 
before swallowing. Compliance will be ensured by a mouth check. 
All doses will be administered after fasting for at least 10 hours and no food will be 
allowed until 4 hours postdose. Except as part of the dosing procedure, water will be 
restricted from 1 hour prior to dosing until 2 hours postdose. 
3.2.2 
Brexpiprazole Conventional Tablets 
Subjects will receive one 2-mg brexpiprazole conventional tablet with 150 mL of 
ordinary-temperature water. Compliance will be ensured by a mouth check. The IMP will 
be administered after fasting for at least 10 hours and no food will be allowed until 
4 hours postdose. Except as part of the dosing procedure, water will be restricted from 
1 hour prior to dosing until 2 hours postdose. 
3.3 
Trial Population 
A total of 21 healthy male subjects at least 20 years of age and below 40 years of age, will 
be enrolled. 
3.4 
Trial Visit Window 
Nominal time points will be used for summary of safety parameters and plasma 
concentration. The examinations on withdrawal and unscheduled visits will be not used in 
the analyses and will be provided in the listings. 
4 
Sample Size  
Based on the BE Guideline1, the sample size was calculated so that the 90% confidence 
intervals of geometric mean ratios for brexpiprazole Cmax and AUCt between ODT (with 
or without water) and conventional tablet would fall within the bioequivalence range of 
0.8 to 1.25. 
In a brexpiprazole 4-mg ODT BA study conducted in Japan (331-102-00019) and 
brexpiprazole bioequivalence studies conducted outside Japan (331-10-243 and 
331-13-209), the within-subject variance for natural log-transformed Cmax and AUCt 
values was greatest for Cmax in Trial 331-13-209 (at 0.035). 


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Assuming a geometric mean ratio of 1.0 for brexpiprazole Cmax between ODT (with and 
without water) and conventional tablet, and a within-subject variance of 0.035 for natural 
log-transformed Cmax, to achieve at least 90% power will require 6 subjects in each 
sequence, 18 in total. Considering the possibility of some subjects being excluded from 
analysis due to discontinuation, etc, the number of subjects was set as 7 for each sequence 
and 21 in total. 
4.1 
Judgment for Conduct of Add-on Subject Study 
If bioequivalence cannot be demonstrated in the initial study because of an insufficient 
number of subjects, an add-on subject study can be performed in accordance with this 
protocol. 
The add-on subject study will be performed using not less than half the number of 
subjects in the initial study. No add-on subject study will be performed in the following 
cases: 
1) If the results of the initial study show that the point estimates of the geometric 
mean ratios for AUCt and Cmax between ODT and conventional tablet do not fall 
within the range of 0.8 to 1.25, and 
2) If the required number of subjects for the add-on subject study estimated from the 
results of the initial study is considered to be a sample size that is ethically or 
scientifically infeasible. 
5 
Statistical Analysis Sets 
5.1.1 
Bioequivalence Analysis Set 
All subjects who provided Cmax or AUCt through Period 1, Period 2, and Period 3 
5.1.2 
Safety Population 
All subjects who received at least one dose of IMP 
5.1.3 
Handling of Missing Data 
There will be no imputation for missing data. 
6 
Primary and Secondary Outcome Variables 
6.1 
Primary Outcome Variables 
Cmax and AUCt of brexpiprazole 


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6.2 
Secondary Outcome Variables 
1) Plasma concentration-time profiles of brexpiprazole 
2) Brexpiprazole AUC∞, tmax, λz, AUC_%Extrap, t1/2,z, CL/F, CL/F/BW, and tlast 
7 
Disposition and Demographic Analysis 
7.1 
Subject Disposition 
The number of screened subjects will be presented. The number and percentage of 
randomized subjects, completed subjects, and discontinued subjects will be presented by 
sequence. The number and percentage of discontinued subjects by primary reason for 
discontinuation will also be presented by sequence. The denominators of percentages will 
be randomized subjects. 
The number and percentage of subjects included in each analysis set will be provided by 
sequence for the randomized subjects. 
7.2 
Demographic and Baseline Characteristics 
For the bioequivalence analysis set and safety analysis set, the descriptive statistics (n, 
mean, SD, min, median and max) of age, height, weight (screening period) and BMI will 
be presented overall and by sequence. The frequency distribution of gender, race, 
ethnicity, country, medical history and current symptoms will be presented overall and by 
sequence. 
7.3 
Treatment Compliance 
Not applicable. 
7.4 
Prior and Concomitant Medication 
The medications will be coded by World Health Organization Drug Dictionary 
(WHODD) version March 1, 2019 Global. The previous and concomitant medications 
will be listed. 
7.5 
Protocol Deviations 
The major protocol deviations will be listed. 
8 
Efficacy Analyses 
Not applicable. 


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9 
Safety Analyses 
Safety analysis will be conducted upon the safety analysis set for each formulation and 
administration method (conventional tablet, ODT without water, ODT with water). 
Baseline is defined as the last measurement immediately before each dosing (for 12-lead 
ECG parameters, the mean value of three measurements on the day before IMP 
administration will be used). 
9.1 
Extent of Exposure 
Subjects who received the IMP will be summarized by each formulation and 
administration method. 
9.2 
Adverse Events 
Medical Dictionary for Regulatory Activities (MedDRA) version 22.0 will be used to 
code AEs. TEAEs in each period are defined as adverse events occurred on or after the 
IMP administration in each period to before the IMP administration in next period or the end 
of study. If multiple occurrences of the same event are observed in the same subject 
during the same period, the highest severity will be used for analysis. 
The incidence of the following events will be summarized by system organ class, 
preferred term (the denominators will be subjects who administered by each formulation 
and administration method). 
 TEAEs 
 TEAEs by severity 
The incidence of the following events will be summarized (the denominators will be 
subjects who administered by each formulation and administration method). 
 TEAEs with an outcome of death 
 Serious TEAEs 
 TEAEs leading to discontinuation of the IMP 
TEAEs potentially causally related to the IMP will also be summarized in the same way. 
9.3 
Clinical Laboratory Data 
For each clinical laboratory parameter except for qualitative urinalysis, the descriptive 
statistics of measured values and of changes from baseline will be calculated by time 
point. For qualitative parameters of clinical laboratory urinalysis, shift tables versus 
baseline at each time point will be produced. For the clinical laboratory parameters except 
for qualitative urinalysis, measured values will be classified as Within Reference Range, 


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Lower Than Reference Range, and More Than Reference Range, using the reference 
range of the trial site, and shift tables versus baseline at each time point will be produced. 
9.4 
Vital Sign Data 
For each vital sign, the descriptive statistics of measured values and of changes from 
baseline will be presented by time point. 
9.5 
Physical Examination Data 
For physical examination, listing of physical findings will be presented by each subject. 
9.6 
Electrocardiogram Data 
For each 12-lead ECG parameter, the descriptive statistics of measured values and of 
changes from baseline will be calculated by time point. For 12-lead ECG assessment of 
normality/abnormality, shift tables versus baseline at each time point will be produced. 
For QTcF and QTcB, categorical analysis of measured values and of changes from 
baseline at each time point will be performed to calculate the number and percentage of 
subjects. The number and percentage of subjects with actual measurements of corrected 
QT interval (QTcF, QTcB) at each time point being > 450 msec, > 480 msec, and > 500 
msec will be determined. The number and percentage of subjects with changes from 
baseline being > 30 msec and > 60 msec will be also determined. 
9.7 
Other Safety Data 
9.7.1.1 
Body Weight 
For body weight, the descriptive statistics of measured values and of changes from 
baseline will be presented. 
9.7.1.2 
The Columbia-Suicide Severity Rating Scale 
C-SSRS data for individual subjects will be listed. 
10 
Pharmacokinetic Analyses 
10.1 
Statistical Analyses of Primary Pharmacokinetic Endpoints 
The following analysis will be performed on the bioequivalence analysis set: 
The Cmax and AUCt of brexpiprazole will be analyzed using the natural log-transformed 
values in a mixed effect model with sequence (1, 2, and 3), formulation and 
administration method (conventional tablet, ODT without water, ODT with water), and 
period (Period 1, Period 2, and Period 3) as fixed effects and the subjects within each 


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sequence as a random effect. The Kenward–Roger method will be used to estimate the 
degrees of freedom in the mixed effect model analysis. The 90% confidence intervals of 
geometric mean ratios for brexpiprazole Cmax and AUCt between ODT (with or without 
water) and conventional tablet will be calculated. If the 90% confidence intervals are 
within the range of 0.8 to 1.25, the 2 formulations and administration methods will be 
judged to be bioequivalent. 
If an add-on subject study is conducted, bioequivalence will be assessed on the same 
basis from the result of combining the initial study and the add-on subject study by 
including study as a fixed effect in the above mixed effect model. 
If there are any subjects who had no evaluable parameters through Period 1, Period 2, and 
Period 3, analysis in which those subjects are included will be performed. 
10.2 Pharmacokinetic Methods 
10.2.1 Pharmacokinetic Analysis 
The PK parameters of brexpiprazole［Cmax, AUCt, AUC∞, tmax, t1/2,z, λz, tlast, CL/F, 
CL/F/BW, AUC_%Extrap, λz (point), λz (lower), λz (upper) and λz (Rsq) ］will be 
calculated through a noncompartmental PK analysis. CL/F/BW will be calculated by 
dividing CL/F by the body weight (kg) before IMP administration in each period. 
10.2.2 Handling of Data 
 If vomiting occurs at a time point less than twice the median tmax, the data for the 
subject who experienced vomiting will be excluded from the bioequivalence 
analysis set. The median tmax that is referenced for that judgment is the median 
tmax of the same group calculated excluding the vomiting case. 
 If blood sampling is conducted outside the time window (refer to PRT Table 
3.7.3-1), the data will be excluded from the calculation of descriptive statistics for 
plasma concentrations at that time point. However, it will be used for the 
calculation of pharmacokinetic parameters, and if the calculation is determined to 
be unsuitable, the parameter will not be adopted. 
 If prohibited medications that may affect the pharmacokinetics of IMP are used, 
data points after the use of prohibited medications in the relevant subjects will be 
excluded from the calculation of descriptive statistics for plasma concentrations. 


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However, it will be used for the calculation of pharmacokinetic parameters, and if 
the calculation is determined to be unsuitable, the parameter will not be adopted. 
 Plasma concentrations below lower limit of quantitation (LLOQ) that occur prior 
to and after the first measurable concentration in each period will be imputed to 0 
(ng/mL) and missing. 
 LLOQ of brexpiprazole (OPC-34712) is 0.5000 ng/mL. 
10.2.3 Calculation of descriptive statistics 
Descriptive statistics will be calculated on the bioequivalence analysis set as follows. 
1) 
Plasma drug concentrations 
 At each blood collection time point, descriptive statistics will be calculated by 
conventional tablet, ODT without water and ODT with water. 
 Descriptive statistics to be calculated for plasma drug concentrations will be 
number of analyzed subjects, number of subjects included in the tabulation, 
arithmetic mean, standard deviation, coefficient of variation, minimum, median, 
and maximum. However, descriptive statistics will be calculated only at the time 
point when the number of subjects included in the tabulation exceeds half of the 
number of analyzed subjects 
2) 
Plasma pharmacokinetic parameters［excluding λz，λz (lower)，λz (upper)，λz 
(point) and λz (Rsq) ］ 
 Descriptive statistics will be calculated for each parameter by conventional tablet, 
ODT without water and ODT with water. 
 Descriptive statistics to be calculated for plasma pharmacokinetic parameters will 
be number of analyzed subjects, number of subjects included in the tabulation, 
arithmetic mean, standard deviation, coefficient of variation, geometric mean, 
minimum, median, and maximum. However, descriptive statistics will be 
calculated only when the number of subjects included in the tabulation exceeds 
half of the number of analyzed subjects. 
11 
Pharmacodynamic Analyses 
Not applicable. 


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12 
Pharmacogenomic Analyses 
Not applicable. 
13 
Interim Analysis 
Not applicable. 
14 
Changes in Planned Analysis 
The typo in the study protocol is corrected as follows.. 
Old: TEAEs leading to discontinuation of the IMP 
New: Discontinuations due to TEAEs 
 


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15 
References 
1 Guideline for Bioequivalence Studies of Generic Products (PFSB/ELD Notification 
No. 0229-10 dated 29 Feb 2012). 
 
 


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Appendix 1 
List of Summary Tables 
CT-1 
Subject Disposition 
CT-2 
Reasons for Discontinuations 
CT-3.1 
Demographic and Baseline Characteristics - Bioequivalence Analysis Set 
CT-3.2 
Demographic and Baseline Characteristics - Safety Analysis Set 
CT-7 
Extent of Exposure 
CT-8.1 
Adverse Events (All Causalities) 
CT-8.2.1 
Incidence of Treatment-Emergent Adverse Events by System Organ Class and 
MedDRA Preferred Term 
CT-8.2.2 
Incidence of Treatment-Emergent Adverse Events by System Organ Class, MedDRA 
Preferred Term and Severity 
CT-8.3.1 
Incidence of IMP-related Treatment-Emergent Adverse Events by System Organ Class 
and MedDRA Preferred Term 
CT-8.3.2 
Incidence of IMP-related Treatment-Emergent Adverse Events by System Organ Class, 
MedDRA Preferred Term and Severity 
CT-9.1 
Listing of Deaths 
CT-9.2 
Listing of Serious Adverse Events Other Than Death 
CT-9.3 
Listing of Discontinuations due to Adverse Events 
CT-10.1.1 
Mean Change from Baseline in Clinical Laboratory Test Results - Serum Chemistry 
CT-10.1.2 
Mean Change from Baseline in Clinical Laboratory Test Results - Hematology 
CT-10.1.3 
Mean Change from Baseline in Clinical Laboratory Test Results - Urinalysis 
CT-10.2.1 
Shift Tables of Clinical Laboratory Test Results - Serum Chemistry 
CT-10.2.2 
Shift Tables of Clinical Laboratory Test Results - Hematology 
CT-10.2.3 
Shift Tables of Clinical Laboratory Test Results - Urinalysis 
CT-10.2.4 
Listing of Individual Clinically Significant Abnormalities of Laboratory Values 
CT-10.3.1 
Shift Tables of Clinical Laboratory Test Results - Qualitative Urinalysis 
CT-11.1 
Mean Change from Baseline in Vital Signs and Weight 
CT-12.1 
Mean Change from Baseline in Electrocardiogram Results 
CT-12.2 
Shift Table of Electrocardiogram Findings 
CT-12.3 
Categorical Analysis of Electrocardiogram Parameters 
PKT-1.1.1.1 
Individual and Summary of Plasma Concentration Following Single Administration 
PKT-1.1.2.1 
Individual and Summary of Plasma Pharmacokinetic Parameters Following Single 
Administration 
PKF-1.1.1.1 
Mean Plasma Concentrations Following Single Administration 
PKF-1.1.16.1 
Individual Plasma Concentrations Following Single Oral Administration for Test Group 
in Comparison to Reference Group 
BE-1.1 
Bioequivalence: Analysis of Variance for Pharmacokinetics 
BE-1.2 
Bioequivalence: Analysis of Variance for Pharmacokinetics (Including Subjects With at 


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Least One evaluable Pharmacokinetic Parameter) 


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Appendix 2 
List of Subject Data Listings 
DREAS-1 
Discontinued Subjects and Reason for Discontinuations 
SUBEX-1 
Subjects Excluded From Analysis Set 
DEMOG-1 
Demographic Characteristics 
SMED-1 
Study Medication Compliance 
AE-1 
Adverse Events 
LAB-1 
Laboratory Test Results - Serum Chemistry 
LAB-2 
Laboratory Test Results - Hematology 
LAB-3 
Laboratory Test Results - Urinalysis 
LAB-4 
Laboratory Test Results - Other 
PDATA-1 
Study Completion Status and Reason for Discontinuation 
PDATA-2 
Inclusion/Exclusion Criteria Not Met 
PDATA-3 
Treatment Assignment 
PDATA-5 
Medical History and Current Symptoms 
PDATA-6.1 
Concomitant Medications 
PDATA-6.2 
Concomitant Therapy 
PDATA-8 
Physical Examination 
PDATA-10 
Vital Signs 
PDATA-11 
Weight 
PDATA-12.1 
Electrocardiogram Results at Central Laboratory 
PDATA-12.2 
Electrocardiogram Results at Trial Site 
PDATA-13.1 
Columbia-Suicide Severity Rating Scale (C-SSRS) - Suicidal Ideation and Intensity 
PDATA-13.2 
Columbia-Suicide Severity Rating Scale (C-SSRS) - Suicidal Behavior 
PDATA-13.3 
Columbia-Suicide Severity Rating Scale (C-SSRS) - Actual Attempts 
PDATA-14 
Pharmacokinetic Blood Draw Time 
PDATA-15 
Meal 
PDATA-16 
Screen Failures 
PDATA-17 
Substance Use 
PDATA-18 
Post-treatment Follow-Up 
PDEV-1 
Protocol Deviations