Clinical trial NCT04118127
Conditions: Schizophrenia
Keywords: Schizophrenia,brexpiprazole,open-label,linical pharmacology
Sponsor: Otsuka Pharmaceutical Co., Ltd.
Start date: 2019-10-17; Completion date: 2021-03-03
Enrollment: 73 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To evaluate the pharmacokinetics (PK), tolerability, and safety of brexpiprazole QW formulation administered as single and multiple doses in patients with schizophrenia.

Detailed description:
A multi-center, open-label clinical pharmacology trial to investigate the PK, tolerability, and safety of brexpiprazole QW formulation administered as single and multiple doses.

The trial comprises the single-dose period (Cohort 1) and the multiple-dose period (Cohort 2). The dose used in the multiple-dose period (Cohort 2) will be determined based on plasma drug concentrations obtained in the single-dose period (Cohort 1).

Arms: arm 1: None
Interventions: intervention 1: 2mg conventional tablet, once-weekly tablets
Intervention descriptions: intervention 1: In each cohort, subjects will receive a brexpiprazole 2 mg conventional tablet on Day 1of Period 1, the QW formulation on Day 1 of Period 2 and 3, as single and multiple dose in a fasted state.

Protocol documents:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
A multi-center, open-label clinical pharmacology trial to investigate the 
pharmacokinetics, tolerability, and safety of brexpiprazole once-weekly (QW) 
formulation administered as single and multiple oral doses in patients with schizophrenia 
 
 
 
 
 
NCT Number: NCT04118127 
PRT NO.: 331-102-00150 
Version Date: 18 Jun 2020 (Version 4.0) 


Protocol 331-102-00150 
 
 
Otsuka Pharmaceutical Co., Ltd. 
 
Investigational Medicinal Product 
Brexpiprazole (OPC-34712) 
 
CLINICAL PROTOCOL 
 
A multi-center, open-label clinical pharmacology trial to investigate the 
pharmacokinetics, tolerability, and safety of brexpiprazole once-weekly (QW) 
formulation administered as single and multiple oral doses in patients with schizophrenia 
 
Protocol No. 331-102-00150 
 
CONFIDENTIAL – PROPRIETARY INFORMATION 
 
Clinical Development Phase: 
1 
Sponsor: 
Otsuka Pharmaceutical Co., Ltd. 
 
 
 
 
 
Immediately Reportable Event: Office of Pharmacovigilance Operations, 
 
Department of Pharmacovigilance,  
 
Otsuka Pharmaceutical Co., Ltd. 
 
e-mail address: IRE_331-102-00150@otsuka.jp 
 
Issue Date: 
14 Jun 2019 
Date of Amendment 1 
09 Sep 2019 
Date of Amendment 2 
28 Jan 2020 
Date of Amendment 3 
18 Jun 2020 
 
Version No.: 
4.0 
(Date of Translation: 
17 May 2021) 


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Protocol Synopsis 
Name of Sponsor: Otsuka Pharmaceutical Co., Ltd. 
Name of Investigational Medicinal Product: 
Brexpiprazole (OPC-34712) 
Protocol No.: 331-102-00150 
Protocol Title: 
A multi-center, open-label clinical pharmacology trial to 
investigate the pharmacokinetics, tolerability, and safety of 
brexpiprazole once-weekly (QW) formulation administered 
as single and multiple oral doses in patients with 
schizophrenia 
Clinical Phase/ 
Trial Type: 
Phase 1 
Clinical pharmacology trial 
Treatment Indication: 
Schizophrenia 
Objectives: 
To evaluate the pharmacokinetics (PK), tolerability, and 
safety of brexpiprazole QW formulation administered as 
single and multiple doses in patients with schizophrenia. 
Trial Design: 
A multi-center, open-label clinical pharmacology trial to 
investigate the PK, tolerability, and safety of brexpiprazole 
QW formulation administered as single and multiple doses. 
The trial comprises the single administration period (Cohort 
1) and the repeated administration period (Cohort 2). The 
dose used in the repeated administration period (Cohort 2) 
will be determined based on plasma drug concentrations 
obtained in the single administration period (Cohort 1). The 
single administration period (Cohort 1) comprises Period 1, 
in which the conventional tablet will be administered, and 
Periods 2 and 3, in which the QW formulation will be 
administered. If the single administration period (Cohort 1) 
fails to produce sufficient plasma drug concentrations, 
another single administration period (Cohort 1’) will be 
added during which the QW formulation will be 
administered at higher single doses. The repeated 
administration period (Cohort 2) comprises Period 1, in 
which subjects will receive a single administration of the 
conventional tablet, and Period 2, in which subjects will 
receive 5 administrations of the QW formulation. 
In the single administration period (Cohort 1), subjects will 
receive a brexpiprazole 2 mg conventional tablet on Day 1 
of Period 1, the QW formulation at 24 mg on Day 1 of 
Period 2, and the QW formulation at 48 mg on Day 1 of 
Period 3, all as single administrations in a fasted state. 
In the single administration period (Cohort 1’), subjects will 
receive a brexpiprazole 2 mg conventional tablet on Day 1 
of Period 1, the QW formulation at 30 mg on Day 1 of 
Period 2, and the QW formulation at 60 or 54 mg on Day 1 
of Period 3, all as single administrations in a fasted state. 


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In the repeated administration period (Cohort 2), subjects 
will receive a single administration of a brexpiprazole 2 mg 
conventional tablet on Day 1 of Period 1, and repeated 
administration of the QW formulation on Days 1, 8, 15, 22, 
and 29 of Period 2. The doses of the QW formulation will 
be determined based on the results of the single 
administration period (Cohort 1 and, as necessary, Cohort 
1’). 
Subject Population: 
Patients with schizophrenia from 18 years of age to under 
65 years of age 
Single administration period (Cohort 1): 20 subjects 
Single administration period (Cohort 1’): 20 subjects (as 
necessary) 
Repeated administration period (Cohort 2): 20 subjects 
Inclusion/Exclusion 
Criteria: 
[For all cohorts] 
Inclusion criteria 
 Patients at least 18 years of age and below the age of 
65 at the time of informed consent 
 Patients with a diagnosis of schizophrenia based on 
the Diagnostic and Statistical Manual of Mental 
Disorders, 5th edition (DSM-5®) 
 Patients who are able to be hospitalized for the 
protocol-defined hospitalization period 
 Patients with a body mass index [BMI = body 
weight (kg)/height (m)2] of 18.5 kg/m2 or higher and 
lower than 35.0 kg/m2 at screening 
 Persons who provide written informed consent 
before commencement of any trial-related 
procedures and whom the investigator or 
subinvestigator judges to be capable of following all 
the conditions of this trial 
 Patients who, in the judgement of the investigator or 
subinvestigator, have stable psychotic symptoms 
maintained by administration of an antipsychotic 
(other than clozapine) within the dosing range 
indicated below, before commencement of 
investigational medicinal product (IMP) 
administration 
 Antipsychotic medication comprising no more than 
two active components 
 A daily dose equivalent to no more than 600 mg/day 
of chlorpromazine 
 If multiple antipsychotics are taken in the same 
day, this is to be the combined equivalent dose. 


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 Chlorpromazine equivalent doses are based on 
Appendix 5. 
However, this does not include administration of 
antipsychotic medication at doses equivalent to less 
than 100 mg/day of chlorpromazine, which are not 
expected to have any antipsychotic effect. 
Exclusion criteria 
 Patients with a diagnosis of a concurrent mental 
disorder besides schizophrenia (schizoaffective 
disorder, major depressive disorder, bipolar I 
disorder, bipolar II disorder, general anxiety 
disorder, obsessive-compulsive disorder, post-
traumatic stress disorder, dementia or mild 
neurocognitive disorder, personality disorder, etc) 
based on the DSM-5® diagnostic criteria. However, 
this exclusion does not apply to caffeine- or tobacco-
related disorders. 
 Patients who fail to meet the specified requisite 
washout periods for the prohibited concomitant 
drugs and foods indicated below before 
commencement of IMP administration, or patients 
who are anticipated to take any of the drugs or foods 
in the following table during the study period 
 
Drugs and Foods 
Washout Period 
Adrenaline 
28 days 
Rexulti tablets 
21 days 
Clozapine 
Starting from 
informed consent 
CYP2D6 inhibitors and CYP3A4 inhibitors 
and inducers listed in Appendix 3 
(Except topical agents listed in Appendix 4 
for which use with the IMP is permitted) 
14 days 
Other investigational drugs under 
development 
60 days 
Foods and beverages containing St. John’s 
Wort, Ginkgo biloba, goldenseal, or 
echinacea (Echinacea purpurea) 
14 days 
Foods and beverages containing grapefruit, 
Seville orange, or star fruit 
7 days 
 
 Patients who have previously undergone 
gastrointestinal surgery that could affect PK 
evaluations 
 Patients who are using clozapine at the time of 
informed consent 


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 Patients who have received electroconvulsive 
therapy within 60 days before commencement of 
IMP administration 
 Patients with clinically problematic disorders of the 
nervous system, liver, kidneys, metabolic system, 
blood system, immune system, cardiovascular 
system, respiratory system, or digestive system 
(However, such patients may be included if the 
condition is mild or well-controlled and is 
considered to not affect safety or PK evaluations.) 
 Patients who fall under any of the following criteria 
at screening 
 Inadequately controlled hypertension (diastolic 
blood pressure of > 95 mmHg) 
 Symptomatic hypotension 
 Orthostatic hypotension, defined as a decrease of 
≥ 30 mmHg in systolic blood pressure or a decrease 
of ≥ 20 mmHg in diastolic blood pressure after 
standing for at least 3 minutes compared with the 
supine values prior to standing 
 Patients with any of the following laboratory or 
electrocardiogram (ECG) values at screening 
(according to the results from the central laboratory 
or the central ECG laboratory) 
Platelets: ≤ 75000/mm3(/μL) 
Hemoglobin: ≤ 9 g/dL 
Neutrophils, absolute: 
≤ 1000/mm3 
AST: 
> 2 × upper limit of normal 
ALT: 
> 2 × upper limit of normal 
CPK: 
> 3 × upper limit of normal 
Creatinine: ≥ 2 mg/dL 
QTcF > 450 msec 
 Patients meeting any of the following criteria 
 Patients with type 1 diabetes mellitus or patients 
with type 2 diabetes mellitus being treated with 
insulin 
 Patients with type 2 diabetes mellitus who have not 
been maintained on a stable regimen of anti-diabetic 
medication(s) or undergone diet/exercise therapy for 
at least 28 days prior to screening 
 Patients meeting either of the following criteria for 
poor blood glucose control at screening 
a) Glycosylated hemoglobin (HbA1c) of ≥ 7.0% 
according to the global standard value [NGSP 
value] 


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b) Fasting blood glucose level of ≥ 126 mg/dL or 
nonfasting blood glucose level of ≥ 200 mg/dL 
 Patients who have undergone major surgery or blood 
transfusion or who have made a blood donation 
(whole blood or blood plasma) within 30 days 
before the acquisition of informed consent 
 Patients who have met the DSM-5® diagnostic 
criteria for substance-related or addictive disorder, 
including alcohol and benzodiazepines but excluding 
caffeine and tobacco, within 180 days before 
commencement of IMP administration 
 Patients with a positive drug test at screening 
(However, such patients may be included if their 
condition is not diagnosed as substance-related or 
addictive disorder, according to the DSM-5® 
diagnostic criteria.) 
 Patients with a history or complication of epilepsy or 
seizures, except for childhood febrile seizures, post-
traumatic seizures, alcohol withdrawal seizures, etc 
 Patients with a history or a complication of 
neuroleptic malignant syndrome 
 Patients with a complication of hypothyroidism or 
hyperthyroidism (except in cases where the 
condition has been kept stable for at least 90 days 
through drug therapy) or patients who show 
abnormal values for thyroid-stimulating hormone 
(TSH) and free thyroxin (FT4) in the screening 
examination 
 Patients with a complication of ischemic heart 
disease, myocardial infarction, or congestive heart 
failure (whether controlled or uncontrolled), or with 
a history of angioplasty, stenting, or coronary artery 
bypass surgery 
 Patients whose clinical symptoms have worsened to 
the point where use of prohibited concomitant 
therapy or medication is required during the washout 
period for prior medication 
 Patients who before commencement of IMP 
administration are judged to have a significant risk 
of committing suicide based on medical history or 
diagnosis, who have shown suicidal behavior within 
the past 2 years, or who have answered “yes” to 
Question 4 or 5 in the Columbia-Suicide Severity 
Rating Scale (C-SSRS) within the past 24 months 


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 Female patients who are nursing or have a positive 
pregnancy test result before administration of the 
IMP 
 Sexually active male patients and sexually active 
female patients of child-bearing potential who do not 
agree to practice 2 methods of birth control or 
remain abstinent during this trial and for 30 days 
after the final administration of IMP. If practicing 
birth control, 2 of the following methods must be 
used: vasectomy, tubal ligation, intrauterine device, 
or condom (all methods approved or certified in 
Japan) 
 Patients with a history of allergy to more than one 
medication 
 Patients with a history of hypersensitivity or allergy 
to brexpiprazole 
 Patients who have participated in another clinical 
trial within 60 days before commencement of IMP 
administration 
 Patients who have been compulsorily hospitalized 
under the Mental Health and Welfare Law of Japan 
 Patients judged by the investigator or 
subinvestigator to be unsuitable for participation in 
the trial 
Trial Site(s): 
Approximately 20 sites within Japan 
Investigational Medicinal 
Products, Dose, Dosage 
regimen, Treatment period, 
Formulation, Mode of 
Administration: 
[Brexpiprazole QW formulation] 
 Cohort 1 (single administration period) 
On Day 1 of each of Periods 2 and 3 in Cohort 1 (single 
administration period), subjects will receive a single oral 
administration of the QW formulation at the dose 
specified in the following table together with 
approximately 150 mL of water in the morning after at 
least 10 hours of fasting. Subjects are not to take any 
food until 4 hours after administration. Subjects are not 
to take any fluids from 1 hour before administration of 
the QW formulation until 2 hours after administration, 
except for the water taken at the time of administration. 
 
Dose 
Treatment 
period 
Period 2 
Period 3 
Regimen 
Dose 
Tablet 
No. of 
tablets 
Dose 
Tablet 
No. of 
tablets 
1 
24 mg 
24 mg 
tablet 
1 
tablet 
48 mg 
24 mg 
tablet 
2 
tablets 


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 Cohort 1’ (as necessary) (single administration period) 
On Day 1 of each of Periods 2 and 3 in Cohort 1’ (single 
administration period), subjects will receive a single oral 
administration of the QW formulation together with 
approximately 150 mL of water in the morning after at 
least 10 hours of fasting. Subjects are not to take any 
food until 4 hours after administration. Subjects are not 
to take any fluids from 1 hour before administration of 
the QW formulation until 2 hours after administration, 
except for the water taken at the time of administration. 
The doses of the QW formulation used in Cohort 1’ (as 
necessary) (single administration period) will be 
determined according to the protocol-defined criteria for 
progression to the repeated administration period 
(Cohort 2) from the single administration period (Cohort 
1 and Cohort 1’ [as necessary]), and the QW 
formulation will be administered as per regimen 1 or 2 
shown in the following table. 
 
Dose 
Treatment 
period 
Period 2 
Period 3 
Regimen 
Dose 
Tablet 
No. of 
tablets 
Dose 
Tablet 
No. of 
tablets 
1 
30 mg 
30 mg 
tablet 
1 
tablet 
54 mg 
24 mg 
tablet 
30 mg 
tablet 
1 
tablet 
each 
2 
30 mg 
30 mg 
tablet 
1 
tablet 
60 mg 
30 mg 
tablet 
2 
tablets 
 Cohort 2 (repeated administration period) 
Subjects will be orally administered the QW formulation 
together with approximately 150 mL of water in the 
morning after at least 10 hours of fasting, as per one of 
regimens 1 to 5 shown in the following table based on 
the results of the single administration period (Cohort 1 
and Cohort 1’ [as necessary]). Subjects are not to take 
any food until 4 hours after administration. Subjects are 
not to take any fluids from 1 hour before administration 
of the QW formulation until 2 hours after 
administration, except for the water taken at the time of 
administration. 
 
Dose 
Treatment 
period 
Period 2 
Day 
1  
8, 15, 22, and 29 
Regimen 
Dose 
Tablet 
No. of 
tablets 
Dose 
Tablet 
No. of 
tablets 
1 
24 mg 
24 mg 
tablet 
1 
tablet 
48 mg 
24 mg 
tablet 
2 
tablets 


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2 
18 mg 
18 mg 
tablet 
1 
tablet 
36 mg 
18 mg 
tablet 
2 
tablets 
3 
24 mg 
24 mg 
tablet 
1 
tablet 
42 mg 
18 mg 
tablet 
24 mg 
tablet 
1 
tablet 
each 
4 
30 mg 
30 mg 
tablet 
1 
tablet 
54 mg 
24 mg 
tablet 
30 mg 
tablet 
1 
tablet 
each 
5 
30 mg 
30 mg 
tablet 
1 
tablet 
60 mg 
30 mg 
tablet 
2 
tablets 
[Other IMPs: Brexpiprazole 2 mg conventional tablet] 
On Day 1 of Period 1 in each cohort, subjects will receive a 
single oral administration of a brexpiprazole 2 mg 
conventional tablet together with approximately 150 mL of 
water in the morning after at least 10 hours of fasting. 
Subjects are not to take any food until 4 hours after 
administration. Subjects are not to take any fluids from 1 
hour before administration of the conventional tablet until 2 
hours after administration, except for the water taken at the 
time of administration. 
Trial Assessments: 
[For all cohorts] 
PK: plasma drug concentrations 
Safety: adverse events, clinical laboratory tests, physical 
examination, vital signs (blood pressure, pulse rate, and 
body temperature), weight, 12-lead ECG, C-SSRS, Drug-
induced Extrapyramidal Symptoms Scale (DIEPSS), 
concomitant medications and therapies 
Screening/Other: demographics, pregnancy test, urine drug 
screening, CYP2D6 genotyping, Clinical Global Impression 
- Severity of illness (CGI-S), Clinical Global Impression - 
Improvement (CGI-I), blood sampling for DNA storage 
Criteria for Evaluation: 
PK endpoints: 
Plasma concentrations and PK parameters of brexpiprazole 
after single and repeated administration of QW formulation 
Safety (For all cohorts): 
Adverse events, clinical laboratory tests, physical 
examination, vital signs (blood pressure, pulse rate, and 
body temperature), weight, 12-lead ECG, DIEPSS, C-SSRS 
Pharmacogenomics: CYP2D6 genotyping 
Other: CGI-S, CGI-I 
Statistical Methods: 
Statistical methods for PK endpoints 
The PK parameters of brexpiprazole for the QW 
formulation and conventional tablet at each dose will be 
determined through noncompartmental PK analysis. 
Descriptive statistics of the following variables will be 
produced: 


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[Brexpiprazole QW formulation] 
 Period 2 of the single administration period (Cohort 
1 and Cohort 1’ [as necessary]) 
a) Plasma concentration of brexpiprazole after a 
single administration of the QW formulation 
b) PK parameters of brexpiprazole after a single 
administration of the QW formulation 
Cmax, tmax, tlast, Cmax/D 
c) Relative Cmax of brexpiprazole for the QW 
formulation as compared with a conventional 
tablet 
Relative Cmax (%) 
= (Cmax of QW formulation/dose of QW 
formulation)/(Cmax of conventional tablet/dose 
of conventional tablet) × 100 
 Period 3 of the single administration period (Cohort 
1 and Cohort 1’ [as necessary]) 
a) Plasma concentration of brexpiprazole after a 
single administration of the QW formulation 
b) PK parameters of brexpiprazole after a single 
administration of the QW formulation 
Cmax, AUC∞, AUCt, tmax, λz, AUC_%Extrap, 
t1/2,z, CL/F, CL/F/BW, tlast, Cmax/D, AUC∞/D, 
AUCt/D 
c) Relative bioavailability of brexpiprazole for the 
QW formulation as compared with a 
conventional tablet 
Relative bioavailability (%) 
= (AUC∞ of QW formulation/dose of QW 
formulation) /(AUC∞ of conventional tablet/dose 
of conventional tablet) × 100 
d) Relative Cmax of brexpiprazole for the QW 
formulation as compared with a conventional 
tablet 
Relative Cmax (%) 
= (Cmax of QW formulation/dose of QW 
formulation)/(Cmax of conventional tablet/dose 
of conventional tablet) × 100 
 Period 2 of the repeated administration period 
(Cohort 2) 
a) Plasma concentration of brexpiprazole after the 
fifth administration of the QW formulation 


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b) PK parameters of brexpiprazole after the fifth 
administration of the QW formulation 
Cmax, AUC168h, tmax, λz, t1/2,z, CL/F, CL/F/BW, 
tlast, Cmax/D, AUC168h/D 
c) Plasma trough concentrations of brexpiprazole 
from the first administration of the QW 
formulation to after the fifth administration 
(C168h) 
d) Accumulation of brexpiprazole after the fifth 
administration of the QW formulation as 
compared with that after the first administration 
[R5,ac(C168h)] 
[Brexpiprazole conventional tablet] (for all cohorts, Period 
1) 
 Plasma concentration of brexpiprazole after a single 
administration of a conventional tablet 
 PK parameters of brexpiprazole after a single 
administration of a conventional tablet 
Cmax, AUC∞, AUCt, tmax, λz, AUC_%Extrap, t1/2,z, 
CL/F, CL/F/BW, tlast, Cmax/D, AUC∞/D, AUCt/D 
Rationale for target number of subjects: 
The target number of subjects is not based on a statistical 
hypothesis test. A simulation was performed with the PK 
model created based on PK data of the conventional tablet 
and QW-A formulation used in the QW-A formulation 
group in Trial 331-102-00021 conducted in Japan, and the 
probability that the mean plasma concentration of 
brexpiprazole after repeated administration of the QW-A 
formulation would be within the target range of 
concentration was determined. On the basis of this 
probability, the sample size was determined to be 20 
subjects each for the single administration period (Cohort 1) 
and the repeated administration period (Cohort 2). Likewise, 
the sample size for an additional single administration 
period (Cohort 1’) with a new dose was also determined to 
be 20 subjects. 
Trial Duration: 
October 2019 to May 2021 
The duration of trial participation for each subject will be a 
maximum of 105 days for the single administration period 
(Cohort 1 and, as necessary, Cohort 1’) and a maximum of 
108 days for the repeated administration period (Cohort 2) 
(each period including a washout period). Each period is 
indicated below. In cases where subjects withdrawn from 
the single administration period (Cohort 1) at the discretion 


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of the sponsor subsequently take part in the trial again, the 
duration of their trial participation will be a maximum of 85 
days if they resume participation in the trial from Period 2 
and a maximum of 58 days if they resume participation in 
the trial from Period 3. 
 Screening 
All cohorts: Between 28 days and 1 day before the first 
administration of the IMP 
 Period 1 
All cohorts: Day 1 of IMP administration to Day 20 
(including a washout period of 20 days [+ 8 days max]) 
 Period 2 
Cohort 1 and Cohort 1’ (as necessary) (single 
administration period): Day 1 of IMP administration to 
Day 27 (including a washout period of 27 days [+ 8 days 
max]) 
Cohort 2 (repeated administration period): Day 1 of IMP 
administration to Day 42 
 Period 3 
Cohort 1 and Cohort 1’ (as necessary) (single 
administration period): Day 1 of IMP administration to 
Day 14 
 Follow-up 
Cohort 1 and Cohort 1’ (as necessary) (single 
administration period): Day 28 of IMP administration to 
Day 30 in Period 3 
Cohort 2 (repeated administration period): Day 56 of 
IMP administration to Day 60 in Period 2 
 


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Table of Contents 
Protocol Synopsis ........................................................................................... 2 
Table of Contents ......................................................................................... 13 
List of In-text Tables ................................................................................... 20 
List of In-text Figures .................................................................................. 21 
List of Appendices........................................................................................ 22 
List of Abbreviations and Definitions of Terms ....................................... 23 
1 
Introduction ........................................................................................ 25 
1.1 
Nonclinical Data ................................................................................................26 
1.2 
Clinical Data ......................................................................................................27 
1.2.1 
Clinical Pharmacology Trial for Comparative Investigation of the 
Pharmacokinetics, Tolerability, and Safety of Three Types of QW 
Formulation Administered as Single Oral Doses in Patients With 
Schizophrenia (Japan 331-102-00021) ...........................................................27 
1.2.2 
Clinical Data of Conventional Tablet of Brexpiprazole .................................29 
1.2.2.1 
Phase 1 Multiple-dose Trial in Subjects With Schizophrenia or 
Schizoaffective Disorder (US 331-08-205) ................................................29 
1.2.2.2 
QT/QTc Trial in Subjects With Schizophrenia or Schizoaffective 
Disorder (US 331-10-242) ..........................................................................29 
1.2.2.3 
Phase 1 Multiple-dose Trial in Subjects With Schizophrenia (Japan 
331-10-001) .................................................................................................30 
1.2.2.4 
Dose-finding Trial in Subjects With Schizophrenia (Japan 331-10-
002) .............................................................................................................31 
1.2.2.5 
Long-term Trial in Subjects With Schizophrenia (Japan 331-10-003) .......31 
1.3 
Pharmacokinetics ...............................................................................................32 
1.4 
Known and Potential Risks and Benefits ..........................................................34 
2 
Trial Rationale and Objectives.......................................................... 34 
2.1 
Trial Rationale ...................................................................................................34 
2.2 
Rationale for CYP2D6 Genotyping and DNA Storage .....................................36 
2.3 
Dosing Rationale ...............................................................................................37 
2.3.1 
Regimen ..........................................................................................................37 
2.3.2 
Dose ................................................................................................................37 
2.3.2.1 
Single Administration Period (Cohort 1 and Cohort 1’ [as 
Necessary]) ..................................................................................................37 


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2.3.2.1.1 
Cohort 1 ...................................................................................................37 
2.3.2.1.2 
Cohort 1’ (as Necessary) .........................................................................38 
2.3.2.2 
Repeated Administration Period (Cohort 2) ...............................................39 
2.4 
Trial Objectives .................................................................................................40 
3 
Trial Design ......................................................................................... 40 
3.1 
Type/Design of Trial .........................................................................................40 
3.1.1 
Cohort 1 (Single Administration Period) ........................................................43 
3.1.2 
Cohort 1’ (Additional Single Administration Period, as Necessary) .............43 
3.1.3 
Cohort 2 (Repeated Administration Period) ...................................................44 
3.2 
Trial Treatments ................................................................................................44 
3.2.1 
Dose, Regimen and Treatment Period ............................................................44 
3.2.1.1 
Cohort 1 (Single Administration Period) ....................................................44 
3.2.1.1.1 
Administration of Brexpiprazole Conventional Tablet ...........................44 
3.2.1.1.2 
Administration of Brexpiprazole QW Formulation ................................44 
3.2.1.2 
Cohort 1’ (as Necessary) (Single Administration Period) ..........................45 
3.2.1.2.1 
Administration of Brexpiprazole Conventional Tablet ...........................45 
3.2.1.2.2 
Administration of Brexpiprazole QW Formulation ................................45 
3.2.1.3 
Cohort 2 (Repeated Administration Period) ...............................................46 
3.2.1.3.1 
Administration of Brexpiprazole Conventional Tablet ...........................46 
3.2.1.3.2 
Administration of Brexpiprazole QW Formulation ................................46 
3.3 
Trial Population .................................................................................................46 
3.3.1 
Number of Subjects and Description of Population .......................................46 
3.3.1.1 
Number of Subjects .....................................................................................46 
3.3.1.2 
Trial Population ...........................................................................................47 
3.3.2 
Subject Numbering .........................................................................................47 
3.4 
Eligibility Criteria ..............................................................................................47 
3.4.1 
Informed Consent ...........................................................................................47 
3.4.2 
Inclusion Criteria ............................................................................................49 
3.4.3 
Exclusion Criteria ...........................................................................................50 
3.5 
Endpoints ...........................................................................................................53 
3.5.1 
Pharmacokinetic Endpoints ............................................................................53 
3.5.2 
Safety (for All Cohorts) ..................................................................................53 


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3.5.3 
Pharmacogenomics .........................................................................................53 
3.5.4 
Other ...............................................................................................................53 
3.6 
Measures to Minimize/Avoid Bias ....................................................................53 
3.7 
Trial Procedures ................................................................................................54 
3.7.1 
General Inpatient Procedures ..........................................................................61 
3.7.2 
Dietary Requirements .....................................................................................62 
3.7.3 
Schedule of Assessments ................................................................................62 
3.7.3.1 
Screening (for All Cohorts) .........................................................................62 
3.7.3.2 
Administration of Brexpiprazole Conventional Tablet (Period 1) (for 
All Cohorts) .................................................................................................64 
3.7.3.2.1 
Day 1 of Period 1 .....................................................................................64 
3.7.3.2.1.1 
Enrollment of Subjects .........................................................................64 
3.7.3.2.1.2 
Within 1 Day Predose ..........................................................................64 
3.7.3.2.1.3 
Postdose ...............................................................................................65 
3.7.3.3 
QW Formulation Single Administration Periods (Periods 2 and 3 of 
Cohort 1 and Cohort 1’ [as Necessary]) ......................................................65 
3.7.3.4 
QW Formulation Repeated Administration Period (Period 2 of 
Cohort 2) .....................................................................................................65 
3.7.3.5 
Follow-up After IMP Administration (for All Cohorts) .............................65 
3.7.4 
Prior and Concomitant Medications ...............................................................65 
3.7.5 
Safety Assessments .........................................................................................66 
3.7.5.1 
Adverse Events ...........................................................................................66 
3.7.5.2 
Clinical Laboratory Assessments ................................................................66 
3.7.5.3 
Urine Drug Screening .................................................................................67 
3.7.5.4 
Physical Examination and Vital Sign Assessments ....................................68 
3.7.5.5 
Weight .........................................................................................................69 
3.7.5.6 
Electrocardiogram Assessments..................................................................69 
3.7.5.7 
Columbia-Suicide Severity Rating Scale ....................................................69 
3.7.5.8 
Drug-induced Extrapyramidal Symptoms Scale .........................................70 
3.7.6 
Pharmacokinetic Assessments ........................................................................70 
3.7.6.1 
Time Points for Blood Sampling ................................................................71 
3.7.6.1.1 
Brexpiprazole Conventional Tablet .........................................................71 
3.7.6.1.2 
Brexpiprazole QW Formulation ..............................................................71 


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3.7.6.2 
Pharmacokinetic Plasma Samples ...............................................................72 
3.7.7 
CYP2D6 Genetic Testing ...............................................................................72 
3.7.7.1 
Deoxyribonucleic Acid Blood Samples for CYP2D6 Genetic Testing ......72 
3.7.8 
Future Biospecimen Research Samples ..........................................................72 
3.7.8.1 
DNA Storage ...............................................................................................72 
3.7.8.1.1 
Objective of DNA Storage ......................................................................72 
3.7.8.1.2 
Target Subjects of DNA Storage .............................................................73 
3.7.8.1.3 
Blood Samples for DNA Storage ............................................................73 
3.7.8.1.4 
Genomic/Genetic Analysis ......................................................................73 
3.7.8.1.5 
Informed Consent for DNA Storage ........................................................73 
3.7.8.1.6 
Disclosure of Genomic/Genetic Analysis Results to Subjects ................74 
3.7.9 
Other Evaluations ...........................................................................................74 
3.7.9.1 
Clinical Global Impression - Severity of Illness .........................................74 
3.7.9.2 
Clinical Global Impression - Improvement.................................................74 
3.7.10 
End of Trial .....................................................................................................75 
3.8 
Procedure for Progression to the Repeated Administration Period (Cohort 
2) From the Single Administration Period (Cohort 1 and Cohort 1’ [as 
Necessary]) ........................................................................................................75 
3.8.1 
Criteria for Progression to Cohort 2 ...............................................................75 
3.8.2 
Doses of Brexpiprazole QW Formulation in the Repeated 
Administration Period (Cohort 2) ...................................................................76 
3.9 
Stopping Rules, Withdrawal Criteria, and Procedures ......................................77 
3.9.1 
Entire Trial ......................................................................................................77 
3.9.2 
Individual Site .................................................................................................77 
3.9.3 
Individual Subject Discontinuation ................................................................77 
3.9.3.1 
Treatment Discontinuation ..........................................................................77 
3.9.3.2 
Criteria for Withdrawal Before Dose Increase of the QW Formulation .....78 
3.9.3.3 
Documenting Reasons for Discontinuation ................................................78 
3.9.3.4 
Withdrawal of Consent ...............................................................................79 
3.9.3.5 
Procedures to Encourage Continued Trial Participation .............................80 
3.10 
Screen Failures ..................................................................................................81 
3.11 
Definition of Completed Subjects .....................................................................81 
3.12 
Definition of Subjects Lost to Follow-up ..........................................................81 


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3.13 
Subject Compliance ...........................................................................................82 
3.14 
Protocol Deviations ...........................................................................................82 
4 
Restrictions .......................................................................................... 82 
4.1 
Prohibited Medications......................................................................................82 
4.2 
Prohibited Therapies ..........................................................................................83 
4.3 
Restricted Medications ......................................................................................83 
4.4 
Other Restrictions ..............................................................................................84 
5 
Reporting of Adverse Events ............................................................. 85 
5.1 
Definitions .........................................................................................................85 
5.2 
Eliciting and Reporting Adverse Events ...........................................................87 
5.3 
Immediately Reportable Events ........................................................................88 
5.4 
Potential Serious Hepatotoxicity .......................................................................89 
5.5 
Pregnancy ..........................................................................................................89 
5.6 
Procedure for Breaking the Blind ......................................................................90 
5.7 
Follow-up of Adverse Events ............................................................................90 
5.7.1 
Follow-up of Nonserious Adverse Events ......................................................90 
5.7.2 
Follow-up of Serious Adverse Events and Immediately Reportable 
Events .............................................................................................................91 
5.7.3 
Follow-up and Reporting of Serious Adverse Events Occurring After 
the End of Trial Date (Final Day of Observation) ..........................................91 
6 
Pharmacokinetic/Pharmacodynamic/Pharmacogenomic 
Analysis ................................................................................................ 92 
6.1 
Pharmacokinetic Methods .................................................................................92 
6.1.1 
Brexpiprazole QW Formulation .....................................................................92 
6.1.1.1 
Period 2 of the Single Administration Period (Cohort 1 and Cohort 1’ 
[as Necessary]) ............................................................................................92 
6.1.1.2 
Period 3 of the Single Administration Period (Cohort 1 and Cohort 1’ 
[as Necessary]) ............................................................................................92 
6.1.1.3 
Period 2 of the Repeated Administration Period (Cohort 2) .......................93 
6.1.2 
Brexpiprazole Conventional Tablet (for All Cohorts, Period 1) ....................93 
6.2 
Pharmacodynamic Methods ..............................................................................93 
6.3 
Pharmacokinetic/Pharmacodynamic Methods ..................................................93 
6.4 
Pharmacogenomic Methods ..............................................................................93 


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7 
Statistical Analysis .............................................................................. 93 
7.1 
Determination of Sample Size ...........................................................................94 
7.2 
Datasets for Analysis .........................................................................................94 
7.2.1 
Pharmacokinetic Analysis Set ........................................................................94 
7.2.2 
Safety Analysis Set .........................................................................................94 
7.3 
Handling of Missing Data .................................................................................94 
7.4 
Primary and Secondary Endpoint Analyses ......................................................94 
7.4.1 
Primary Endpoint Analyses ............................................................................94 
7.4.2 
Secondary Endpoint Analyses ........................................................................94 
7.5 
Analysis of Demographic and Other Baseline Characteristics .........................94 
7.6 
Safety Analysis ..................................................................................................95 
7.6.1 
Adverse Events ...............................................................................................95 
7.6.2 
Clinical Laboratory Data ................................................................................95 
7.6.3 
Physical Examination Data .............................................................................95 
7.6.4 
Vital Signs Data ..............................................................................................96 
7.6.5 
Electrocardiogram Data ..................................................................................96 
7.6.6 
Other Safety Data ...........................................................................................96 
7.6.6.1 
Drug-Induced Extrapyramidal Symptoms Scale .........................................96 
7.6.6.2 
Columbia-Suicide Severity Rating Scale ....................................................96 
7.7 
Pharmacodynamic Analysis ..............................................................................96 
7.8 
Analyses of Other Endpoints .............................................................................96 
7.8.1 
Clinical Global Impression - Severity of Illness and Clinical Global 
Impression - Improvement ..............................................................................96 
8 
Management of Investigational Medicinal Product ........................ 97 
8.1 
Packaging and Labeling ....................................................................................97 
8.2 
Storage ...............................................................................................................97 
8.3 
Accountability ...................................................................................................97 
8.4 
Returns and Destruction ....................................................................................97 
8.5 
Reporting of Product Quality Complaints .........................................................97 
8.5.1 
Eliciting and Reporting Product Quality Complaints .....................................98 
8.5.2 
Information Required for Reporting Product Quality Complaints .................98 
8.5.3 
Return Process for Product Quality Complaints .............................................99 
8.5.4 
Assessment/Evaluation ...................................................................................99 


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9 
Records Management ......................................................................... 99 
9.1 
Source Documents .............................................................................................99 
9.2 
Data Collection ..................................................................................................99 
9.3 
File Management at the Trial Site ...................................................................100 
9.4 
Record Retention at the Trial Site ...................................................................100 
10 
Quality Control and Quality Assurance ......................................... 101 
10.1 
Monitoring .......................................................................................................101 
10.2 
Auditing ...........................................................................................................101 
10.3 
Protocol Deviations .........................................................................................101 
11 
Ethics and Responsibility ................................................................. 102 
12 
Confidentiality .................................................................................. 103 
13 
Amendment Policy ............................................................................ 103 
14 
Publication Authorship Requirements ........................................... 104 
15 
References .......................................................................................... 104 
 


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List of In-text Tables 
Table 1.2-1 
Three QW Formulations Used in Trial 331-102-00021 ............... 28 
Table 1.2-2 
Main Pharmacokinetic Parameters of Each QW Formulation 
in Trial 331-102-00021 ................................................................. 28 
Table 1.3-1 
Estimated Pharmacokinetic Parameters of Brexpiprazole QW 
Formulation at Steady State Based on Simulation ........................ 33 
Table 1.3-2 
Pharmacokinetic Parameters of Brexpiprazole at Steady State .... 33 
Table 3.2.1.1.2-1 
Doses (Cohort 1) (Single Administration Period) ........................ 45 
Table 3.2.1.2.2-1 
Doses (Cohort 1’ [as Necessary] [Single Administration 
Period]) ......................................................................................... 45 
Table 3.2.1.3.2-1 
Doses (Cohort 2 [Repeated Administration Period]) .................... 46 
Table 3.4.2-1 
Inclusion Criteria (for All Cohorts) .............................................. 49 
Table 3.4.3-1 
Exclusion Criteria (for All Cohorts) ............................................. 50 
Table 3.7-1 
Schedule of Assessments (Cohort 1 and Cohort 1’ [as 
Necessary]; Single Administration Period) .................................. 55 
Table 3.7-2 
Schedule of Assessments (Cohort 2; Repeated 
Administration Period).................................................................. 57 
Table 3.7-3 
Acceptable Windows for Observations, Tests, and 
Assessments Following a Single Administration of 
Conventional Tablet (Period 1 of Cohort 1 and Cohort 1’ [as 
Necessary] [Single Administration Period] and Period 1 of 
Cohort 2 [Repeated Administration Period]) ................................ 59 
Table 3.7-4 
Acceptable Windows for Observations, Tests, and 
Assessments Following a Single Administration of QW 
Formulation (Period 2 of Cohort 1 and Cohort 1’ [as 
Necessary] [Single Administration Period]) ................................. 59 
Table 3.7-5 
Acceptable Windows for Observations, Tests, and 
Assessments Following a Single Administration of QW 
Formulation (Period 3 of Cohort 1 and Cohort 1’ [as 
Necessary] [Single Administration Period]) ................................. 60 
Table 3.7-6 
Acceptable Windows for Observations, Tests, and 
Assessments Following Repeated Administration of QW 
Formulation (Period 2 of Cohort 2 [Repeated Administration 
Period]) ......................................................................................... 61 
Table 3.7.5.2-1 
Clinical Laboratory Assessments .................................................. 67 
 


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List of In-text Figures 
Figure 3.1-1 
Trial Design .................................................................................. 42 
 


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List of Appendices 
Appendix 1 
Handling and Shipping of Bioanalytical Samples ...................... 107 
Appendix 2 
CYP2D6 Genotyping Table ........................................................ 109 
Appendix 3 
List of CYP Inhibitors/Inducers .................................................. 112 
Appendix 4 
Criteria for Allowing Concomitant Use of Topical CYP2D6 
Inhibitors, CYP3A4 Inhibitors, and CYP3A4 Inducers .............. 115 
Appendix 5 
Equivalent Conversion of Antipsychotics .................................. 118 
Appendix 6 
Protocol Amendments/Administrative Changes ......................... 120 
 


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List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
ADHD 
Attention deficit hyperactivity disorder 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BE 
Bioequivalence 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CGI-I 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity of Illness 
CIOMS 
Council for International Organizations of Medical Science 
CPK 
Creatine phosphokinase 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP2D6 
Cytochrome P450 2D6 
CYP3A4 
Cytochrome P450 3A4 
DIEPSS 
Drug-Induced Extrapyramidal Symptoms Scale 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EM 
Extensive metabolizer 
GCP 
Good Clinical Practice 
γ-GTP 
Gamma glutamyl transpeptidase 
HbA1c 
Glycosylated hemoglobin 
hCG 
Human chorionic gonadotropin 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IM 
Intermediate metabolizer 
IRB 
Institutional review board 
IRE 
Immediately reportable event 
LDH 
Lactic dehydrogenase 
LSMD 
Least square mean difference 
MDD 
Major depressive disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum tolerated dose 
OROS 
Osmotic-controlled release oral delivery system 
PANSS 
Positive and Negative Syndrome Scale 
PCS 
Potentially Clinically Significant 
PK 
Pharmacokinetic 
PM 
Poor metabolizer 
PQC 
Product quality complaint 
QTc 
QT corrected for heart rate 
QTcF 
QT interval as corrected by Fridericia’s formula 
QW 
Quaque (Once) Weekly 
TEAE 
Treatment-emergent adverse event 
WOCBP 
Women of child-bearing potential 
AUC 
Area under the concentration time curve 
AUC 
Area under the concentration time curve from time zero to infinity 
AUC/D 
Area under the concentration time curve per dose 
AUC_%Extrap 
Ratio of area under the concentration-time curve from tlast to infinity versus 
AUC∞ 


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Abbreviation 
Definition 
AUCt 
Area under the concentration time curve calculated to the last observable 
concentration at time t 
AUCt/D 
AUCt per dose 
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 
Cmax/D 
Cmax per dose 
λz 
Terminal elimination rate constant 
t1/2,z 
Terminal phase elimination half life 
tlast 
Time of the last measurable concentration 
tmax 
Time to maximum (peak) plasma concentration 
 


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1 
Introduction 
Schizophrenia is a condition primarily characterized by positive symptoms such as 
hallucinations and delusions and negative symptoms such as apathy, lack of spontaneity, 
and social withdrawal, and is likely to have a chronic course. The prevalence of 
schizophrenia in the world is reported to be around 0.5%, though this percentage varies 
depending on the country,1,2 and approximately 713,000 people are affected with the 
disease in Japan (based on the 2011 Patient Survey by the Ministry of Health, Labour and 
Welfare).3 In the acute phase characterized by hallucinations, delusions, and psychomotor 
agitation, impulsive behaviors and positive symptoms should be controlled, while in the 
maintenance phase, it is vital to prevent flare/relapse of symptoms, maintain the 
alleviated condition, and improve cognitive function or at least not impair cognitive 
function in the course of treatment. In either treatment phase, continuous treatment for an 
appropriate period is considered to contribute to the alleviation of symptoms as well as to 
good outcomes by preventing flare/relapse from occurring.4 However, in comparison 
with other chronic diseases, schizophrenia is generally associated with poor drug 
adherence due mainly to lack of consciousness of disease and cognitive impairment on 
the part of patients. 
As a measure to improve patient adherence to medication, long-acting drugs have been 
introduced into clinical practice. In Japan, multiple injections are commercially available 
including long-acting injections of haloperidol decanoate and fluphenazine decanoate as 
typical antipsychotics, and long-acting injectable suspensions of risperidone and 
paliperidone palmitate and long-acting injections of aripiprazole hydrate as atypical 
antipsychotics. 
Brexpiprazole is a new chemical entity discovered by Otsuka Pharmaceutical Co., Ltd. 
(hereinafter referred to as "Otsuka") that works through a combination of partial agonist 
activity at dopamine D2 receptors5 and serotonin 1A (5-HT1A) receptors 6,7 and 
antagonist activity at serotonin 2A (5-HT2A) receptors.5 
Brexpiprazole was studied in clinical trials in the US and Europe and was first granted 
marketing approval in the US in July 2015 as treatment for schizophrenia and an 
adjunctive therapy to antidepressants for the treatment of major depressive disorder 
(MDD). Further development of this drug for other psychiatric disorders is now ongoing 
in the US. Brexpiprazole was also proven to be effective and safe in clinical trials in 
Japanese patients with schizophrenia and was granted approval in Japan in January 2018. 
The drug is currently undergoing further development for other psychiatric conditions in 
Japan as well. 


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The currently approved regimen for brexpiprazole in Japan and other countries is once-
daily oral administration. As stated above, maintenance of drug compliance is considered 
instrumental in alleviating symptoms and achieving favorable outcomes in the treatment 
of schizophrenia, but currently the only commercially available long-acting 
antipsychotics are all injectable formulations. This situation indicates that there is an 
unmet medical need for more easy-to-use long-acting antipsychotics. 
With the goal of improving the current status of pharmacotherapy for schizophrenia, 
Otsuka is developing an oral brexpiprazole once-weekly formulation (hereinafter referred 
to as "QW formulation") that can reduce the dosing frequency with the same "less 
invasive" route of administration as the existing brexpiprazole. 
In order to find the most appropriate QW formulation, Otsuka conducted a clinical 
pharmacology trial (Japan 331-102-00021) in Japan for comparative investigation of the 
pharmacokinetics (PK), tolerability, and safety of 3 types of the brexpiprazole QW 
formulation administered as single oral doses in patients with schizophrenia. Otsuka then 
performed a simulation at the steady state using a model created based on the PK results 
from Trial 331-102-00021. The results suggested that the QW-A formulation, using 
brexpiprazole fumarate as the bulk form and the osmotic-controlled release oral delivery 
system (OROS) as the release control system, has a favorable PK profile. 
Prompted by these findings, development of a brexpiprazole QW formulation is currently 
being carried out based on the QW-A formulation. 
1.1 
Nonclinical Data 
As the QW formulation to be administered in this trial contains brexpiprazole fumarate as 
the active pharmaceutical ingredient, repeated-dose oral toxicity studies in rats and 
monkeys and in vitro and in vivo genotoxicity studies have been conducted. 
A 4-week repeated-dose oral toxicity study of brexpiprazole fumarate was conducted in 
rats. Changes in general condition attributable to the pharmacological action of the drug 
included abnormal posture in males and females at doses of 30 mg/kg/day and higher, 
lacrimation in females at 30 and 100 mg/kg/day, hypothermia, tremor, and lacrimation in 
males at 100 and 300 mg/kg/day, and incomplete eyelid closure in females at doses of 
10 mg/kg/day and higher. Suppressed body weight gain associated with decreased food 
consumption was observed in males at doses of 30 mg/kg/day and higher and in females 
at 100 mg/kg/day. Decreased body temperature was observed in both sexes at doses of 
30 mg/kg/day and higher. Lobular hyperplasia and milk secretion in the mammary glands 
in females at doses of 3 mg/kg/day and higher and feminization of the mammary glands 
in males at doses of 30 mg/kg/day and higher were considered to be due to D2 


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antagonism and the resulting increase in serum prolactin levels.8 In addition, mucification 
of the vagina at 3 mg/kg/day and higher and of the uterine cervix at 10 mg/kg/day and 
higher were considered to be due to activation of luteal function triggered by the increase 
in serum prolactin. Brain lesions observed in males at 300 mg/kg/day and in females at 
100 mg/kg/day were associated with a marked decrease in body temperature, as seen in 
previous toxicity studies of brexpiprazole. In males, histopathological lesions in the testis, 
epididymis, and seminal vesicles were observed at 100 and 300 mg/kg/day. In 
conclusion, the no observed adverse effect level (NOAEL) was determined to be 
30 mg/kg/day for males and 10 mg/kg/day for females under the conditions of the study. 
A 4-week repeated-dose oral toxicity study of brexpiprazole fumarate was conducted in 
monkeys. Clinical signs included tremors in males and females at 3 and 10 mg/kg/day. 
Drowsiness, crouching, and eyelid closure were observed in males and females at 
10 mg/kg/day, and drowsiness was also observed in males at 3 mg/kg/day. Decreased 
mean blood pressure was observed in both sexes at doses of 3 mg/kg/day and higher and 
decreased body temperature was observed in both sexes at 10 mg/kg/day. QT corrected 
for heart rate (QTc) was prolonged in males at 10 mg/kg/day, but only on Day 1. The 
NOAEL was considered to be 1 mg/kg/day for both males and females under the 
conditions of the study. 
In 4-week repeated-dose oral toxicity studies in rats and monkeys, the effects of 
brexpiprazole fumarate were similar to those seen in clinical studies of brexpiprazole. No 
new or unexpected systemic toxicities were observed with brexpiprazole fumarate 
compared to brexpiprazole.9,10,11,12,13,14,15 There was also no apparent difference in the 
toxicokinetic profile between brexpiprazole and brexpiprazole fumarate in both rats and 
monkeys. 
Brexpiprazole fumarate was not genotoxic in a bacterial reverse mutation test, a bone-
marrow micronucleus test in rats, or an unscheduled DNA synthesis test in rats. 
All relevant data from nonclinical studies in animals (including PK and toxicity studies) 
are presented in the Investigator's Brochure (IB). 
1.2 
Clinical Data 
1.2.1 
Clinical Pharmacology Trial for Comparative Investigation of the 
Pharmacokinetics, Tolerability, and Safety of Three Types of QW 
Formulation Administered as Single Oral Doses in Patients With 
Schizophrenia (Japan 331-102-00021) 
A multi-center, open-label, clinical pharmacology trial for comparative investigation of 
the PK, tolerability, and safety following single oral administration of one of three types 


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of brexpiprazole QW formulation (Table 1.2-1) in patients with a diagnosis of 
schizophrenia (295.90) based on the Diagnostic and Statistical Manual of Mental 
Disorders, Fifth edition (DSM-5®). 
Subjects received one brexpiprazole 2 mg conventional tablet and, after a washout period, 
received a single administration of one of three QW formulations (12 mg of 
brexpiprazole). 
Table 1.2-1 
Three QW Formulations Used in Trial 331-102-00021 
Candidate Formulation 
No. of Subjects 
Bulk Form 
Release Control System 
QW-A formulation 
6 
Fumarate 
OROS 
QW-B formulation 
6  
Fumarate 
HG matrix tablet 
QW-C formulation 
8 
Amorphous solid dispersion 
HG matrix tablet 
 
The incidence of adverse events (AEs) at 12 mg of brexpiprazole was 33.3% (2/6) in the 
QW-A formulation group, 33.3% (2/6) in the QW-B formulation group, and 12.5% (1/8) 
in the QW-C formulation group. No AEs occurred in more than 1 subject in any 
formulation group. In addition, no serious adverse events (SAEs), severe AEs, or AEs 
leading to trial discontinuation were reported in any formulation group. 
All QW formulations were associated with extended median tmax as compared with the 
conventional tablet, indicating controlled release of the drug from all QW formulations. 
The mean t1/2,z after dosing of each QW formulation was similar to that after dosing of 
the conventional tablet. The main PK parameters of each QW formulation are shown in 
Table 1.2-2. 
Table 1.2-2 
Main Pharmacokinetic Parameters of Each QW Formulation 
in Trial 331-102-00021 
Candidate 
Formulation 
(mg) 
No. of 
Subjects 
Cmax 
(ng/mL) 
AUC 
(h∙ng/mL) 
tmaxa 
(h) 
t1/2,z 
(h) 
QW-A formulation 
(12 mg) 
6 
61.11 
(39.75) 
6840 
(5360) 
30.13 
(23.25 - 49.57) 
71.5 
(18.2) 
QW-B formulation 
(12 mg) 
6 
46.67 
(16.75) 
4210 
(1260) 
24.60 
(23.30 - 25.58) 
68.4 
(26.3) 
QW-C formulation 
(12 mg) 
8 
63.56 
(23.26) 
7780 
(6170) 
18.09 
(8.60 - 48.00) 
90.2 
(53.9) 
Mean (standard deviation) 
aMedian (minimum - maximum) 
 


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1.2.2 
Clinical Data of Conventional Tablet of Brexpiprazole 
Among clinical trials of the conventional tablet, the results of trials that confirmed safety 
and tolerability at the maximum dose of 12 mg and the results of trials in Japanese 
patients with schizophrenia are summarized below. Refer to the IB for further 
information. 
1.2.2.1 
Phase 1 Multiple-dose Trial in Subjects With Schizophrenia or 
Schizoaffective Disorder (US 331-08-205) 
A total of 48 subjects with schizophrenia or schizoaffective disorder received multiple 
doses of oral brexpiprazole at 2, 4, 6, 8, 10, or 12 mg (6 subjects per dose group plus 2 
subjects per group given brexpiprazole 1 mg as a reference group) for 14 days. 
The Cmax and AUC0-24h increased dose-dependently after multiple-dose administration of 
brexpiprazole (1 to 12 mg). The t1/2,z of brexpiprazole at steady state ranged from 81.14 
to 106.83 hours. 
The incidence of adverse events (AEs) in subjects receiving the investigational medicinal 
product (IMP) (including subjects in the 1-mg reference group) was 89.6% (43/48). 
Adverse events reported in more than 1 subject included anxiety (31.3%, 15/48), 
insomnia (22.9%, 11/48), constipation, headache (14.6%, 7/48 each), stomach 
discomfort, pain in extremity (10.4%, 5/48 each), dyspepsia, agitation, nasal congestion 
(8.3%, 4/48 each), back pain, sedation, oropharyngeal pain (6.3%, 3/48 each), 
tachycardia, tongue disorder, upper respiratory tract infection, blood pressure decreased, 
arthralgia, akathisia, dizziness, and hypotension (4.2%, 2/48 each). Of those, AEs 
reported in more than 1 subject and considered to be related to the IMP were anxiety 
(16.7%, 8/48), insomnia, constipation, stomach discomfort (8.3%, 4/48 each), sedation 
(6.3%, 3/48), tongue disorder, blood pressure decreased, akathisia, and headache (4.2%, 
2/48 each). Serious adverse events (SAEs) reported in the 12-mg group were drug 
hypersensitivity and anxiety in 1 subject each and both events resolved on the day after 
onset. In addition, no AEs in the 12-mg group led to discontinuation, demonstrating good 
tolerability of brexpiprazole at up to 12 mg. 
1.2.2.2 
QT/QTc Trial in Subjects With Schizophrenia or Schizoaffective 
Disorder (US 331-10-242) 
A total of 205 subjects with schizophrenia or schizoaffective disorder received multiple 
doses of brexpiprazole at 4 mg or 12 mg or placebo for 11 days or moxifloxacin once 
daily for one day. The 12-mg group included 67 subjects. 


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The primary endpoint was the time-matched QTcI change from baseline corrected for 
placebo on Day 11 of brexpiprazole treatment. The results demonstrated that there was no 
QTcI prolongation after brexpiprazole treatment at either 4 or 12 mg. 
The incidence of AEs in subjects receiving 12 mg of brexpiprazole was 71.6% (48/67). 
Adverse events reported in more than 1 subject included dizziness (8 subjects, 11.9%), 
akathisia, extrapyramidal disorder, restlessness, headache, nausea (5 subjects each, 
7.5%), constipation, somnolence, insomnia (4 subjects each, 6.0%), orthostatic 
hypotension, vomiting, sedation (3 subjects each, 4.5%), stomach discomfort, 
nasopharyngitis, muscle rigidity, drooling, application site pruritus, vision blurred, 
salivary hypersecretion, anaemia, and diarrhoea (2 subjects each, 3.0%). Of those, AEs 
reported in more than 1 subject and considered to be related to the IMP were dizziness 
(10.4%, 7/67), extrapyramidal disorder (7.5%, 5/67), akathisia, headache (6.0%, 4/67 
each), nausea, sedation, somnolence (4.5%, 3/67 each), constipation, salivary 
hypersecretion, vomiting, muscle rigidity, drooling, and orthostatic hypotension (3.0%, 
2/67 each). No SAEs were reported in the 12-mg group. Adverse events leading to 
discontinuation in the 12-mg group were dizziness, extrapyramidal disorder (3.0%, 2/67 
each), akathisia, psychotic disorder, and joint stiffness (1.5%, 1/67 each). The trial results 
demonstrated good tolerability of brexpiprazole at 12 mg. 
1.2.2.3 
Phase 1 Multiple-dose Trial in Subjects With Schizophrenia 
(Japan 331-10-001) 
A total of 21 subjects with schizophrenia received multiple doses of brexpiprazole at 1, 4, 
or 6 mg once daily for 14 days. 
Overall, 90.5% of subjects (19/21) experienced AEs. The incidence of AEs by treatment 
group was 71.4% (5/7) in the 1-mg group, 100.0% (8/8) in the 4-mg group, and 100.0% 
(6/6) in the 6-mg group. The most frequently reported AEs (incidence ≥ 5% of all 
subjects) were blood prolactin increased (38.1%, 8/21), blood creatine phosphokinase 
increased (14.3%, 3/21), nausea, nasopharyngitis, blood pressure increased, blood 
prolactin decreased, insomnia, and schizophrenia (9.5%, 2/21 each). The majority of 
events, including blood prolactin increased, were considered potentially related to the 
IMP. Serious adverse events of schizophrenia were reported in 2 subjects (1 each in the 
1-mg and 4-mg groups), both of which led to discontinuation. 
The trial results demonstrated the safety and tolerability of brexpiprazole at up to 6 mg in 
Japanese subjects with schizophrenia. 


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1.2.2.4 
Dose-finding Trial in Subjects With Schizophrenia (Japan 331-
10-002) 
A double-blind, placebo-controlled trial was conducted to determine the efficacy, safety, 
and tolerability of fixed-dose brexpiprazole in adult subjects with an acute relapse of 
schizophrenia. This trial had 4 groups: a placebo group and 3 fixed doses of brexpiprazole 
(1, 2, and 4 mg/day). The primary endpoint was change from baseline to Week 6 in 
Positive and Negative Syndrome Scale (PANSS) total score. The primary endpoint of 
change in PANSS total score from baseline at Week 6 showed significant improvement in 
the 2-mg group compared with the placebo group (least squares mean difference [LSMD]: 
−7.32, p = 0.0124). Although there was no significant difference between the 4-mg group 
and the placebo group, improvement in PANSS total score was numerically greater in the 
4-mg group than in the placebo group (LSMD: −3.86, p = 0.1959). Efficacy was observed 
for brexpiprazole in subjects with an acute relapse of schizophrenia. 
The incidence of AEs by treatment group was 70.4% in the 1-mg group, 69.3% in the 2 
mg group, 65.5% in the 4-mg group, and 76.7% in the placebo group. Adverse events 
reported in any of the brexpiprazole groups at an incidence of ≥ 5% and at more than 
double the incidence in the placebo group were vomiting, blood prolactin increased, 
diarrhoea, nausea, and dental caries. There was no evident relationship between the dose 
of brexpiprazole and the incidence of AEs. The majority of AEs reported in brexpiprazole 
groups and placebo group were mild or moderate in severity. A 52-year-old female 
subject in the 4-mg group died of asphyxia. This event was considered to be unrelated to 
the IMP. The incidence of SAEs including death was 7.0% in the 1-mg group, 4.4% in 
the 2-mg group, 4.4% in the 4-mg group, and 4.3% in the placebo group. In all treatment 
groups, schizophrenia was the only SAE that occurred in more than 1 subject. The 
incidence of AEs leading to discontinuation was 16.5% in the 1-mg group, 10.5% in the 
2-mg group, 15.0% in the 4-mg group, and 17.2% in the placebo group. The most 
frequently reported AE leading to discontinuation was schizophrenia for all treatment 
groups. No marked changes were noted in laboratory test values, vital signs, weight, or 
electrocardiogram (ECG) in brexpiprazole groups. 
1.2.2.5 
Long-term Trial in Subjects With Schizophrenia (Japan 331-10-
003) 
This long-term trial conducted in Japan was an open-label trial to evaluate the safety and 
efficacy of long-term administration of brexpiprazole in subjects with schizophrenia, 
either continuing treatment from the dose-finding trial 331-10-002 (rollover subjects) or 
newly enrolled in this trial. 


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All efficacy endpoints, including PANSS total score and Clinical Global Impression-
Severity of Illness (CGI-S) score, remained stable until Week 52. 
The incidence of AEs was 85.2% in newly enrolled subjects, 80.6% in rollover subjects, 
and 83.6% in all subjects. The most frequently reported AE was nasopharyngitis (25.1%) in 
newly enrolled subjects, schizophrenia (26.5%) in rollover subjects, and nasopharyngitis 
(23.1%) in all subjects. Most AEs were mild or moderate in severity. No deaths were 
reported in this trial. The incidence of SAEs was 10.4% in newly enrolled subjects, 18.4% 
in rollover subjects, and 13.2% in all subjects. Serious adverse events reported in more than 
1 subject were schizophrenia in newly enrolled and rollover subjects and dehydration, 
akathisia, and schizophrenia in all subjects. The incidence of AEs leading to 
discontinuation was 10.9% in newly enrolled subjects, 23.5% in rollover subjects, and 
15.3% in all subjects. The most frequently reported AE leading to discontinuation was 
schizophrenia in newly enrolled subjects, rollover subjects, and all subjects. No clinically 
meaningful changes were noted in laboratory test values, vital signs, or ECGs in newly 
enrolled subjects, rollover subjects, or all subjects. The mean change in weight from Period 
2 baseline to the final assessment (last observation carried forward [LOCF]) was 0.34 kg in 
newly enrolled subjects, 2.02 kg in rollover subjects, and 0.93 kg in all subjects. There was 
no marked difference in safety results between newly enrolled subjects and rollover 
subjects, indicating that switchover to brexpiprazole monotherapy from prior treatment 
with existing antipsychotic drugs has no significant impact on safety. 
1.3 
Pharmacokinetics 
A simulation was performed using plasma brexpiprazole concentrations observed after 
dosing of the QW-A formulation at 12 mg in Japanese Trial 331-102-00021 to estimate 
steady-state plasma brexpiprazole concentrations for the QW-A formulation at 24 and 
48 mg. The estimated PK parameters are shown in Table 1.3-1. 
Results from Japanese and non-Japanese clinical trials showing PK parameters of 
repeated administration of brexpiprazole at the clinically recommended doses (Japan: 
2 mg; US: 2 and 4 mg) and the maximum dose of 12 mg at which safety and tolerability 
has been confirmed are summarized in Table 1.3-2. 
The PK of brexpiprazole was similar between Japanese and non-Japanese in healthy 
adults receiving a single dose of brexpiprazole at 0.2 to 6 mg (US 331-07-201 and Japan 
331-07-002) and in subjects with schizophrenia receiving multiple doses of brexpiprazole 
at 1, 4, and 6 mg (US 331-08-205 and Japan 331-10-001). A non-Japanese population PK 
analysis (Trial 331-12-208) did not identify race as a variation factor for the PK of 
brexpiprazole. 


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Table 1.3-1 
Estimated Pharmacokinetic Parameters of Brexpiprazole QW 
Formulation at Steady State Based on Simulation 
Summary 
PK Parameter 
24 mg 
48 mg 
A simulation was 
performed with a PK 
model created based on 
PK data on the QW-A 
formulation (n = 6) from 
Trial 331-102-00021 
(Japan). 
Css,max 
(ng/mL) 
88 
(69.3) 
176 
(139) 
Css,min 
(ng/mL) 
27.6 
(27.8) 
55.1 
(55.6) 
AUC168h 
(ng·h/mL) 
9450 
(7890) 
18900 
(15800) 
Css,max = Maximum plasma concentration at steady state 
Css,min = Minimum plasma concentration at steady state 
Mean (standard deviation) 
 
Table 1.3-2 
Pharmacokinetic Parameters of Brexpiprazole at Steady 
State 
Trial No. 
No. of Subjects 
PK 
Parameter 
2 mg 
4 mg 
12 mg 
331-10-001 (Japan) 
4 mg (N = 7) 
Cmax 
(ng/mL) 
ND 
164.63 
(101.96) 
ND 
AUC24h 
(ng·h/mL) 
ND 
3238 
(2184) 
ND 
AUC24h × 7 a 
(ng·h/mL) 
ND 
22666 
ND 
331-08-205 (US) 
2 mg (N = 6) 
4 mg (N = 5) 
12 mg (N = 4) 
Css,max 
(ng/mL) 
81.2 
(28.3) 
199 
(134) 
382 
(30.3) 
Css,min 
(ng/mL) 
56.8 
(23.0) 
112 
(75.3) 
205 
(51.7) 
AUC24h 
(ng·h/mL) 
1620 
(594) 
3950 
(2860) 
6950 
(797) 
AUC24h × 7 a 
(ng·h/mL) 
11340 
27650 
48650 
331-10-242 (US) 
4 mg (N = 64) 
12 mg (N = 53) 
Cmax 
(ng/mL) 
ND 
 
170 
 (69.8) 
462  
(249) 
Css, min  
(ng/mL) 
ND 
102  
(55.2) 
305 
 (192) 
AUCτ  
(ng·h/mL) 
ND 
3100 
 (1400) 
8880 
 (5110) 
AUCτ × 7 a 
(ng·h/mL) 
ND 
21700 
61260 
Css,max = Maximum plasma concentration at steady state 
Css,min = Minimum plasma concentration at steady state 
Mean (standard deviation) 
ND = No data 
a7-day data of AUC (7 times the mean AUC24h for each dosing interval) 


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1.4 
Known and Potential Risks and Benefits 
Data from overseas phase 1 trials of the conventional tablet of brexpiprazole demonstrate 
safety and good tolerability in healthy adults exposed to single doses of 0.2 to 6 mg and 
multiple doses of 2 mg/day.16,17,18 Data from completed US multiple-dose trials show 
favorable tolerability in patients with schizophrenia or schizoaffective disorder exposed 
to multiple doses of up to 12 mg/day of brexpiprazole,19 in patients with MDD exposed 
to 4 mg/day of brexpiprazole with commercially available antidepressants,20,21 and in 
patients with attention deficit hyperactivity disorder (ADHD) exposed to up to 4 mg/day 
of brexpiprazole with commercially available stimulants. Furthermore, data from 
Japanese phase 1 trials indicate favorable tolerability in healthy adults exposed to single 
doses of up to 4 mg/day22 and in patients with schizophrenia exposed to multiple doses of 
up to 6 mg/day.23 In a Japanese dose-finding trial (331-10-002) in subjects with 
schizophrenia, the primary endpoint of change from baseline at Week 6 in PANSS total 
score in the 2 mg brexpiprazole group was significantly different from that in the placebo 
group. The change observed in the 4 mg group was numerically larger than that in the 
placebo group, though the difference was not significant. Brexpiprazole was well 
tolerated in subjects at doses of 1, 2, and 4 mg/day.24 
Data from completed clinical trials at present indicate that the maximum tolerated dose 
(MTD) of brexpiprazole for healthy adults is 6 mg as single-dose administration and 
2 mg as once-daily, multiple-dose administration (14 days). The MTD of brexpiprazole in 
patients with schizophrenia, MDD, agitation associated with Alzheimer-type dementia, 
and ADHD has not been established. Data from completed phase 1 multiple-dose trials 
indicate tolerability of brexpiprazole at multiple oral doses up to 12 mg/day in patients 
with schizophrenia or schizoaffective disorder, up to 4 mg/day when administered as an 
adjunctive therapy in adult patients with MDD or ADHD, and up to 3 mg/day when 
administered as an adjunctive therapy in elderly patients (70 to 85 years of age) with 
MDD. 
See the IB for further information on brexpiprazole and adverse drug reactions. 
2 
Trial Rationale and Objectives 
2.1 
Trial Rationale 
As described in Section 1 Introduction, maintenance of drug compliance is thought to be 
instrumental in alleviating symptoms and achieving favorable outcomes in the treatment 


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of schizophrenia; however, in comparison with other chronic diseases, schizophrenia is 
generally associated with poor drug adherence due mainly to lack of consciousness of 
disease and cognitive impairment. Long-acting drugs have been introduced into clinical 
practice as a measure to improve patient adherence to medication, but currently the only 
commercially available long-acting antipsychotics are all injectable formulations, thus 
reflecting an unmet medical need for more easy-to-use long-acting antipsychotics. 
Brexpiprazole, a once-daily oral formulation, has demonstrated efficacy and safety in the 
treatment of schizophrenia in clinical trials in subjects with schizophrenia conducted in 
Japan, the US, and Europe and is approved in Japan and overseas as a treatment for 
schizophrenia. Otsuka is now developing a QW formulation, utilizing the same less 
invasive route of administration as conventional brexpiprazole, namely the oral route, but 
with a different formulation to enable reduced dosing frequency. 
In order to find the most appropriate QW formulation, we conducted a clinical 
pharmacology trial (Japan 331-102-00021) in Japan for comparative investigation of the 
PK, tolerability, and safety of 3 types of brexpiprazole QW formulation administered as 
single oral doses in patients with schizophrenia. 
Given that the approved clinical dose of brexpiprazole for schizophrenia in Japan is 2 mg 
and that the dose found to be safe in Japanese subjects in a dose-finding trial (Japan 331-
10-002) and a long-term trial (Japan 331-10-003) is 4 mg, the target PK profile of the 
QW formulation in repeated administration should ideally be as follows: the trough 
concentration should not fall below that for the brexpiprazole 2 mg conventional tablet 
and the peak concentration should not significantly exceed that for the brexpiprazole 
4 mg conventional tablet. 
Data from single 12-mg doses of each QW formulation in Trial 331-102-00021 (Japan) 
were used to estimate plasma brexpiprazole concentrations following repeated 
administration. The results indicate that only the QW-A formulation is likely to attain the 
target PK profile. 
Furthermore, a simulation was performed, using a model created based on the PK results 
for the 12 mg QW-A formulation, to find the dose of the QW formulation that would 
achieve the target PK profile at the steady state. The results suggest that plasma 
brexpiprazole concentrations after administration of the QW formulation at 48 mg will 
generally remain within the target PK profile and will not significantly exceed the peak 
concentration at the steady state observed after administration of the conventional tablet 
at 4 mg. 


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With the above taken into consideration, in this trial, we have decided to use the QW-A 
formulation with OROS to evaluate the PK, tolerability, and safety of the brexpiprazole 
QW formulation following single and repeated oral administration in patients with 
schizophrenia. 
2.2 
Rationale for CYP2D6 Genotyping and DNA Storage 
Cytochrome P450 (CYP) 3A4 and CYP2D6 are involved in the in vitro metabolism of 
brexpiprazole, and CYP2D6 is known to have multiple genotypes with different enzyme 
activities. It has also been shown that CYP2D6 genotypes are involved in the PK 
variability of brexpiprazole. We have decided to investigate CYP2D6 genotypes to 
evaluate their effects on the PK and safety of brexpiprazole. 
We have also decided to store DNA samples to allow for future genomic/genetic analyses 
in those cases where further explanation is required in addition to the results of CYP2D6 
genotyping performed in this trial for the PK of brexpiprazole, new information on genes 
and PK becomes available, and/or genomic/genetic analyses pertaining to responses to 
brexpiprazole (efficacy or safety) and the disease are considered useful. DNA storage 
will be conducted only at the trial sites which have agreed to collect DNA samples for 
storage, and only subjects who have provided written informed consent for DNA storage 
(if the subject is a minor or is hospitalized for reasons of medical protection, his or her 
legally acceptable representative must also give informed consent) will participate in 
DNA storage. With regard to collecting and storing DNA samples during a clinical trial, 
the Ministry of Health, Labour and Welfare (MHLW) states, in Q&A 1 in "Regarding 
Clinical Studies Utilizing Pharmacogenomics (PFSB/ELD Notification No. 0930007 
dated 30 Sep 2008),"25 that it is possible to collect samples from subjects for 
genomic/genetic analyses relevant to evaluation (PK, efficacy, safety, etc) of an IMP in a 
clinical trial, provided (1) the target and time of genomic/genetic analyses have been 
determined at the time of the trial or (2) the target and time of genomic/genetic analyses 
have yet to be determined at the time of the trial but such analyses related to IMP 
evaluation may be considered in the future. The International Council for Harmonisation 
(ICH) also states, in Section 1.4 General Principles in the Guideline on Genomic 
Sampling and Management of Genomic Data E1826 as follows: “With advances in 
science and increased awareness of the impact of genomics, there is a need and an 
opportunity to maximize the value of the collected samples and the data generated from 
them. Therefore, genomic sample acquisition is strongly encouraged in all phases and 
studies of clinical development.” 


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Moreover, this trial has been designed so that sampling for DNA storage can be carried 
out at the same time as scheduled blood sampling to minimize the discomfort to subjects. 
Optional collection and storage of DNA samples is thus justified. 
2.3 
Dosing Rationale 
2.3.1 
Regimen 
The objective of this trial is to evaluate the PK, tolerability, and safety of the 
brexpiprazole QW formulation administered as single and repeated administration in 
patients with schizophrenia. The trial design comprises the single administration period 
(Cohort 1 and, as necessary, Cohort 1’) and the repeated administration period (Cohort 
2). All cohorts include Period 1 in which subjects will receive the brexpiprazole 
conventional tablet as a single administration. In each cohort, following a single 
administration of the conventional tablet, the same subject will undergo a washout period 
and then receive the QW formulation. The purpose of administering the conventional 
tablet is set to reduce the effect of interindividual variability on evaluation of the PK 
profile of the QW formulation. 
In the repeated administration period, subjects will receive the brexpiprazole QW 
formulation once weekly for 5 weeks (a total of 5 administrations). In general, patients on 
antipsychotic medication could experience AEs soon after therapy is initiated. With this 
taken into consideration, treatment will begin with a low dose to confirm the safety and 
tolerability before increasing the dose to the predetermined level. Specifically, a low dose 
will be used only for the first administration and the predetermined dose will be used for 
the subsequent 4 administrations in this trial. Four administrations at the predetermined 
dose is based on the results of a simulation for the QW formulation indicating that 4 
once-weekly administrations of the QW formulation are needed for brexpiprazole 
concentration to reach the steady state. 
2.3.2 
Dose 
2.3.2.1 
Single Administration Period (Cohort 1 and Cohort 1’ [as 
Necessary]) 
2.3.2.1.1 
Cohort 1 
In the single administration period (Cohort 1) of the trial, the same subject will receive a 
single administration of the brexpiprazole 2 mg conventional tablet, undergo the washout 
period, and next receive a single administration of the QW formulation at 24 mg, undergo 
the washout period, and finally receive a single administration of the QW formulation at 
48 mg. 


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A clinical pharmacology trial for comparative investigation of the PK, tolerability, and 
safety of 3 types of brexpiprazole QW formulation administered as single oral doses in 
patients with schizophrenia (Japan 331-102-00021) has demonstrated the safety and 
tolerability of a single 12-mg dose of the QW formulation. The results of a simulation of 
repeated administration of the QW formulation at 48 mg based on the PK results of Trial 
331-102-00021 indicate that plasma brexpiprazole concentrations after repeated 
administration of the QW formulation at 48 mg will remain roughly between the trough 
concentration after administration of the brexpiprazole 2 mg conventional tablet and the 
peak concentration after administration of the 4 mg conventional tablet, thus suggesting 
that plasma brexpiprazole concentrations after repeated administration of the QW 
formulation at 48 mg will not greatly exceed the steady-state peak concentration of the 
4 mg conventional tablet, the dose at which safety has been confirmed in Japanese 
patients. Furthermore, the mean steady-state Cmax at the maximum dose of 12 mg at 
which safety and tolerability was confirmed in an overseas repeated administration trial 
(331-08-205) and an overseas QT/QTc trial (331-10-242) of brexpiprazole conventional 
tablets in subjects with schizophrenia and schizoaffective disorder was 382 and 
462 ng/mL, respectively, and the estimated mean steady-state Cmax after repeated 
administration of brexpiprazole QW formulation at 48 mg (176 ng/mL) was lower than 
either of these results. In view of these findings, the dose was set at 48 mg for the QW 
formulation to be used in the single administration period (Cohort 1). However, since 
there is no clinical experience of administering either the brexpiprazole QW formulation 
or the conventional tablet at doses higher than 12 mg, subjects will be first given the QW 
formulation at a dose of 24 mg and only subjects for whom safety and tolerability has 
been confirmed will then receive the drug at 48 mg. For the conventional tablet, the dose 
was set at 2 mg, the recommended dose for schizophrenia. 
2.3.2.1.2 
Cohort 1’ (as Necessary) 
Prior to the commencement of the repeated administration period (Cohort 2), a simulation 
of repeated administration of the 2 mg conventional tablet and the QW formulation at 48 
mg will be performed using data on plasma brexpiprazole concentrations of the 
conventional tablet and QW formulation from the single administration period (Cohort 
1). Then, on the basis of the PK and safety results, the appropriateness of a 48 mg dose of 
the QW formulation used in the repeated administration period (Cohort 2) will be 
assessed. The decision on whether or not to implement Cohort 1’ will be made based on 
comprehensive assessment of the above. 
If the comprehensive assessment indicates that the trough concentration for repeated 
administration of the QW formulation at 48 mg is likely to fall below that for the 2 mg 


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conventional tablet, another single administration period will be added as Cohort 1’. The 
doses used in Cohort 1’ will be either of the following based on the results of a 
simulation. 
 A single administration of the QW formulation at 30 mg followed by a single 
administration of the QW formulation at 54 mg 
or 
 A single administration of the QW formulation at 30 mg followed by a single 
administration of the QW formulation at 60 mg 
 
2.3.2.2 
Repeated Administration Period (Cohort 2) 
In the repeated administration period (Cohort 2) of the trial, the same subject will receive 
a single administration of the brexpiprazole 2 mg conventional tablet, undergo the 
washout period, and next receive a single administration of the QW formulation at 24 mg 
and, subsequently, 4 administrations of the QW formulation at 48 mg once weekly. The 
rationale for selecting 48 mg for the QW formulation and 2 mg for the conventional 
tablet is presented in Section 2.3.2.1 Single Administration Period (Cohort 1 and Cohort 
1’ [as Necessary]). In general, patients on antipsychotic medication could experience AEs 
soon after therapy is initiated. With this taken into consideration, treatment will begin 
with a low dose to confirm the safety and tolerability before increasing the dose to the 
predetermined level; 24 mg is therefore selected for the first administration of the QW 
formulation. The repeated administration period (Cohort 2) will use one of the following 
regimens depending on the results of the single administration period (Cohort 1 and 
Cohort 1’ [as necessary]) (Section 3.8.1 Criteria for Progression to Cohort 2:  
 A single administration of a 2 mg conventional tablet  washout  the first 
administration of the QW formulation at 30 mg  4 administrations of the QW 
formulation at 60 mg 
 A single administration of a 2 mg conventional tablet  washout  the first 
administration of the QW formulation at 30 mg  4 administrations of the QW 
formulation at 54 mg 
 A single administration of a 2 mg conventional tablet  washout  the first 
administration of the QW formulation at 24 mg  4 administrations of the QW 
formulation at 42 mg 
 A single administration of a 2 mg conventional tablet  washout  the first 
administration of the QW formulation at 18 mg  4 administrations of the QW 
formulation at 36 mg 
 


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2.4 
Trial Objectives 
The objective of the clinical trial is to evaluate the PK, tolerability, and safety of 
brexpiprazole QW formulation administered as single and repeated administration in 
patients with schizophrenia. 
3 
Trial Design 
3.1 
Type/Design of Trial 
This is a multi-center, open-label, clinical pharmacology trial to investigate the PK, 
tolerability, and safety of brexpiprazole QW formulation administered as single and 
repeated administration in patients with a diagnosis of schizophrenia (295.90) based on 
the DSM-5®. The trial comprises the single administration period (Cohort 1) and the 
repeated administration period (Cohort 2). The dose used in the repeated administration 
period (Cohort 2) will be determined based on plasma drug concentrations obtained in the 
single administration period (Cohort 1). The single administration period (Cohort 1) 
comprises Period 1, in which the conventional tablet will be administered, and Periods 2 
and 3, in which the QW formulation will be administered. If the single administration 
period (Cohort 1) fails to produce sufficient plasma drug concentrations, another single 
administration period (Cohort 1’) will be added during which the QW formulation will be 
administered at higher single doses. Only if progression to the repeated administration 
period (Cohort 2) is judged to be appropriate based on the results of the single 
administration period (Cohort 1 and Cohort 1’ [as necessary]), will the repeated 
administration period (Cohort 2) be implemented (see Figure 3.1-1). The repeated 
administration period (Cohort 2) comprises Period 1, in which subjects will receive a 
single administration of the conventional tablet, and Period 2, in which subjects will 
receive 5 administrations of the QW formulation. 
In the single administration period (Cohort 1), subjects will receive a brexpiprazole 2 mg 
conventional tablet on Day 1 of Period 1, the QW formulation at 24 mg on Day 1 of 
Period 2, and the QW formulation at 48 mg on Day 1 of Period 3, all as single 
administrations in a fasted state. 
In the single administration period (Cohort 1’), subjects will receive a brexpiprazole 2 mg 
conventional tablet on Day 1 of Period 1, the QW formulation at 30 mg on Day 1 of 
Period 2, and the QW formulation at 60 or 54 mg on Day 1 of Period 3, all as single 
administrations in a fasted state. 
In the repeated administration period (Cohort 2), subjects will receive a single 
administration of a brexpiprazole 2 mg conventional tablet on Day 1 of Period 1, and 


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repeated administration of the QW formulation on Days 1, 8, 15, 22, and 29 of Period 2. 
The doses of the QW formulation will be determined based on the results of the single 
administration period (Cohort 1 and Cohort 1’ [as necessary]). 
In the single administration period (Cohort 1 and Cohort 1’ [as necessary]), subjects will 
be required to be hospitalized at the trial site from the day of IMP administration (Day 1) 
through the eighth day following IMP administration (Day 8) in Period 1 (conventional 
tablet) and Periods 2 and 3 (QW formulation). For the other parts of the single 
administration period, they may remain in the trial site or make trial visits on an 
outpatient basis. In Period 1 (conventional tablet) of the repeated administration period 
(Cohort 2), subjects will be required to be hospitalized at the trial site from the day of 
IMP administration (Day 1) through the eighth day following IMP administration (Day 
8). For the other parts of Period 1, they may remain in the trial site or make trial visits on 
an outpatient basis. In Period 2 (QW formulation) of the repeated administration period 
(Cohort 2), subjects will be required to be hospitalized at the trial site from the day of the 
first IMP administration (Day 1) through Day 16, from Day 22 through Day 23, and from 
Day 29 through Day 36. For the other parts of Period 2, they may remain in the trial site 
or make visits on an outpatient basis. 


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Figure 3.1-1 
Trial Design 
Single Administration Period [Cohort 1] and [Cohort 1’ (as Necessary)]
Screening period
Screening
Informed consent (start of the trial)
IMP administration (Day 1)
IMP administration (Day 1)
IMP administration (Day 1)
Screening period
Screening
Informed consent (start of the trial)
IMP administration (Day 1)
IMP administration (Day 1)
*The dose may be changed depending on the results of the single administration period (Cohort 1 and Cohort 1’ [as necessary]).
Period 1
Period 2
Period 3
Follow-up period
(Days −28 to −1 of IMP
administration in Period 1)
(20 days)
(27 days)
(14 days)
(Days 28 to 30 of IMP
administration in Period 3)
Patients with
schizophrenia
Informed consent &
screening
Single administration of
1 brexpiprazole 2 mg
tablet
Single administration of QW
formulation 24 mg*
Single administration of QW
formulation 48 mg*
Judgement
for
progression
to Cohort 2
Postdose follow-up
*Whether or not to add Cohort 1’, and the doses used in Cohort 1’ will be determined based on the results of Cohort 1.
Period 1
Period 2
Follow-up period
The doses may be changed depending on the results of the single administration period
(Cohort 1 and Cohort 1’ [as necessary]).
Repeated Administration Period
[Cohort 2]
(Days −28 to −1 of IMP
administration in Period 1)
(20 days)
(42 days)
(Days 56 to 60 of Period 2)
Postdose follow-up
Patients with
schizophrenia
Informed consent &
screening
Single administration of
1 brexpiprazole 2 mg
tablet
Repeated administration of QW formulation
Day 1: 24 mg*
Days 8, 15, 22, 29: 48 mg*
Washout 
period
20 days (+ 8 
days max)
Subjects must stay at the trial site from the day of IMP administration (Day 1) through 
Day 8 in each Period. For the other parts of each Period, subjects may remain in the trial 
site or make trial visits on an outpatient basis.
Washout 
period
27 days (+ 8 
days max)
Washout 
period
20 days (+ 8 
days max)
Subjects must stay at the trial site from the day of the first 
IMP administration (Day 1) through Day 16, from Day 22 
through Day 23, and from Day 29 through Day 36 in Period 
2. For the other parts of the Period 2, subjects may remain in 
the trial site or make trial visits on an outpatient basis.
IMP administration (Day 8)
IMP administration (Day 15)
IMP administration (Day 22)
IMP administration (Day 29)
Subjects must stay at 
the trial site from the 
day of IMP 
administration (Day 
1) through Day 8 in 
Period 1. For the 
other parts of the 
Period 1, subjects 
may remain in the 
trial site or make 
trial visits on an 
outpatient basis.


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3.1.1 
Cohort 1 (Single Administration Period) 
Subjects judged eligible at screening will receive one brexpiprazole 2 mg conventional 
tablet on Day 1 of Period 1, one 24 mg tablet of the QW formulation on Day 1 of Period 
2, and two 24 mg tablets of the QW formulation on Day 1 of Period 3, all as a single oral 
administration in a fasted state. The trial includes a washout period of 20 days (+ 8 days 
max) between IMP administration in Period 1 and IMP administration in Period 2 and a 
washout period of 27 days (+ 8 days max) between IMP administration in Period 2 and 
IMP administration in Period 3. Brexpiprazole-naïve subjects should be monitored after 
conventional tablet administration in Period 1 to check if they are free from allergic or 
hypersensitive reactions. Following administration of the QW formulation in Period 2, 
safety must be carefully evaluated. Subjects who meet any of the criteria for withdrawal 
before dose increase as specified in Section 3.9.3.2 Criteria for Withdrawal Before Dose 
Increase of the QW Formulation must be withdrawn from the trial and not advance to 
Period 3. If a subject withdrawn from the trial at the discretion of the sponsor after 
receiving a brexpiprazole 2 mg conventional tablet in Period 1 and undergoing the 
examinations scheduled for up to Day 14 of Period 1 subsequently takes part in the trial 
again, the subject will be allowed to resume participation in the trial from Period 2. If a 
subject withdrawn from the trial at the discretion of the sponsor after receiving a 24 mg 
tablet of the QW formulation in Period 2 and undergoing the examinations scheduled for 
up to Day 14 of Period 2 subsequently takes part in the trial again, the subject will be 
allowed to resume participation in the trial from Period 3. 
3.1.2 
Cohort 1’ (Additional Single Administration Period, as Necessary) 
A simulation of repeated administration will be performed based on the results of Cohort 
1 (single administration period). If steady-state plasma brexpiprazole concentrations of 
the QW formulation are estimated to fall far below the steady-state trough concentration 
for the 2 mg conventional tablet, Cohort 1’ will be added. 
The design described in Section 3.1.1 Cohort 1 (Single Administration Period) applies to 
Cohort 1’ as well. 
The doses of the QW formulation to be used in Cohort 1’ (as necessary) (single 
administration period) will be determined according to Section 3.8 Procedure for 
Progression to the Repeated Administration Period (Cohort 2) From the Single 
Administration Period (Cohort 1 and Cohort 1’ [as Necessary]), and the QW formulation 
will be administered in a fasted state as per regimen 1 or 2 shown in Table 3.2.1.2.2-1. 
Brexpiprazole-naïve subjects should be monitored after conventional tablet 
administration in Period 1 to check if they are free from allergic or hypersensitive 


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reactions. Following administration of the QW formulation in Period 2, safety must be 
carefully evaluated. Subjects who meet any of the criteria for withdrawal before dose 
increase as specified in Section 3.9.3.2 Criteria for Withdrawal Before Dose Increase of 
the QW Formulation must be withdrawn from the trial and not advance to Period 3. 
3.1.3 
Cohort 2 (Repeated Administration Period) 
Subjects judged eligible at screening will receive a single administration of a 
brexpiprazole 2 mg conventional tablet on Day 1 of Period 1 in a fasted state. The trial 
includes a washout period of 20 days (+ 8 days max) between IMP administration in 
Period 1 and IMP administration in Period 2. Subjects will then receive repeated 
administration of the QW formulation in a fasted state as per one of the regimens 1 to 5 
shown in Table 3.2.1.3.2-1 on Days 1, 8, 15, 22, and 29 of Period 2. Brexpiprazole-naïve 
subjects should be monitored after conventional tablet administration in Period 1 to check 
if they are free from allergic or hypersensitive reactions. Following administration of the 
QW formulation in Period 2, safety must be carefully evaluated. Subjects who meet any 
of the criteria for withdrawal before dose increase as specified in Section 3.9.3.2 Criteria 
for Withdrawal Before Dose Increase of the QW Formulation after IMP administration 
on Day 1 must be withdrawn from the trial without dose increase. 
3.2 
Trial Treatments 
3.2.1 
Dose, Regimen and Treatment Period 
3.2.1.1 
Cohort 1 (Single Administration Period) 
3.2.1.1.1 
Administration of Brexpiprazole Conventional Tablet  
On Day 1 of Period 1, subjects will receive a single oral administration of a brexpiprazole 
2 mg conventional tablet together with approximately 150 mL of water in the morning 
after at least 10 hours of fasting. Subjects are not to take any food until 4 hours after 
administration. Subjects are not to take any fluids from 1 hour before administration of 
the conventional tablet until 2 hours after administration, except for the water taken at the 
time of administration. 
3.2.1.1.2 
Administration of Brexpiprazole QW Formulation 
On Day 1 of each of Periods 2 and 3 in Cohort 1 (single administration period), subjects 
will receive a single oral administration of the QW formulation at the dose specified in 
Table 3.2.1.1.2-1 together with approximately 150 mL of water in the morning after at 
least 10 hours of fasting. Subjects are not to take any food until 4 hours after 
administration. Subjects are not to take any fluids from 1 hour before administration of 


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the QW formulation until 2 hours after administration, except for the water taken at the 
time of administration. 
Table 3.2.1.1.2-1 
Doses (Cohort 1) (Single Administration Period) 
 
Dose 
Treatment 
period 
Period 2 
Period 3 
Regimen 
Dose 
Tablet 
No. of Tablets 
Dose 
Tablet 
No. of Tablets 
1 
24 mg 
24 mg tablet 
1 tablet 
48 mg 
24 mg tablet 
2 tablets 
 
3.2.1.2 
Cohort 1’ (as Necessary) (Single Administration Period) 
3.2.1.2.1 
Administration of Brexpiprazole Conventional Tablet  
On Day 1 of Period 1, subjects will receive a single oral administration of a brexpiprazole 
2 mg conventional tablet together with approximately 150 mL of water in the morning 
after at least 10 hours of fasting. Subjects are not to take any food until 4 hours after 
administration. Subjects are not to take any fluids from 1 hour before administration of 
the conventional tablet until 2 hours after administration, except for the water taken at the 
time of administration. 
3.2.1.2.2 
Administration of Brexpiprazole QW Formulation 
On Day 1 of each of Periods 2 and 3 in Cohort 1’ (as necessary) (single administration 
period), subjects will receive a single oral administration of the QW formulation together 
with approximately 150 mL of water in the morning after at least 10 hours of fasting. 
Subjects are not to take any food until 4 hours after administration. Subjects are not to 
take any fluids from 1 hour before administration of the QW formulation until 2 hours 
after administration, except for the water taken at the time of administration. The doses of 
the QW formulation to be used in Cohort 1’ (as necessary) (single administration period) 
will be determined according to Section 3.8 Procedure for Progression to the Repeated 
Administration Period (Cohort 2) From the Single Administration Period (Cohort 1 and 
Cohort 1’ [as Necessary]), and the QW formulation will be administered in a fasted state 
as per regimen 1 or 2 shown in Table 3.2.1.2.2-1.  
Table 3.2.1.2.2-1 
Doses (Cohort 1’ [as Necessary] [Single Administration 
Period]) 
 
Dose 
Treatment 
period 
Period 2 
Period 3 
Regimen 
Dose 
Tablet 
No. of Tablets 
Dose 
Tablet 
No. of Tablets 
1 
30 mg 
30 mg tablet 
1 tablet 
54 mg 
24 mg tablet 
30 mg tablet 
1 tablet each 
2 
30 mg 
30 mg tablet 
1 tablet 
60 mg 
30 mg tablet 
2 tablets 


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3.2.1.3 
Cohort 2 (Repeated Administration Period) 
3.2.1.3.1 
Administration of Brexpiprazole Conventional Tablet  
On Day 1 of Period 1, subjects will receive a single oral administration of a brexpiprazole 
2 mg conventional tablet together with approximately 150 mL of water in the morning 
after at least 10 hours of fasting. Subjects are not to take any food until 4 hours after 
administration. Subjects are not to take any fluids from 1 hour before administration of 
the conventional tablet until 2 hours after administration, except for the water taken at the 
time of administration. 
3.2.1.3.2 
Administration of Brexpiprazole QW Formulation 
In Period 2, subjects will be orally administered the QW formulation together with 
approximately 150 mL of water in the morning after at least 10 hours of fasting, as per 
one of regimens 1 to 5 shown in Table 3.2.1.3.2-1 based on the results of the single 
administration period (Cohort 1 and Cohort 1’ [as necessary]). Subjects are not to take 
any food until 4 hours after administration. Subjects are not to take any fluids from 1 
hour before administration of the QW formulation until 2 hours after administration, 
except for the water taken at the time of administration. 
Table 3.2.1.3.2-1 
Doses (Cohort 2 [Repeated Administration Period]) 
 
Dose 
Treatment 
period 
Period 2 
Day 
1 
8, 15, 22, and 29 
Regimen 
Dose 
Tablet 
No. of Tablets 
Dose 
Tablet 
No. of Tablets 
1 
24 mg 
24 mg tablet 
1 tablet 
48 mg 
24 mg tablet 
2 tablets 
2 
18 mg 
18 mg tablet 
1 tablet 
36 mg 
18 mg tablet 
2 tablets 
3 
24 mg 
24 mg tablet 
1 tablet 
42 mg 
18 mg tablet 
24 mg tablet 
1 tablet each 
4 
30 mg 
30 mg tablet 
1 tablet 
54 mg 
24 mg tablet 
30 mg tablet 
1 tablet each 
5 
30 mg 
30 mg tablet 
1 tablet 
60 mg 
30 mg tablet 
2 tablets 
 
3.3 
Trial Population 
3.3.1 
Number of Subjects and Description of Population 
3.3.1.1 
Number of Subjects 
The target number of subjects is 40 in total: 20 subjects completing assessment on Day 
14 of Period 3 in the single administration period (Cohort 1) and 20 subjects completing 
assessment on Day 42 of Period 2 in the repeated administration period (Cohort 2). If 
another single administration period (Cohort 1’) with new doses is added, the target 


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number of subjects for Cohort 1’ (as necessary) is also 20 subjects completing assessment 
on Day 14 of Period 3 of this cohort (in that case, making a total of 60 subjects) (see 
Section 7.1 Determination of Sample Size). 
3.3.1.2 
Trial Population 
Patients from 18 years of age to under 65 years of age with a diagnosis of schizophrenia 
(295.90) based on DSM-5® 
3.3.2 
Subject Numbering 
Each subject who provided written consent to participate in the trial will be assigned a 
unique subject identifier (site number [3 digits] + subject number [S + 5 digits]). The site 
number will be designated by the sponsor. A subject number is a serial in-site number 
starting with S00001, which is given to each subject in chronological order of provision 
of consent. Each subject who takes part in the trial again following withdrawal from the 
trial at the discretion of the sponsor will be assigned the same subject identifier that was 
assigned to them at the time when they first participated in the trial. 
3.4 
Eligibility Criteria 
Exceptions for eligibility criteria will not be permitted during the trial, either by the 
investigator, subinvestigator, or by the medical monitor. 
3.4.1 
Informed Consent 
Informed consent will be obtained from all subjects (and the subjects' legal 
representatives if they are minors or are hospitalized for reasons of medical protection) 
on their voluntary decision. Consent will be documented on a written informed consent 
form (ICF). The ICF will be approved by the same institutional review board (IRB) that 
approves this protocol. In cases where subjects withdrawn from the trial at the discretion 
of the sponsor subsequently take part in the trial again, informed consent will also be 
obtained from all such subjects (and their legal representatives if they are minors or are 
hospitalized for reasons of medical protection) on their voluntary decision. 
Each ICF will comply with the International Council for Harmonisation (ICH) Good 
Clinical Practice (GCP) Guideline2. and local regulatory requirements. 
Investigators or subinvestigators may discuss the possibility for entry with a potential 
subject (and the subject's legal representative if the subject is a minor or is hospitalized 
for reasons of medical protection) without first obtaining consent. However, informed 
consent must be obtained and documented prior to initiation of any procedures that are 


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performed solely for the purpose of determining eligibility for research, including 
withdrawal from current medication(s). 
Potential subjects (and the subjects' legal representatives if they are minors or are 
hospitalized for reasons of medical protection) 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 plain 
language to the subject (and the subject's legal representative if the subject is a minor or 
is hospitalized for reasons of medical protection) by the investigator or subinvestigator, 
the IRB approved written ICF will be signed and dated by both the subject (and the 
subject's legal representative if the subject is a minor or is hospitalized for reasons of 
medical protection) 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 (and the subject's 
legal representative if the subject is a minor or is hospitalized for reasons of medical 
protection) will receive a copy of the signed ICF; the original shall be kept on file by the 
investigator or subinvestigator. 
Subjects (and the subjects' legal representatives if they are minors or are hospitalized for 
reasons of medical protection) 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 an informed and voluntary decision as to 
whether or not they wish to continue their participation in the trial. 
For CYP2D6 genetic testing and DNA storage, separately from the main trial, written 
informed consent will be obtained from subjects (and the subjects' legal representatives if 
they are minors or are hospitalized for reasons of medical protection) on their voluntary 
decision in a similar manner. CYP2D6 genetic testing is mandatory and those subjects 
(and the subjects' legal representatives if they are minors or are hospitalized for reasons 
of medical protection) who do not consent to CYP2D6 genetic testing cannot participate 
in the trial. On the other hand, DNA storage is optional and refusal to allow DNA storage 
will not affect trial participation. In cases where subjects withdrawn from the trial at the 
discretion of the sponsor subsequently take part in the trial again, written informed 
consent will be obtained from them (and their legal representatives if they are minors or 
are hospitalized for reasons of medical protection) on their voluntary decision, if they 
have yet to complete CYP2D6 genetic testing. 


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3.4.2 
Inclusion Criteria 
Subjects are required to meet the inclusion criteria in Table 3.4.2-1. 
Subjects withdrawn from the trial at the discretion of the sponsor will have to be 
reevaluated to ensure they still meet the inclusion criteria in Table 3.4.2-1 if they are to 
take part in the trial again. 
Table 3.4.2-1 
Inclusion Criteria (for All Cohorts) 
1 Patients at least 18 years of age and below the age of 65 at the time of informed 
consent 
2 Patients with a diagnosis of schizophrenia based on DSM-5® 
3 Patients who are able to be hospitalized for the protocol-defined hospitalization 
period. 
4 Patients with a body mass index [BMI = body weight (kg)/height (m)2] of 
18.5 kg/m2 or higher and lower than 35.0 kg/m2 at screening 
5 Persons who provide written informed consent before commencement of any trial-
related procedures and whom the investigator or subinvestigator judges to be 
capable of following all the conditions of this trial 
6 Patients who, in the judgement of the investigator or subinvestigator, have stable 
psychotic symptoms maintained by administration of an antipsychotic (other than 
clozapine) within the dosing range indicated below, before commencement of IMP 
administration 
 Antipsychotic medication comprising no more than two active components 
 A daily dose equivalent to no more than 600 mg/day of chlorpromazine 
 If multiple antipsychotics are taken in the same day, this is to be the 
combined equivalent dose. 
 Chlorpromazine equivalent doses are based on Appendix 5. 
However, this does not include administration of antipsychotic medication at doses 
equivalent to less than 100 mg/day of chlorpromazine, which are not expected to 
have any antipsychotic effect. 
 
[Rationale for inclusion criteria] 
1. This criterion is based on epidemiological data on age at onset and prevalence of 
schizophrenia. An age of 18 years was set as the lower limit because individuals of 
this age, a high age in adolescence, are old enough to take responsibility for their 
own health and drug therapy, and are competent for informed consent. An age of 
less than 65 years was set as the upper limit so as to exclude the elderly for their 
safety and because they are more likely to suffer complications, which may have 
an effect on the safety evaluation. The upper limit of age is also based on the 
guideline, Studies in Support of Special Populations: Geriatrics (PAB/NDD 
Notification No. 104, dated 02 Dec 1993), in which the elderly are defined as 
individuals aged 65 years or older. 


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2. This criterion was set to identify patients with schizophrenia. 
3. This criterion was set in consideration of subject safety and possible effects on PK 
evaluation. 
4. This criterion was set to reduce possible interindividual variations in PK due to 
obesity. Considering that the subjects in this trial are patients, the upper limit for 
obesity or adiposity was set as a BMI of less than 35.0 kg/m2 based on the criteria 
proposed by the Japan Society for the Study of Obesity. 
5. This criterion was set for ethical reasons. 
6. This criterion was set in consideration of subject safety. 
 
3.4.3 
Exclusion Criteria 
Subjects will be excluded if they meet any of the exclusion criteria in Table 3.4.3-1. 
Subjects withdrawn from the trial at the discretion of the sponsor cannot take part in the 
trial again if they meet any of the exclusion criteria in Table 3.4.3-1. 
Table 3.4.3-1 
Exclusion Criteria (for All Cohorts) 
1 
Patients with a diagnosis of a concurrent mental disorder besides schizophrenia 
(schizoaffective disorder, major depressive disorder, bipolar I disorder, bipolar II 
disorder, general anxiety disorder, obsessive-compulsive disorder, post-traumatic 
stress disorder, dementia or mild neurocognitive disorder, personality disorder, 
etc) based on DSM-5® (However, this exclusion does not apply to caffeine- or 
tobacco-related disorders) 
2 
Patients who fail to meet the specified requisite washout periods for the 
prohibited concomitant drugs and foods indicated below before commencement 
of IMP administration, or patients who are anticipated to take any of the drugs or 
foods in the following table during the study period 
Drugs and Foods 
Washout Period 
Adrenaline 
28 days 
Rexulti tablets (planned) 
21 days 
Clozapine 
Starting from 
informed consent 
CYP2D6 inhibitors and CYP3A4 inhibitors and inducers listed in 
Appendix 3 (Except topical agents listed in Appendix 4 for which use 
with the IMP is permitted) 
14 days 
Other investigational drugs under development 
60 days 
Foods and beverages containing St. John’s Wort, Ginkgo biloba, 
goldenseal, or echinacea (Echinacea purpurea) 
14 days 
Foods and beverages containing grapefruit, Seville orange, or star fruit 
7 days 
  
3 
Patients who have previously undergone gastrointestinal surgery that could affect 
PK evaluations 
4 
Patients who are using clozapine at the time of informed consent 
5 
Patients who have received electroconvulsive therapy within 60 days before 
commencement of IMP administration 


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Table 3.4.3-1 
Exclusion Criteria (for All Cohorts) 
6 
Patients with clinically problematic disorders of the nervous system, liver, 
kidneys, metabolic system, blood system, immune system, cardiovascular 
system, respiratory system, or digestive system (However, such patients may be 
included if the condition is mild or well-controlled and is considered to not affect 
safety or PK evaluations.)  
7 
Patients who fall under any of the following criteria at screening 
 Inadequately controlled  hypertension (diastolic blood pressure of 
> 95 mmHg) 
 Symptomatic hypotension 
 Orthostatic hypotension, defined as a decrease of ≥ 30 mmHg in systolic 
blood pressure or a decrease of ≥ 20 mmHg in diastolic blood pressure after 
standing for at least 3 minutes compared with the supine values prior to 
standing 
8 
Patients with any of the following laboratory or ECG values at screening 
(according to the results from the central laboratory or the central ECG 
laboratory) 
Platelets:  75000/mm3(/μL) 
Hemoglobin: ≤ 9 g/dL 
Neutrophils, absolute: 
 ≤ 1000/mm3 
AST: 
 > 2 × upper limit of normal 
ALT: 
 > 2 × upper limit of normal 
CPK: 
 > 3 × upper limit of normal 
Creatinine:  2 mg/dL 
QTcF > 450 msec 
  
9 
Patients meeting any of the following criteria 
 Patients with type 1 diabetes mellitus or patients with type 2 diabetes mellitus 
being treated with insulin 
 Patients with type 2 diabetes mellitus who have not been maintained on a 
stable regimen of anti-diabetic medication(s) or undergone diet/exercise 
therapy for at least 28 days prior to screening 
 Patients meeting either of the following criteria for poor blood glucose 
control at screening 
a) Glycosylated hemoglobin (HbA1c) of ≥ 7.0% according to the global 
standard value [NGSP value] 
b) Fasting blood glucose level of ≥ 126 mg/dL or nonfasting blood 
glucose level of ≥ 200 mg/dL 
10 
Patients who have undergone major surgery or blood transfusion or who have 
made a blood donation (whole blood or blood plasma) within 30 days before the 
acquisition of informed consent 
11 
Patients who have met the DSM-5® diagnostic criteria for substance-related or 
addictive disorder, including alcohol and benzodiazepines but excluding caffeine 
and tobacco, within 180 days before commencement of IMP administration 


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Table 3.4.3-1 
Exclusion Criteria (for All Cohorts) 
12 
Patients with a positive drug test at screening (However, such patients may be 
included if their condition is not diagnosed as substance-related or addictive 
disorder, according to the DSM-5® diagnostic criteria.) 
13 
Patients with a history or complication of epilepsy or seizures, except for 
childhood febrile seizures, post-traumatic seizures, alcohol withdrawal seizures, 
etc 
14 
Patients with a history or a complication of neuroleptic malignant syndrome 
15 
Patients with a complication of hypothyroidism or hyperthyroidism (except in 
cases where the condition has been kept stable for at least 90 days through drug 
therapy) or patients who show abnormal values for thyroid-stimulating hormone 
(TSH) and free thyroxin (FT4) in the screening examination 
16 
Patients with a complication of ischemic heart disease, myocardial infarction, or 
congestive heart failure (whether controlled or uncontrolled), or with a history of 
angioplasty, stenting, or coronary artery bypass surgery 
17 
Patients whose clinical symptoms have worsened to the point where use of 
prohibited concomitant therapy or medication is required during the washout 
period for prior medication 
18 
Patients who before commencement of IMP administration are judged to have a 
significant risk of committing suicide based on medical history or diagnosis, who 
have shown suicidal behavior within the past 2 years, or who have answered 
“yes” to Questions 4 or 5 in the Columbia-Suicide Severity Rating Scale (C-
SSRS) within the last 24 months. 
19 
Female patients who are nursing or have a positive pregnancy test result before 
administration of the IMP 
20 
Sexually active male patients and sexually active female patients of child-bearing 
potential who do not agree to practice 2 methods of birth control or remain 
abstinent during this trial and for 30 days after the final administration of IMP. If 
practicing birth control, 2 of the following methods must be used: vasectomy, 
tubal ligation, intrauterine device, or condom (all methods approved or certified 
in Japan) 
21 
Patients with a history of allergy to more than one medication 
22 
Patients with a history of hypersensitivity or allergy to brexpiprazole 
23 
Patients who have participated in another clinical trial within 60 days before 
commencement of IMP administration 
24 
Patients who have been compulsorily hospitalized under the Mental Health and 
Welfare Law of Japan 
25 
Patients judged by the investigator or subinvestigator to be unsuitable for 
participation in the trial 
 
Subjects excluded for positive drug test are not eligible to be rescreened for participation 
in the trial. However, subjects excluded for other reasons may be rescreened if the 
exclusion characteristic has changed. In the event that the subject is rescreened, a new 


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ICF must be signed, a new subject number assigned, and all screening procedures 
repeated. 
[Rationale for Exclusion Criteria] 
1, 25. 
These criteria are specified to exclude patients considered to be 
inappropriate for inclusion in this trial. 
2, 6. 
These criteria are specified in consideration of safety and PK. 
3. 
This criterion is specified in consideration of PK. 
5. 
This criterion is specified in consideration of safety, as 
concomitant use of electroconvulsive therapy is likely to lower 
the convulsive threshold. 
4, 7 to 17, 20 to 24. These criteria were set based on safety consideration. 
18. 
This criterion is specified to minimize the risk of suicide during 
the trial period. 
19. 
This criterion is specified in consideration on safety, as the safety 
of brexpiprazole during pregnancy or while breastfeeding has not 
yet been established. 
 
3.5 
Endpoints 
3.5.1 
Pharmacokinetic Endpoints 
Plasma concentrations and PK parameters of brexpiprazole after single and repeated 
administration of QW formulation 
3.5.2 
Safety (for All Cohorts) 
Adverse events, clinical laboratory tests, physical examination, vital signs (blood 
pressure, pulse rate, and body temperature), weight, 12-lead ECG, Drug-Induced 
Extrapyramidal Symptoms Scale (DIEPSS), Columbia-Suicide Severity Rating Scale (C-
SSRS) 
3.5.3 
Pharmacogenomics 
CYP2D6 genotyping 
3.5.4 
Other 
CGI-S, Clinical Global Impression-Improvement (CGI-I) 
3.6 
Measures to Minimize/Avoid Bias 
This trial has an open-label design. 


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3.7 
Trial Procedures 
Trial assessment time points are summarized in Table 3.7-1 and Table 3.7-2. Acceptable 
windows for observations, tests, and assessments are shown in Table 3.7-3 to Table 3.7-6. 
 


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Table 3.7-1 
Schedule of Assessments (Cohort 1 and Cohort 1’ [as Necessary]; Single Administration Period) 
 
Note 1: This table shows time points for assessments and should be used together with Section 3.7.3 Schedule of Assessments, which summarizes the timing 
of assessments and activities by trial period/trial day. 
Note 2: If Cohort 1’ (as necessary) (single administration period) is added, the doses of the QW formulation used in Periods 2 and 3 may be changed (Section 
3.2 Trial Treatments). 
aIf IMP administration takes place within 14 days after the same test was performed during screening, a repeat test is not required. 
Treatment Period
Screening
Follow-up
Day
-28 to -1
2
3
4
6
8
11
14
3
4
6
8
14
3
4
6
8
11
14
Hours postdose
Predose
0 2 4 6 8 12 24 48 72
120
168
240
312
Predose
0 3 9 24 36 48 72 120
168
312
Predose
0 3 9 24 36 48 72 120
168
240
312
Informed consent
X
Informed consent to CYP2D6 genotyping
X
Informed consent to blood sampling for
DNA storage (optional)
X
Inclusion/exclusion criteria
X
Demographics (including height)
X
Urine drug screening
X
Xf
Xf
Pregnancy test (women of childbearing
potential only)
X
Xf
X
Xf
X
Xf
X
X
Blood sampling for CYP2D6 genotyping
X
Blood sampling for DNA storage
(optional)
X
Subject enrollment
X
X
X
X
IMP administration
X
X
X
Blood sampling for plasma drug
concentration measurement
Xg
X X X X X
X
X
X
X
X
X
X
Xg
X X X
X
X
X
Xg
X X X
X
X
X
X
X
X
X
X
Clinical laboratory testsd
X
X
X
X
X
X
X
X
Physical examination
X
Xg
X
X
X
Xg
X X X
X
X
X
X
X
X
Xg
X X X
X
X
X
X
X
X
X
X
X
Vital signs (blood pressure, pulse rate,
body temperature)
X
Xg
X
X
X
Xg
X X
X
X
X
X
Xg
X X
X
X
X
X
X
Weight
X
Xf
X
Xf
X
X
Xf
X
X
X
12-lead ECGe
X
Xa,f
X
X
X X
X
X
X
X X
X
X
X
X
DIEPSS
Xf
X
X
Xf
X
X
X
Xf
X
X
X
X
X
C-SSRS
X
Xf
X
X
X
Xf
X
X
X
X
X
X
Xf
X
X
X
X
X
X
X
X
CGI-S
Xf
X
X
Xf
X
X
Xf
X
X
X
CGI-I
X
X
X
X
X
X
X
Adverse events
Concomitant medications and therapies
Hospitalization period
Outpatient
visits
permitted
Outpatient
visits
permitted
Period 1 (2 mg Conventional Tablet)
Period 2 (24 mg QW Formulation)
Period 3 (48 mg QW Formulation)
Early
Termination
b
1
1
2
1
2
Days 28-
30
Hospitalization
Outpatient
visits
permitted
Hospitalization
Hospitalization
Outpatient visits permitted
Washout period
c
Washout period
c


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bIf the subject refuses an early termination (ET) assessment or if the investigator or subinvestigator finds it impossible to perform an ET assessment in 
emergencies or for other reasons, only feasible observation/tests will be performed. 
cA washout period of 20 days (+ 8 days max) will be placed between IMP administration in Period 1 and IMP administration in Period 2 and a washout period 
of 27 days (+ 8 days max) will be placed between IMP administration in Period 2 and IMP administration in Period 3. 
dA thyroid function test will be performed only at 1 time point: screening. 
eMust be performed prior to blood sampling for plasma drug concentration measurement and clinical laboratory tests. 
fMust be performed within 1 day predose. 
gMust be performed within 2 hours predose. 


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Table 3.7-2 
Schedule of Assessments (Cohort 2; Repeated Administration Period) 
 
Note 1: This table shows time points for assessments and should be used together with Section 3.7.3 Schedule of Assessments, which summarizes the timing 
of assessments and activities by trial period/trial day. 
Note 2: The doses of the QW formulation may be changed depending on the results of Cohort 1 and Cohort 1’ (as necessary) (single administration period) 
(Section 3.2 Trial Treatments). 
aIf IMP administration takes place within 14 days after the same test was performed during screening, a repeat test is not required. 
bIf the subject refuses an early termination (ET) assessment or if the investigator or subinvestigator finds it impossible to perform an ET assessment in 
emergencies or for other reasons, only feasible observation/tests will be performed. 
cA washout period of 20 days (+ 8 days max) will be placed between IMP administration in Period 1 and IMP administration in Period 2. 
Day
2
3
4
6
9
10
11
13
16
18
23
25
31 32
34
36
39
42
Days postdose (1 day postdose defined as
the day of most immediate administration)
2
3
4
6
2
3
4
6
2
4
2
4
3
4
6
8
11
14
Hours postdose
Predose
0 2 4 6 8 12 24 48 72
120
168
240
312
Predose
Administration
(1)
9
Predose
Administration
(2)
h
9
Predose
Administration
(3)
h
Predose
Administration
(4)
h
Predose
Administration
(5)
i
3
9
24 36 48 72 120
168
240
312
Informed consent
X
Informed consent to CYP2D6 genotyping
X
Informed consent to blood sampling for
DNA storage (optional)
X
Inclusion/exclusion criteria
X
Demographics (including height)
X
Urine drug screening
X
Xf
Pregnancy test (women of childbearing
potential only)
X
Xf
X
Xf
X
X
Blood sampling for CYP2D6 genotyping
X
Blood sampling for DNA storage
(optional)
X
Subject enrollment
X
X
X
IMP administration
X
X
X
X
X
X
Blood sampling for plasma drug
concentration measurement
Xg
X X X X X
X
X
X
X
X
X
X
Xg
Xg
Xg
Xg
Xg
X
X
X
X
X
X
X
X
X
X
X
Clinical laboratory testsd
X
X
X
Xf
X
Xf
Xf
Xf
X
X
Physical examination
X
Xg
X
X
X
Xg
X X
X
X
X
Xg
X
X
X
X
X
Xg
X
X
Xg
X
X
Xg
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs (blood pressure, pulse rate,
body temperature)
X
Xg
X
X
X
Xg
X X
X
X
Xg
X
X
X
X
Xg
X
X
Xg
X
X
Xg
X
X
X
X
X
X
Weight
X
Xf
X
Xf
Xf
Xf
Xf
Xf
X
X
12-lead ECGe
X
Xa,f
X
X
X X
X
Xf
X
X
X
Xf
X
X
Xf
X
X
Xf
X
X
X
X
X
DIEPSS
Xf
X
X
Xf
X
Xf
X
Xf
Xf
Xf
X
X
X
X
C-SSRS
X
Xf
X
X
X
Xf
X
X
X
X
Xf
X
X
X
X
Xf
X
X
Xf
X
X
Xf
X
X
X
X
X
X
X
X
CGI-S
Xf
X
X
Xf
Xf
Xf
Xf
Xf
X
X
X
CGI-I
X
X
Xf
Xf
Xf
Xf
X
X
X
Adverse events
Concomitant medications and therapies
Hospitalization period
Outpatient
visits
permitted
Outpatient
visits
permitted
Outpatient
visits
permitted
Treatment Period
1
2
3
Early termination
b
24 mg QW Formulation
1
15
1
1
1
1
1
-28 to -1
Screening
Hospitalization
Hospitalization
8
Days
56-60
2
Hospitalization
Outpatient visits permitted
Follow-up
Period 1 (2 mg Conventional Tablet)
Period 2
Washout period
c
22
29
30
48 mg QW Formulation
Hospitalization
Outpatient
visits
permitted
4
6
8
11
14


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dA thyroid function test will be performed only at 1 time point: screening. 
eMust be performed prior to blood sampling for plasma drug concentration measurement and clinical laboratory tests. 
fMust be performed within 1 day predose. 
gMust be performed within 2 hours predose. 
hWith Day 1 defined as the day of the first administration, administration on Days 8, 15, and 22 must take place within  24 hours of the clock time when the 
first administration occurred. 
iWith Day 1 defined as the day of the first administration, administration on Day 29 must take place within  5 hours of the clock time when the first 
administration occurred. 
 


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Table 3.7-3 
Acceptable Windows for Observations, Tests, and 
Assessments Following a Single Administration of 
Conventional Tablet (Period 1 of Cohort 1 and Cohort 1’ [as 
Necessary] [Single Administration Period] and Period 1 of 
Cohort 2 [Repeated Administration Period]) 
Time Point 
Acceptable Window for All Observations, Tests, and Assessments 
(Including Blood Sampling for Plasma Drug Concentration 
Measurement) 
Predose 
Blood sampling for plasma drug concentration measurement, physical 
examination, vital signs: within 2 hours predose 
Other: within 1 day predose 
2, 4, 6, 8, 12 hours postdose 
 30 minutes 
24, 48, 72 hours postdose 
 2 hours 
120 hours postdose 
−2 to + 4 hours 
168 hours postdose 
 4 hours 
240, 312 hours postdose 
 24 hours 
In cases of withdrawal, only feasible observations/tests/assessments will be performed. 
 
Table 3.7-4 
Acceptable Windows for Observations, Tests, and 
Assessments Following a Single Administration of QW 
Formulation (Period 2 of Cohort 1 and Cohort 1’ [as 
Necessary] [Single Administration Period]) 
Time Point 
Acceptable Window for All Observations, Tests, and Assessments 
(Including Blood Sampling for Plasma Drug Concentration 
Measurement) 
Predose 
Blood sampling for plasma drug concentration measurement, physical 
examination, vital signs: within 2 hours predose 
Other: within 1 day predose 
3 hours postdose 
 30 minutes 
9 hours postdose 
 30 minutes 
Only 12-lead ECG:  60 minutes 
24, 36, 48, 72 hours postdose 
 2 hours 
120 hours postdose 
−2 to + 4 hours 
168 hours postdose 
 4 hours 
312 hours postdose 
 24 hours 
In cases of withdrawal, only feasible observations/tests/assessments will be performed. 
 


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Table 3.7-5 
Acceptable Windows for Observations, Tests, and 
Assessments Following a Single Administration of QW 
Formulation (Period 3 of Cohort 1 and Cohort 1’ [as 
Necessary] [Single Administration Period]) 
Time Point 
Acceptable Window for All Observations, Tests, and Assessments 
(Including Blood Sampling for Plasma Drug Concentration 
Measurement) 
Predose 
Blood sampling for plasma drug concentration measurement, physical 
examination, vital signs: within 2 hours predose 
Other: within 1 day predose 
3 hours postdose 
 30 minutes 
9 hours postdose 
 30 minutes 
Only 12-lead ECG:  60 minutes 
24, 36, 48, 72 hours postdose  2 hours 
120 hours postdose 
−2 to + 4 hours 
168 hours postdose 
 4 hours 
240, 312 hours postdose 
 24 hours 
In cases of withdrawal, only feasible observations/tests/assessments will be performed. 
 


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Table 3.7-6 
Acceptable Windows for Observations, Tests, and 
Assessments Following Repeated Administration of QW 
Formulation (Period 2 of Cohort 2 [Repeated Administration 
Period]) 
Day of QW 
Formulation 
Administration 
(Day 1 is defined 
as the day of the 
first 
administration) 
Time Point 
(0 hour [1 day 
postdose] is defined as 
the time and day of the 
most immediate 
administration) 
Plasma Drug 
Concentration 
Measurement 
Other Observations, Tests, 
Assessments 
Day 1 
Day 8a 
Predose 
Within 2 hours predose 
Physical examination, vital 
signs: 
within 2 hours predose 
Other: within 1 day predose 
9 hours postdose 
NA 
 4 hours 
2, 3, 4, 6 days  
NA 
Within the same day 
Day 15a 
Day 22a 
Predose 
Within 2 hours predose 
Physical examination, vital 
signs: 
within 2 hours predose 
Other: within 1 day predose 
2 days  
NA 
Within the same day 
4 days  
NA 
 1 day 
Day 29 (last)b 
Predose 
Within 2 hours predose 
Physical examination, vital 
signs: 
within 2 hours predose 
Other: within 1 day predose 
3 hours postdose 
 30 minutes 
 30 minutes 
9 hours postdose 
 30 minutes 
 30 minutes 
24, 36, 48, 72 hours 
postdose 
 
 2 hours 
 2 hours 
120 hours postdose 
−2 to + 4 hours 
−2 to + 4 hours 
168 hours postdose 
 4 hours 
 4 hours 
240 hours postdose 
312 hours postdose 
 24 hours 
 24 hours 
In cases of withdrawal, only feasible observations/tests/assessments will be performed. 
aWith Day 1 defined as the day of the first administration, administration on Days 8, 15, and 22 must 
take place within  24 hours of the clock time when the first administration occurred. 
bWith Day 1 defined as the day of the first administration, administration on Day 29 must take place 
within  5 hours of the clock time when the first administration occurred. 
 
3.7.1 
General Inpatient Procedures 
Subjects will remain either in a seated or semi recumbent position for the first 4 hours 
following IMP administration except during brief periods where protocol related 
procedures need to be performed. 


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3.7.2 
Dietary Requirements 
See Section 3.2 Trial Treatments. 
3.7.3 
Schedule of Assessments 
3.7.3.1 
Screening (for All Cohorts) 
Prior to initiation of any protocol-related procedures, the procedures and characteristics 
of the trial will be explained to the subject and written informed consent will be obtained 
from the subject (and the subject's legal representative if the subject is a minor or is 
hospitalized for reasons of medical protection). The following subject information will be 
recorded on source documents and the electronic case report form (eCRF). 
 Date of informed consent 
 Subject identifier 
 Previous subject identifier, if the subject was rescreened 
 Date of informed consent for CYP2D6 genetic testing* 
 Date of informed consent for DNA storage (optional)* 
* Informed consent will be obtained before blood sampling for CYP2D6 genetic testing and blood 
sampling for DNA storage (optional). 
In cases where subjects withdrawn from the trial at the discretion of the sponsor 
subsequently take part in the trial again and resume participation in the same cohort, the 
procedures and characteristics of the trial will be explained to them and written informed 
consent will be obtained from them (and their legal representatives if they are minors or 
are hospitalized for reasons of medical protection) prior to initiation of any protocol-
related procedures. The following subject information will be recorded on the source 
documents and the eCRF. 
 Date on which informed consent was obtained again 
 Subject identifier 
 Date of informed consent for CYP2D6 genetic testing** 
 Date of informed consent for DNA storage (optional)** 
** Informed consent will be obtained before blood sampling for CYP2D6 genetic testing and blood 
sampling for DNA storage (optional). However, if blood samples had already been collected before 
the subject was withdrawn from the trial, it will not be necessary to obtain consent again. 
After informed consent is obtained, the following observations, tests, and assessments 
will be performed as screening procedures within 28 days before IMP administration in 
Period 1 (Days −28 to −1), and the subject's eligibility to participate in the trial will be 
assessed. 


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[Items] 
 Inclusion/exclusion criteria 
 Demographics (date of birth, sex, country [Japan], race, ethnicity, complications, 
medical history) 
 Height, weight, and body mass index (BMI): Height will be measured in increments 
of 0.1 cm. For a height measured to the second or further decimal place, the number 
will be rounded off to the first decimal place. BMI will be determined based on height 
and weight measurements at screening, using the following formula: BMI = weight 
(kg) / height (m)2. 
 Urine drug screening 
 Urine pregnancy test (women of childbearing potential only) 
 Clinical laboratory tests (blood and urine samplings) 
 Physical examination 
 Vital signs (blood pressure, pulse rate, and body temperature): Blood pressure and 
pulse rate will be measured in the supine position (performed first), sitting position, 
and standing position after each position is maintained for at least 3 minutes (blood 
pressure and pulse rate measurements in the supine and standing positions will take 
place only at screening). 
 12-Lead ECG (performed prior to blood sampling for clinical laboratory tests) 
 C-SSRS (the “Baseline/Screening Version” will be used) 
 AEs 
 Concomitant medications and therapies 
In cases where subjects withdrawn from the trial at the discretion of the sponsor 
subsequently take part in the trial again and resume participation in the same cohort, the 
following observations, tests, and assessments will be performed as screening procedures, 
after informed consent is obtained, within 28 days (Days −28 to −1) before IMP 
administration in the treatment period (Period 2 or 3) in which they are to resume 
participation in the trial, and their eligibility to participate in the trial will be assessed. 
[Items] 
 Inclusion/exclusion criteria 
 Height,* weight, and BMI*: Height will be measured in increments of 0.1 cm. For a 
height measured to the second or further decimal place, the number will be rounded 
off to the first decimal place. BMI will be determined based on height and weight 
measurements at screening, using the following formula: BMI = weight (kg) / height 
(m)2. 
* The height measurement obtained at screening when the subject first participated in the trial may be 
used. In that case, the height measurement obtained at screening when the subject first participated in 
the trial should be used in calculation of BMI. 
 Urine drug screening 


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 Urine pregnancy test (women of childbearing potential only) 
 Clinical laboratory tests (blood and urine sampling) 
 Physical examination 
 Vital signs (blood pressure, pulse rate, and body temperature): Blood pressure and 
pulse rate will be measured in the supine position (performed first), sitting position, 
and standing position after each position is maintained for at least 3 minutes (blood 
pressure and pulse rate measurements in the supine and standing positions will take 
place only at screening). 
 12-Lead ECG (performed prior to blood sampling for clinical laboratory tests) 
 C-SSRS (the "Since Last Visit" will be used) 
 AEs 
 Concomitant medications and therapies 
 
3.7.3.2 
Administration of Brexpiprazole Conventional Tablet (Period 1) 
(for All Cohorts) 
3.7.3.2.1 
Day 1 of Period 1 
3.7.3.2.1.1 
Enrollment of Subjects 
On Day 1 of Period 1, one brexpiprazole conventional tablet will be administered to 
eligible subjects. 
3.7.3.2.1.2 
Within 1 Day Predose 
The following will be performed. 
 Pregnancy test 
 Blood sampling for CYP2D6 genetic testing (including blood sampling for DNA 
storage [optional]) 
 Blood sampling for plasma drug concentration measurement (within 2 hours predose) 
 Physical examination (within 2 hours predose) 
 Vital signs (blood pressure, pulse rate, and body temperature) (within 2 hours 
predose) 
 Weight 
 12-Lead ECG 
 DIEPSS 
 C-SSRS (The "Since Last Visit" will be used) 
 CGI-S 
 AEs 
 Concomitant medications and therapies 


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12-Lead ECG may be omitted if IMP administration takes place within 14 days after the 
same test was performed during screening. 
3.7.3.2.1.3 
Postdose 
The investigator or subinvestigator will perform the observations, tests, and assessments 
indicated in Table 3.7-1 and Table 3.7-2 and record their dates and results. 
3.7.3.3 
QW Formulation Single Administration Periods (Periods 2 and 
3 of Cohort 1 and Cohort 1’ [as Necessary]) 
The investigator or subinvestigator will enroll subjects who he/she thinks can safely 
receive IMP administration in Periods 2 and 3, perform the observations, tests, and 
assessments indicated in Table 3.7-1, and record their dates and results. Subjects 
withdrawn from the trial at the discretion of the sponsor will only be enrolled again to 
resume participation in the trial from Period 2 or 3 if they are confirmed to be eligible. 
3.7.3.4 
QW Formulation Repeated Administration Period (Period 2 of 
Cohort 2) 
The investigator or subinvestigator will enroll subjects who he/she thinks can safely 
receive IMP administration in Period 2, perform the observations, tests, and assessments 
indicated in Table 3.7-2, and record their dates and results. 
3.7.3.5 
Follow-up After IMP Administration (for All Cohorts) 
The following observations, tests, and assessments will be performed between Day 28 
and Day 30 of Period 3 of Cohort 1 and Cohort 1’ (as necessary) (single administration 
period) and between Day 56 and Day 60 of Period 2 of Cohort 2 (repeated administration 
period). 
[Items] 
 Physical examination 
 DIEPSS 
 AEs 
 
3.7.4 
Prior and Concomitant Medications 
The investigator or subinvestigator will record on the source documents and eCRF all 
medications (name of drug, purpose of use, dose, frequency, route of administration, start 
and end dates of treatment) and therapies (name of therapy, purpose of use, start and end 
dates of treatment) taken by the subject from 30 days prior to signing of informed consent 
through the end of assessment on Day 14 of Period 3 or the end of early termination (ET) 
assessment in Cohort 1 and Cohort 1’ (as necessary) (single administration period) and 


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from 30 days prior to signing of informed consent through the end of assessment on Day 
42 of Period 2 or the ET assessment in Cohort 2. The investigator or subinvestigator will 
record all medications (name of drug, purpose of use, dose, frequency, route of 
administration, start and end dates of treatment) and therapies (name of therapy, purpose 
of use, start and end dates of treatment) taken by the subject for treatment of an AE or 
which caused an AE until the end of the trial (defined as the last date of contact or date of 
final contact attempt) on the source documents and eCRF. For subjects who were 
withdrawn from the trial at the discretion of the sponsor and resume participation in the 
trial from Period 2 or 3, medications and therapies will be recorded in the same manner 
after participation in the trial is resumed. Medications and therapies that were introduced 
after withdrawal from the trial at the discretion of the sponsor and terminated up to 30 
days before the date on which the subject provided his/her signature for re-consent will 
be recorded as far as possible. 
3.7.5 
Safety Assessments 
3.7.5.1 
Adverse Events 
Refer to Section 5 Reporting of Adverse Events for the methods and timing for assessing, 
recording, and analyzing AEs. 
3.7.5.2 
Clinical Laboratory Assessments 
Data on laboratory test items shown in Table 3.7.5.2-1 will be collected at scheduled time 
points using measuring kits supplied by the central laboratory. The investigator or 
subinvestigator will review, sign, and date the laboratory assessment report submitted by 
the central laboratory and record the dates on which blood and urine samples are taken on 
the source documents and eCRF. 
A pregnancy test (human chorionic gonadotropin [hCG] in urine) will be conducted in 
women of child-bearing potential (WOCBP) prior to trial intervention; results must be 
available prior to the administration of the IMP. 


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Table 3.7.5.2-1 
Clinical Laboratory Assessments 
Hematology 
Hemoglobin 
Hematocrit 
Red blood cell (RBC) count 
White blood cell (WBC) count with differential 
(neutrophils, lymphocytes, monocytes, eosinophils, 
basophils) 
Platelet count 
 
Urinalysis 
Occult blood 
Glucose 
Microscopic analysis of RBC/WBC count (per high 
powered field) 
pH 
Protein 
Ketones 
Specific gravity 
 
Serum Chemistry 
Alkaline phosphatase (ALP) 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Albumin 
Bilirubin, total 
Blood urea nitrogen (BUN) 
Uric acid 
Cholesterol, total 
Creatinine 
Gamma glutamyl transpeptidase (γ-GTP) 
Glucose 
Lactic dehydrogenase (LDH) 
Serum electrolytes (Na, K, Cl, Ca, Mg, P, 
HCO3) 
Protein, total 
Triglycerides 
Creatine phosphokinase (CPK) 
Prolactin 
Glycosylated hemoglobin (HbA1c) 
Insulin 
 
Thyroid function testa 
Thyroid-stimulating hormone (TSH), free 
thyroxine (FT4) 
aWill be performed at only 1 time point: screening. 
 
3.7.5.3 
Urine Drug Screening 
Data on the following items will be collected at scheduled time points using measuring 
kits supplied by the central laboratory. The investigator or subinvestigator will record the 
dates on which urine samples are taken on the eCRF. 
 Amphetamines 
 Barbiturates 
 Benzodiazepines 
 Cannabinoids 
 Cocaine 
 Marijuana 
 Opiates 
 Phencyclidine 
 


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3.7.5.4 
Physical Examination and Vital Sign Assessments 
A physical examination will be performed at scheduled time points. The physical 
examination includes the head, ears, eyes, nose, throat, chest, abdomen, urogenital 
system, limbs, nerves, skin, and mucosa. 
At screening, all physical findings observed after informed consent will be recorded, 
together with the date of examination, on the source documents and eCRF. Thereafter, 
whether a physical examination is performed or not and, if performed, the date of 
examination will be recorded on the source documents and eCRF. For subjects who were 
withdrawn from the trial at the discretion of the sponsor and subsequently take part in the 
trial again, whether a physical examination is performed or not at screening and 
subsequent time points and, if performed, the date of examination will be recorded on the 
source documents and eCRF. 
It is preferable to have the same physician perform all physical examinations for any 
individual subject throughout the course of the trial wherever possible. Any new, 
clinically relevant, postscreening physical findings obtained from the start of the trial to 
the physical examination before IMP administration on Day 1 of Period 2 and any new, 
clinically relevant physical findings obtained after the start of IMP administration in 
Period 2 in comparison with those obtained before IMP administration on Day 1 of 
Period 2 will be recorded as AEs on the source documents and eCRF. For subjects who 
were withdrawn from the trial at the discretion of the sponsor and resume participation in 
the trial from Period 2, any new, clinically relevant physical findings obtained during the 
screening period in comparison with those obtained at the first screening before 
withdrawal and any new, clinically relevant physical findings obtained during Periods 2 
and 3 in comparison with those obtained before IMP administration in Period 2 will be 
recorded as AEs on the source documents and eCRF. For subjects who were withdrawn 
from the trial at the discretion of the sponsor and resume participation in the trial from 
Period 3, any new, clinically relevant physical findings obtained during the screening 
period and Period 3 in comparison with those obtained before IMP administration in 
Period 2 before withdrawal will be recorded as AEs on the source documents and eCRF. 
Vital signs will be measured at scheduled time points. Body temperature (axillary) will be 
measured in increments of 0.1°C and the date and result of measurement will be recorded 
on the source documents and eCRF. Blood pressure (systolic and diastolic) and pulse rate 
will be measured in a sitting position following at least 3 minutes' rest and the date and 
result of measurement will be recorded on the source documents and eCRF. At screening 
only, blood pressure and pulse rate will also be measured in the supine and standing 
positions. 


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3.7.5.5 
Weight 
Weight will be measured at scheduled time points. Weight should be measured in 0.1 kg 
increments using the same scale and the standard measurement method (the subject 
should wear his/her usual clothes but without shoes) throughout the course of the trial. 
The date and result of measurement will be recorded on the source documents and eCRF. 
3.7.5.6 
Electrocardiogram Assessments 
Electrocardiography will be performed at scheduled time points using a 12-lead 
electrocardiograph supplied by the central ECG laboratory. 
An ECG will be taken after the subject has remained at rest for at least 5 minutes in a 
supine position. The heart rate, RR interval, PR interval, QRS interval, QT interval, and 
corrected QT interval (QTcF) will be measured. The central ECG laboratory will analyze 
the measurements and submit an ECG analysis report to the sponsor and the investigator 
or subinvestigator. 
The investigator or subinvestigator will review, sign, and date each ECG reading by 
referring to the ECG analysis report and record the date of ECG, whether the ECG is 
normal/abnormal, and findings on the source documents and eCRF. The ECG should be 
performed prior to any blood sampling (if applicable) at scheduled time points. 
3.7.5.7 
Columbia-Suicide Severity Rating Scale 
Columbia-Suicide Severity Rating Scale will be performed at scheduled time points. The 
C-SSRS assesses the occurrence, severity, and frequency of suicidal ideation/behavior 
during the assessment period. This assessment consists of the "Baseline/Screening 
Version," which assesses the history of suicide-related events and suicidal ideation in the 
lifetime and within the last 24 months, and the "Since Last Visit Version," which focuses 
on suicidality since the last assessment in the trial. The "Baseline/Screening Version" will 
be used at screening and the "Since Last Visit" will be used at subsequent time points for 
C-SSRS assessment. The date and result of assessment will be recorded on the source 
documents and eCRF. 
The presence of suicidal ideation 1 to 2 will be assessed with "yes" or "no," and if the 
answer to 2 is "yes," suicidal ideation 3 to 5 will be assessed. If the answer to suicidal 
ideation 1 or 2 is "yes," the intensity of ideation will also be rated. Intensity of ideation 
will be rated on a 5-point scale for frequency and duration and a 6-point scale for 
controllability, deterrents, and reasons for ideation. 


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The following suicidal behavior will also be assessed with "yes" or "no," and if the 
answer is "yes," details will be assessed, and the total numbers of each suicide attempt 
will be recorded. 
If there is an actual attempt, actual lethality/physical damage will be rated on a 6-point 
scale, and if actual lethality/physical damage is 0, potential lethality will be rated on a 3-
point scale. 
Suicidal ideation: 
1. Wish to be dead 
2. Non-specific active suicidal thoughts 
3. Active suicidal ideation with any methods (not plan) without intent to act 
4. Active suicidal ideation with some intent to act, without specific plan 
5. Active suicidal ideation with specific plan and intent 
Suicidal behavior: 
Actual attempt, non-suicidal self-injurious behavior, interrupted attempt 
aborted attempt, preparatory acts or behavior, suicidal behavior, suicide (only for "Since 
Last Visit") 
3.7.5.8 
Drug-induced Extrapyramidal Symptoms Scale 
The investigator or subinvestigator will use DIEPSS at scheduled time points to assess 
the following 9 items on a 5-point scale from 0 (none, normal) to 4 (severe). The date and 
result of assessment will be recorded on the source documents and eCRF. 
1. Gait                2. Bradykinesia      3. Sialorrhea      4. Muscle rigidity       5. Tremor 
6. Akathisia        7. Dystonia            8. Dyskinesia     9. Global severity 
3.7.6 
Pharmacokinetic Assessments 
Plasma concentrations of brexpiprazole will be analyzed using validated high-
performance liquid chromatography-tandem mass spectrometry. Additional metabolites 
that are not identified in the protocol may also be analyzed if new information becomes 
available. If the need arises, plasma may be used in the study of analysis methods. 
The bioanalytical laboratory will submit the results of drug concentration measurement in 
the form of an electronic file to the sponsor. It is therefore not necessary to record the 
measurement results on the source documents and eCRF. 


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3.7.6.1 
Time Points for Blood Sampling 
3.7.6.1.1 
Brexpiprazole Conventional Tablet 
In Period 1 of both the single administration period (Cohort 1 and Cohort 1’ [as 
necessary]) and the repeated administration period (Cohort 2), blood samples after dosing 
of a conventional tablet will be collected at the time points shown in Table 3.7-1 and 
Table 3.7-2 or at withdrawal. Acceptable windows for blood sampling after dosing of a 
conventional tablet are shown in Table 3.7-3. 
3.7.6.1.2 
Brexpiprazole QW Formulation 
In Periods 2 and 3 of the single administration period (Cohort 1 and Cohort 1’ [as 
necessary]) and Period 2 of the repeated administration period (Cohort 2), blood samples 
after dosing of the QW formulation will be collected at the time points shown in Table 
3.7-1 and Table 3.7-2 or at withdrawal. Acceptable windows for blood sampling after 
dosing of the QW formulation are shown in Table 3.7-4 to Table 3.7-6. 
[Rationale for time points for blood sampling] 
Time points for blood sampling for the conventional tablet were determined based on the 
following: A single oral dose trial (331-07-002), a multiple oral dose trial (331-10-001), a 
bioequivalence trial of oral solution (331-10-005), and a bioavailability trial of orally 
disintegrating tablets (331-102-00019) were conducted in Japan. After conventional 
tablets 2 mg and 4 mg were administered as a single dose, the median tmax for the 
unchanged drug was 6 hours, and the mean elimination half-life, which was determined 
at 3 to 8 time points between 36 to 312 hours postdose, was 52.9 to 72.7 hours. A total of 
13 time points, namely, predose and 2, 4, 6, 8, 12, 24, 48, 72, 120, 168, 240, and 312 
hours postdose, were set for blood sampling in Period 1 of both the single administration 
period (Cohort 1 and Cohort 1’ [as necessary]) and the repeated administration period 
(Cohort 2) to cover the PK process from absorption to elimination, with reference to the 
results of the above 4 trials as well as "Partial Amendments to Guideline for 
Bioequivalence Studies of Generic Products (PFSB/ELD Notification No.0229-10 dated 
29 Feb 2012)" (hereinafter referred to as "BE Guideline"), Section 3 Test, A. II. 1. 5) 
Measurement of biological samples, b. Sampling schedule. 
Time points for blood sampling for the QW formulation were determined with reference 
to the PK data on the OROS formulation from a clinical pharmacology trial (Japan 331-
102-00021) for comparative investigation of the PK, tolerability, and safety of 3 types of 
brexpiprazole QW formulation administered as single oral doses in patients with 
schizophrenia and with reference to the BE Guideline. A total of 11 time points, namely, 
predose and 3, 9, 24, 36, 48, 72, 120, 168, 240, and 312 hours postdose, were set for 


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blood sampling in Period 3 of the single administration period (Cohort 1 and Cohort 1’ 
[as necessary]) and for the fifth administration in Period 2 of the repeated administration 
period (Cohort 2) to cover the PK process from absorption to elimination. For each of the 
first to fourth administrations of the QW formulation, 168 hours postdose, the time point 
of trough concentration, was set for blood sampling to ascertain if the plasma 
brexpiprazole concentration has reached the steady state. In addition, a total of 7 time 
points, namely, predose and 3, 9, 24, 36, 48, and 168 hours postdose, were set for blood 
sampling in Period 2 of the single administration period (Cohort 1 and Cohort 1’ [as 
necessary] to obtain samples for use in estimation of parameters with a population PK 
analysis model. 
3.7.6.2 
Pharmacokinetic Plasma Samples 
All plasma samples will be shipped to the bioanalytical laboratory. Detailed handling and 
shipping instructions are provided in Appendix 1. 
3.7.7 
CYP2D6 Genetic Testing 
CYP2D6 genotype and phenotype will be analyzed. CYP2D6*1, *2, *4, *5, *10, *14, 
*18, *21, and *41 alleles will be analyzed. The CYP2D6 genotype will be determined for 
each subject based on the CYP2D6 genotyping table (Appendix 2). In addition, based on 
the CYP2D6 genotype, the phenotype will be classified into the following 4 types: 
extensive metabolizer (EM), intermediate metabolizer (IM), poor metabolizer (PM), and 
unknown. The results of CYP2D6 genetic testing will not, in principle, be disclosed to 
subjects 
The genetic test laboratory will submit the results of CYP2D6 genetic testing in the form 
of an electronic file to the sponsor. It is therefore not necessary to record the test results 
on the source documents and eCRF. 
3.7.7.1 
Deoxyribonucleic Acid Blood Samples for CYP2D6 Genetic 
Testing 
All blood samples will be shipped to the genetic test laboratory. Detailed handling and 
shipping instructions are provided in Appendix 1. 
3.7.8 
Future Biospecimen Research Samples 
3.7.8.1 
DNA Storage 
3.7.8.1.1 
Objective of DNA Storage 
DNA storage will be conducted to enable future exploratory investigation regarding 
specific DNA mutations related to individual differences in responses to brexpiprazole 


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(efficacy, safety, or PK) and/or specific DNA mutations related to disease onset, severity, 
progression, etc. 
3.7.8.1.2 
Target Subjects of DNA Storage 
Blood samples for DNA storage will be collected at the trial sites where DNA storage has 
been approved by the IRB. Only subjects from whom written informed consent for DNA 
storage has been obtained on a voluntary basis will be included (if the subject is a minor 
or hospitalized for reasons of medical protection, written consent must also be obtained 
from the subject’s legal representative). 
3.7.8.1.3 
Blood Samples for DNA Storage 
All blood samples will be shipped to the DNA storage facility. Detailed handling and 
shipping instructions are provided in Appendix 1. DNA samples will be stored until the 
earliest of the following time points: 1) when genomic/genetic analysis is judged to be 
unnecessary, 2) when 15 years have passed since receipt of informed consent for the first 
DNA storage, 3) when the subject withdraws consent to participate in DNA storage. 
3.7.8.1.4 
Genomic/Genetic Analysis 
Genomic/genetic analysis will be performed only when considered useful for the purpose 
described in Section 3.7.8.1.1 Objective of DNA Storage. 
If it is decided to perform genomic/genetic analysis, a pharmacogenomic research 
protocol will be prepared and the analysis will be carried out in compliance with the 
applicable local regulations to be followed when conducting analysis, after obtaining 
approval from the sponsor’s IRB. The results will not be included in the clinical study 
report. A separate study report will be produced instead. 
Target genes for genomic/genetic analysis have yet to be identified and a genomewide 
association analysis using DNA chips, microarrays, next-generation sequencers, etc, may 
also be performed; however, the results will still only be used for the purpose specified in 
Section 3.7.8.1.1 Objective of DNA Storage. 
DNA samples for genomic/genetic analysis will be double-coded at the DNA storage 
facility and then shipped to the genomic/genetic analysis facility (yet to be determined), 
where genomic/genetic analysis will be performed under a double-coded condition. 
3.7.8.1.5 
Informed Consent for DNA Storage 
Information for Subjects and ICF for DNA storage and genomic/genetic analysis using 
stored DNA will be prepared and written informed consent will be obtained from each 
subject consenting to participate in DNA storage. The date of consent will be recorded on 
the source documents and eCRF. 


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If the subject withdraws consent to participate in DNA storage during the DNA storage 
period, the sponsor will instruct the DNA storage facility to dispose of the subject’s DNA 
sample. The DNA storage facility will then dispose of the DNA sample while 
maintaining subject anonymity. However, if the subject’s sample has become 
unidentifiable, for example, if information (eg, a code table) that links a DNA sample 
with subject information has been discarded, the disposal of the DNA sample of the 
subject who has withdrawn consent may become impossible. However, withdrawal from 
the trial will not be considered withdrawal of consent for DNA storage. Even if they 
request their sample(s) to be destroyed, subjects will not lose any benefits, medical 
treatment, or legal rights which they are allowed. Any results of genomic/genetic analysis 
obtained prior to the withdrawal of consent will not be disposed of. 
3.7.8.1.6 
Disclosure of Genomic/Genetic Analysis Results to Subjects 
Even if genomic/genetic analysis provides some information, such findings would only 
be exploratory or at an early stage of research, and therefore their scientific reliability and 
accuracy would not have been fully confirmed. Since disclosure of information the 
reliability of which has not been scientifically established would be of no benefit to the 
subjects, the sponsor will not, in principle, disclose the results of genomic/genetic 
analysis to the subjects. 
3.7.9 
Other Evaluations 
3.7.9.1 
Clinical Global Impression - Severity of Illness 
The investigator or subinvestigator will assess the severity of schizophrenia on the 
following 8-point scale using the CGI-S at scheduled time points. The date and result of 
assessment will be recorded on the source documents and eCRF. 
0. Not assessed        1. Normal, not at all ill     2. Borderline mentally ill      3. Mildly ill 
4. Moderately ill      5. Markedly ill                  6. Severely ill  
7. Among the most extremely ill patients 
3.7.9.2 
Clinical Global Impression - Improvement 
The investigator or subinvestigator will assess the improvement of schizophrenia on the 
following 8-point scale using the CGI-I at scheduled time points. In Period 1, the current 
condition of the subject at the start of Period 1 will be assessed and in Period 2 and 
Period 3 (Cohort 1 and Cohort 1’ [as necessary] [single administration period] only), 
improvement from the start of Period 2 will be assessed. The date and results of 
assessment will be recorded on the source documents and eCRF. 


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0. Not assessed    1. Very much improved      2. Much improved    3. Minimally improved 
4. No change        5. Minimally worse            6. Much worse          7. Very much worse 
3.7.10 
End of Trial 
The end of trial date is defined as the end date of follow-up of the last subject completing 
the trial, or if the subject is lost to follow-up, the date of the last contact attempt. 
3.8 
Procedure for Progression to the Repeated Administration Period 
(Cohort 2) From the Single Administration Period (Cohort 1 and 
Cohort 1’ [as Necessary]) 
3.8.1 
Criteria for Progression to Cohort 2 
The sponsor will determine through discussions, and consultation with the medical expert 
as necessary, whether or not to progress to the repeated administration period (Cohort 2) 
based on the results of the PK, safety, and CYP2D6 genotype profiles in the single 
administration period (Cohort 1 and Cohort 1’ [as necessary]). 
1) PK criteria and procedure for progression to Cohort 2 
Using plasma brexpiprazole concentration data on the conventional tablet and QW 
formulation from Cohort 1 (single administration period), repeated administration 
of the 2 mg conventional tablet and the QW formulation at 48 mg will be simulated 
to ascertain if the dose of 48 mg is appropriate for the QW formulation to be used 
in Cohort 2 (repeated administration period). If the results of the simulation predict 
that the QW formulation at 48 mg will produce plasma concentrations far below the 
trough concentration after repeated dosing of the conventional tablet at 2 mg, then 
Cohort 1’ (single administration period) will be added with the QW formulation at 
a dose of 54 or 60 mg to assess the safety and tolerability and the doses to be used 
in Cohort 2 (repeated administration period) will be reassessed. If Cohort 1’ (single 
administration period) is added, a simulation will be performed, and its results will 
be reviewed in the same manner as in Cohort 1 to ascertain if the selected dose is 
appropriate for the QW formulation to be used in Cohort 2 (repeated administration 
period). Conversely, if the results of the simulation predict that the QW formulation 
at 48 mg will produce plasma concentrations far exceeding the peak concentration 
after repeated dosing of the conventional tablet at 4 mg, an appropriate dose for 
repeated administration of the QW formulation will be estimated (36 or 42 mg) 
based on the results of the simulation and a decision will be made on whether or not 
to progress to Cohort 2 (repeated administration period). 
In the event that the sponsor finds it impossible to come to a decision alone, the 
sponsor will consult the medical expert as necessary and determine through 
discussions whether or not to progress to Cohort 2 (repeated administration period). 
The contents of the discussions will also be recorded. 
2) Safety criteria and procedure for progression to Cohort 2 
If the safety results of the QW formulation in Cohort 1 or Cohort 1’ (as necessary) 
(single administration period) meet any of the following criteria, the sponsor will 


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consult the medical expert and determine through discussions whether or not to 
progress to the repeated administration period (Cohort 2). The contents of the 
discussions will also be recorded. 
Between dosing of the QW formulation in Period 2 and 14 days after dosing of the 
QW formulation in Period 3, 
a) At least 1 subject experienced an IMP-related SAE or at least 2 subjects 
experienced a severe IMP-related AE. Adverse events associated with 
exacerbation of the underlying disease will be comprehensively assessed 
through discussions between the medical expert and the sponsor to determine 
the feasibility of progression to Cohort 2 (repeated administration period). 
b) At least 1 subject experienced IMP-related abnormal blood pressure (systolic 
blood pressure of < 80 mmHg). 
c) At least 1 subject experienced any of the following IMP-related abnormal 
ECGs: 
i) QTc interval (QTcF) of > 500 ms (results at the central ECG laboratory) 
ii) Prolongation in QTc interval (QTcF) by > 60 ms from baseline (predose in 
Period 2) (results at the central ECG laboratory) 
 
3.8.2 
Doses of Brexpiprazole QW Formulation in the Repeated 
Administration Period (Cohort 2) 
The doses of the QW formulation in Cohort 2 (repeated administration period) may be 
any of the following depending on the PK results in Cohort 1 and Cohort 1’ (as 
necessary) (single administration period): 
 If the results of Cohort 1 (single administration period) with the QW formulation 
at 48 mg indicate that progression to the repeated administration period (Cohort 2) 
is appropriate: 
 The same subject will receive a single administration of a 2 mg conventional 
tablet, undergo the washout period, and next receive the first administration of the 
QW formulation at 24 mg and, subsequently, 4 administrations of the QW 
formulation at 48 mg. 
 If the results of Cohort 1 (single administration period) indicate that the doses 
need to be changed (based on the results of Cohort 1’ [single administration 
period]): 
 A single administration of a 2 mg conventional tablet  washout  the first 
administration of the QW formulation at 30 mg  4 administrations of the QW 
formulation at 60 mg 
 A single administration of a 2 mg conventional tablet  washout  the first 
administration of the QW formulation at 30 mg  4 administrations of the QW 
formulation at 54 mg 
 If the results of Cohort 1 (single administration period) indicate that the doses 
need to be changed (based on the results of a simulation): 


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 A single administration of a 2 mg conventional tablet  washout  the first 
administration of the QW formulation at 24 mg  4 administrations of the QW 
formulation at 42 mg 
 A single administration of a 2 mg conventional tablet  washout  the first 
administration of the QW formulation at 18 mg  4 administrations of the QW 
formulation at 36 mg 
In the event that CYP2D6 genotype-related dose adjustment of the QW formulation is 
considered necessary on the basis of the results of Cohort 1 and Cohort 1’ (as necessary) 
(single administration period), the sponsor will determine the doses in the repeated 
administration period (Cohort 2) after discussions with the medical expert as necessary. 
The contents/results of the discussions will be recorded. 
3.9 
Stopping Rules, Withdrawal Criteria, and Procedures 
3.9.1 
Entire Trial 
In the event of sponsor termination or suspension of the trial for any reason, prompt 
notification will be given to the heads of the trial sites and regulatory authorities in 
accordance with regulatory requirements. 
3.9.2 
Individual Site 
Individual trial site participation may be discontinued by the sponsor, the investigator, or 
the IRB 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 
site. 
3.9.3 
Individual Subject Discontinuation 
3.9.3.1 
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 ET and follow-up 
assessments with ET assessments conducted as soon as possible after the subject is 
withdrawn. 


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3.9.3.2 
Criteria for Withdrawal Before Dose Increase of the QW 
Formulation 
Subjects who meet any of the following criteria after a single administration of the QW 
formulation in Period 2 of Cohort 1 and Cohort 1’ (as necessary) (single administration 
period) or after the first administration of the QW formulation in Period 2 of Cohort 2 
(repeated administration period) will be withdrawn from the trial without dose increase or 
further administration of the QW formulation. 
If, by 2 weeks after a single administration of the QW formulation in Period 2 of Cohort 
1 and Cohort 1’ (as necessary) (single administration period) or by 1 week after the first 
administration of the QW formulation in Period 2 of Cohort 2 (repeated administration 
period): 
 Subject experiences either of the following AEs: 
 An IMP-related SAE 
 A severe IMP-related AE 
If the event is associated with exacerbation of the underlying disease, the subject 
can remain in the trial at the discretion of the investigator. 
 Subject experiences IMP-related abnormal blood pressure (systolic blood pressure 
of < 80 mmHg) 
 Subject experiences any of the following IMP-related abnormal ECGs: 
 QTc interval (QTcF) of > 500 ms 
 Prolongation in QTc interval (QTcF) by > 60 ms from baseline (predose in Period 
2) 
 Subject shows hypersensitivity or allergic reaction to brexpiprazole 
 The investigator or subinvestigator judges the subject to be unsuitable for dose 
increase of the brexpiprazole QW formulation. 
 
3.9.3.3 
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 eCRF. 
 Adverse event: 
 Continuation of IMP would place the subject at undue risk as determined by the 
investigator or subinvestigator 
 Safety concern possibly, probably, or likely related to IMP 
 SAE 
 Exacerbation or progression of the underlying disease 


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 Meeting the criteria for withdrawal before dose increase 
 Subject decides to discontinue because of annoyance or discomfort due to a 
nonserious AE which is not otherwise determined to be an undue hazard 
 Subject vomits within 12 hours after IMP administration 
 Subject shows allergic reaction or hypersensitivity to brexpiprazole 
 Withdrawal of informed consent by the legal representative of the subject 
 Withdrawal of informed consent by the subject 
 Lost to follow-up 
 Pregnancy (see Section 5.5 Pregnancy) 
 Investigator’s or subinvestigator’s decision (other than AE) 
 Major protocol deviation 
 Termination of all or part of the trial by the sponsor 
 Other (record details) 
If the subject discontinues IMP due to an AE, the investigator, subinvestigator, or other 
trial personnel, will make every effort to follow the event until the event is resolved or 
stabilized, or the subject is lost to follow-up or has died. The procedures in Section 5.7 
Follow-up of Adverse Events must be followed. 
3.9.3.4 
Withdrawal of Consent 
All subjects (and subjects’ legal representatives if subjects are minors or are hospitalized 
for reasons of medical protection) have the right to withdraw their consent from further 
participation in the trial at any time without prejudice. Subjects (and subjects’ legal 
representatives if subjects are minors or are hospitalized for reasons of medical 
protection) cannot withdraw consent for use of data already collected as part of the trial, 
but only for future participation. The investigator or subinvestigator can also discontinue 
a subject’s participation in the trial at any time if medically necessary. Unless the subject 
(and the subject’s legal representative if the subject is a minor or is hospitalized for 
reasons of medical protection) provides their written withdrawal of consent or there is 
other written documentation by the investigator or subinvestigator confirming the verbal 
intent of the subject (and the subject’s legal representative if the subject is a minor or is 
hospitalized for reasons of medical protection) to completely withdraw from the trial, 
subjects should be followed for all protocol-specified evaluations and assessments, if 
possible. 
Complete withdrawal of consent requires refusal by a subject (and the subject’s legal 
representative if the subject is a minor or is hospitalized for reasons of medical 
protection) of ALL of the following methods of follow-up (these methods of follow-up 
will also be noted in the trial ICF): 


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 Participation in all follow-up procedures specified in the protocol (whether in-clinic, 
by telephone, or by an in-home visit). 
 Participation in a subset of protocol specified follow-up procedures (by a frequency 
schedule and method, as agreed by subject and staff). 
 Contact of the subject by trial personnel, even if only by telephone, to assess current 
medical condition, and obtain necessary medical or laboratory reports relevant to the 
trial’s objectives. 
 Contact of alternative person(s) who have been designated in source records as being 
available to discuss the subject’s medical condition, even if only by telephone, mail, 
or e-mail (eg, family, spouse, partner, legal representative, friend, neighbor, or 
physician). 
 Access to medical information from alternative sources (eg, hospital/clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, social media sources). 
Withdrawal of consent is a critical trial event and therefore should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent. 
The reasons of a subject (and the subject’s legal representative if the subject is a minor or 
is hospitalized for reasons of medical protection) for an intended withdrawal need to be 
completely understood, documented, and managed to protect the rights of the subject and 
the integrity of the trial. A subject (and the subject’s legal representative if the subject is a 
minor or is hospitalized for reasons of medical protection) may initially express their 
desire to discontinue IMP administration, which is not equivalent to a complete 
withdrawal of consent for further participation (see Section 3.9.3.1 Treatment 
Discontinuation). A subject (and the subject’s legal representative if the subject is a 
minor or is hospitalized for reasons of medical protection) may, however, indicate that 
further trial participation is creating a burden on their work or social schedule. Therefore, 
the investigator or subinvestigator should follow the procedures outlined in 
Section 3.9.3.3 Documenting Reasons for Discontinuation to determine if the subject can 
continue participation in the trial if modifications to his/her treatment and/or schedule of 
assessments can be accommodated. Only subjects (and subjects’ legal representatives if 
subjects are minors or are hospitalized for reasons of medical protection) who withdraw 
their permission for all of the above degrees of follow-up are considered to have 
completely withdrawn their consent to participate in the trial. 
3.9.3.5 
Procedures to Encourage Continued Trial Participation 
In all cases of impending IMP discontinuation or consent withdrawal, investigators or 
subinvestigators will be given instructions to meet and discuss with the subject (and the 
subject’s legal representative if the subject is a minor or is hospitalized for reasons of 
medical protection) their options of continuing in the trial, preferably on therapy. The 


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investigator or subinvestigator should ensure understanding and documentation of the 
reasons why the subject (and the subject’s legal representative if the subject is a minor or 
is hospitalized for reasons of medical protection) wishes to withdraw consent. 
3.10 
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 not enrolled in the trial prior to IMP 
administration on Day 1 of Period 1 in each cohort. 
It is permissible for subjects who sign an ICF but who are not enrolled in the trial prior to 
IMP administration on Day 1 of Period 1 to be rescreened. In the event that rescreening is 
not completed within the original screening period, consent must be newly obtained and a 
new subject identifier must be assigned. However, for those subjects who were 
withdrawn from the trial at the discretion of the sponsor and who agree to take part in the 
trial again and sign the ICF again, but who are not enrolled in the trial prior to IMP 
administration on Day 1 of their scheduled treatment period (Period 2 or 3), the same 
subject identifier as the original will also be used for the repeated rescreening. 
For screen failures, the following information will be recorded on the source documents 
and screen failure-specific eCRF: 
Subject identifier, date of visit, date of obtaining informed consent, date of birth, sex, 
date of screen failure determination, reason for screen failure, country (Japan), race, and 
ethnicity. 
3.11 
Definition of Completed Subjects 
The trial period is defined as the time period during which subjects are evaluated in 
regard to the primary objectives of the trial irrespective of whether the subject actually 
receives all doses of the IMP. Subjects who complete the last scheduled sampling for PK 
assessments for the PK trial will be defined as trial completers. For the purposes of this 
trial, subjects who complete assessment on Day 14 of Period 3 in Cohort 1 or Cohort 1’ 
(as necessary) (single administration period) or on Day 42 of Period 2 in Cohort 2 
(repeated administration period) will be defined as trial completers. 
3.12 
Definition of Subjects Lost to Follow-up 
Subjects who cannot be contacted during or before the treatment period and those who do 
not have a known reason for discontinuation (eg, withdrawal of consent or AE, etc.) will 
be defined as subjects lost to follow-up. 


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The investigator, 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 
telephone, the site will attempt to contact the subject via certified mail or an alternative 
similar method where appropriate, before assigning a “lost to follow-up” status. If a 
subject becomes lost to follow-up, the results of the investigation (whether or not the 
subject was contacted, occurrence or non-occurrence of AEs, date of contact, method of 
contact) will be recorded in the source data and the eCRF. 
3.13 
Subject Compliance 
The time of administration and the dose of each IMP will be recorded on the source 
documents and eCRF. Information on missed doses and whether the IMP was taken in an 
inappropriate manner will also be recorded on the source documents and eCRF. An oral 
check will be performed immediately after IMP administration to ensure that the subject 
has swallowed the IMP. 
3.14 
Protocol Deviations 
In the event of a significant deviation from the protocol due to an emergency, accident, or 
mistake (eg, violation of informed consent process, IMP dispensing or subject dosing 
error, treatment assignment error, subject enrolled in violation of eligibility criteria or 
concomitant therapy criteria), the investigator, subinvestigator, or designee will contact 
the sponsor at the earliest possible time by telephone. The investigator or subinvestigator 
and sponsor will come as quickly as possible to a joint decision regarding the subject’s 
continuation in the trial. This decision will be documented by the investigator or 
subinvestigator and the sponsor, and reviewed by the site monitor. 
4 
Restrictions 
4.1 
Prohibited Medications 
The use of the following drugs between each specified date and the completion of 
assessment on Day 14 of Period 3 in Cohort 1 or Cohort 1’ (as necessary) (single 
administration period) or on Day 42 of Period 2 in Cohort 2 (repeated administration 
period) or the completion of ET assessment is prohibited: 
 CYP2D6 inhibitors and CYP3A4 inhibitors and inducers listed in Appendix 3 (from 
14 days prior to IMP administration in Period 1*), excluding the topical agents listed 
in Appendix 4 for which concomitant use with the IMP is permitted.  
 Rexulti tablets (from 21 days prior to IMP administration in Period 1*) 
 Clozapine (from informed consent) 
 Adrenaline (from 28 days prior to IMP administration in Period 1*) 


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 Other investigational medicinal products under development (unapproved drugs) 
(from 60 days prior to IMP administration in Period 1*) 
* For subjects who were withdrawn from the trial at the discretion of the sponsor and resume 
participation in the trial from Period 2 or 3, the use of the drugs is prohibited from 14, 21, 28, and 60 
days, respectively, before IMP administration in the treatment period (Period 2 or 3) in which they are 
to resume participation in the trial. 
 
4.2 
Prohibited Therapies 
The use of the following therapy between 60 days prior to IMP administration in Period 
1* of each cohort and the completion of assessment on Day 14 of Period 3 in Cohort 1 or, 
Cohort 1’ (as necessary) (single administration period) or on Day 42 of Period 2 in 
Cohort 2 (repeated administration period) or the completion of ET assessment is 
prohibited: 
 Electroconvulsive therapy 
* For subjects who were withdrawn from the trial at the discretion of the sponsor and resume 
participation in the trial from Period 2 or 3, the use of the therapy is prohibited from 60 days before 
IMP administration in the treatment period (Period 2 or 3) in which they are to resume participation 
in the trial. 
 
4.3 
Restricted Medications 
The use of the following drugs between Day 1 of Period 1* of each cohort and the 
completion of assessment on Day 14 of Period 3 in Cohort 1 or Cohort 1’ (as necessary) 
(single administration period) or on Day 42 of Period 2 in Cohort 2 (repeated 
administration period) or the completion of ET assessment is restricted: 
* For subjects who were withdrawn from the trial at the discretion of the sponsor and resume 
participation in the trial from Period 2 or 3, the use of the drugs is restricted from Day 1 of IMP 
administration in the treatment period (Period 2 or 3) in which they are to resume participation in the 
trial. 
 Other antipsychotic drugs 
The use of other antipsychotic drugs at a steady dose and regimen will be permitted 
within the dosing range indicated below. The dose or frequency may be reduced at 
the discretion of the investigator or subinvestigator in response to symptom 
improvement or maintenance or from a safety perspective. 
Upper limit of dose and regimen 
 Antipsychotic medication comprising no more than two active components 
 A daily dose equivalent to no more than 600 mg/day of chlorpromazine 
 If multiple antipsychotics are taken in the same day, this is to be the combined 
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 Chlorpromazine equivalent doses are based on the conversion values listed in 
Appendix 5. 
However, this does not include administration of antipsychotic medication at doses 
equivalent to less than 100 mg/day of chlorpromazine, which are not expected to 
have any antipsychotic effect. 
 Antiparkinsonian drugs 
The use of antiparkinsonian drugs will be permitted only when the subject has 
extrapyramidal symptoms and the investigator or subinvestigator concludes that these 
drugs should be used. In that case, the dose and regimen should comply with the 
package insert. However, preventive use will be prohibited. Therefore, subjects who 
have no extrapyramidal symptoms but are taking antiparkinsonian drugs at the time of 
informed consent must temporarily discontinue the medication. Extrapyramidal 
symptoms should be assessed using DIEPSS prior to new use or dose increase of an 
antiparkinsonian drug. It is not permitted for any antiparkinsonian drug to be 
administered within 12 hours prior to DIEPSS assessment. 
 β-Blockers 
The use of β-blockers will be permitted only for the treatment of nonpsychiatric 
complications (eg, cardiovascular disorders) and only if the dose and regimen remain 
unchanged from before participation in the trial. 
 
4.4 
Other Restrictions 
 The consumption of foods and beverages containing grapefruit, Seville orange, or star 
fruit between 7 days prior to IMP administration in Period 1* of each cohort and the 
completion of assessment on Day 14 of Period 3 in Cohort 1 or Cohort 1’ (as 
necessary) (single administration period) or on Day 42 of Period 2 in Cohort 2 
(repeated administration period) or the completion of ET assessment is prohibited. 
 The consumption of foods and beverages containing St. John's Wort, Ginkgo biloba, 
goldenseal, or echinacea (Echinacea purpurea) between 14 days prior to IMP 
administration in Period 1* of each cohort and the completion of assessment on Day 
14 of Period 3 in Cohort 1 or Cohort 1’ (as necessary) (single administration period) 
or on Day 42 of Period 2 in Cohort 2 (repeated administration period) or the 
completion of ET assessment is prohibited. 
* For subjects who were withdrawn from the trial at the discretion of the sponsor and resume 
participation in the trial from Period 2 or 3, the consumption of these foods and beverages is 
prohibited from 7 and 14 days, respectively, before IMP administration in the treatment period 
(Period 2 or 3) in which they are to resume participation in the trial. 
 


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5 
Reporting of Adverse Events 
5.1 
Definitions 
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. Adverse events would not include information recorded 
as complications at screening for preplanned procedures for which the underlying 
condition was known and no worsening occurred. An adverse drug reaction is any 
untoward and unintended response to an IMP related to any dose administered. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE. 
 
An SAE includes any event that results in any of the following outcomes: 
 Death 
 Life-threatening; ie, the subject was, in the opinion of the investigator or 
subinvestigator, at immediate risk of death from the event as it occurred. It does not 
include an event that, had it occurred in a more severe form, might have caused death. 
 Persistent or significant incapacity/disability or substantial disruption of the ability to 
conduct normal life functions. 
 Requires inpatient hospitalization or prolongs hospitalization 
 Hospitalization itself should not be reported as an SAE; whenever possible the 
reason for the hospitalization should be reported. 
 Hospitalizations or prolonged hospitalizations for social admissions (ie, those 
required for reasons of convenience or other nonmedical need) are not considered 
SAEs. 
 Congenital anomaly/birth defect. 
 Other medically significant events that, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above, eg, allergic bronchospasm requiring 
intensive treatment in an emergency room or home, blood dyscrasias or convulsions 
that do not result in hospitalization, or the development of drug dependency or drug 
abuse. 
Nonserious AEs are all AEs that do not meet the criteria for a “serious” AE. 
 
Immediately Reportable Event (IRE): 
 Any SAE 
 Any AE related to occupational exposure. 


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 Potential serious hepatotoxicity (see Section 5.4 Potential Serious Hepatotoxicity) 
 Pregnancies are also defined as IREs. Although normal pregnancy is not an AE, it 
will mandate IMP discontinuation and must be reported on an IRE form to the 
sponsor. Pregnancy will only be recorded on the AE eCRF if there is a complication 
or abnormality in the newborn. 
 
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 verify whether this is an abnormal (ie, clinically 
relevant) change from baseline for that individual subject. This determination, however, 
does not necessarily need to be made the first time an abnormal value is observed. The 
investigator or subinvestigator may repeat the laboratory test or request additional tests to 
verify the results of the original laboratory tests. If this laboratory value is considered 
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 meets the criteria for an SAE, this is considered an AE. 
 
Severity: Adverse events will be graded on a 3-point scale and reported as indicated on 
the eCRF. The intensity of an AE is defined as follows: 
1 = Mild: 
 
Discomfort noticed, but no disruption to daily activity. 
2 = Moderate:  
Discomfort sufficient to reduce or affect normal daily activity. 
3 = Severe: 
 
Inability to work or perform normal daily activity. 
 
IMP Causality: Assessment of causal relationship of an AE to the use of IMP is defined 
as follows: 
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 causal relationship between the IMP and the AE. 
 
Date of Onset and Recovery (for diarrhea and vomiting, date and time of onset and date 
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Date of onset: The date of onset of an AE or date of confirmation of an AE. If the 
severity or seriousness of the reported event changes, the date of exacerbation will be 
taken as the “date of onset of AE.” 
Date of recovery: The date of recovery of an AE or date of confirmation of recovery of 
an AE. For clinical laboratory items, this shall be the date of blood or urine sampling. In 
the case of death, this shall be the date of death. 
 
Outcome: 
The outcome of an AE will be selected from the following 6 categories (one only). If the 
subject died, the date of death will be recorded; if the subject’s condition was ameliorated 
(recovering), unrecovered, or unknown, the date of outcome confirmation will be 
recorded. 
 Recovered 
 Ameliorated (recovering) 
 Unrecovered 
 Recovered but with sequelae 
 Death 
 Unknown (for some reason, a follow-up investigation could not be performed even 
once) 
 
5.2 
Eliciting and Reporting Adverse Events 
The investigator or subinvestigator will periodically assess subjects for the occurrence of 
AEs. To avoid bias in eliciting AEs, subjects should be asked the nonleading question: 
“How have you felt since your last visit?” All AEs (serious and nonserious) reported by 
the subject must be recorded on the source documents and eCRFs provided by the 
sponsor. The name of an AE, date of onset, date of recovery, seriousness, severity, causal 
relationship to the IMP, and outcome will be recorded on the source documents and 
eCRF. 
Adverse event and SAE collection is to begin after a subject has signed the ICF and 
continue until the end of trial date. Adverse events occurring in the screening period and 
Period 1 will be assessed in comparison with the subject’s condition at the time of 
consent/screening, and AEs occurring in Period 2 and Period 3 (Cohort 1 and Cohort 1’ 
(as necessary) [single administration period] only) will be assessed in comparison with 
the subject’s condition at the start of Period 2. For subjects who were withdrawn from the 


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trial at the discretion of the sponsor and resume participation in the trial from Period 2 or 
3, AEs and SAEs will be collected from the time participation in the trial resumes until 
the end of the trial. However, AEs that occur after withdrawal from the trial at the 
discretion of the sponsor and resolve before the date on which the subject provided 
his/her signature for re-consent will also be collected as far as possible. Adverse events 
will be assessed based on the following: 
 Subjects who resume participation in the trial from Period 2: Adverse events 
occurring in the screening period will be assessed in comparison with their condition 
at the time of consent/screening when they first participated in the trial, and AEs 
occurring in Period 2 and Period 3 will be assessed in comparison with their condition 
prior to IMP administration in Period 2. 
 Subjects who resume participation in the trial from Period 3: Adverse events 
occurring in the screening period and Period 3 will be assessed in comparison with 
their condition at the start of Period 2 when they first participated in the trial. 
Use medical terminology in AE reporting. Adverse events should be reported as a single 
unifying diagnosis whenever possible or, in the absence of a unifying diagnosis, as 
individual signs or symptoms. Exacerbation or disease progression should be reported as 
an AE only if there are unusual or severe clinical features that were not present, or 
experienced earlier, or not expected based on the course of the condition. 
A reported AE that undergoes a change in severity or seriousness must be reported as a 
new AE on the eCRF. 
In addition, the sponsor must be notified immediately by e-mail of any IREs according to 
the procedure outlined below, in Section 5.3 Immediately Reportable Events. Special 
attention should be paid to recording hospitalization and concomitant medications. 
5.3 
Immediately Reportable Events 
The investigator or subinvestigator must report any SAEs, AEs related to occupational 
exposure, potential serious hepatotoxicity, or confirmed pregnancy immediately after the 
investigator, subinvestigator, or designee becomes aware of the event. The IRE form and 
so on should be completed and sent by e-mail 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 eCRF.) Due consideration must be 
given to the subject’s privacy when an IRE form is sent by e-mail, etc. 
Subjects experiencing SAEs or IREs should be followed clinically as described in Section 
5.7.2 Follow-up of Serious Adverse Events and Immediately Reportable Events. It is 
expected that the investigator or subinvestigator will provide or arrange appropriate 


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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), total 
bilirubin should also be evaluated. If the total bilirubin is ≥ 2 times the ULN, complete 
the IRE form and so on with all values listed and also report as an AE on the eCRF. 
5.5 
Pregnancy 
Women of child-bearing potential are defined as female subjects for whom menstruation 
has started and who are not documented as sterile (ie, have had a bilateral oophorectomy 
and/or hysterectomy or who have been postmenopausal for at least 12 months). 
For WOCBP and for men who are sexually active, there must be a documented 
agreement that the subject and/or their partner will take effective measures (ie, double 
barrier method) to prevent pregnancy during the course of the trial and for 30 days after 
the last dose of IMP. Unless the subject or their partner is sterile (ie, women who have 
had a bilateral oophorectomy and/or hysterectomy or who have been postmenopausal for 
at least 12 consecutive months; or men who have had a bilateral orchidectomy) or 
remains abstinent, 2 of the following precautions must be used: vasectomy, tubal ligation, 
intrauterine device, or condom (all methods approved or certified in Japan). Any single 
method of birth control, including vasectomy and tubal ligation, may fail, leading to 
pregnancy. The contraceptive method will be documented at each trial visit. 
Before enrolling WOCBP in this clinical trial, investigators or subinvestigators must 
review the below guidelines about trial participation with all WOCBP. The topics should 
generally include: 
 General information 
 Informed consent form 
 Pregnancy prevention information 
 Drug interactions with hormonal contraceptives 
 Contraceptives in current use 
 Guidelines for the follow-up of a reported pregnancy 
Before trial enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy. The subject must sign an informed consent form stating that the above-
mentioned risk factors and the consequences were discussed with her. 


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A urine and/or serum pregnancy test for hCG will be performed at screening on all 
WOCBP. If a urine test is performed and is positive, the investigator or subinvestigator 
will follow up with a confirmatory serum test. 
During the trial, all WOCBP should be instructed to contact the investigator or 
subinvestigator immediately if they suspect they might be pregnant (eg, missed or late 
menstrual cycle). 
If a subject is suspected to be pregnant before she receives IMP, the IMP administration 
must be withheld until the results of the pregnancy test are available. If the pregnancy is 
confirmed, the subject must not receive the IMP and must not be enrolled in the trial. If 
pregnancy is suspected while the subject is taking IMP, the IMP must be withheld 
immediately (if reasonable, taking into consideration any potential withdrawal risks) until 
the result of the serum pregnancy test is known. If pregnancy is confirmed, the IMP will 
be permanently discontinued in an appropriate manner (eg, dose tapering if necessary for 
subject safety) and the subject will be withdrawn from the trial. 
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 so on, and forward it to the 
sponsor. The sponsor will forward Pregnancy Surveillance Form(s) for monitoring the 
outcome of the pregnancy. This procedure also applies to the case where the partner of a 
subject becomes pregnant. 
Protocol-required procedures for trial discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered, if indicated. In addition, the 
investigator or subinvestigator must report to the sponsor, on appropriate Pregnancy 
Surveillance Form(s), follow-up information regarding the course of the pregnancy, 
including perinatal and neonatal outcome. Infants will be followed for a minimum of 6 
months from the date of birth. 
5.6 
Procedure for Breaking the Blind 
Not applicable. 
5.7 
Follow-up of Adverse Events 
5.7.1 
Follow-up of Nonserious Adverse Events 
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE eCRF with the current status (ongoing or resolved/recovered) noted. All nonserious 
events (that are not IREs) that are ongoing at the end of trial date (final day of 


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observation) will be recorded as ongoing on the eCRF. For any AE having been 
identified throughout the trial, during analysis, additional relevant medical history 
information may be requested by the sponsor to further ascertain causality (including, but 
not limited to, information such as risk-related behavior, family history and occupation). 
The follow-up information after the end of trial date (final day of observation) will be 
recorded in the subject’s medical record. 
5.7.2 
Follow-up of Serious Adverse Events and Immediately 
Reportable Events 
This trial requires that subjects be actively monitored for SAEs and IREs up to the end of 
trial date (final day of observation). 
Serious AEs and IREs that are identified or ongoing at the end of trial date must be 
recorded on the AE eCRF page. Between the end of trial date for the individual subject 
and the end of trial date for the last subject, if any new information regarding an SAE or 
IRE becomes available (eg, the event is resolved), this must be reported to the sponsor 
using the IRE form and so on, and the information must be recorded on the AE eCRF 
page. 
The investigator or subinvestigator will follow SAEs and IREs, and will continue to 
report any significant information to the sponsor until the events are resolved or 
stabilized, or the subject is lost to follow-up or has died, using the IRE form and so on. 
Resolved means that the subject has returned to the baseline state of health, and stabilized 
means that the investigator or subinvestigator does not expect any further improvement or 
worsening of the subject’s condition. 
5.7.3 
Follow-up and Reporting of Serious Adverse Events Occurring 
After the End of Trial Date (Final Day of Observation) 
Any new SAEs or IREs reported to the investigator or subinvestigator, which occur after 
the end of trial date (final day of observation) and are determined by the investigator or 
subinvestigator to be associated with the use of the IMP, should be reported to the 
sponsor. This includes SAEs and IREs that are captured on follow-up telephone contact 
or at any other time point after the defined trial period. The investigator or 
subinvestigator will follow SAEs and IREs identified after the defined trial period and 
continue to report any significant follow-up information to the sponsor until the events 
are resolved or stabilized, or the subject is lost to follow-up or has died, using the IRE 
form and so on. 


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6 
Pharmacokinetic/Pharmacodynamic/Pharmacogenomic 
Analysis 
6.1 
Pharmacokinetic Methods 
The PK parameters of brexpiprazole for the QW formulation and conventional tablet at 
each dose will be determined through noncompartmental PK analysis. Descriptive 
statistics of the following variables will be produced. 
6.1.1 
Brexpiprazole QW Formulation 
6.1.1.1 
Period 2 of the Single Administration Period (Cohort 1 and 
Cohort 1’ [as Necessary]) 
 Plasma concentration of brexpiprazole after a single administration of the QW 
formulation 
 PK parameters of brexpiprazole after a single administration of the QW 
formulation 
Cmax, tmax, tlast, Cmax/D 
 Relative Cmax of brexpiprazole for the QW formulation as compared with a 
conventional tablet  
Relative Cmax (%) 
= (Cmax of QW formulation/dose of QW formulation)/(Cmax of conventional 
tablet/dose of conventional tablet) × 100 
 
6.1.1.2 
Period 3 of the Single Administration Period (Cohort 1 and 
Cohort 1’ [as Necessary]) 
 Plasma concentration of brexpiprazole after a single administration of the QW 
formulation 
 PK parameters of brexpiprazole after a single administration of the QW 
formulation 
Cmax, AUC∞, AUCt, tmax, λz, AUC_%Extrap, t1/2,z, CL/F, CL/F/BW, tlast, Cmax/D, 
AUC∞/D, AUCt/D 
 Relative bioavailability of brexpiprazole for the QW formulation as compared 
with a conventional tablet 
Relative bioavailability (%) 
= (AUC∞ of QW formulation/dose of QW formulation)/(AUC∞ of conventional 
tablet/dose of conventional tablet) × 100 
 Relative Cmax of brexpiprazole for the QW formulation as compared with a 
conventional tablet 
Relative Cmax (%) 


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= (Cmax of QW formulation/dose of QW formulation)/(Cmax of conventional 
tablet/dose of conventional tablet) × 100 
 
6.1.1.3 
Period 2 of the Repeated Administration Period (Cohort 2) 
 Plasma concentration of brexpiprazole after the fifth administration of the QW 
formulation 
 PK parameters of brexpiprazole after the fifth administration of the QW 
formulation 
Cmax, AUC168h, tmax, λz, t1/2,z, CL/F, CL/F/BW, tlast, Cmax/D, AUC168h/D 
 Plasma trough concentrations of brexpiprazole from the first administration of the 
QW formulation to after the fifth administration of the QW formulation (C168h) 
 Accumulation of brexpiprazole after the fifth administration of the QW 
formulation as compared with that after the first administration [R5,ac(C168h)] 
 
6.1.2 
Brexpiprazole Conventional Tablet (for All Cohorts, Period 1) 
 Plasma concentration of brexpiprazole after a single administration of a 
conventional tablet 
 PK parameters of brexpiprazole after a single administration of a conventional 
tablet 
Cmax, AUC∞, AUCt, tmax, λz, AUC_%Extrap, t1/2,z, CL/F, CL/F/BW, tlast, Cmax/D, 
AUC∞/D, AUCt/D 
 
6.2 
Pharmacodynamic Methods 
No pharmacodynamic (PD) analysis is planned. 
6.3 
Pharmacokinetic/Pharmacodynamic Methods 
No PK/PD analysis is planned. 
6.4 
Pharmacogenomic Methods 
A list of data obtained from CYP2D6 genetic assessment will be provided without 
summarization. See Section 3.7.8.1.4 Genomic/Genetic Analysis for genomic/genetic 
analysis. 
7 
Statistical Analysis 
This section defines datasets for analysis and describes the methods for analyzing 
endpoints. A detailed statistical analysis plan is provided in a separate Statistical Analysis 
Plan. The Statistical Analysis Plan will be finalized prior to data lock. 


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7.1 
Determination of Sample Size 
The target number of subjects is not based on a statistical hypothesis test. A simulation 
was performed with the PK model created based on PK data on the conventional tablet 
and QW-A formulation used in the QW-A formulation group in Trial 331-102-00021 
conducted in Japan, and the probability that the mean plasma concentration of 
brexpiprazole after repeated administration of the QW-A formulation would be within the 
target range of concentration was determined. On the basis of this probability, the sample 
size was determined to be 20 subjects each for the single administration period (Cohort 1) 
and the repeated administration period (Cohort 2). Likewise, the sample size for an 
additional single administration period (Cohort 1’) with a new dose was also determined 
to be 20 subjects. 
7.2 
Datasets for Analysis 
7.2.1 
Pharmacokinetic Analysis Set 
The PK analysis set will consist of subjects who received the QW formulation and had 
plasma drug concentration measurements. The following subjects will be excluded from 
the PK analysis set: 
 Subjects who vomited within 12 hours postdose 
 
7.2.2 
Safety Analysis Set 
The safety analysis set will consist of all subjects who received any QW formulation. 
7.3 
Handling of Missing Data 
Data imputation will not be performed for missing data. 
7.4 
Primary and Secondary Endpoint Analyses 
7.4.1 
Primary Endpoint Analyses 
See Section 6.1 Pharmacokinetic Methods. 
7.4.2 
Secondary Endpoint Analyses 
See Section 6.1 Pharmacokinetic Methods. 
7.5 
Analysis of Demographic and Other Baseline Characteristics 
Depending on data characteristics, frequency distribution or descriptive statistics of 
demographic and other baseline characteristics will be produced for the single 


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administration period (Cohort 1 and Cohort 1’ [as necessary]) and the repeated 
administration period (Cohort 2) based on PK and safety analysis sets. 
7.6 
Safety Analysis 
Each safety endpoint will be summarized for each dose (Periods 2 and 3) of the QW 
formulation in the single administration period (Cohort 1 and Cohort 1’ [as necessary]) 
and for the repeated administration period (Cohort 2) based on safety analysis set. 
The baseline for statistical analysis is defined as data measured immediately prior to IMP 
administration in Period 2. 
7.6.1 
Adverse Events 
All AEs will be coded by system organ class and the ICH Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term. The incidence of the following events 
will be summarized: 
 AEs occurring after administration of the QW formulation (treatment-emergent 
adverse events [TEAEs]) 
 TEAEs by severity 
 TEAEs with an outcome of death 
 Serious TEAEs 
 TEAEs leading to discontinuation of the trial 
The above summaries will also be prepared for TEAEs potentially causally related to the 
IMP. 
7.6.2 
Clinical Laboratory Data 
Descriptive statistics of actual measurements and changes from baseline of laboratory test 
parameters (excluding qualitative urinalysis) at each time point will be produced. 
For each laboratory parameter (excluding qualitative parameters), measurements will be 
classified as "lower than the lower limit of the reference range," "within the reference 
range," and "higher than the upper limit of the reference range" using the reference range 
specified by the central laboratory, and a shift table from baseline will be produced. For 
each qualitative laboratory parameter, a shift table from baseline will be produced. 
The number and percentage of subjects with abnormal changes that are potentially 
clinically significant (PCS) will be determined. The number and percentage of subjects 
with abnormal changes in liver function (Hy's Law cases) will be determined. 
7.6.3 
Physical Examination Data 
A list of physical findings will be provided. 


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7.6.4 
Vital Signs Data 
Descriptive statistics of actual measurements and changes from baseline of each 
parameter at each time point will be produced. The number and percentage of subjects 
with PCS in vital signs and weight will be determined. 
7.6.5 
Electrocardiogram Data 
A shift table from baseline for normal/abnormal finding of 12-lead ECG will be 
produced. 
Descriptive statistics of actual measurements and changes from baseline at each time 
point will be produced. 
The number and percentage of subjects with actual measurements of corrected QT 
interval (QTcF) at each time point in each period 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 determined. 
7.6.6 
Other Safety Data 
7.6.6.1 
Drug-Induced Extrapyramidal Symptoms Scale 
For the DIEPSS total score (sum of items 1 to 8) and the score for each item, descriptive 
statistics of actual measurements and changes from baseline at each time point will be 
produced. 
7.6.6.2 
Columbia-Suicide Severity Rating Scale 
The number and percentage of subjects with each C-SSRS item (suicidality, suicidal 
ideation, suicidal behavior, completed suicide, emergence of suicidal ideation, emergence 
of serious suicidal ideation, worsening of suicidal ideation, and emergence of suicidal 
behavior) at each time point will be determined. 
7.7 
Pharmacodynamic Analysis 
No PD analysis is planned. 
7.8 
Analyses of Other Endpoints 
7.8.1 
Clinical Global Impression - Severity of Illness and Clinical 
Global Impression - Improvement 
A list of subjects whose CGI-S or CGI-I has worsened will be provided. 


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8 
Management of Investigational Medicinal Product 
Refer to the investigator’s brochure on brexpiprazole for details regarding IMP 
management. 
8.1 
Packaging and Labeling 
The IMP will be provided to the IMP manager by the sponsor or designated agent. The 
IMP will be supplied as packages. Each package used in the dosing period will be labeled 
to clearly disclose “the IMP is intended only for clinical research,” the protocol number, 
IMP name, number of tablets, lot number, expiry date, storage conditions, sponsor’s 
name and address, and precautions for use. 
8.2 
Storage 
The IMP will be stored in a securely locked cabinet or enclosure. Access will be limited 
to the IMP manager. The IMP manager may not provide IMP to any subject not 
participating in this protocol. 
The IMP must be stored according to the storage conditions indicated on the clinical 
label. 
The clinical 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 (including the 
investigational product and active control) received, dispensed, administered, or returned. 
8.4 
Returns and Destruction 
Upon completion or termination of the trial, all unused and/or partially used IMP must be 
returned to the sponsor or a designated agent. 
All IMP returned to the sponsor must be accompanied by appropriate documentation and 
be identified by protocol number and trial site number on the outermost shipping 
container. Returned supplies should be in the original containers. The assigned trial 
monitor will facilitate the return of unused and/or partially used IMP. 
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 


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deficiencies or dissatisfaction related to identity, quality, labeling, packaging, reliability, 
safety, durability, tampering, counterfeiting, theft, effectiveness, or performance of a drug 
product or medical device after it is released for distribution. Examples include, but are 
not limited to, communications involving: 
 Failure/malfunction of a product to meet any of its specifications 
 Incorrect or missing labeling 
 Packaging issues (eg, damaged, dirty, crushed, missing product) 
 Blister defects (eg, missing, empty blisters) 
 Bottle defects (eg, under/over-fill, no safety seal) 
 Product defect (eg, odor, chipped, broken, embossing illegible) 
 Loss or theft of product 
 
8.5.1 
Eliciting and Reporting Product Quality Complaints 
The investigator, subinvestigator, or designee must record all PQCs identified through 
any means from the receipt of the IMP from the sponsor, or sponsor’s designee, through 
and including reconciliation and up to destruction, including subject dosing. The 
investigator, subinvestigator, or designee must notify the sponsor via e-mail immediately 
after becoming aware of the PQC according to the procedure outlined in Section 8.5.2 
Information Required for Reporting Product Quality Complaints. 
 PQC_331-102-00150@otsuka.jp 
Identification of a PQC by the subject should be reported to the investigator or 
subinvestigator, who should then follow the reporting mechanisms listed above. 
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) 
 Clinical protocol reference (number or trial name) 
 Dosage form/strength (if known) 
 Pictures (if available) 
 Complaint sample availability for return 
 


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8.5.3 
Return Process for Product Quality Complaints 
Indicate during the report of the PQC if the complaint sample is available for return. If 
the complaint sample is available for return, the sponsor will provide instructions for 
complaint sample return, when applicable. 
It must be documented in the site accountability record that a complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation. 
8.5.4 
Assessment/Evaluation 
Assessment and evaluation of PQCs will be handled by the sponsor. 
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, medical 
records, electronic data, screening logs, and recorded data from automated instruments. 
All source documents pertaining to this trial will be maintained by the trial site and made 
available for direct inspection by authorized persons. 
Investigator(s)/trial site(s) will permit trial-related monitoring, audits, IRB review, and 
regulatory inspection(s) by providing direct access to source data/documents by 
authorized persons as defined in the ICF. Information on drug concentration 
measurements, CYP2D6 genetic testing, and DNA storage (eg, master copies of reports, 
measurement data) will be stored at the bioanalytical laboratory, genetic test laboratory, 
and DNA storage facility, respectively. 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, an investigator or subinvestigator will 
document all significant observations and findings in the medical records. At a minimum, 
these records will contain: 
 Documentation of the informed consent process, including any revised consents; 
 Documentation of the investigator’s or subinvestigator’s decision to enroll the subject 
into the trial, the review of all inclusion/exclusion criteria prior to 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 


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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 
designees) who made an entry in the medical records. 
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the medical records as 
described above. Any changes to information in the medical records and other source 
documents will be initialed and dated on the day the change is made by a trial site staff 
member authorized to make the change. Changes will be made by striking a single line 
through erroneous data (so as not to obliterate the original data), and clearly entering the 
correct data (eg, wrong data right data). If the reason for the change is not apparent, a 
brief explanation for the change will be written in the source documentation by the 
investigator or subinvestigator. If electronic data systems are being utilized, a full audit 
trail of changes must be maintained. 
Information from the medical records and other source documents will be entered by trial 
site personnel directly onto 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 investigator 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 documents as well as completed eCRF 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 the longest of the 
following 3 periods. However, if the sponsor requires a longer period of archiving, the 
head of the trial site will consult with the sponsor on the period and procedures of record 
retention. 
 Until the date 2 years after manufacturing and marketing approval date; however, if 
the head of the trial site receives notification from the sponsor that development has 
been terminated or that results of the trial will not be submitted with the approval 
application, until the date 3 years after receipt of such notification. 
 Until the date 3 years after termination or completion of the trial. 
 Until the date on which it is decided to end DNA storage 


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The trial site must not dispose of any records relevant to this trial without either (1) 
written permission from the sponsor or (2) providing an opportunity for the sponsor to 
collect such records. The trial site will be responsible to maintain adequate and accurate 
electronic or hard copy source documents of all observations and data generated during 
this trial. Such documentation is subject to inspection by the sponsor and relevant 
regulatory authorities. 
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 monitors will visit the site during the trial, as well as communicate frequently 
via telephone, e-mail, and written communications. In addition, all investigators or 
subinvestigators and trial site clinical personnel will undergo initial and ongoing training 
for this particular trial, and this training will be clearly documented. 
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 eCRFs 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 the following. 
 Subjects who were enrolled in the trial even though they did not satisfy the entry 
criteria 


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 Subjects who fell under the withdrawal criteria during the trial but were not 
withdrawn from the trial 
 Subjects who received the wrong treatment or dose 
 Subjects who received a prohibited concomitant therapy 
The FDA defines a protocol deviation/violation as an unplanned excursion from the 
protocol that is not implemented or intended as a systematic change. 
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 
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. 
Investigators or subinvestigators are expected to document potential protocol deviations 
as well as their medical assessment regarding continuation of the subject(s) due to the 
protocol deviation. Of the protocol deviations, only major deviations will be recorded in 
eCRFs. 
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 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 eCRFs, IRE forms, etc, the investigator or 
subinvestigator and their staff will take measures to ensure adequate care in protecting 


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subject privacy. To this end, a subject number or subject identifier 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 investigator. 
12 
Confidentiality 
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission. Subject confidentiality requirements of the region 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/or other materials 
collected shall be used solely in accordance with this protocol, unless otherwise agreed to 
in writing by the sponsor. 
Subjects will be identified only by unique subject identifiers in eCRFs. 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 
subinvestigators will wait for IRB approval/favorable opinion of the amended protocol 
before implementing the change(s). Administrative amendments are defined as having no 
effect on the safety of subjects, conduct or management of the trial, trial design, or the 
quality or safety of IMP(s) used in the trial. A protocol change intended to eliminate an 
apparent immediate hazard to subjects should be implemented immediately, followed by 
IRB notification within local applicable timelines. The sponsor will submit protocol 
amendments to the applicable regulatory agency within local applicable timelines. 
When the IRB, investigators, or the sponsor 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 


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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 
criteria (http://www.icmje.org/recommendations). According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met: 
 Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND 
 Drafting the work or revising it critically for important intellectual content; AND 
 Final approval of the version to be published; AND 
 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 
Messias EL, Chen CY, Eaton WW. Epidemiology of schizophrenia: Review of 
findings and myths. Psychiatr Clin North Am. 2007;30:323-38. 
2 
McGrath J, Saha S, Chant D, Welham J. Schizophrenia: a concise overview of 
incidence, prevalence, and mortality. Epidemiol Rev. 2008;30:67-76. 
3 
Ministry of Health, Labour and Welfare [website on the Internet]. Tokyo: MHLW. 
MHLW Statistical Chart Database. 2011 Patient Survey. First volume No. 62 Table 
total number of patients, by sex and age group × by classification of diseases. 
4 
The Japanese Society of Neuropsychopharmacology, editor. Guideline for 
Pharmacological Therapy of Schizophrenia, issued 01 Jun 2016. 
5 
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. 
6 
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.  


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7 
Shibusawa K. Binding affinity of OPC-331 for dopamine and serotonin receptors. 
Otsuka Study No. 026328, Otsuka Report No. 020549, 2007. 
8 
Hashimoto K. Effect on serum prolactin levels in rats treated with single oral 
administration of OPC-34712. Otsuka Study No. 026050, Otsuka Report No. 020467, 
2007. 
9 
Hashimoto K. One-week repeated oral dose toxicity study of OPC-34712 in rats. 
Otsuka Study No. 024288, Otsuka Report No. 019075, 2006. 
10 Hashimoto K. Four-week repeated oral dose toxicity study of OPC-34712 in rats. 
Otsuka Study No.024495, Otsuka Report No. 019254, 2007. 
11 Hashimoto K. Thirteen-week repeated oral dose toxicity study of OPC-34712 with a 
4-week recovery test in rats. Otsuka Study No. 024963, Otsuka Report No. 020367, 
2007. 
12 Ishida S. Twenty-six-week repeated oral dose toxicity study of OPC-331 with 13-
week recovery test in rats. Otsuka Study No. 028625, Otsuka Report No. 023880, 
2010. 
13 Yoneyama S. Four-week repeated oral dose toxicity study of OPC-331 in cynomolgus 
monkeys. Otsuka Study No. 024290, Otsuka Report No. 019594, 2007. 
14 Yoneyama S. Thirteen-week repeated oral dose toxicity study of OPC-331 in 
cynomolgus monkeys with a four-week recovery test. Otsuka Study No. 024962, 
Otsuka Report No. 020474, 2007. 
15 Yoneyama S. Thirty-nine-week repeated oral dose toxicity study of OPC-331 in 
cynomolgus monkeys. Otsuka Study No. 028626, Otsuka Report No. 024584, 2010. 
16 Nyilas M. 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 21 Jan 2010. 
17 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 17 Mar 2010. 
18 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 23 Apr 2010. 
19 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 09 Apr 2010. 
20 Skuban A. A phase 1, multi-center, randomized, double-blind, placebo-controlled 
study to assess the safety, tolerability, and pharmacokinetics of ascending high doses 
of OPC-34712 as adjunctive therapy in the treatment of subjects with major 
depressive disorder. Otsuka Clinical Study Report for Protocol 331-09-221, issued 30 
Jul 2010. 
21 Zheng Y-P. A phase 1, single-center, randomized, double-blind, placebo-controlled 
study to assess the safety, tolerability, and pharmacokinetics of ascending multiple 


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oral doses of OPC-34712 as adjunctive therapy in the treatment of adults with 
attention-deficit/hyperactivity disorder. Otsuka Clinical Study Report for Protocol 
331-09-220, issued 09 Aug 2010. 
22 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 (Japanese), 26 Dec 2013 (English). 
23 Otsuka Pharmaceutical Co, Ltd. A repeated-dose trial of OPC-34712 in patients with 
schizophrenia. Otsuka Protocol 331-10-001, issued 08 Jun 2011. 
24 Otsuka Pharmaceutical Co, Ltd. A Dose-finding Trial of OPC-34712 in patients with 
schizophrenia. Otsuka Protocol 331-10-002, issued 18 Dec 2015. 
25 Regarding Clinical Trials Using Pharmacogenomics. PFSB/ELD Notification No. 
0930007; 2008. 
26 Regarding Genomic Sampling and Management of Genomic Data. PSEHB/PED 
Notification No. 0118-1; 2018 
27 International Conference on Harmonisation. Guideline for Good Clinical Practice: 
E6(R1). Geneva, Switzerland: International Conference on Harmonisation; 1996. 
 


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Appendix 1 
Handling and Shipping of Bioanalytical Samples 
 Information to be written on the label and recording 
Write on the label affixed to each storage tube the required information such as protocol 
number, subject identifier, date of sampling, time point of sampling, description of 
sample, laboratory parameters, aliquot number (only for samples for drug concentration 
measurement; eg, aliquot 1, aliquot 2). 
Be sure to enter the actual date of sampling (the actual date and time of sampling for drug 
concentration measurement), not the scheduled date and time, on the source documents 
and CRF. 
 Handling and shipping of samples for drug concentration measurement 
Collect a blood sample into a 2 mL vacuum blood collection tube containing sodium 
heparin using a venipuncture technique or an indwelling catheter. If an indwelling 
catheter is used, the catheter may be flushed with normal saline or heparin. Following 
sampling, slowly invert the tube a few times to mix well. Within 45 minutes of the 
sample being taken, perform refrigerated centrifugation at approximately 4°C 
(approximately 3,000 rpm [approximately 1,710 × G] for approximately 10 minutes). 
Transfer plasma aliquots into 2 appropriately labeled storage tubes (in the case of a small 
sample, transfer 0.3 mL of the sample into one storage tube and the remaining sample 
into the other). Within 90 minutes of the sample being taken, place the 2 plasma samples 
in a freezer at a temperature no higher than –20°C. Within 3 business days of sampling, 
ship plasma samples to the central laboratory, which will in turn send them to the 
bioanalytical laboratory. When shipping, place samples together with plenty of dry ice in 
a well-insulated container. The samples will be stored in a freezer at a temperature no 
higher than –70°C at the bioanalytical laboratory. 
Unused plasma samples are to be stored at the bioanalytical laboratory and will be 
disposed of after the clinical study report is completed. 
 Handling and shipping of samples for CYP2D6 genetic testing 
Collect a blood sample into a 2 mL vacuum blood collection tube containing EDTA 
dipotassium using a venipuncture technique or an indwelling catheter. If an indwelling 
catheter is used, the catheter may be flushed with normal saline. Following sampling, 
slowly invert the tube 8 to 10 times to mix well, and transfer the blood sample into an 
appropriately labeled storage tube. Within 60 minutes of the sample being taken, place 
the sample in a freezer at a temperature no higher than –20°C. Within 3 business days of 
sampling, ship blood samples to the central laboratory, which will in turn send them to 
the genetic test laboratory. When shipping, place samples together with plenty of dry ice 
in a well-insulated container. The samples will be stored in a freezer at a temperature no 


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higher than –70°C at the genetic test laboratory. The genetic test laboratory will extract 
DNA from blood samples and store DNA samples in a freezer at a temperature no higher 
than –70°C. 
Unused DNA samples are to be stored at the genetic test laboratory and will be disposed 
of with subject anonymity being maintained following the institutional procedure after 
the clinical study report is completed. 
 Handling and shipping of samples for DNA storage 
Collect a blood sample into a 2 mL vacuum blood collection tube containing EDTA 
dipotassium using a venipuncture technique or an indwelling catheter. If an indwelling 
catheter is used, the catheter may be flushed with normal saline. Following sampling, 
slowly invert the tube 8 to 10 times to mix well, and transfer the blood sample into an 
appropriately labeled storage tube. Within 60 minutes of the sample being taken, place 
the sample in a freezer at a temperature no higher than –20°C. Within 3 business days of 
sampling, ship blood samples to the central laboratory, which will in turn send them to 
the DNA storage facility. When shipping, place samples together with plenty of dry ice in 
a well-insulated container. The samples will be stored in a freezer at a temperature no 
higher than –70°C at the DNA storage facility. The DNA storage facility will double-
code samples by assigning a personal code to each sample, extract DNA from blood 
samples, and store DNA samples in a freezer at a temperature no higher than −70°C. 
Upon the sponsor's request, the DNA storage facility will dispose of DNA samples while 
maintaining subject anonymity following the institutional procedure. 
 


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Appendix 2 
CYP2D6 Genotyping Table 
 
E = EM, I = IM, P = PM 
 
Allele 
*position 
Genotype 
Phenotype 
100 
1758 
1846 
2573 
2850 
2988 
4125 
4180 
del/C 
del/G 
del/G 
del/- 
del/C 
del/G 
del/- 
del/G 
*1/*5 
IM 
del/C 
del/G 
del/G 
del/- 
del/T 
del/G 
del/- 
del/C 
*2/*5 
IM 
del/T 
del/G 
del/A 
del/- 
del/C 
del/G 
del/- 
del/C 
*4/*5 
PM 
del/T 
del/G 
del/A 
del/- 
del/C 
del/G 
del/- 
del/G 
del/T 
del/G 
del/A 
del/- 
del/T 
del/G 
del/- 
del/C 
del/C 
del/G 
del/A 
del/- 
del/C 
del/G 
del/- 
del/G 
del/del del/del 
del/del 
del/del 
del/del 
del/del 
del/del 
del/del 
*5/*5 
PM 
del/T 
del/G 
del/G 
del/- 
del/C 
del/G 
del/- 
del/C 
*5/*10 
IM 
del/T 
del/A 
del/G 
del/- 
del/T 
del/G 
del/- 
del/C 
*5/*14A 
PM 
del/C 
del/A 
del/G 
del/- 
del/T 
del/G 
del/- 
del/C 
*5/*14B 
IM 
del/C 
del/G 
del/G 
del/- 
del/C 
del/G 
del/9bp 
del/G 
*5/*18 
PM 
del/C 
del/G 
del/G 
del/insC 
del/T 
del/G 
del/- 
del/C 
*5/*21 
PM 
del/C 
del/G 
del/G 
del/- 
del/T 
del/A 
del/- 
del/C 
*5/*41 
IM 
C/C 
G/G 
G/G 
-/- 
C/C 
G/G 
-/- 
G/G 
*1/*1 
EM 
C/C 
G/G 
G/G 
-/- 
C/T 
G/G 
-/- 
C/G 
*1/*2 
EM 
C/T 
G/G 
A/G 
-/- 
C/C 
G/G 
-/- 
G/G 
*1/*4 
IM 
C/C 
G/G 
A/G 
-/- 
C/C 
G/G 
-/- 
G/G 
C/T 
G/G 
G/G 
-/- 
C/C 
G/G 
-/- 
C/G 
*1/*10 
EM 
C/C 
A/G 
G/G 
-/- 
C/T 
G/G 
-/- 
C/G 
*1/*14B 
EM 
C/T 
A/G 
G/G 
-/- 
C/T 
G/G 
-/- 
C/G 
*1/*14A 
IM 
C/C 
G/G 
G/G 
-/- 
C/C 
G/G 
-/9bp 
G/G 
*1/*18 
IM 
C/C 
G/G 
G/G 
-/insC 
C/T 
G/G 
-/- 
C/G 
*1/*21 
IM 
C/C 
G/G 
G/G 
-/- 
C/T 
A/G 
-/- 
C/G 
*1/*41 
EM 
C/C 
G/G 
G/G 
-/- 
T/T 
G/G 
-/- 
C/C 
*2/*2 
EM  
C/T 
G/G 
A/G 
-/- 
C/T 
G/G 
-/- 
C/C 
*2/*4 
IM  
C/C 
G/G 
A/G 
-/- 
C/T 
G/G 
-/- 
C/G 
C/T 
G/G 
A/G 
-/- 
T/T 
G/G 
-/- 
C/C 
*1
*2
*10 *14B *41
*4
*5 *14A *18
*21
*1
E
E
E
E
E
I
I
I
I
I
*2
E
E
E
E
I
I
I
I
I
*10
I
I
I
I
I
I
I
I
*14B
I
I
I
I
I
I
I
*41
I
I
I
I
I
I
*4
P
P
P
P
P
*5
P
P
P
P
*14A
P
P
P
*18
P
P
*21
P


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Allele 
*position 
Genotype 
Phenotype 
100 
1758 
1846 
2573 
2850 
2988 
4125 
4180 
C/T 
G/G 
G/G 
-/- 
C/T 
G/G 
-/- 
C/C 
*2/*10 
EM 
C/C 
A/G 
G/G 
-/- 
T/T 
G/G 
-/- 
C/C 
*2/*14B 
EM 
C/T 
A/G 
G/G 
-/- 
T/T 
G/G 
-/- 
C/C 
*2/*14A 
IM 
C/C 
G/G 
G/G 
-/- 
C/T 
G/G 
-/9bp 
C/G 
*2/*18 
IM 
C/C 
G/G 
G/G 
-/insC 
T/T 
G/G 
-/- 
C/C 
*2/*21 
IM 
C/C 
G/G 
G/G 
-/- 
T/T 
A/G 
-/- 
C/C 
*2/*41 
EM 
T/T 
G/G 
A/A 
-/- 
C/C 
G/G 
-/- 
C/C 
 
 
 
 
 
 
 
*4/*4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PM 
 
 
 
 
 
 
 
 
T/T 
G/G 
A/A 
-/- 
C/C 
G/G 
-/- 
C/G 
T/T 
G/G 
A/A 
-/- 
C/T 
G/G 
-/- 
C/C 
C/T 
G/G 
A/A 
-/- 
C/C 
G/G 
-/- 
C/G 
T/T 
G/G 
A/A 
-/- 
C/C 
G/G 
-/- 
G/G 
T/T 
G/G 
A/A 
-/- 
C/T 
G/G 
-/- 
C/G 
C/T 
G/G 
A/A 
-/- 
C/C 
G/G 
-/- 
G/G 
T/T 
G/G 
A/A 
-/- 
T/T 
G/G 
-/- 
C/C 
C/T 
G/G 
A/A 
-/- 
C/T 
G/G 
-/- 
C/G 
C/C 
G/G 
A/A 
-/- 
C/C 
G/G 
-/- 
G/G 
T/T 
G/G 
A/G 
-/- 
C/C 
G/G 
-/- 
C/C 
*4/*10 
IM 
T/T 
G/G 
A/G 
-/- 
C/C 
G/G 
-/- 
C/G 
T/T 
G/G 
A/G 
-/- 
C/T 
G/G 
-/- 
C/C 
T/T 
A/G 
A/G 
-/- 
C/T 
G/G 
-/- 
C/C 
*4/*14A 
PM 
C/T 
A/G 
A/G 
-/- 
C/T 
G/G 
-/- 
C/C 
*4/*14A or 
*4/*14B 
Unknown 
T/T 
A/G 
A/G 
-/- 
C/T 
G/G 
-/- 
C/G 
*4/*14A 
PM 
C/T 
A/G 
A/G 
-/- 
C/T 
G/G 
-/- 
C/G 
*4/*14A or 
*4/*14B 
Unknown 
T/T 
A/G 
A/G 
-/- 
T/T 
G/G 
-/- 
C/C 
*4/*14A 
PM 
C/T 
A/G 
A/G 
-/- 
T/T 
G/G 
-/- 
C/C 
*4/*14A or 
*4/*14B 
Unknown 
C/T 
A/G 
A/G 
-/- 
C/T 
G/G 
-/- 
C/G 
*4/*14A or 
*4/*14B 
C/C 
A/G 
A/G 
-/- 
C/T 
G/G 
-/- 
C/G 
*4/*14B 
IM 
C/T 
G/G 
A/G 
-/- 
C/C 
G/G 
-/9bp 
C/G 
*4/*18 
PM 
C/T 
G/G 
A/G 
-/- 
C/C 
G/G 
-/9bp 
G/G 
C/T 
G/G 
A/G 
-/- 
C/T 
G/G 
-/9bp 
C/G 
C/C 
G/G 
A/G 
-/- 
C/C 
G/G 
-/9bp 
G/G 
C/T 
G/G 
A/G 
-/insC 
C/T 
G/G 
-/- 
C/C 
*4/*21 
PM 
C/T 
G/G 
A/G 
-/insC 
C/T 
G/G 
-/- 
C/G 
C/T 
G/G 
A/G 
-/insC 
T/T 
G/G 
-/- 
C/C 
C/C 
G/G 
A/G 
-/insC 
C/T 
G/G 
-/- 
C/G 
C/T 
G/G 
A/G 
-/- 
C/T 
A/G 
-/- 
C/C 
*4/*41 
IM 
C/T 
G/G 
A/G 
-/- 
C/T 
A/G 
-/- 
C/G 
C/T 
G/G 
A/G 
-/- 
T/T 
A/G 
-/- 
C/C 
C/C 
G/G 
A/G 
-/- 
C/T 
A/G 
-/- 
C/G 
T/T 
G/G 
G/G 
-/- 
C/C 
G/G 
-/- 
C/C 
*10/*10 
IM 
T/T 
A/G 
G/G 
-/- 
C/T 
G/G 
-/- 
C/C 
*10/*14A 
IM 


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Allele 
*position 
Genotype 
Phenotype 
100 
1758 
1846 
2573 
2850 
2988 
4125 
4180 
C/T 
A/G 
G/G 
-/- 
C/T 
G/G 
-/- 
C/C 
*10/*14B 
IM 
C/T 
G/G 
G/G 
-/- 
C/C 
G/G 
-/9bp 
C/G 
*10/*18 
IM 
C/T 
G/G 
G/G 
-/insC 
C/T 
G/G 
-/- 
C/C 
*10/*21 
IM 
C/T 
G/G 
G/G 
-/- 
C/T 
A/G 
-/- 
C/C 
*10/*41 
IM 
C/T 
A/A 
G/G 
-/- 
T/T 
G/G 
-/- 
C/C 
*14A/*14B 
IM 
C/C 
A/A 
G/G 
-/- 
T/T 
G/G 
-/- 
C/C 
*14B/*14B 
T/T 
A/A 
G/G 
-/- 
T/T 
G/G 
-/- 
C/C 
*14A/*14A 
PM 
C/T 
A/G 
G/G 
-/- 
C/T 
G/G 
-/9bp 
C/G 
*14A/*18 
PM 
C/C 
A/G 
G/G 
-/- 
C/T 
G/G 
-/9bp 
C/G 
*14B/*18 
IM 
C/T 
A/G 
G/G 
-/insC 
T/T 
G/G 
-/- 
C/C 
*14A/*21 
PM 
C/C 
A/G 
G/G 
-/insC 
T/T 
G/G 
-/- 
C/C 
*14B/*21 
IM 
C/T 
A/G 
G/G 
-/- 
T/T 
A/G 
-/- 
C/C 
*14A/*41 
IM 
C/C 
A/G 
G/G 
-/- 
T/T 
A/G 
-/- 
C/C 
*14B/*41 
C/C 
G/G 
G/G 
-/- 
C/C 
G/G 
9bp/9bp 
G/G 
*18/*18 
PM 
C/C 
G/G 
G/G 
-/insC 
C/T 
G/G 
-/9bp 
C/G 
*18/*21 
PM 
C/C 
G/G 
G/G 
-/- 
C/T 
A/G 
-/9bp 
C/G 
*18/*41 
IM 
C/C 
G/G 
G/G 
insC/insC 
T/T 
G/G 
-/- 
C/C 
*21/*21 
PM 
C/C 
G/G 
G/G 
-/insC 
T/T 
A/G 
-/- 
C/C 
*21/*41 
IM 
C/C 
G/G 
G/G 
-/- 
T/T 
A/A 
-/- 
C/C 
*41/*41 
IM 
C/T 
G/G 
A/G 
-/- 
C/C 
G/G 
-/- 
C/G 
*1/*4  
or *4/*10 
IM 
C/T 
G/G 
A/G 
-/- 
C/T 
G/G 
-/- 
C/G 
*1/*4  
or *2/*4 
IM 
*position: https://www.pharmvar.org/gene/CYP2D6 
If the genotype cannot be determined, the genotype will be classified as "not 
determinable (ND)." 
If the genotype cannot be determined or if the phenotype cannot be singled out, the 
phenotype will be classified as "unknown." 
 


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Appendix 3 
List of CYP Inhibitors/Inducers 
CYP3A4 inhibitors 
Mechanism of Action 
Generic Name 
Remarks 
Dyslipidemia drug 
Atorvastatin 
 
Dyslipidemia drug 
Lomitapide 
 
Immunosuppressant 
Ciclosporin 
 
Immunosuppressant 
Tacrolimus 
 
Antiemetic 
Aprepitant 
 
Antiemetic 
Fosaprepitant 
 
Anti-arrhythmia drug 
Amiodarone 
 
Anti-arrhythmia drug 
Quinidine 
 
Anti-arrhythmia drug 
Verapamil 
 
Antihypertensive 
Amlodipine 
 
Antihypertensive 
Felodipine 
 
Vasodilator 
Diltiazem 
 
Anxiolytic 
Alprazolam 
 
Anxiolytic 
Tofisopam 
 
Antidepressant 
Fluvoxamine 
 
Antiparkinsonian drug 
Istradefylline 
 
Antimicrobial drug 
Azithromycin 
 
Antimicrobial drug 
Erythromycin 
 
Antimicrobial drug 
Clarithromycin 
 
Antimicrobial drug 
Ciprofloxacin 
 
Antifungal drug 
Itraconazole 
 
Antifungal drug 
Clotrimazole 
 
Antifungal drug 
Ketoconazole 
 
Antifungal drug 
Fluconazole 
 
Antifungal drug 
Voriconazole 
 
Antifungal drug 
Miconazole 
 
Antiplatelet drug 
Cilostazol 
 
Antiplatelet drug 
Ticagrelor 
 
Antituberculosis drug 
Isoniazid 
 
Antitumor drug 
Imatinib 
 
Antitumor drug 
Crizotinib 
 
Antitumor drug 
Nilotinib 
 
Antitumor drug 
Pazopanib 
 
Antitumor drug 
Bicalutamide 
 
Antitumor drug 
Lapatinib 
 
Anti-HIV drug 
Atazanavir 
 
Anti-HIV drug 
Indinavir 
 
Anti-HIV drug 
Indinavir/ritonavir 
 
Anti-HIV drug 
Elvitegravir/ritonavir 
 
Anti-HIV drug 
Cobicistat 
 
Anti-HIV drug 
Saquinavir 
 
Anti-HIV drug 
Saquinavir/ritonavir 
 


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Mechanism of Action 
Generic Name 
Remarks 
Anti-HIV drug 
Danoprevir/ritonavir 
 
Anti-HIV drug 
Darunavir/ritonavir 
 
Anti-HIV drug 
Tipranavir/ritonavir 
 
Anti-HIV drug 
Nelfinavir 
 
Anti-HIV drug 
Paritaprevir/ritonavir/(ombitasvir and/or 
dasabuvir) 
 
Anti-HIV drug 
Fosamprenavir 
 
Anti-HIV drug 
Ritonavir 
 
Anti-HIV drug 
Lopinavir/ritonavir 
 
Oral contraceptive drugs 
Oral contraceptive drugs 
 
Muscle relaxant 
Chlorzoxazone 
 
Gastric acid suppressant 
Cimetidine 
 
Gastric acid suppressant 
Ranitidine 
 
Hepatitis C drug 
Telaprevir 
 
Food with functional 
claims 
Gingko biloba 
 
Supplement 
Goldenseal (yellow puccoon) 
 
CYP3A4 inducers 
Mechanism of Action 
Generic Name 
Remarks 
Adrenocortical hormone 
preparations 
Adrenocortical hormone preparations 
Including the following 
drugs 
cortisone, hydrocortisone, 
prednisolone, 
methylprednisolone, 
triamcinolone, 
dexamethasone, 
betamethasone, 
fludrocortisone, prasterone 
Pulmonary hypertension 
drug 
Bosentan 
 
Diabetes mellitus drug 
Pioglitazone 
 
Central stimulant 
Modafinil 
 
Antiemetic 
Aprepitant 
 
Antihormone drug 
Enzalutamide 
 
Antihormone drug 
Mitotane 
 
Antiepileptic 
Carbamazepine 
 
Antiepileptic 
Clobazam 
 
Antiepileptic 
Phenytoin 
 
Antiepileptic 
Fosphenytoin 
 
Antiepileptic 
Phenobarbital 
*Includes the following 
phenobarbital derivatives 
phenobarbital, amobarbital, 
pentobarbital, barbital, 
secobarbital, primidone 
Antiepileptic 
Rufinamide 
 
Antituberculosis drug 
Rifampicin 
 
Antitumor drug 
Vemurafenib 
 
Anti-HIV drug 
Etravirine 
Anti-HIV drug 
Efavirenz 
 
Anti-HIV drug 
Rifabutin 
 
Supplement 
Echinacea (Echinacea purpurea) 
 
Supplement 
St. John's wort 
 


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CYP2D6 inhibitors 
Mechanism of Action 
Generic Name 
Remarks 
Hyperuricemia drug 
Febuxostat 
 
Antihypertensive drug 
Labetalol 
 
Antihypertensive drug 
Hydralazine 
 
Antihypertensive drug 
Diltiazem 
 
Anti-arrhythmia drug 
Verapamil 
 
Anti-arrhythmia drug 
Propafenone 
 
Anti-arrhythmia drug 
Quinidine 
 
Anti-arrhythmia drug 
Amiodarone 
 
Oral contraceptive drug 
Ethinylestradiol 
Oral contraceptive drug 
Levonorgestrel 
 
Oral contraceptive drug 
Norethisterone 
 
Oral contraceptive drug 
Desogestrel 
 
Gastric acid suppressant 
Ranitidine 
 
Gastric acid suppressant 
Cimetidine 
 
Analgesic 
Methadone 
 
Anti-inflammatory 
analgesic 
Celecoxib 
 
Antihistamine 
Diphenhydramine 
 
Antiepileptic 
Clobazam 
 
Antifungal drug 
Terbinafine 
 
Hyperthyroidism drug 
Cinacalcet 
 
Antidepressant 
Venlafaxine 
 
Antidepressant 
Paroxetine 
 
Antidepressant 
Fluvoxamine 
 
Antidepressant 
Duloxetine 
 
Antidepressant 
Sertraline 
 
Antidepressant 
Escitalopram 
 
Antitumor drug 
Vemurafenib 
 
Antitumor drug 
Pazopanib 
 
Antitumor drug 
Gefitinib 
 
Antitumor drug 
Imatinib 
 
Antitumor drug 
Abiraterone 
 
Anti-HIV drug 
Ritonavir 
 
Anti-HIV drug 
Cobicistat 
 
Overactive bladder drug 
Mirabegron 
 
Lupus erythematosus drug 
Hydroxychloroquine 
 
Supplement 
Echinacea (Echinacea purpurea) 
 


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Appendix 4 
Criteria for Allowing Concomitant Use of Topical CYP2D6 
Inhibitors, CYP3A4 Inhibitors, and CYP3A4 Inducers 
Section 4.1 Prohibited Medications in this protocol lists CYP2D6 inhibitors, CYP3A4 
inhibitors, and CYP3A4 inducers as prohibited concomitant medications in view of 
pharmacokinetic interactions. This appendix provides a definition of “topical” CYP2D6 
inhibitors, CYP3A4 inhibitors, and CYP3A4 inducers. 
1. Conditions Pertaining to Topical Agents in This Document 
In view of possible drug-drug interactions between the IMP and concomitant 
medications, the use of drugs that have a systemic effect and are absorbed from the 
gastrointestinal tract or mucosa and predominantly transferred into the systemic 
circulation should be avoided. However, concomitant use of “topical” CYP2D6 
inhibitors, CYP3A4 inhibitors, and CYP3A4 inducers is permitted under the condition 
that they are unlikely to enter the systemic circulation as defined below. 
Topical agents that may possibly enter the systemic circulation based on their route of 
administration or dosage form, even if they meet both of the following conditions, should 
be reviewed individually with reference to Section 2. 
Other Remarks About 
Topical Agents in this appendix, and any questions or concerns should be communicated 
to the sponsor.  
[Conditions under which a topical agent can be used concomitantly with the IMP] 
A topical agent is defined as a drug that: 
1) Is intended to have a local effect, AND 
2) Does not reach the gastrointestinal tract. 
2) In consideration of possible absorption from the gastrointestinal tract and 
possible impact on metabolic enzymes present in the gastrointestinal epithelium. 
 
2. Other Remarks About Topical Agents 
Criteria for permitting/prohibiting concomitant use for each dosage form are indicated 
below. Classification of dosage form is based on the Japanese Pharmacopoeia 
Seventeenth Edition, General Rules for Preparations, [3] Official Monographs, excerpted 
below (see Section 3. Dosage Forms That May Fall Under Common Topical Agents 
(Excerpt From the Japanese Pharmacopoeia Seventeenth Edition, General Rules for 
Preparations, [3] Official Monographs) for the excerpt table). 
 “Preparations for inhalation” and “preparations for nasal application” are not included 
as topical agents and must not be used concomitantly with the IMP because they are 
likely to enter the systemic circulation. 


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 “Preparations for vaginal application” and “preparations for rectal application” are 
not included as topical agents and must not be used concomitantly with the IMP 
because they are likely to enter the systemic circulation. 
 “Preparations for oro-mucosal application,” except “preparations for gargles,” are not 
included as topical agents and must not be used concomitantly with the IMP because 
some preparations are intended to have a systemic effect or can reach the 
gastrointestinal tract. 
 “Preparations for ophthalmic application” and “preparations for otic application” are 
included as topical agents and can be used concomitantly with the IMP. 
 “Preparations for cutaneous application,” except “patches” intended to have a 
systemic effect, are included as topical agents and can be used concomitantly with the 
IMP. 
 
3. Dosage Forms That May Fall Under Common Topical Agents (Excerpt From 
the Japanese Pharmacopoeia Seventeenth Edition, General Rules for 
Preparations, [3] Official Monographs) 
Topical agents are broadly classified primarily by the route of administration and 
application site, and subclassified by the configuration, function, and characteristics of 
the drug formulation. 
Table 1 
Definition of Topical CYP2D6 Inhibitors, CYP3A4 Inhibitors, 
and CYP3A4 Inducers 
Route of 
Administration/ 
Application Site 
Configuration/Function/Characteristics of the Drug 
Formulation 
Concomitant 
Use as a 
Topical Agenta 
2. Preparations for 
oro-mucosal 
application 
2.1. Tablets for oro-mucosal 
application 
2.1.1. Troches/lozenges 
Not permitted 
2.1.2. Sublingual tablets 
Not permitted 
2.1.3. Buccal tablets 
Not permitted 
2.1.4. Mucoadhesive tablets 
Not permitted 
2.1.5. Medicated chewing gums 
Not permitted 
2.2. Liquids and solutions for 
oro-mucosal application 
2.2.1. Preparations for gargles 
Permitted 
2.3. Sprays for oro-mucosal 
application 
 
Not permitted 
2.4. Semi-solid preparations 
for oro-mucosal application 
 
Not permitted 
5. Preparations for 
inhalation 
5.1. Inhalations 
5.1.1. Dry powder inhalers 
Not permitted 
5.1.2. Inhalation liquids and 
solutions 
Not permitted 
5.1.3. Metered-dose inhalers 
Not permitted 
6. Preparations for 
ophthalmic 
application 
6.1. Ophthalmic liquids and 
solutions 
 
Permitted 
6.2. Ophthalmic ointments 
 
Permitted 
7. Preparations for 
otic application 
7.1. Ear preparations 
 
Permitted 


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Table 1 
Definition of Topical CYP2D6 Inhibitors, CYP3A4 Inhibitors, 
and CYP3A4 Inducers 
Route of 
Administration/ 
Application Site 
Configuration/Function/Characteristics of the Drug 
Formulation 
Concomitant 
Use as a 
Topical Agenta 
8. Preparations for 
nasal application 
8.1. Nasal preparations 
8.1.1. Nasal dry powder inhalers 
Not permitted 
8.1.2. Nasal liquids and 
solutions 
Not permitted 
9. Preparations for 
rectal application 
9.1. Suppositories for rectal 
application 
 
Not permitted 
9.2. Semi-solid preparations 
for rectal application 
 
 
Not permitted 
9.3. Enemas for rectal 
application 
 
Not permitted 
10. Preparations for 
vaginal application 
10.1. Tablets for vaginal use 
 
Not permitted 
10.2. Suppositories for 
vaginal use 
 
Not permitted 
11. Preparations for 
cutaneous 
application 
11.1. Solid dosage forms for 
cutaneous application 
11.1.1. Powders for cutaneous 
application 
Permitted 
11.2. Liquids and solutions 
for cutaneous application 
11.2.1. Liniments 
Permitted 
11.2.2. Lotions 
Permitted 
11.3. Sprays for cutaneous 
application 
11.3.1. Aerosols for cutaneous 
application 
Permitted 
11.3.2. Pump sprays for 
cutaneous application 
Permitted 
11.4. Ointments 
 
Permitted 
11.5. Creams 
 
Permitted 
11.6. Gels 
 
Permitted 
11.7. Patches 
11.7.1. Tapes 
Not permittedb 
11.7.2. Cataplasms/ 
gel patches 
Not permittedb 
aClassified based on Sections 1 and 2 above. 
bConcomitant use of agents intended to have a local effect is permitted. 
 
 


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Appendix 5 
Equivalent Conversion of Antipsychotics 
The daily chlorpromazine (CP) equivalent dose will be calculated by the following 
formula, using the equivalence conversion values of antipsychotics (Table 1). 
Daily CP equivalent dose = Daily dose of antipsychotic (mg) / equivalent conversion 
value of antipsychotic × 100 
Table 1 
Equivalent Conversion Table for Antipsychotics (by Route of 
Administration) 
Drug Name 
Route of Administration 
Equivalent Conversion 
Value Used for 
Calculation 
Article 
Providing 
Evidence 
Oral drugs 
Aripiprazole 
Oral 
4 
1-d 
Asenapine 
Oral 
2.5 
1-e 
Oxypertine 
Oral 
80 
1-d 
Olanzapine 
Oral 
2.5 
1-d 
Quetiapine 
Oral 
66 
1-d 
Clocapramine 
Oral 
40 
1-d 
Chlorpromazine 
Oral 
100 
1-d 
Spiperone 
Oral 
1 
1-d 
Sultopride 
Oral 
200 
1-d 
Sulpiride 
Oral 
200 
1-d 
Zotepine 
Oral 
66 
1-d 
Tiapride 
Oral 
100 
1-d 
Timiperone 
Oral 
1.3 
1-d 
Trifluoperazine 
Oral 
5 
1-d 
Nemonapride 
Oral 
4.5 
1-d 
Paliperidone 
Oral 
1.5 
1-d 
Haloperidol 
Oral 
2 
1-d 
Pipamperone 
Oral 
200 
1-d 
Pimozide 
Oral 
4 
1-d 
Fluphenazine 
Oral 
2 
1-d 
Prochlorperazine 
Oral 
15 
1-d 
Blonanserin 
Oral 
4 
1-d 
Propericiazine 
Oral 
20 
1-d 
Bromperidol 
Oral 
2 
1-d 
Perphenazine 
Oral 
10 
1-d 
Perospirone 
Oral 
8 
1-d 
Mosapramine 
Oral 
33 
1-d 
Moperone 
Oral 
12.5 
1-d 
Risperidone 
Oral 
1 
1-d 
Reserpine 
Oral 
0.15 
1-d 
Levomepromazine 
Oral 
100 
1-d 


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Table 1 
Equivalent Conversion Table for Antipsychotics (by Route of 
Administration) 
Drug Name 
Route of Administration 
Equivalent Conversion 
Value Used for 
Calculation 
Article 
Providing 
Evidence 
Prolonged action drugs for injection 
Aripiprazole 
Prolonged action drug for 
injection 
100 mg/4 weeks 
1-f 
Paliperidone 
palmitate 
Prolonged action drug for 
injection 
18.75 mg/4 weeks 
1-f 
Haloperidol 
decanoate 
Prolonged action drug for 
injection 
30 mg/4 weeks 
1-b 
Fluphenazine 
decanoate 
Prolonged action drug for 
injection 
15 mg/4 weeks 
1-f 
Risperidone 
Prolonged action drug for 
injection 
10 mg/2 weeks 
1-c 
Injected formulations 
Haloperidol 
Intramuscular/intravenous 
administration 
1 
1-d 
Chlorpromazine 
Intramuscular 
administration 
33 
1-b 
Levomepromazine 
Intramuscular 
administration 
25 
1-b 
Sulpiride 
Intramuscular 
administration 
50 
1-b 
Perphenazine 
Intramuscular 
administration 
2 
1-b 
Prochlorperazine 
Intramuscular 
administration 
2.1 
1-b 
Timiperone 
Intramuscular 
administration 
0.19 
1-b 
1-a: Inagaki A, Inada T. No. 18: 2006 Psychotropic Dose Equivalence. Japanese Journal of Clinical 
Psychopharmacology. 2006;9:1443-7. 
1-b: Inagaki A, Inada T. No. 20: Dose Equivalence of Antipsychotics for Injection. Japanese Journal of 
Clinical Psychopharmacology. 2007;10:2373-7. 
1-c: Inagaki A, Inada T. No. 22: Dose Equivalence of Prolonged Action Antipsychotics (3): Risperidone 
Long Acting Formulation for Injection. Japanese Journal of Clinical Psychopharmacology. 
2010;13:1349-53. 
1-d: Inagaki A, Inada T. No. 23: Dose Equivalence of New Antipsychotics (6): Paliperidone Sustained 
Release Formulation. Japanese Journal of Clinical Psychopharmacology. 2012;15:397-404. 
1-e: Inagaki A, Inada T. No. 26: Dose Equivalence of New Antipsychotics (7): Asenapine. Japanese 
Journal of Clinical Psychopharmacology. 2017;20:88-97. 
1-f 
: Inagaki A, Inada T. No. 25: Dose Equivalence of Prolonged Action Antipsychotics (4): 
Aripiprazole Prolonged Action Water Suspension Formulation for Intramuscular Injection. Japanese 
Journal of Clinical Psychopharmacology. 2015;18:1475-1480. 
 
 
 


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Appendix 6 
Protocol Amendments/Administrative Changes 
 
Amendment: Number: 1 
Issue Date: 
09 Sep 2019 
 
PURPOSE: 
Reconsideration/modification of the trial duration and clarification of descriptions 
 
BACKGROUND: 
The trial duration was reconsidered and modified. Ambiguous descriptions were clarified. 
 
MODIFICATIONS TO PROTOCOL: 
Sectional Revisions: 
Location 
Before Change 
After Change 
Protocol Synopsis 
Trial Duration: 
November 2019 to March 2021 
October 2019 to March 2021 
Section 5.3 
Immediately Reportable Events 
… (Please note that the IRE form 
is a specific form provided by 
the sponsor and is NOT the AE 
eCRF.) 
… (Please note that the IRE form 
is a specific form provided by 
the sponsor and is NOT the AE 
eCRF.) Due consideration must 
be given to the subject’s privacy 
when an IRE form is sent by e-
mail, etc. 
Chapter 11 
Ethics and Responsibility 
Further, in preparing and 
handling eCRFs, the investigator 
or subinvestigator and their staff 
… 
Further, in preparing and 
handling eCRFs, IRE forms, etc, 
the investigator or 
subinvestigator and their staff … 
 
ADDITIONAL RISK TO THE SUBJECT 
There is no additional risk to the subjects. 
 


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Amendment: Number: 2 
Issue Date: 
28 Jan 2020 
 
PURPOSE: 
Acceptance of re-enrollment of subjects who were withdrawn from the trial at the 
discretion of the sponsor, clarification of the relevant procedures, 
reconsideration/modification of prohibited medications, modification of the trial duration 
in association with withdrawal from the trial at the discretion of the sponsor, and 
correction of clerical errors 
 
BACKGROUND: 
Some subjects were withdrawn from the trial at the discretion of the sponsor. The sponsor 
has decided to allow re-enrollment of these subjects in the trial. The trial duration was 
reconsidered and modified in association with withdrawal from the trial at the discretion 
of the sponsor, prohibited medications were reconsidered and modified, and clerical 
errors were corrected. 
 
MODIFICATIONS TO PROTOCOL: 
Sectional Revisions: 
 
Location 
Before Change 
After Change 
Protocol Synopsis 
Trial Duration: 
October 2019 to March 2021 
October 2019 to May 2021 
Protocol Synopsis 
Trial Duration: 
… Each period is indicated 
below. 
… Each period is indicated below. In 
cases where subjects withdrawn from 
the single administration period 
(Cohort 1) at the discretion of the 
sponsor subsequently take part in the 
trial again, the duration of their trial 
participation will be a maximum of 
85 days if they resume participation 
in the trial from Period 2 and a 
maximum of 58 days if they resume 
participation the trial from Period 3. 
Section 3.1.1 
Cohort 1 (Single 
Administration Period) 
Following administration of 
the QW formulation in Period 
2, …must be withdrawn from 
the trial and not advance to 
Period 3. 
Following administration of the QW 
formulation in Period 2, …must be 
withdrawn from the trial and not 
advance to Period 3. If a subject 
withdrawn from the trial at the 


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Location 
Before Change 
After Change 
discretion of the sponsor after 
receiving a brexpiprazole 2 mg 
conventional tablet in Period 1 and 
undergoing the examinations 
scheduled for up to Day 14 of Period 
1 subsequently takes part in the trial 
again, the subject will be allowed to 
resume participation in the trial from 
Period 2. If a subject withdrawn from 
the trial at the discretion of the 
sponsor after receiving a 24 mg tablet 
of the QW formulation in Period 2 
and undergoing the examinations 
scheduled for up to Day 14 of Period 
2 subsequently takes part in the trial 
again, the subject will be allowed to 
resume participation in the trial from 
Period 3. 
Section 3.3.2 
Subject Numbering 
… which is given to each 
subject in chronological order 
of provision of consent. 
… which is given to each subject in 
chronological order of provision of 
consent. Each subject who takes part 
in the trial again following 
withdrawal from the trial at the 
discretion of the sponsor will be 
assigned the same subject identifier 
that was assigned to them at the time 
when they first participated in the 
trial. 
Section 3.4.1 
Informed Consent 
The ICF will be approved by 
the same institutional review 
board (IRB) that approves this 
protocol. 
The ICF will be approved by the 
same institutional review board (IRB) 
that approves this protocol. In cases 
where subjects withdrawn from the 
trial at the discretion of the sponsor 
subsequently take part in the trial 
again, informed consent will also be 
obtained from all such subjects (and 
their legal representatives if they are 
minors or are hospitalized for reasons 
of medical protection) on their 
voluntary decision. 
Section 3.4.1 
Informed Consent 
On the other hand, DNA 
storage is optional … will not 
affect trial participation. 
On the other hand, DNA storage is 
optional … will not affect trial 
participation. In cases where subjects 
withdrawn from the trial at the 
discretion of the sponsor 
subsequently take part in the trial 
again, written informed consent will 
be obtained from them (and their 
legal representatives if they are 
minors or are hospitalized for reasons 
of medical protection) on their 
voluntary decision, if they have yet to 
complete CYP2D6 genetic testing. 


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Location 
Before Change 
After Change 
Section 3.4.2 
Inclusion Criteria 
Subjects are required to meet 
the inclusion criteria in Table 
3.4.2-1. 
Subjects are required to meet the 
inclusion criteria in Table 3.4.2-1. 
Subjects withdrawn from the trial at 
the discretion of the sponsor will have 
to be reevaluated to ensure they still 
meet the inclusion criteria in Table 
3.4.2-1 if they are to take part in the 
trial again. 
Section 3.4.3 
Exclusion Criteria 
Subjects will be excluded if 
they meet any of the exclusion 
criteria in Table 3.4.3-1. 
Subjects will be excluded if they meet 
any of the exclusion criteria in Table 
3.4.3-1. 
Subjects withdrawn from the trial at 
the discretion of the sponsor cannot 
take part in the trial again if they meet 
any of the exclusion criteria in Table 
3.4.3-1. 
Section 3.7.3.1 
Screening (for All Cohorts) 
*Informed consent will be 
obtained before blood 
sampling for CYP2D6 genetic 
testing and blood sampling for 
DNA storage (optional). 
After informed consent is 
obtained, … 
*Informed consent will be obtained 
before blood sampling for CYP2D6 
genetic testing and blood sampling 
for DNA storage (optional). 
In cases where subjects withdrawn 
from the trial at the discretion of the 
sponsor subsequently take part in the 
trial again and resume participation in 
the same cohort, the procedures and 
characteristics of the trial will be 
explained to them and written 
informed consent will be obtained 
from them (and their legal 
representatives if they are minors or 
are hospitalized for reasons of 
medical protection) prior to initiation 
of any protocol-related procedures. 
The following subject information 
will be recorded on the source 
documents and the eCRF. 
 
Date on which informed consent 
was obtained again 
 
Subject identifier 
 
Date of informed consent for 
CYP2D6 genetic testing** 
 
Date of informed consent for 
DNA storage (optional)** 
**Informed consent will be obtained 
before blood sampling for CYP2D6 
genetic testing and blood sampling 
for DNA storage (optional). However, 
if blood samples had already been 
collected before the subject was 
withdrawn from the trial, it will not 
be necessary to obtain consent again. 


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Location 
Before Change 
After Change 
After informed consent is obtained, 
… 
Section 3.7.3.1 
Screening (for All Cohorts) 
 
Height, …will be 
determined … BMI = 
weight (kg) / height (m)2. 
… 
 
Vital signs … will take 
place only at screening). 
 
Height, …will be determined … 
BMI = weight (kg) / height (m)2. 
… 
 
Vital signs … will take place 
only at screening). 
Note*: A minor revision was made in 
the Japanese original, but no changes 
are required in the English translation. 
Section 3.7.3.1 
Screening (for All Cohorts) 
… 
 
Concomitant medications 
and therapies 
… 
 
Concomitant medications and 
therapies 
In cases where subjects withdrawn 
from the trial at the discretion of the 
sponsor subsequently take part in the 
trial again and resume participation in 
the same cohort, the following 
observations, tests, and assessments 
will be performed as screening 
procedures, after informed consent is 
obtained, within 28 days (Days −28 to 
−1) before IMP administration in the 
treatment period (Period 2 or 3) in 
which they are to resume 
participation in the trial, and their 
eligibility to participate in the trial 
will be assessed. 
[Items] 
 
Inclusion/exclusion criteria 
 
Height,* weight, and body mass 
index (BMI)*: Height will be 
measured in increments of 
0.1 cm. For a height measured to 
the second or further decimal 
place, the number will be 
rounded off to the first decimal 
place. BMI will be determined 
based on height and weight 
measurements at screening, using 
the following formula: BMI = 
weight (kg) / height (m)2. 
*The height measurement obtained at 
screening when the subject first 
participated in the trial may be used. 
In that case, the height measurement 
obtained at screening when the 
subject first participated in the trial 
should be used in calculation of BMI. 
 
Urine drug screening 


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Location 
Before Change 
After Change 
 
Urine pregnancy test (women of 
childbearing potential only) 
 
Clinical laboratory tests (blood 
and urine sampling) 
 
Physical examination 
 
Vital signs (blood pressure, pulse 
rate, and body temperature): 
Blood pressure and pulse rate 
will be measured in the supine 
position (performed first), sitting 
position, and standing position 
after each position is maintained 
for at least 3 minutes (blood 
pressure and pulse rate 
measurements in the supine and 
standing positions will take place 
only at screening). 
 
12-Lead ECG (performed prior 
to blood sampling for clinical 
laboratory tests) 
 
C-SSRS (the "Since Last Visit" 
will be used) 
 
AEs 
 
Concomitant medications and 
therapies 
Section 3.7.3.3 
QW Formulation Single 
Administration Periods 
(Periods 2 and 3 of Cohort 1 
and Cohort 1’ [as Necessary]) 
The investigator or 
subinvestigator will … and 
record their dates and results. 
The investigator or subinvestigator 
will … and record their dates and 
results. Subjects withdrawn from the 
trial at the discretion of the sponsor 
will only be enrolled again to resume 
participation in the trial from Period 2 
or 3 if they are confirmed to be 
eligible. 
Section 3.7.4 
Prior and Concomitant 
Medications 
The investigator or 
subinvestigator will … on the 
source documents and eCRF. 
The investigator or subinvestigator 
will … on the source documents and 
eCRF. For subjects who were 
withdrawn from the trial at the 
discretion of the sponsor and resume 
participation in the trial from Period 2 
or 3, medications and therapies will 
be recorded in the same manner after 
participation in the trial is resumed. 
Medications and therapies that were 
introduced after withdrawal from the 
trial at the discretion of the sponsor 
and terminated up to 30 days before 
the date on which the subject 
provided his/her signature for re-
consent will be recorded as far as 
possible. 


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Location 
Before Change 
After Change 
Section 3.7.5.4 
Physical Examination and 
Vital Sign Assessments 
… the date of examination will 
be recorded on the source 
documents and eCRF. 
… the date of examination will be 
recorded on the source documents 
and eCRF. For subjects who were 
withdrawn from the trial at the 
discretion of the sponsor and 
subsequently take part in the trial 
again, whether a physical 
examination is performed or not at 
screening and subsequent time points 
and, if performed, the date of 
examination will be recorded on the 
source documents and eCRF. 
Section 3.7.5.4 
Physical Examination and 
Vital Sign Assessments 
It is preferable to have the 
same physician perform all 
physical examinations for any 
individual subject throughout 
the course of the trial wherever 
possible. Any new, clinically 
relevant findings at 
postscreening physical 
examinations will be recorded 
as AEs on the source 
documents and eCRF. 
It is preferable to have the same 
physician perform all physical 
examinations for any individual 
subject throughout the course of the 
trial wherever possible. Any new, 
clinically relevant, postscreening 
physical findings obtained from the 
start of the trial to the physical 
examination before IMP 
administration on Day 1 of Period 2 
and any new, clinically relevant 
physical findings obtained after the 
start of IMP administration in Period 
2 in comparison with those obtained 
before IMP administration on Day 1 
of Period 2 will be recorded as AEs 
on the source documents and eCRF. 
For subjects who were withdrawn 
from the trial at the discretion of the 
sponsor and resume participation in 
the trial from Period 2, any new, 
clinically relevant physical findings 
obtained during the screening period 
in comparison with those obtained at 
the first screening before withdrawal 
and any new, clinically relevant 
physical findings obtained during 
Periods 2 and 3 in comparison with 
those obtained before IMP 
administration in Period 2 will be 
recorded as AEs on the source 
documents and eCRF. For subjects 
who were withdrawn from the trial at 
the discretion of the sponsor and 
resume participation in the trial from 
Period 3, any new, clinically relevant 
physical findings obtained during the 
screening period and Period 3 in 
comparison with those obtained 
before IMP administration in Period 2 
before withdrawal will be recorded as 
AEs on the source documents and 
eCRF. 


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Location 
Before Change 
After Change 
Section 3.10 
Screen Failures 
In the event that rescreening is 
not completed … new subject 
identifier must be assigned. 
In the event that rescreening is not 
completed …new subject identifier 
must be assigned. However, for those 
subjects who were withdrawn from 
the trial at the discretion of the 
sponsor, who agree to take part in the 
trial again and sign the ICF again, but 
who are not enrolled in the trial prior 
to IMP administration on Day 1 of 
their scheduled treatment period 
(Period 2 or 3), the same subject 
identifier as the original will also be 
used for the repeated rescreening. 
Section 4.1 
Prohibited Medications 
No asterisk or footnote 
Asterisks were added to each “Period 
1” in the itemized list. 
The following footnote was added: 
*For subjects who were withdrawn 
from the trial at the discretion of the 
sponsor and resume participation in 
the trial from Period 2 or 3, the use of 
the drugs is prohibited from 14, 21, 
28, and 60 days, respectively, before 
IMP administration in the treatment 
period (Period 2 or 3) in which they 
are to resume participation in the trial. 
Section 4.2 
Prohibited Therapies 
No asterisk or footnote 
An asterisk was added to “Period 1.” 
The following footnote was added: 
*For subjects who were withdrawn 
from the trial at the discretion of the 
sponsor and resume participation in 
the trial from Period 2 or 3, the use of 
the therapy is prohibited from 60 days 
before IMP administration in the 
treatment period (Period 2 or 3) in 
which they are to resume 
participation in the trial. 
Section 4.3 
Restricted Medications 
No asterisk or footnote 
An asterisk was added to “Period 1.” 
The following footnote was added: 
*For subjects who were withdrawn 
from the trial at the discretion of the 
sponsor and resume participation in 
the trial from Period 2 or 3, the use of 
the drugs is restricted from Day 1 of 
IMP administration in the treatment 
period (Period 2 or 3) in which they 
are to resume participation in the trial. 
Section 4.4 
Other Restrictions 
No asterisk or footnote 
Asterisks were added to each “Period 
1” in the itemized list. 
The following footnote was added: 
*For subjects who were withdrawn 
from the trial at the discretion of the 
sponsor and resume participation in 
the trial from Period 2 or 3, the 


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Location 
Before Change 
After Change 
consumption of these foods and 
beverages is prohibited from 7 and 14 
days, respectively, before IMP 
administration in the treatment period 
(Period 2 or 3) in which they are to 
resume participation in the trial. 
Section 5.2 
Eliciting and Reporting 
Adverse Events 
Adverse event and SAE 
collection is … the subject’s 
condition at the start of Period 
2. 
Adverse event and SAE collection is 
… the subject’s condition at the start 
of Period 2. For subjects who were 
withdrawn from the trial at the 
discretion of the sponsor and resume 
participation in the trial from Period 2 
or 3, AEs and SAEs will be collected 
from the time participation in the trial 
resumes until the end of the trial. 
However, AEs that occur after 
withdrawal from the trial at the 
discretion of the sponsor and resolve 
before the date on which the subject 
provided his/her signature for re-
consent will also be collected as far as 
possible. Adverse events will be 
assessed based on the following: 
 
Subjects who resume 
participation in the trial from 
Period 2: Adverse events 
occurring in the screening period 
will be assessed in comparison 
with their condition at the time of 
the consent/screening when they 
first participated in the trial, and 
AEs occurring in Period 2 and 
Period 3 will be assessed in 
comparison with their condition 
prior to IMP administration in 
Period 2. 
 
Subjects who resume 
participation in the trial from 
Period 3: Adverse events 
occurring in the screening period 
and Period 3 will be assessed in 
comparison with their condition 
at the start of Period 2 when they 
first participated in the trial. 
Appendix 3 
List of CYP 
Inhibitors/Inducers 
 
CYP3A4 inducers 
No description 
The following was added to CYP3A4 
inducers: 
 
Mechanism of Action: Antiepileptic 
Generic Name: Fosphenytoin 
Remarks: no addition 
Appendix 3 
List of CYP 
Inhibitors/Inducers 
 
Remarks: 
*Includes the following 
phenobarbital derivatives 
phenobarbital, amobarbital, 
Remarks: 
*Includes the following phenobarbital 
derivatives 
phenobarbital, amobarbital, 


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Location 
Before Change 
After Change 
CYP3A4 inducers 
pentobarbital, barbital, 
secobarbital, primidone 
pentobarbital, barbital, secobarbital, 
primidone 
Note*: A minor revision was made in 
the Japanese original, but no changes 
are required in the English translation. 
 
ADDITIONAL RISK TO THE SUBJECT 
There is no additional risk to the subjects. 


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Amendment: Number: 3 
Issue Date: 
18 Jun 2020 
 
PURPOSE: 
Reconsideration/modification of the assessment schedule in response to the results from 
Cohort 1 and clarification of descriptions 
 
BACKGROUND: 
The assessment schedule was reconsidered and modified in response to the results from 
Cohort 1. Ambiguous descriptions were clarified. 
 
MODIFICATIONS TO PROTOCOL: 
Sectional Revisions: 
 
Location 
Before Change 
After Change 
Section 3.1.3 
Cohort 2 (Repeated 
Administration Period) 
 
The following was added to the end 
of the section. 
Following administration of the 
QW formulation in Period 2, safety 
must be carefully evaluated. 
Subjects who meet any of the 
criteria for withdrawal before dose 
increase as specified in Section 
3.9.3.2 Criteria for Withdrawal 
Before Dose Increase of the QW 
Formulation after IMP 
administration on Day 1 must be 
withdrawn from the trial without 
dose increase. 
Section 3.7 
Trial Procedures 
Table 3.7-2 Schedule of 
Assessments (Cohort 2; 
Repeated Administration 
Period) 
 
Clinical laboratory tests were added 
to Day 10 of Period 2. 
 
ADDITIONAL RISK TO THE SUBJECT 
There is no additional risk to the subjects. 


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131 
Version 4.0, 18 Jun 2020 
 
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 concurrent medications, the efficacy and safety parameters and the 
conduct of the trial in general. I am aware that this protocol must be approved by the 
Institutional Review Board (IRB) responsible for such matters in the clinical trial facility 
where 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 implementation of any substantial amendments to 
this protocol. If, however, there is an immediate hazard to subjects, I will implement the 
amendment immediately, and provide the information to the IRB within the required 
local applicable timelines. Administrative changes to the protocol will be transmitted to 
the IRB for informational purposes only, if required by local regulations. 
I agree to provide all subjects with informed consent forms, as required by the applicable 
regulations and by ICH guidelines. I agree to report to the sponsor any adverse events in 
accordance with the terms of the sponsor's Clinical Trial Agreement and the relevant 
regional regulation(s) and guideline(s). I further agree to provide all required information 
regarding financial certification or disclosure to the sponsor for all investigators and 
subinvestigators in accordance with the terms of the relevant regional regulation(s). I 
understand that participation in the protocol involves a commitment to publish the data 
from this trial in a cooperative publication before publication of efficacy and safety 


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132 
Version 4.0, 18 Jun 2020 
 
results on an individual basis may occur, and I consent to be acknowledged in any such 
cooperative publications that result. 
 
 
 
 
 
 
  
 
 
 
 
 
 
Principal Investigator’s Name 
 
 
  Name of Trial Site 
 
________________________________________                  
Signature 
 
 
 
 
Date 
 
The sponsor’s signature for this Agreement is provided as an electronic signature. The 
electronic signature page is attached to this Agreement. 
 

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
A multi-center, open-label clinical pharmacology trial to investigate the 
pharmacokinetics, tolerability, and safety of brexpiprazole once-weekly (QW) 
formulation administered as single and multiple oral doses in patients with schizophrenia 
 
 
 
 
 
NCT Number: NCT04118127 
PRT NO.: 331-102-00150 
Version Date: 31 Mar 2021 (Version 1.0) 


Otsuka Pharmaceutical Co., Ltd.
Investigational New Drug
Brexpiprazole (OPC-34712)
Protocol No. 331-102-00150
A multi-center, open-label clinical pharmacology trial to investigate the 
pharmacokinetics, tolerability, and safety of brexpiprazole once-weekly (QW) 
formulation administered as single and multiple oral doses in patients with schizophrenia
Statistical Analysis Plan
Version: 1.0
Date: Mar 31 2021
Protocol Date:  Jun 18 2020
Confidential
May not be used, divulged, published, or otherwise disclosed without the prior written 
consent of Otsuka Pharmaceutical Co., Ltd. 


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Table of Contents
Table of Contents ..........................................................................................2
List of Appendices .........................................................................................5
List of Abbreviations and Definition of Terms...........................................6
1
Introduction..........................................................................................8
2
Trial Objectives ....................................................................................8
3
Trial Design...........................................................................................8
3.1
Type/Design of Trial ...........................................................................................8
3.1.1
Cohort 1 (Single Administration Period)........................................................11
3.1.2
Cohort 1’ (Additional Single Administration Period, as Necessary) .............11
3.1.3
Cohort 2 (Repeated Administration Period)...................................................12
3.2
Trial Treatments ................................................................................................12
3.2.1
Dose, Regimen and Treatment Period............................................................12
3.2.1.1
Cohort 1 (Single Administration Period)....................................................12
3.2.1.1.1
Administration of Brexpiprazole Conventional Tablet ...........................12
3.2.1.1.2
Administration of Brexpiprazole QW Formulation ................................12
3.2.1.2
Cohort 1’ (as Necessary) (Single Administration Period) ..........................13
3.2.1.2.1
Administration of Brexpiprazole Conventional Tablet ...........................13
3.2.1.2.2
Administration of Brexpiprazole QW Formulation ................................13
3.2.1.3
Cohort 2 (Repeated Administration Period) ...............................................14
3.2.1.3.1
Administration of Brexpiprazole Conventional Tablet ...........................14
3.2.1.3.2
Administration of Brexpiprazole QW Formulation ................................14
3.3
Trial Population.................................................................................................14
3.4
Trial Visit Window............................................................................................14
4
Sample Size .........................................................................................15
5
Statistical Analysis Sets......................................................................15
5.1
Pharmacokinetic Analysis Set...........................................................................15
5.2
Safety Analysis Set............................................................................................15
5.3
Handling of Missing Data .................................................................................15
6
Primary and Secondary Outcome Variables:..................................15
7
Disposition and Demographic Analysis............................................15


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7.1
Subject Disposition ...........................................................................................15
7.2
Demographic and Baseline Characteristics.......................................................16
7.3
Medical History.................................................................................................17
7.4
Treatment Compliance ......................................................................................17
7.5
Prior and Concomitant Medications..................................................................17
7.6
Protocol Deviations...........................................................................................17
8
Efficacy Analysis ................................................................................17
9
Safety Analyses...................................................................................17
9.1
Extent of Exposure............................................................................................18
9.2
Adverse Events..................................................................................................18
9.3
Clinical Laboratory Data...................................................................................18
9.4
Vital Sign Data..................................................................................................19
9.5
Physical Examination Data ...............................................................................19
9.6
Electrocardiogram Data.....................................................................................19
9.7
Other Safety Data..............................................................................................19
9.7.1
DIEPSS...........................................................................................................19
9.7.2
C-SSRS...........................................................................................................20
10
Pharmacokinetic Analyses.................................................................20
10.1
Statistical Analyses of Primary and Secondary Pharmacokinetic 
Endpoints...........................................................................................................20
10.1.1
Brexpiprazole QW Formulation .....................................................................20
10.1.1.1
Period 2 of the Single Administration Period (Cohort 1 and Cohort 1’ 
[as Necessary])............................................................................................20
10.1.1.2
Period 3 of the Single Administration Period (Cohort 1 and Cohort 1’ 
[as Necessary])............................................................................................21
10.1.1.3
Period 2 of the Repeated Administration Period (Cohort 2).......................21
10.1.2
Brexpiprazole Conventional Tablet (for All Cohorts, Period 1) ....................21
10.2
Technical Details of Pharmacokinetic Statistical Analyses ..............................22
11
Pharmacodynamic Analyses..............................................................23
12
Pharmacogenomic Analyses..............................................................23
13
Analyses of Other Endpoints.............................................................23
13.1
Clinical Global Impression - Severity of Illness and Clinical Global 
Impression - Improvement ................................................................................23


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14
Interim Analysis .................................................................................23
15
Changes in the Planned Analyses .....................................................23
16
References ...........................................................................................24


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List of Appendices
Appendix 1
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance.........................................................................25
Appendix 2
Criteria for Identifying Vital Signs and Body Weight of 
Potential Clinical Relevance..........................................................26
Appendix 3
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance.........................................................................26
Appendix 4
List of Summary Tables.................................................................27
Appendix 5
List of Subject Data Listings .........................................................32


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List of Abbreviations and Definition of Terms
Abbreviation
Definition
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BMI
Body mass index
BUN
Blood urea nitrogen
CGI-I
Clinical Global Impression-Improvement
CGI-S
Clinical Global Impression-Severity of Illness
CPK
Creatine phosphokinase
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP2D6
Cytochrome P450 2D6
CYP3A4
Cytochrome P450 3A4
DIEPSS
Drug-Induced Extrapyramidal Symptoms Scale
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
ECG
Electrocardiogram
IMP
Investigational Medicinal Product
LDH
Lactic dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
PCS
Potentially Clinically Significance
PK
Pharmacokinetic
PT
Preferred Term
QTc
QT corrected for heart rate
QTcF
QT interval as corrected by Fridericia’s formula
QW
Quaque (Once) Weekly
SOC
System Organ Class
TEAE
Treatment-emergent adverse event
ULN
Upper Limit of Normal
WHO-DD
World Health Organization Drug Dictionary
AUC
Area under the concentration time curve
AUC
Area under the concentration time curve from time zero to infinity
AUC/D
Area under the concentration time curve per dose
AUC_%Extrap
Ratio of area under the concentration-time curve from tlast to infinity versus AUC∞
AUCt
Area under the concentration time curve calculated to the last observable concentration 
at time t
AUCt/D
AUCt per dose
AUC168h
Area under the concentration-time curve from time zero to 168 hours
AUC168h/D
AUC168h per dose
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
Cmax/D
Cmax per dose
LLOQ
Lower limit of quantification
λz
Terminal elimination rate constant
λz(point)
Number of points used in computing λz
λz(lower)
Lower limit on time for values to be included in the calculation of λz
λz(upper)
Upper limit on time for values to be included in the calculation of λz


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λz(RSQ)
Goodness of fit statistic for the terminal elimination phase, adjusted for the number of 
points used in the estimation of λz
t1/2,z
Terminal phase elimination half life
tlast
Time of the last measurable concentration
tmax
Time to maximum (peak) plasma concentration


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1
Introduction
This statistical analysis plan describes the statistical methodology and data analysis 
algorithms and conventions to be applied for statistical analysis in this trial. This plan is 
based on version 3.0 of Protocol No. 331-102-00150, dated 28 Jan 2020.
2
Trial Objectives
The objective of the clinical trial is to evaluate the PK, tolerability, and safety of 
brexpiprazole QW formulation administered as single and repeated administration in 
patients with schizophrenia.
3
Trial Design
3.1
Type/Design of Trial
This is a multi-center, open-label, clinical pharmacology trial to investigate the PK, 
tolerability, and safety of brexpiprazole QW formulation administered as single and 
repeated administration in patients with a diagnosis of schizophrenia (295.90) based on 
the DSM-5®. The trial comprises the single administration period (Cohort 1) and the 
repeated administration period (Cohort 2). The dose used in the repeated administration 
period (Cohort 2) will be determined based on plasma drug concentrations obtained in the 
single administration period (Cohort 1). The single administration period (Cohort 1) 
comprises Period 1, in which the conventional tablet will be administered, and Periods 2 
and 3, in which the QW formulation will be administered. If the single administration 
period (Cohort 1) fails to produce sufficient plasma drug concentrations, another single 
administration period (Cohort 1’) will be added during which the QW formulation will be 
administered at higher single doses. Only if progression to the repeated administration 
period (Cohort 2) is judged to be appropriate based on the results of the single 
administration period (Cohort 1 and Cohort 1’ [as necessary]), will the repeated 
administration period (Cohort 2) be implemented (see Figure 3.1-1). The repeated 
administration period (Cohort 2) comprises Period 1, in which subjects will receive a 
single administration of the conventional tablet, and Period 2, in which subjects will 
receive 5 administrations of the QW formulation.
In the single administration period (Cohort 1), subjects will receive a brexpiprazole 2 mg 
conventional tablet on Day 1 of Period 1, the QW formulation at 24 mg on Day 1of 
Period 2, and the QW formulation at 48 mg on Day 1 of Period 3, all as single 
administrations in a fasted state.


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In the single administration period (Cohort 1’), subjects will receive a brexpiprazole 2 mg 
conventional tablet on Day 1 of Period 1, the QW formulation at 30 mg on Day 1 of 
Period 2, and the QW formulation at 60 or 54 mg on Day 1 of Period 3, all as single 
administrations in a fasted state.
In the repeated administration period (Cohort 2), subjects will receive a single 
administration of a brexpiprazole 2 mg conventional tablet on Day 1 of Period 1, and 
repeated administration of the QW formulation on Days 1, 8, 15, 22, and 29 of Period 2. 
The doses of the QW formulation will be determined based on the results of the single 
administration period (Cohort 1 and Cohort 1’ [as necessary]).
In the single administration period (Cohort 1 and Cohort 1’ [as necessary]), subjects will 
be required to be hospitalized at the trial site from the day of IMP administration (Day 1) 
through the eighth day following IMP administration (Day 8) in Period 1 (conventional 
tablet) and Periods 2 and 3 (QW formulation). For the other parts of the single 
administration period, they may remain in the trial site or make trial visits on an 
outpatient basis. In Period 1 (conventional tablet) of the repeated administration period 
(Cohort 2), subjects will be required to be hospitalized at the trial site from the day of 
IMP administration (Day 1) through the eighth day following IMP administration (Day 
8). For the other parts of Period 1, they may remain in the trial site or make trial visits on 
an outpatient basis. In Period 2 (QW formulation) of the repeated administration period 
(Cohort 2), subjects will be required to be hospitalized at the trial site from the day of the 
first IMP administration (Day 1) through Day 16, from Day 22 through Day 23, and from 
Day 29 through Day 36. For the other parts of Period 2, they may remain in the trial site 
or make visits on an outpatient basis.


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Figure 3.1-1
Trial Design
Single Administration Period [Cohort 1] and [Cohort 1’ (as Necessary)]
Screening period
Screening
Informed consent (start of the trial)
IMP administration (Day 1)
IMP administration (Day 1)
IMP administration (Day 1)
Screening period
Screening
Informed consent (start of the trial)
IMP administration (Day 1)
IMP administration (Day 1)
*The dose may be changed depending on the results of the single administration period (Cohort 1 and Cohort 1’ [as necessary]).
Period 1
Period 2
Period 3
Follow-up period
(Days −28 to −1 of IMP
administration in Period 1)
(20 days)
(27 days)
(14 days)
(Days 28 to 30 of IMP
administration in Period 3)
Patients with
schizophrenia
Informed consent &
screening
Single administration of
1 brexpiprazole 2 mg
tablet
Single administration of QW
formulation 24 mg*
Single administration of QW
formulation 48 mg*
Judgement
for
progression
to Cohort 2
Postdose follow-up
*Whether or not to add Cohort 1’, and the doses used in Cohort 1’ will be determined based on the results of Cohort 1.
Period 1
Period 2
Follow-up period
The doses may be changed depending on the results of the single administration period
(Cohort 1 and Cohort 1’ [as necessary]).
Repeated Administration Period
[Cohort 2]
(Days −28 to −1 of IMP
administration in Period 1)
(20 days)
(42 days)
(Days 56 to 60 of Period 2)
Postdose follow-up
Patients with
schizophrenia
Informed consent &
screening
Single administration of
1 brexpiprazole 2 mg
tablet
Repeated administration of QW formulation
Day 1: 24 mg*
Days 8, 15, 22, 29: 48 mg*
Washout 
period
20 days (+ 8 
days max)
Subjects must stay at the trial site from the day of IMP administration (Day 1) through 
Day 8 in each Period. For the other parts of each Period, subjects may remain in the trial 
site or make trial visits on an outpatient basis.
Washout 
period
27 days (+ 8 
days max)
Washout 
period
20 days (+ 8 
days max)
Subjects must stay at the trial site from the day of the first 
IMP administration (Day 1) through Day 16, from Day 22 
through Day 23, and from Day 29 through Day 36 in Period 
2. For the other parts of the Period 2, subjects may remain in 
the trial site or make trial visits on an outpatient basis.
IMP administration (Day 8)
IMP administration (Day 15)
IMP administration (Day 22)
IMP administration (Day 29)
Subjects must stay at 
the trial site from the 
day of IMP 
administration (Day 
1) through Day 8 in 
Period 1. For the 
other parts of the 
Period 1, subjects 
may remain in the 
trial site or make 
trial visits on an 
outpatient basis.


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3.1.1
Cohort 1 (Single Administration Period)
Subjects judged eligible at screening will receive one brexpiprazole 2 mg conventional 
tablet on Day 1 of Period 1, one 24 mg tablet of the QW formulation on Day 1 of Period 
2, and two 24 mg tablets of the QW formulation on Day 1 of Period 3, all as a single oral 
administration in a fasted state. The trial includes a washout period of 20 days (+ 8 days 
max) between IMP administration in Period 1 and IMP administration in Period 2 and a 
washout period of 27 days (+ 8 days max) between IMP administration in Period 2 and 
IMP administration in Period 3. Brexpiprazole-naïve subjects should be monitored after 
conventional tablet administration in Period 1 to check if they are free from allergic or 
hypersensitive reactions. Following administration of the QW formulation in Period 2, 
safety must be carefully evaluated. Subjects who meet any of the criteria for withdrawal 
before dose increase as specified in Protocol Section 3.9.3.2 Criteria for Withdrawal 
Before Dose Increase of the QW Formulation must be withdrawn from the trial and not 
advance to Period 3. If a subject withdrawn from the trial at the discretion of the sponsor 
after receiving a brexpiprazole 2 mg conventional tablet in Period 1 and undergoing the 
examinations scheduled for up to Day 14 of Period 1 subsequently takes part in the trial 
again, the subject will be allowed to resume participation in the trial from Period 2. If a 
subject withdrawn from the trial at the discretion of the sponsor after receiving a 24 mg 
tablet of the QW formulation in Period 2 and undergoing the examinations scheduled for 
up to Day 14 of Period 2 subsequently takes part in the trial again, the subject will be 
allowed to resume participation in the trial from Period 3.
3.1.2
Cohort 1’ (Additional Single Administration Period, as Necessary)
A simulation of repeated administration will be performed based on the results of Cohort 
1 (single administration period). If steady-state plasma brexpiprazole concentrations of 
the QW formulation are estimated to fall far below the steady-state trough concentration 
for the 2 mg conventional tablet, Cohort 1’ will be added.
The design described in Section 3.1.1 Cohort 1 (Single Administration Period) applies to 
Cohort 1’ as well.
The doses of the QW formulation to be used in Cohort 1’ (as necessary) (single 
administration period) will be determined according to Protocol Section 3.8 Procedure for 
Progression to the Repeated Administration Period (Cohort 2) From the Single 
Administration Period (Cohort 1 and Cohort 1’ [as Necessary]), and the QW formulation 
will be administered in a fasted state as per regimen 1 or 2 shown in Table 3.2.1.2.2-1. 
Brexpiprazole-naïve subjects should be monitored after conventional tablet 
administration in Period 1 to check if they are free from allergic or hypersensitive 


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reactions. Following administration of the QW formulation in Period 2, safety must be 
carefully evaluated. Subjects who meet any of the criteria for withdrawal before dose 
increase as specified in Protocol Section 3.9.3.2 Criteria for Withdrawal Before Dose 
Increase of the QW Formulation must be withdrawn from the trial not advance to Period 
3.
3.1.3
Cohort 2 (Repeated Administration Period)
Subjects judged eligible at screening will receive a single administration of a 
brexpiprazole 2 mg conventional tablet on Day 1 of Period 1 in a fasted state. The trial 
includes a washout period of 20 days (+ 8 days max) between IMP administration in 
Period 1 and IMP administration in Period 2. Subjects will then receive repeated 
administration of the QW formulation in a fasted state as per one of the regimens 1 to 5 
shown in Table 3.2.1.3.2-1 on Days 1, 8, 15, 22, and 29 of Period 2. Brexpiprazole-naïve 
subjects should be monitored after conventional tablet administration in Period 1 to check 
if they are free from allergic or hypersensitive reactions.
3.2
Trial Treatments
3.2.1
Dose, Regimen and Treatment Period
3.2.1.1
Cohort 1 (Single Administration Period)
3.2.1.1.1
Administration of Brexpiprazole Conventional Tablet 
On Day 1 of Period 1, subjects will receive a single oral administration of a brexpiprazole 
2 mg conventional tablet together with approximately 150 mL of water in the morning 
after at least 10 hours of fasting. Subjects are not to take any food until 4 hours after 
administration. Subjects are not to take any fluids from 1 hour before administration of 
the conventional tablet until 2 hours after administration, except for the water taken at the 
time of administration.
3.2.1.1.2
Administration of Brexpiprazole QW Formulation
On Day 1 of each of Periods 2 and 3 in Cohort 1 (single administration period), subjects 
will receive a single oral administration of the QW formulation at the dose specified in 
Table 3.2.1.1.2-1 together with approximately 150 mL of water in the morning after at 
least 10 hours of fasting. Subjects are not to take any food until 4 hours after 
administration. Subjects are not to take any fluids from 1 hour before administration of 
the QW formulation until 2 hours after administration, except for the water taken at the 
time of administration.


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Table 3.2.1.1.2-1
Doses (Cohort 1) (Single Administration Period)
Dose
Treatment 
period
Period 2
Period 3
Regimen
Dose
Tablet
No. of Tablets
Dose
Tablet
No. of Tablets
1
24 mg
24 mg tablet
1 tablet
48 mg
24 mg tablet
2 tablets
3.2.1.2
Cohort 1’ (as Necessary) (Single Administration Period)
3.2.1.2.1
Administration of Brexpiprazole Conventional Tablet 
On Day 1 of Period 1, subjects will receive a single oral administration of a brexpiprazole 
2 mg conventional tablet together with approximately 150 mL of water in the morning 
after at least 10 hours of fasting. Subjects are not to take any food until 4 hours after 
administration. Subjects are not to take any fluids from 1 hour before administration of 
the conventional tablet until 2 hours after administration, except for the water taken at the 
time of administration.
3.2.1.2.2
Administration of Brexpiprazole QW Formulation
On Day 1 of each of Periods 2 and 3 in Cohort 1’ (as necessary) (single administration 
period), subjects will receive a single oral administration of the QW formulation together 
with approximately 150 mL of water in the morning after at least 10 hours of fasting. 
Subjects are not to take any food until 4 hours after administration. Subjects are not to 
take any fluids from 1 hour before administration of the QW formulation until 2 hours 
after administration, except for the water taken at the time of administration. The doses of 
the QW formulation to be used in Cohort 1’ (as necessary) (single administration period) 
will be determined according to Protocol Section 3.8 Procedure for Progression to the 
Repeated Administration Period (Cohort 2) From the Single Administration Period 
(Cohort 1 and Cohort 1’ [as Necessary]), and the QW formulation will be administered in 
a fasted state as per regimen 1 or 2 shown in Table 3.2.1.2.2-1. 
Table 3.2.1.2.2-1
Doses (Cohort 1’ [as Necessary] [Single Administration 
Period])
Dose
Treatment 
period
Period 2
Period 3
Regimen
Dose
Tablet
No. of Tablets
Dose
Tablet
No. of Tablets
1
30 mg
30 mg tablet
1 tablet
54 mg
24 mg tablet
30 mg tablet
1 tablet each
2
30 mg
30 mg tablet
1 tablet
60 mg
30 mg tablet
2 tablets


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3.2.1.3
Cohort 2 (Repeated Administration Period)
3.2.1.3.1
Administration of Brexpiprazole Conventional Tablet 
On Day 1 of Period 1, subjects will receive a single oral administration of a brexpiprazole 
2 mg conventional tablet together with approximately 150 mL of water in the morning 
after at least 10 hours of fasting. Subjects are not to take any food until 4 hours after 
administration. Subjects are not to take any fluids from 1 hour before administration of 
the conventional tablet until 2 hours after administration, except for the water taken at the 
time of administration.
3.2.1.3.2
Administration of Brexpiprazole QW Formulation
In Period 2, subjects will be orally administered the QW formulation together with 
approximately 150 mL of water in the morning after at least 10 hours of fasting, as per 
one of regimens 1 to 5 shown in Table 3.2.1.3.2-1 based on the results of the single 
administration period (Cohort 1 and Cohort 1’ [as necessary]). Subjects are not to take 
any food until 4 hours after administration. Subjects are not to take any fluids from 1 
hour before administration of the QW formulation until 2 hours after administration, 
except for the water taken at the time of administration.
Table 3.2.1.3.2-1
Doses (Cohort 2 [Repeated Administration Period])
Dose
Treatment 
period
Period 2
Day
1
8, 15, 22, and 29
Regimen
Dose
Tablet
No. of Tablets
Dose
Tablet
No. of Tablets
1
24 mg
24 mg tablet
1 tablet
48 mg
24 mg tablet
2 tablets
2
18 mg
18 mg tablet
1 tablet
36 mg
18 mg tablet
2 tablets
3
24 mg
24 mg tablet
1 tablet
42 mg
18 mg tablet
24 mg tablet
1 tablet each
4
30 mg
30 mg tablet
1 tablet
54 mg
24 mg tablet
30 mg tablet
1 tablet each
5
30 mg
30 mg tablet
1 tablet
60 mg
30 mg tablet
2 tablets
3.3
Trial Population
Patients from 18 years of age to under 65 years of age with a diagnosis of schizophrenia 
(295.90) based on DSM-5®
3.4
Trial Visit Window
Nominal time points will be used for summary of safety parameters and plasma 
concentration.


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4
Sample Size 
The target number of subjects is not based on a statistical hypothesis test. A simulation 
was performed with the PK model created based on PK data on the conventional tablet 
and QW-A formulation used in the QW-A formulation group in Trial 331-102-00021 
conducted in Japan, and the probability that the mean plasma concentration of 
brexpiprazole after repeated administration of the QW-A formulation would be within the 
target range of concentration was determined. On the basis of this probability, the sample 
size was determined to be 20 subjects each for the single administration period (Cohort 1) 
and the repeated administration period (Cohort 2). Likewise, the sample size for an 
additional single administration period (Cohort 1’) with a new dose was also determined 
to be 20 subjects.
5
Statistical Analysis Sets
5.1
Pharmacokinetic Analysis Set
The PK analysis set will consist of subjects who received the QW formulation and had 
plasma drug concentration measurements. The following subjects will be excluded from 
the PK analysis set:

Subjects who vomited within 12 hours postdose
5.2
Safety Analysis Set
The safety analysis set will consist of all subjects who received any QW formulation.
5.3
Handling of Missing Data
Data imputation will not be performed for missing data.
6
Primary and Secondary Outcome Variables:
Plasma drug concentrations and pharmacokinetics parameters of brexpiprazole after 
single or multiple administrations of the QW formulation.
7
Disposition and Demographic Analysis
7.1
Subject Disposition
The subject dispositions will be summarized for the single administration period (Cohort 
1 and Cohort 1’ [as necessary]) and the repeated administration period (Cohort 2).


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The number of screened subjects will be presented. The numbers and percentages of 
following subjects will be summarized. 

For the single administration period (Cohort 1 and Cohort 1’ [as necessary]):
1) Subjects treated with conventional tablet
2) Subjects withdrawn in period 1
3) Subjects treated with QW formulation in period 2
4) Subjects withdrawn in period 2
5) Subjects treated with QW formulation in period 3
6) Subjects completed in period 3
7) Subjects withdrawn in period 3
8) Subjects analyzed for PK
9) Subjects analyzed for safety

For the repeated administration period (Cohort 2):
1) Subjects treated with conventional tablet
2) Subjects withdrawn in period 1
3) Subjects treated with QW formulation in period 2
4) Subjects completed in period 2
5) Subjects withdrawn in period 2
6) Subjects analyzed for PK
7) Subjects analyzed for safety
The denominators for each period are subjects treated with IMP in each period. The 
denominators for the analysis sets are subjects treated with QW formulation.
The numbers and percentages of subjects withdrawn in each period will also be 
summarized by primary reason for discontinuation.
Subjects who discontinue by the sponsor’s circumstances and participate again will be 
counted once using final completion status. Listing of information regarding first 
discontinuation for these subjects will presented.
7.2
Demographic and Baseline Characteristics
Depending on data characteristics, frequency distribution or descriptive statistics of 
demographic and other baseline characteristics will be produced for the single 
administration period (Cohort 1 and Cohort 1’ [as necessary]) and the repeated 
administration period (Cohort 2) based on PK and safety analysis sets.
Continuous variables (age, height, weight at screening, and BMI) will be summarized 
using summary statistics (mean, SD, min, median, max). Categorical variables (sex, race, 


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detailed ethnicity, country, medical history, complications and CYP2D6 phenotype) will 
be summarized by number and percentage of subjects.
For subjects who discontinue by the sponsor’s circumstances and participate again, data 
at first screening will be used.
7.3
Medical History
Listing of medical history will be presented.
7.4
Treatment Compliance
Information for administration of IMP is described in Section 7.1 and 9.1.
7.5
Prior and Concomitant Medications
Medications will be coded using World Health Organization Drug Dictionary (WHO-
DD) version Sep 2019 Global B3. Listing of prior and concomitant medication will be 
presented.
7.6
Protocol Deviations
A listing of major protocol deviations will be presented.
8
Efficacy Analysis
Not applicable. 
9
Safety Analyses
Each safety endpoint will be summarized for each dose (Periods 2 and 3) of the QW 
formulation in the single administration period (Cohort 1 and Cohort 1’ [as necessary]) 
and for the repeated administration period (Cohort 2) based on safety analysis set.
The baseline for statistical analysis is defined as data measured immediately prior to IMP 
administration in Period 2. 
Adverse events (AEs) in each period are defined as AEs occurred on or after the IMP 
administration in each period to before the IMP administration in next period or the end of 
study.
Potentially clinically significant (potentially clinically significance [PCS]) abnormalities 
in each period will include the values measured on or after the IMP administration in each 
period to before the IMP administration in next period or the end of study.


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9.1
Extent of Exposure
For the repeated administration period (Cohort 2), the number of administrations will be 
summarized using frequency distribution.
9.2
Adverse Events 
All AEs will be coded by system organ class (SOC) and Medical Dictionary for 
Regulatory Activities (MedDRA version 23.1) preferred term (PT). 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 SOC and PT:

AEs occurring after administration of the QW formulation (treatment-emergent 
adverse events [TEAEs])

TEAEs by severity

TEAEs with an outcome of death

Serious TEAEs

TEAEs leading to discontinuations of the trial

TEAEs by onset time (1-7 and 8-14 for Cohort 1 and Cohort 1’ [as necessary]; 1-7 8-
14, 15-21, 22-28, 29-35, 36-42 for Cohort 2)
The above summaries will also be prepared for TEAEs potentially causally related to the 
IMP.
Incidences of the AEs occurring in period 1 will be summarized by SOC and PT for 
subjects treated with conventional tablet.
9.3
Clinical Laboratory Data
Descriptive statistics of actual measurements and changes from baseline of laboratory test 
parameters (excluding qualitative urinalysis) at each time point will be produced.
For each laboratory parameter (excluding qualitative parameters), measurements will be 
classified as "lower than the lower limit of the reference range," "within the reference 
range," and "higher than the upper limit of the reference range" using the reference range 
specified by the central laboratory, and a shift table from baseline will be produced.
 For qualitative laboratory parameters, a shift table from baseline will be produced.
The number and percentage of subjects with PCS laboratory test abnormalities will be 
determined. The criteria of PCS laboratory test abnormalities are provided in Appendix 1.


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The number and percentage of subjects with abnormal changes in liver function (Hy's 
Law cases) will be determined.
Definition of Hy’s Law Cases: 
ALT or AST >= 3xULN (or Baseline) and Bilirubin (total) >= 2xULN or Baseline
9.4
Vital Sign Data
Descriptive statistics of actual measurements and changes from baseline of each 
parameter at each time point will be produced. 
The number and percentage of subjects with PCS in vital signs and weight will be 
determined. The criteria of PCS vital sign abnormalities are provided in Appendix 2.
9.5
Physical Examination Data
Physical examination findings will be listed by subject.
9.6
Electrocardiogram Data
A shift table from baseline for normal/abnormal finding of 12-lead ECG will be produced.
Descriptive statistics of actual measurements and changes from baseline of each 
parameter at each time point will be produced.
The number and percentage of subjects with actual measurements of corrected QT 
interval (QTcF) 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 determined.
Incidence of PCS ECG abnormalities will also be summarized. The criteria of PCS ECG 
abnormalities are provided in Appendix 3.
9.7
Other Safety Data
9.7.1
DIEPSS
For the DIEPSS total score (sum of items 1 to 8) and the score for each item, descriptive 
statistics of actual measurements and changes from baseline at each time point will be 
produced. 


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9.7.2
C-SSRS
The number and percentage of subjects with each C-SSRS item (suicidality, suicidal 
ideation, suicidal behavior, completed suicide, emergence of suicidal ideation, emergence 
of serious suicidal ideation, worsening of suicidal ideation, and emergence of suicidal 
behavior) at each time point will be determined.
The definitions for each assessment other than completed suicide are defined as follows.
1) Suicidality: Defined as reporting any suicidal ideation or behavior
2) Suicidal ideation: Defined as reporting any type of suicidal ideation
3) Suicidal behavior: Defined as reporting any type of suicidal behavior
4) Emergence of suicidal ideation: Defined as having no suicidal ideation at baseline 
and reporting any type of ideation at postbaseline
5) Emergence of serious suicidal ideation: Defined as having no suicidal ideation at 
baseline and reporting serious suicidal ideation with a score of 4 or 5 on the 
suicidal ideation severity rating at postbaseline
6) Worsening of suicidal ideation: Defined as having a more severe rating in suicidal 
ideation rating assessment at postbaseline than at baseline
7) Emergence of suicidal behavior: Defined as having no suicidal behavior at 
baseline and reporting any type of behavior at postbaseline
10
Pharmacokinetic Analyses
10.1
Statistical Analyses of Primary and Secondary Pharmacokinetic 
Endpoints
The PK parameters of brexpiprazole (OPC-34712) for the QW formulation and 
conventional tablet at each dose will be determined using noncompartmental PK analysis. 
Descriptive statistics of the following variables will be produced.
10.1.1
Brexpiprazole QW Formulation
10.1.1.1
Period 2 of the Single Administration Period (Cohort 1 and 
Cohort 1’ [as Necessary])
1) Plasma concentration of OPC-34712 after a single administration of the QW 
formulation
2) PK parameters of OPC-34712 after a single administration of the QW formulation
Cmax, tmax, tlast, Cmax/D
3) Relative Cmax of OPC-34712 for the QW formulation as compared with a 
conventional tablet 
Relative Cmax (%)


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= (Cmax of QW formulation/dose of QW formulation)/(Cmax of conventional 
tablet/dose of conventional tablet) × 100
10.1.1.2
Period 3 of the Single Administration Period (Cohort 1 and 
Cohort 1’ [as Necessary])
1) Plasma concentration of OPC-34712 after a single administration of the QW 
formulation
2) PK parameters of OPC-34712 after a single administration of the QW formulation
Cmax, AUC∞, AUCt, tmax, λz, AUC_%Extrap, t1/2,z, CL/F, CL/F/BW, tlast, Cmax/D, 
AUC∞/D, AUCt/D
3) Relative bioavailability of OPC-34712 for the QW formulation as compared with 
a conventional tablet
Relative bioavailability (%)
= (AUC∞ of QW formulation/dose of QW formulation)/(AUC∞ of conventional 
tablet/dose of conventional tablet) × 100
4) Relative Cmax of OPC-34712 for the QW formulation as compared with a 
conventional tablet
Relative Cmax (%)
= (Cmax of QW formulation/dose of QW formulation)/(Cmax of conventional 
tablet/dose of conventional tablet) × 100
10.1.1.3
Period 2 of the Repeated Administration Period (Cohort 2)
1) Plasma concentration of OPC-34712 after the fifth administration of the QW 
formulation
2) PK parameters of OPC-34712 after the fifth administration of the QW 
formulation
Cmax, AUC168h, tmax, λz, t1/2,z, CL/F, CL/F/BW, tlast, Cmax/D, AUC168h/D
3) Plasma trough concentrations of OPC-34712 from the first to fifth administration 
of the QW formulation (C168h)
10.1.2
Brexpiprazole Conventional Tablet (for All Cohorts, Period 1)
1) Plasma concentration of OPC-34712 after a single administration of a 
conventional tablet
2) PK parameters of OPC-34712 after a single administration of a conventional 
tablet
Cmax, AUC∞, AUCt, tmax, λz, AUC_%Extrap, t1/2,z, CL/F, CL/F/BW, tlast, Cmax/D, 
AUC∞/D, AUCt/D


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10.2
Technical Details of Pharmacokinetic Statistical Analyses
1) Using the PK analysis set, the following analysis will be performed.
a) For each concentration in Section 10.1.1.1 1), Section 10.1.1.2 1), Section 
10.1.1.3 1) and 3), and Section 10.1.2 1)), descriptive statistics will be 
calculated by cohort, period, and treatment at each blood collection time point. 
The descriptive statistics to be calculated 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, the descriptive statistics will be calculated only when the number of 
subjects included in the tabulation exceeds half of the number of analyzed 
subjects. 
b) For each parameter in Section 10.1.1.1 2) and 3), Section 10.1.1.2 2), 3), and 
4), Section 10.1.1.3 2), and Section 10.1.2 2), descriptive statistics will be 
calculated by cohort, period, and treatment. For the PK parameters except for 
tmax and tlast, the descriptive statistics to be calculated 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. For tmax and tlast, descriptive statistics to be calculated 
will be number of analyzed subjects, minimum, median, and maximum. 
However, the descriptive statistics will be calculated only when the number of 
subjects included in the tabulation exceeds half of the number of analyzed 
subjects. For λz and λz(Rsq), λz(point), λz(upper) and λz(lower), which is 
outputted as reference values when calculating λz, no descriptive statics will 
be calculated.
2) Nonacceptance of data will be determined in accordance with the following 
conditions in this trial.
a) If blood sampling is conducted outside the time window for the analyses (see 
Table 3.7-3, Table 3.7-4 Table 3.7-5, Table 3.7-6 in the protocol), 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 PK parameters, and if the calculation of PK parameters is determined to be 
unsuitable, the parameter will not be adopted. 
b) None of the plasma concentrations after use of drugs or food (see Appendix 3 
in the protocol) which may inhibit or induce CYP2D6 or CYP3A4 activity 
will be used for calculating descriptive statistics at that time. 
3) The plasma concentrations below the lower limit of quantitation (LLOQ) that 
occur prior to the first measurable concentration of IMP administration in each 
period will be imputed to 0 (ng/mL) and if occur after the first measureable 
concentration, LLOQ will be set to missing. The LLOQ of OPC-34712 is 0.5000 
ng/mL.
4) If the PK sampling at the time of discontinuation is performed within the 
acceptable time window, the plasma concentrations will be used for the 
calculation of summary statistics.


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5) The PK parameters will be determined by subject and treatment using a 
noncompartmental PK analysis under the following conditions.
a) The actual time postdose will be used.
b) For the λz estimation, no weighting will be used for a regression equation.
c) For the AUC calculation, a linear trapezoidal rule will be used.
d) For the calculation of the weight correction parameters, the weight 
immediately before OPC-34712 administration of each period will be used.
11
Pharmacodynamic Analyses
Not applicable.
12
Pharmacogenomic Analyses
Not applicable. 
13
Analyses of Other Endpoints
13.1
Clinical Global Impression - Severity of Illness and Clinical Global 
Impression - Improvement
A list of subjects whose CGI-S or CGI-I has worsened will be provided.
14
Interim Analysis
Not applicable.
15 Changes in the Planned Analyses
The analysis plan in the Protocol Section 6.1.1.3 was corrected as follows.
<Old>
4) Accumulation of brexpiprazole after the fifth administration of the QW 
formulation as compared with that after the first administration [R5,ac(C168h)]
<New>
None
<Reason for the change>
No need to calculate the parameters.


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16
References
Not applicable.


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


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Appendix 2
Criteria for Identifying Vital Signs and Body Weight of 
Potential Clinical Relevance
Variable
Criterion Valuea
Change Relative to Baselinea
Pulse Rate
> 120 bpm
< 50 bpm
 15 bpm increase
 15 bpm decrease
Systolic Blood Pressure
> 180 mmHg
< 90 mmHg
 20 mmHg increase
 20 mmHg decrease
Diastolic Blood Pressure
> 105 mmHg
< 50 mmHg
 15 mmHg increase
 15 mmHg decrease
Weight
-
 7% increase
 7% decrease
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column.
Appendix 3
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance 
Variable
Criterion Valuea
Change Relative to Baselinea
Heart Rate
 120 bpm
 50 bpm
increase of   15 bpm
decrease of  15 bpm
PR
 200 msec
increase of   50 msec
QRS
 120 msec
increase of  20 msec
QTcF
> 450 msec
(males and females)
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column.


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Appendix 4
List of Summary Tables
CT-1.1
Subject Disposition (Cohort 1)
CT-1.2
Subject Disposition (Cohort 1’)
CT-1.3
Subject Disposition (Cohort 2)
CT-2.1.1
Reasons for Discontinuation  in Period 1 (Cohort 1)
CT-2.1.2
Reasons for Discontinuation  in Period 1 (Cohort 1’)
CT-2.1.3
Reasons for Discontinuation  in Period 1 (Cohort 2)
CT-2.2.1
Reasons for Discontinuation  in Period 2 (Cohort 1)
CT-2.2.2
Reasons for Discontinuation  in Period 2 (Cohort 1’)
CT-2.2.3
Reasons for Discontinuation  in Period 2 (Cohort 2)
CT-2.2.1
Reasons for Discontinuation  in Period 3 (Cohort 1)
CT-2.3.2
Reasons for Discontinuation  in Period 3 (Cohort 1’)
CT-3.1.1
Demographic and Baseline Characteristics - Pharmacokinetic Analysis Set (Cohort 1)
CT-3.1.2
Demographic and Baseline Characteristics - Pharmacokinetic Analysis Set (Cohort 1’)
CT-3.1.3
Demographic and Baseline Characteristics - Pharmacokinetic Analysis Set (Cohort 2)
CT-3.2.1
Demographic and Baseline Characteristics - Safety Analysis Set (Cohort 1)
CT-3.2.2
Demographic and Baseline Characteristics - Safety Analysis Set (Cohort 1’)
CT-3.2.3
Demographic and Baseline Characteristics - Safety Analysis Set (Cohort 2)
CT-7.1
Extent of Exposure (Cohort 2)
CT-8.1.1
Adverse Events (All Causalities) (Cohort 1)
CT-8.1.2
Adverse Events (All Causalities) (Cohort 1’)
CT-8.1.3
Adverse Events (All Causalities) (Cohort 2)
CT-8.2.1.1
Incidence of Treatment-Emergent Adverse Events by System Organ Class and 
MedDRA Preferred Term (Cohort 1)
CT-8.2.1.2
Incidence of Treatment-Emergent Adverse Events by System Organ Class and 
MedDRA Preferred Term (Cohort 1’)
CT-8.2.1.3
Incidence of Treatment-Emergent Adverse Events by System Organ Class and 
MedDRA Preferred Term (Cohort 2)
CT-8.2.2.1
Incidence of Treatment-Emergent Adverse Events by System Organ Class, MedDRA 
Preferred Term and Severity (Cohort 1)
CT-8.2.2.2
Incidence of Treatment-Emergent Adverse Events by System Organ Class, MedDRA 
Preferred Term and Severity (Cohort 1’)
CT-8.2.2.3
Incidence of Treatment-Emergent Adverse Events by System Organ Class, MedDRA 
Preferred Term and Severity (Cohort 2)
CT-8.3.1.1
Incidence of Drug-Related Treatment-Emergent Adverse Events by System Organ 
Class and MedDRA Preferred Term (Cohort 1)
CT-8.3.1.2
Incidence of Drug-Related Treatment-Emergent Adverse Events by System Organ 
Class and MedDRA Preferred Term (Cohort 1’)


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CT-8.3.1.3
Incidence of Drug-Related Treatment-Emergent Adverse Events by System Organ 
Class and MedDRA Preferred Term (Cohort 2)
CT-8.3.2.1
Incidence of Drug-related Treatment-Emergent Adverse Events by System Organ 
Class, MedDRA Preferred Term and Severity (Cohort 1)
CT-8.3.2.2
Incidence of Drug-related Treatment-Emergent Adverse Events by System Organ 
Class, MedDRA Preferred Term and Severity (Cohort 1’)
CT-8.3.2.3
Incidence of Drug-related Treatment-Emergent Adverse Events by System Organ 
Class, MedDRA Preferred Term and Severity (Cohort 2)
CT-8.4.1.1
Incidence of Serious Treatment-Emergent Adverse Events by System Organ Class and 
MedDRA Preferred Term (Cohort 1)
CT-8.4.1.2
Incidence of Serious Treatment-Emergent Adverse Events by System Organ Class and 
MedDRA Preferred Term (Cohort 1’)
CT-8.4.1.3
Incidence of Serious Treatment-Emergent Adverse Events by System Organ Class and 
MedDRA Preferred Term (Cohort 2)
CT-8.4.2.1
Incidence of Serious Drug-related Treatment-Emergent Adverse Events by System 
Organ Class and MedDRA Preferred Term (Cohort 1)
CT-8.4.2.2
Incidence of Serious Drug-related Treatment-Emergent Adverse Events by System 
Organ Class and MedDRA Preferred Term (Cohort 1’)
CT-8.4.2.3
Incidence of Serious Drug-related Treatment-Emergent Adverse Events by System 
Organ Class and MedDRA Preferred Term (Cohort 2)
CT-8.5.1.1
Incidence of Discontinuations due to Treatment-Emergent Adverse Events by System 
Organ Class and MedDRA Preferred Term (Cohort 1)
CT-8.5.1.2
Incidence of Discontinuations due to Treatment-Emergent Adverse Events by System 
Organ Class and MedDRA Preferred Term (Cohort 1’)
CT-8.5.1.3
Incidence of Discontinuations due to Treatment-Emergent Adverse Events by System 
Organ Class and MedDRA Preferred Term (Cohort 2)
CT-8.5.2.1
Incidence of Discontinuations due to Drug-related Treatment-Emergent Adverse 
Events by System Organ Class and MedDRA Preferred Term (Cohort 1)
CT-8.5.2.2
Incidence of Discontinuations due to Drug-related Treatment-Emergent Adverse 
Events by System Organ Class and MedDRA Preferred Term (Cohort 1’)
CT-8.5.2.3
Incidence of Discontinuations due to Drug-related Treatment-Emergent Adverse 
Events by System Organ Class and MedDRA Preferred Term (Cohort 2)
CT-8.6.1.1
Incidence of Treatment-Emergent Adverse Events by System Organ Class, MedDRA 
Preferred Term and Onset Time (Cohort 1)
CT-8.6.1.2
Incidence of Treatment-Emergent Adverse Events by System Organ Class, MedDRA 
Preferred Term and Onset Time (Cohort 1’)
CT-8.6.1.3
Incidence of Treatment-Emergent Adverse Events by System Organ Class, MedDRA 
Preferred Term and Onset Time (Cohort 2)
CT-8.6.2.1
Incidence of Drug-related Treatment-Emergent Adverse Events by System Organ 
Class, MedDRA Preferred Term and Onset Time (Cohort 1)
CT-8.6.2.2
Incidence of Drug-related Treatment-Emergent Adverse Events by System Organ 
Class, MedDRA Preferred Term and Onset Time (Cohort 1’)
CT-8.6.2.3
Incidence of Drug-related Treatment-Emergent Adverse Events by System Organ 
Class, MedDRA Preferred Term and Onset Time (Cohort 2)


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CT-8.7.1
Incidence of Adverse Events in Period 1 by System Organ Class and MedDRA 
Preferred Term (Cohort 1)
CT-8.7.2
Incidence of Adverse Events in Period 1 by System Organ Class and MedDRA 
Preferred Term (Cohort 1’)
CT-8.7.3
Incidence of Adverse Events in Period 1 by System Organ Class and MedDRA 
Preferred Term (Cohort 2)
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-10.1.1.1
Mean Change from Baseline in Clinical Laboratory Test Results - Serum Chemistry  
(Cohort 1)
CT-10.1.1.2
Mean Change from Baseline in Clinical Laboratory Test Results - Serum Chemistry  
(Cohort 1’)
CT-10.1.1.3
Mean Change from Baseline in Clinical Laboratory Test Results - Serum Chemistry 
(Cohort 2) 
CT-10.1.2.1
Mean Change from Baseline in Clinical Laboratory Test Results - Hematology 
(Cohort 1)
CT-10.1.2.2
Mean Change from Baseline in Clinical Laboratory Test Results - Hematology 
(Cohort 1’)
CT-10.1.2.3
Mean Change from Baseline in Clinical Laboratory Test Results - Hematology 
(Cohort 2)
CT-10.1.3.1
Mean Change from Baseline in Clinical Laboratory Test Results - Urinalysis (Cohort 
1)
CT-10.1.3.2
Mean Change from Baseline in Clinical Laboratory Test Results - Urinalysis (Cohort 
1’)
CT-10.1.3.3
Mean Change from Baseline in Clinical Laboratory Test Results - Urinalysis (Cohort 
2)
CT-10.2.1.1
Shift Tables of Clinical Laboratory Test Results - Serum Chemistry (Cohort 1)
CT-10.2.1.2
Shift Tables of Clinical Laboratory Test Results - Serum Chemistry (Cohort 1’)
CT-10.2.1.3
Shift Tables of Clinical Laboratory Test Results - Serum Chemistry (Cohort 2)
CT-10.2.2.1
Shift Tables of Clinical Laboratory Test Results - Hematology (Cohort 1)
CT-10.2.2.2
Shift Tables of Clinical Laboratory Test Results - Hematology (Cohort 1’)
CT-10.2.2.3
Shift Tables of Clinical Laboratory Test Results - Hematology (Cohort 2)
CT-10.2.3.1
Shift Tables of Clinical Laboratory Test Results - Urinalysis (Cohort 1)
CT-10.2.3.2
Shift Tables of Clinical Laboratory Test Results - Urinalysis (Cohort 1’)
CT-10.2.3.3
Shift Tables of Clinical Laboratory Test Results - Urinalysis (Cohort 2)
CT-10.3.1
Shift Tables of Clinical Laboratory Test Results - Qualitative Urinalysis (Cohort 1)
CT-10.3.2
Shift Tables of Clinical Laboratory Test Results - Qualitative Urinalysis (Cohort 1’)
CT-10.3.3
Shift Tables of Clinical Laboratory Test Results - Qualitative Urinalysis (Cohort 2)
CT-10.4.1.1
Incidence of Potentially Clinically Significant Laboratory Test Abnormalities (Cohort 
1)


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CT-10.4.1.2
Incidence of Potentially Clinically Significant Laboratory Test Abnormalities (Cohort 
1’)
CT-10.4.1.3
Incidence of Potentially Clinically Significant Laboratory Test Abnormalities (Cohort 
2)
CT-10.4.2
Listing of Potentially Clinically Significant Laboratory Test Abnormalities
CT-10.5.1.1
Incidence of Potential Hy's Law Cases (Cohort 1)
CT-10.5.1.2
Incidence of Potential Hy's Law Cases (Cohort 1’)
CT-10.5.1.3
Incidence of Potential Hy's Law Cases (Cohort 2)
CT-10.5.2
Listing of Potential Hy's Law Cases
CT-11.1.1
Mean Change from Baseline in Vital Signs and Weight (Cohort 1)
CT-11.1.2
Mean Change from Baseline in Vital Signs and Weight (Cohort 1’)
CT-11.1.3
Mean Change from Baseline in Vital Signs and Weight (Cohort 2)
CT-11.2.1.1
Incidence of Potentially Clinically Significant Vital Sign Abnormalities and Body 
Weight Changes (Cohort 1)
CT-11.2.1.2
Incidence of Potentially Clinically Significant Vital Sign Abnormalities and Body 
Weight Changes (Cohort 1’)
CT-11.2.1.3
Incidence of Potentially Clinically Significant Vital Sign Abnormalities and Body 
Weight Changes (Cohort 2)
CT-11.2.2
Listing of Potentially Clinically Significant Vital Sign Abnormalities
CT-11.2.3
Listing of Potentially Clinically Significant Body Weight Changes
CT-12.1.1
Mean Change from Baseline in Electrocardiogram Results (Cohort 1)
CT-12.1.2
Mean Change from Baseline in Electrocardiogram Results (Cohort 1’)
CT-12.1.3
Mean Change from Baseline in Electrocardiogram Results (Cohort 2)
CT-12.2.1
Shift Table of Electrocardiogram Findings (Cohort 1)
CT-12.2.2
Shift Table of Electrocardiogram Findings (Cohort 1’)
CT-12.2.3
Shift Table of Electrocardiogram Findings (Cohort 2)
CT-12.3.1
Categorical Analysis of Electrocardiogram Parameters (Cohort 1)
CT-12.3.2
Categorical Analysis of Electrocardiogram Parameters (Cohort 1’)
CT-12.3.3
Categorical Analysis of Electrocardiogram Parameters (Cohort 2)
CT-12.4.1.1
Incidence of Potentially Clinically Significant ECG Abnormalities (Cohort 1)
CT-12.4.1.2
Incidence of Potentially Clinically Significant ECG Abnormalities (Cohort 1’)
CT-12.4.1.3
Incidence of Potentially Clinically Significant ECG Abnormalities (Cohort 2)
CT-12.4.2
Listing of Potentially Clinically Significant ECG Abnormalities
CT-13.1.1
Mean Change from Baseline in DIEPSS (Cohort 1)
CT-13.1.2
Mean Change from Baseline in DIEPSS (Cohort 1’)
CT-13.1.3
Mean Change from Baseline in DIEPSS (Cohort 2)
CT-14.1.1
Columbia-Suicide Severity Rating Scale (C-SSRS) - Incidences of Suicidality (Cohort 
1)


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CT-14.1.2
Columbia-Suicide Severity Rating Scale (C-SSRS) - Incidences of Suicidality (Cohort 
1’)
CT-14.1.3
Columbia-Suicide Severity Rating Scale (C-SSRS) - Incidences of Suicidality (Cohort 
2)
CT-15.1
Listing of Subjects whose CGI-S has Worsened
CT-15.2
Listing of Subjects whose CGI-I has Worsened
PKT-X.X.1.X
Individual and Summary of Plasma Concentration Following Single Administration
PKT-X.X.2.X
Individual and Summary of Plasma Pharmacokinetic Parameters Following Single 
Administration
PKT-X.X.3.X
Individual and Summary of Plasma Concentration Following Multiple Administration
PKT-X.X.4.X
Individual and Summary of Plasma Trough Concentration Following Administration
PKT-X.X.5.X
Individual and Summary of Plasma Pharmacokinetic Parameters Following Multiple 
Administration
PKT-X.X.7.X:
Individual and Summary of Pharmacokinetic Parameter Ratios of QW Formulation to 
Conventional Tablet Following Oral Administration of OPC-34712
PKF-X.X.1.X
Mean Plasma Concentrations Following Single Administration
PKF-X.X.2.X
Median Plasma Concentrations Following Single Administration
PKF-X.X.3.X
Plasma Concentrations Following Single Administration
PKF-X.X.5.X
Mean Plasma Concentrations Following Multiple Administration
PKF-X.X.6.X
Median Concentrations Following Multiple Administration
PKF-X.X.7.X
Mean Plasma Trough Concentrations Following Administration
PKF-X.X.8.X
Median Trough Concentrations Following Administration
PKF-X.X.12.X
Plasma Concentrations Following Multiple Administration
PKF-X.X.13.X
Plasma Trough Concentrations Following Administration
PKF-X.X.19.X
Mean Plasma Concentrations Following Oral Administration of QW Formulation 
Versus Conventional Tablet
PKF-X.X.20.X
Individual Plasma Concentrations Following Oral Administration of QW Formulation 
Versus Conventional Tablet


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Appendix 5
List of Subject Data Listings
DREAS-1
Discontinued Subjects and Reason for Discontinuation
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
Inclusion/Exclusion Criteria Not Met
PDATA-2
Treatment Assignment
PDATA-3
Study Completion Status
PDATA-5
Medical History and Complications
PDATA-6.1
Concomitant Medications
PDATA-6.2
Concomitant Therapy
PDATA-8
Physical Examination
PDATA-10
Vital Signs
PDATA-11
Weight
PDATA-12
Electrocardiogram Results
PDATA-13
Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS)
PDATA-14.1
Columbia-Suicide Severity Rating Scale (C-SSRS) - Suicidal Ideation and Intensity
PDATA-14.2
Columbia-Suicide Severity Rating Scale (C-SSRS) - Suicidal Behavior
PDATA-14.3
Columbia-Suicide Severity Rating Scale (C-SSRS) - Actual Attempts
PDATA-15.1
Clinical Global Impression‐Severity (CGI-S)
PDATA-15.2
Clinical Global Impression - Improvement (CGI-I)
PDATA-16
Pharmacokinetic Blood Draw Time
PDATA-17
DNA Storage
PDATA-18
CYP2D6 Genetic Test
PDATA-19
Post-treatment Follow-up
PDATA-20
Screen Failures
PDATA-21
Subjects who discontinue by the sponsor’s circumstances and participate again
PDEV-1
Major Protocol Deviations