A Multi-center, Randomized, Double-blind, Placebo-controlled, Parallel Group-comparison Trial to Assess the Efficacy and Safety of Brexpiprazole as Adjunctive Therapy in Patients With Major Depressive Disorder
Phase: PHASE2
Conditions: Major Depressive Disorder
Sponsor: Otsuka Pharmaceutical Co., Ltd.

 
 
CLINICAL STUDY PROTOCOL 
 
 
 
A multi-center, randomized, double-blind, placebo-controlled, parallel group-comparison trial to 
assess the efficacy and safety of brexpiprazole as adjunctive therapy in patients with major depressive 
disorder 
 
 
 
 
NCT Number: NCT03697603 
PRT NO.: 331-102-00058 
Version Date: 23 Jan 2020 (Version 3.0) 

Protocol 331-102-00058 
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Otsuka Pharmaceutical Co., Ltd. 
 
Investigational Medicinal Product 
Brexpiprazole 
 
CLINICAL PROTOCOL 
 
A multi-center, randomized, double-blind, placebo-controlled, parallel group-comparison 
trial to assess the efficacy and safety of brexpiprazole as adjunctive therapy in patients 
with major depressive disorder 
 
Protocol No. 331-102-00058 
 
 
CONFIDENTIAL – PROPRIETARY INFORMATION 
 
Clinical Development Phase:  
2/3 
Sponsor: 
Otsuka Pharmaceutical Co., Ltd. 
Immediately Reportable Event: 
 
 
 
 
 
 
 
 
 
 
 
Issue Date: 
23 May 2018 
Amendment 1: 
23 Oct 2018 
Amendment 2: 
23 Jan 2020 
Version No.: 
3.0 

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Protocol Synopsis 
Name of Sponsor: Otsuka Pharmaceutical 
Co., Ltd. 
Name of Investigational Medicinal Product:  
Brexpiprazole (OPC-34712) 
Protocol No.: 331-102-00058 
 
Protocol Title: 
A multi-center, randomized, double-blind, placebo-controlled, 
parallel group-comparison trial to assess the efficacy and safety of 
brexpiprazole as adjunctive therapy in patients with major depressive 
disorder 
Clinical Phase/ 
Type of Trial: 
Phase 2/3 
Confirmatory study 
Treatment 
Indication: 
Patients with major depressive disorder ("major depressive disorder, 
single episode" or "major depressive disorder, recurrent episode") 
according to the classification criteria of the Diagnostic and 
Statistical Manual of Mental Disorders, fifth edition (DSM-5®) 
Objectives: 
Primary endpoint: To assess the dosage and efficacy of brexpiprazole 
as adjunctive therapy vs placebo in combination with antidepressants 
(selective serotonin reuptake inhibitor [SSRI] or serotonin-
noradrenaline reuptake inhibitor [SNRI]) in patients with major 
depressive disorder whose response to single-antidepressant therapy 
(SSRI or SNRI) was inadequate 
Secondary endpoint: To assess the safety of brexpiprazole as 
adjunctive therapy vs placebo in combination with antidepressants 
(SSRI or SNRI) in patients with major depressive disorder whose 
response to single-antidepressant therapy (SSRI or SNRI) was 
inadequate 
Trial Design: 
A multi-center, randomized, double-blind, placebo-controlled, 
parallel group-comparison trial 
Subject 
Population: 
The double-blind period (Phase B) of this trial will be conducted in 
patients ≥ 20 to < 65 years of age with major depressive disorder 
who showed inadequate response to commercially available 
antidepressant (SSRI or SNRI) in an 8-week evaluation performed in 
the antidepressant treatment period (Phase A). 
The planned number of subjects proceeding to the double-blind 
period (Phase B) is set as follows: brexpiprazole 1 mg/day group: 
240; brexpiprazole 2 mg/day group: 240; placebo group: 240; total: 
720. 
Inclusion/Exclusi
on Criteria: 
Inclusion criteria 
At screening 
1) Outpatients, or inpatients at the time of informed consent 
whose treatment status can be successfully shifted to 
outpatient status before enrollment in the antidepressant 
treatment period (Phase A) 
2) Male and female patients ≥ 20 to < 65 years of age (at the 

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time of informed consent) 
3) Patients who have a level of comprehension sufficient to 
allow them to give written informed consent to all of the 
observation/examination/evaluation items specified in the 
protocol, and who can understand the contents of the trial 
4) Patients with a DSM-5 classification-based diagnosis of 
"major depressive disorder, single episode" or "major 
depressive disorder, recurrent episode," and whose current 
episode has persisted for at least 8 weeks 
5) Patients who have received 1 to 3 adequate antidepressant 
drug treatments for the current major depressive episode and 
whose response to all of the treatments has been inadequate. 
Adequate antidepressant drug treatment: 
Treatment with an antidepressant at an approved dose for at 
least 6 weeks (for combination therapy, treatment for at least 
3 weeks) 
Inadequate response: 
With complete recovery from depressive symptoms and not 
the slightest improvement considered as 100% and 0%, 
respectively, patients carry out self-evaluations for 
improvement by antidepressant drug treatments used to date, 
from among 4 grades (< 25% Improvement, 25% to 49% 
Improvement, 50% to < 75% Improvement, and ≥ 75% 
Improvement), with the evaluations corresponding to < 25% 
Improvement or 25% to 49% Improvement classified as 
inadequate response. 
Patients who, among 1 to 3 adequate antidepressant drug 
treatments, have received treatment for ≥ 6 weeks at least 
once (receiving only combination therapies for ≥ 3 weeks 
does not qualify) are eligible for selection. 
6) Patients with a total score of ≥ 18 on the 17-item Hamilton 
Rating Scale for Depression (HAM-D), based on the 
evaluation conducted at screening 
At the initiation of the antidepressant treatment period (Phase A) 
7) Outpatients 
8) Subjects with a HAM-D 17-item total score of ≥ 18 based on 
the evaluation at the initiation of the antidepressant treatment 
period (Phase A) 
At the initiation of the double-blind period (Phase B) (criteria for 
proceeding) 
9) Outpatients 
10) Subjects with a HAM-D 17-item total score of ≥ 14 at 
Week 8 of the antidepressant treatment period (Phase A) 
11) Subjects in whom the reduction rate for HAM-D 17-item total 

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scores is < 50% at Week 8 of the antidepressant treatment 
period (Phase A), as compared with at the initiation of the 
antidepressant treatment period (Phase A). 
12) Subjects in whom Clinical Global Impression – Improvement 
(CGI-I) scores have been consistently 3 (minimally 
improved) to 7 (very much worse) throughout the 
antidepressant treatment period (Phase A) 
Exclusion criteria 
At screening 
1) Women who are pregnant or breastfeeding or who have 
positive pregnancy test (urine) results at screening 
2) Sexually active male subjects or sexually active female 
subjects of childbearing potential, who will not agree to 
practice 2 different methods of birth control or to remain 
abstinent during the trial and for 30 days after the final 
investigational medicinal product (IMP) administration. For 
birth control, 2 of the following methods must be used: 
vasectomy, tubal ligation, vaginal diaphragm, intra-uterine 
contraceptive device (IUD), oral contraceptives, or condom 
with spermicide. 
3) Patients who have received at least 4 appropriate 
antidepressant drug treatments for the current major 
depressive episode but whose response was inadequate to all 
treatments 
4) Patients receiving treatment with antipsychotics and 
psychostimulants for the current major depressive episode 
(excluding the use of sulpiride for depression/depressive state 
or gastric/duodenal ulcer) 
5) Patients with a treatment history showing that all 
antidepressants (including those not used for the current 
major depressive episode) cannot be tolerated 
6) Patients with a history of electroconvulsive therapy 
7) Patients with a diagnosis of any of the following diseases 
according to DSM-5 
a) Neurocognitive disorders 
b) Schizophrenia spectrum and other psychotic disorders 
c) Bipolar and related disorders 
d) Feeding and eating disorders 
e) Obsessive-compulsive disorder 
f) Panic disorder 
g) Posttraumatic stress disorder 
8) Patients with a diagnosis of any personality disorders 
(borderline personality disorder, antisocial personality 

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disorder, paranoid personality disorder, schizoid personality 
disorder, schizotypal personality disorder, and histrionic 
personality disorder) according to DSM-5 
9) Patients experiencing hallucinations or delusions, or showing 
mood-incongruent psychotic features, in the current major 
depressive episode 
10) Patients receiving a new psychotherapy within 6 weeks prior 
to informed consent 
11) Patients who have previously taken brexpiprazole 
12) Patients who have participated in other clinical trials within 
60 days prior to informed consent 
13) Patients with a HAM-D score for suicide (No. 11) of ≥ 3 at 
screening, those answering "Yes" to question 4 or 5 of 
Columbia-Suicide Severity Rating Scale (C-SSRS), or those 
who are, based on current psychiatric symptoms or past 
medical history, at high risk of suicide during the trial in the 
opinion of the investigator or subinvestigator 
14) Patients with clinically significant neurological, hepatic, 
renal, metabolic, hematological, immunological, 
cardiovascular, pulmonary, or gastrointestinal disorders; 
patients can be enrolled if the conditions are mild or well 
controlled and will not hamper assessment of safety and 
efficacy. 
15) 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 (assessed based on results 
from the central laboratory) 
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 
16) Patients with substance abuse or substance dependence, 
including alcohol and benzodiazepines, based on DSM-5 
diagnostic criteria within 180 days prior to informed consent; 
caffeine and nicotine are not included 
17) Patients with a complication of hypothyroidism or 
hyperthyroidism at informed consent (excluding those in a 

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stable condition due to medications for the previous 90 days 
or longer at acquisition of informed consent), or abnormal 
thyroid stimulating hormone (TSH) and free thyroxine (FT4) 
levels at screening (assessed based on results from the central 
laboratory) 
18) Patients meeting any of the following criteria or showing 
symptoms at screening 
a) Poorly controlled hypertension (diastolic blood pressure 
of > 95 mmHg) 
b) Hypotension with symptoms 
c) Orthostatic hypotension in which blood pressure after 3 
minutes of standing is ≥ 30 mmHg lower for systolic 
blood pressure or ≥ 20 mmHg lower for diastolic blood 
pressure, compared with pressures in the supine position 
before standing 
19) Patients with a complication of ischemic heart disease, 
myocardial infarction, or congestive heart failure (irrespective 
of well or poorly controlled), and patients with a history of 
angioplasty, stent placement, or coronary artery bypass 
20) Patients with a history of neuroleptic malignant syndrome or 
serotonin syndrome 
21) Patients with a history or complication of epilepsy or 
epileptic seizures, excluding pediatric febrile seizures, post-
traumatic seizures, alcohol withdrawal seizures, and other 
seizures 
22) Patients with the following clinical laboratory test values or 
electrocardiogram (ECG) parameters at screening (assessed 
based on results from the central laboratory and central ECG 
measurement facility) 
a) Platelet count: ≤ 75,000 /mm3 
b) Hemoglobin: ≤ 9 g/dL 
c) Absolute neutrophil count: ≤ 1000 /mm3 
d) Aspartate aminotransferase (AST): > 2 times the upper 
limit of the reference range 
e) Alanine aminotransferase (ALT): > 2 times the upper 
limit of the reference range 
f) Creatine phosphokinase (CPK): > 3 times the upper limit 
of the reference range 
g) Creatinine: ≥ 2 mg/dL 
h) QT interval as corrected by Fridericia’s formula (QTcF): 
≥ 450 msec 
23) Patients with a history of hypersensitivity to antidepressants 

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24) Patients with a history or complication of allergy to more than 
one medication 
25) The following patients falling under the contraindications in 
the package insert for brexpiprazole tablet 
a) Patients in a coma 
b) Patients under the strong influence of central nervous 
system depressants including barbiturate 
analogs/anesthetics 
c) Patient receiving adrenaline 
d) Patient with a history of hypersensitivity to components 
of brexpiprazole tablet 
26) Patients who otherwise should not participate in the trial in 
the opinion of the investigator or subinvestigator 
At the initiation of the antidepressant treatment period (Phase A) 
27) Pregnant or breastfeeding female subjects, or those with 
positive pregnancy test (urine) results at the initiation of the 
antidepressant treatment period (Phase A) 
28) Subjects newly requiring hospitalization for the current major 
depressive episode during the screening period 
29) Patients with a HAM-D score for suicide (No. 11) of ≥ 3 at 
the initiation of the antidepressant treatment period (Phase 
A), those answering "Yes" to question 4 or 5 of C-SSRS, or 
those who are, based on current psychiatric symptoms or past 
medical history, at high risk of suicide during the trial in the 
opinion of the investigator or subinvestigator 
30) Patients meeting any of the following criteria or showing 
symptoms at the initiation of the antidepressant treatment 
period (Phase A) 
a) Poorly controlled hypertension (diastolic blood pressure 
of > 95 mmHg) 
b) Hypotension with symptoms 
c) Orthostatic hypotension in which blood pressure after 3 
minutes of standing is ≥ 30 mmHg lower for systolic 
blood pressure or ≥ 20 mmHg lower for diastolic blood 
pressure, compared with pressures in the supine position 
before standing 
31) Subjects receiving treatment with monoamine oxidase 
(MAO) inhibitors within 2 weeks before the initiation of the 
antidepressant treatment period (Phase A) 
32) Subjects using benzodiazepines (excluding ultrashort-acting 
sleep inducers) within 1 week before the initiation of the 
antidepressant treatment period (Phase A) 
33) Subjects with urinary retention, if receiving milnacipran 

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34) Subjects with poorly controlled angle closure glaucoma, if 
receiving duloxetine 
35) Subjects who otherwise should not participate in the trial in 
the opinion of the investigator or subinvestigator 
Trial Sites: 
170 sites within Japan 
Investigational 
Medicinal 
Products, Dose, 
Dosage Regimen, 
Treatment Period, 
Formulation, 
Mode of 
Administration: 
Antidepressant Treatment period (Phase A) 
1) Drugs: 
Among commercially available SSRIs (fluvoxamine maleate, 
paroxetine hydrochloride hydrate, sertraline hydrochloride, 
and escitalopram oxalate) and SNRIs (milnacipran 
hydrochloride, duloxetine hydrochloride, and venlafaxine 
hydrochloride), one antidepressant different from the prior 
medications of antidepressant*, plus the placebo tablet 
*Antidepressant that meets the definition for "adequate 
antidepressant drug treatment" and has been taken at the time 
of informed consent. 
2) Dose and regimen: 
In the antidepressant treatment period (Phase A), subjects will 
orally receive an antidepressant (SSRI or SNRI), which is 
different from the antidepressant prior medications, plus a 
placebo tablet once daily in a single-blind manner. The 
antidepressant (SSRI or SNRI) will be administered at the 
dose and regimen specified in the package insert, and the 
dose of the antidepressant will be progressively increased, 
within the approved dose range, to the maximum dose, as far 
as possible, in accordance with subject status; for the last 
2 weeks of the 8-week period, dose and regimen will be 
fixed. When an antidepressant cannot be administered at a 
fixed dose and regimen for the last 2 weeks of the 8-week 
antidepressant treatment period (Phase A) for tolerability-
related reasons, the subject will be withdrawn from the trial. 
3) Treatment period: 8 weeks 
 
Double-blind period (Phase B) 
Subjects who meet the criteria for proceeding to the double-blind 
period (Phase B) based on the assessment at Week 8 of the 
antidepressant treatment period (Phase A) will proceed to the double-
blind period (Phase B). 
1) Drugs: 
• One commercially available antidepressant (SSRI or SNRI) 
used in the antidepressant treatment period (Phase A) 
• IMP: 
− 1 mg/day group: Brexpiprazole 1 mg tablet 
− 2 mg/day group: Brexpiprazole 1 mg tablet (until the 

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observations, examinations, and evaluations performed at 
Week 1) and brexpiprazole 2 mg tablet (following the 
observations, examinations, and evaluations performed at 
Week 1) 
− Placebo group: Placebo tablet 
2) Dose and regimen: 
• Commercially available antidepressant (SSRI or SNRI): 
An antidepressant (SSRI or SNRI) used in the antidepressant 
treatment period (Phase A) will be continued with no changes 
from the final dose and regimen; no changes in dose, 
regimen, or drug will be allowed. 
• IMP: 
− 1 mg/day group: One brexpiprazole 1 mg tablet will be 
orally administered once daily. 
− 2 mg/day group: Treatment will be started at 1 mg of 
brexpiprazole per day and one brexpiprazole 1 mg tablet 
will be orally administered once daily until the 
observations, examinations, and evaluations performed at 
Week 1. Following the observations, examinations, and 
evaluations performed at Week 1, one brexpiprazole 2 mg 
tablet will be orally administered once daily. 
− Placebo group: One placebo tablet will be orally 
administered once daily. 
3) Treatment period: 6 weeks 
 
Antidepressant-responder Treatment-continuation Period (Phase 
A+) 
Antidepressant responders who do not meet the criteria for 
proceeding to the double-blind period (Phase B) based on the 
assessment at Week 8 of the antidepressant treatment period (Phase 
A) will proceed to the antidepressant-responder treatment-
continuation period (Phase A+). 
1) Drugs: 
The antidepressant (SSRI or SNRI) used in the antidepressant 
treatment period (Phase A) plus a placebo tablet 
2) Dose and regimen: 
Subjects will receive an antidepressant (SSRI or SNRI) used 
in the antidepressant treatment period (Phase A) with no 
changes from the final dose and regimen, plus oral placebo (1 
tablet) once daily in a single-blind manner. 
3) Treatment period: 6 weeks 

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Trial 
Assessments: 
Efficacy: 
Montgomery Åsberg Depression Rating Scale (MADRS), CGI-I, 
Clinical Global Impression — Severity of Illness (CGI-S), HAM-D, 
the Montgomery Åsberg Depression Rating Scale Self-assessment 
(MADRS-S), Sheehan Disability Scale (SDS) 
 
Safety: 
Adverse events, laboratory tests, vital signs (body temperature, 
diastolic blood pressure and systolic blood pressure, and pulse rate 
[supine, sitting, and standing positions]), physical examinations, 
waist circumference, body weight, 12-lead ECG, pregnancy test, C-
SSRS, Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS), 
Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia 
Rating Scale (BARS) 
 
Screening: 
Subject demographics, height 
 
Pharmacokinetic and Pharmacogenomic Assessments and 
 
Plasma brexpiprazole concentrations, CYP2D6 genetic testing
 
Criteria for 
Evaluation 
Primary Endpoints: 
Mean changes from baseline (Week 8 of the antidepressant treatment 
period [Phase A]) in MADRS total scores at Week 6 of the double-
blind period (Phase B) 
 
Secondary Endpoints: 
• MADRS response rate at Week 6 of the double-blind period 
(Phase B) 
The proportion of subjects in whom MADRS total scores at 
Week 6 of the double-blind period (Phase B) have been reduced 
by at least 50% from baseline (Week 8 of the antidepressant 
treatment period [Phase A]) 
• MADRS remission rate at Week 6 of the double-blind period 
(Phase B) 
The proportion of subjects in whom MADRS total scores at 
Week 6 of the double-blind period (Phase B) have been reduced 
by at least 50% from baseline (Week 8 of the antidepressant 
treatment period [Phase A]), with their MADRS total scores, at 
Week 6 of the double-blind period (Phase B), being ≤ 10 
• CGI-I improvement rate at Week 6 of the double-blind period 
(Phase B) 
The proportion of subjects who score 1 or 2 on the CGI-I scale at 
Week 6 of the double-blind period (Phase B) 

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• Mean changes in CGI-S at Week 6 of the double-blind period 
(Phase B) 
Mean changes from baseline (Week 8 of the antidepressant 
treatment period [Phase A]) in CGI-S at Week 6 of the double-
blind period (Phase B) 
• Mean changes in HAM-D 17-item total scores at Week 6 of the 
double-blind period (Phase B) 
Mean changes from baseline (Week 8 of the antidepressant 
treatment period [Phase A]) in HAM-D 17-item total scores at 
Week 6 of the double-blind period (Phase B) 
• Mean changes in mean SDS scores at Week 6 of the double-blind 
period (Phase B) 
Mean changes from baseline (Week 8 of the antidepressant 
treatment period [Phase A]) in mean SDS scores at Week 6 of the 
double-blind period (Phase B) 
• Mean changes in MADRS-S total scores at Week 6 of the 
double-blind period (Phase B) 
Mean changes from baseline (Week 8 of the antidepressant 
treatment period [Phase A]) in MADRS-S total scores at Week 6 
of the double-blind period (Phase B) 
 
Safety Endpoints: 
Adverse events, laboratory tests, vital signs (body temperature, 
diastolic blood pressure and systolic blood pressure, and pulse rate 
[supine, sitting, and standing positions]), physical examinations, 
waist circumference, body weight, body mass index, 12-lead ECG, 
C-SSRS, DIEPSS, AIMS, BARS 
 
Pharmacokinetic and Pharmacogenomic Endpoints: 
Plasma brexpiprazole concentrations, CYP2D6 genetic testing 
Statistical 
Methods: 
Statistical Methods for Primary Endpoints: 
The primary endpoint is mean changes from baseline (Week 8 of the 
antidepressant treatment period [Phase A]) in MADRS total scores at 
Week 6 of the double-blind period (Phase B). For the primary 
analysis, Mixed-model Repeated Measure (MMRM) analysis will be 
performed using the observed cases data set in full analysis set. The 
statistical hypotheses will be tested, based on differences in least 
square means between each brexpiprazole group and the placebo 
group, which are calculated by MMRM. To adjust for multiplicity of 
tests, due to there being 2 comparisons with the placebo group, a 
fixed-sequence approach will be used to control overall type 1 error 
rates. Comparison between the brexpiprazole 2 mg/day group and 
placebo group will be performed first; only when significance is 
observed at a two-sided significance level of 5%, will comparison 
between the brexpiprazole 1 mg/day group and placebo group be 

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performed at a two-sided significance level of 5%. 
The MMRM will include treatment group (brexpiprazole 1 mg/day 
group, brexpiprazole 2 mg/day group, and placebo group), time point 
(double-blind period [Phase B] Weeks 1, 2, 3, 4, 5, and 6), and 
interaction between treatment group and time point as factors, and 
baseline and interaction between baseline and time point as 
covariates. Unstructured error variance-covariance structure will be 
assumed. For a degree-of-freedom approximation, the Kenward-
Roger method will be used. 
For each time point, least square means of each treatment group and 
differences in least square means between each brexpiprazole group 
and the placebo group, as well as the two-sided 95% confidence 
intervals (CIs) will be determined. 
 
Rationale for target number of subjects: 
In phase 3, double-blind, placebo-controlled trials of fixed doses of 
brexpiprazole (331-10-227, 331-10-228, and 331-13-214) conducted 
outside Japan, changes from baseline in MADRS total scores at 
Week 6 of the double-blind period (Phase B) have been analyzed by 
the MMRM method (for 331-10-227 and 331-10-228 trials, based on 
the results for efficacy from an analysis of subgroups meeting the 
inclusion criteria that had been revised in the middle of the trials), 
which demonstrated that the differences between the brexpiprazole 
groups (the 3 mg group in 331-10-227 trial, and the 2 mg group in 
331-10-228 and 331-13-214 trials) and the placebo group were −1.9, 
−3.2, and −2.3, respectively, and that the standard deviations 
obtained from standard errors and numbers of subjects at Week 6 of 
the double-blind period (Phase B) were 7.2, 7.7, and 8.2, 
respectively. On the assumption that the difference in changes from 
baseline in MADRS total scores at Week 6 of the double-blind 
period (Phase B) is −2.4 for the brexpiprazole group compared with 
the placebo group with a standard deviation of 7.7, this trial will 
require 218 subjects per group to ensure a power of 90% in a two-
sided test with a significance level of 0.05. We have decided that the 
planned number of subjects for randomization will be 240 per group, 
assuming that 7% of subjects will discontinue the trial during the 
double-blind period (Phase B) and some subjects will be excluded 
from analysis. 
Trial Duration: 
01 Jun 2018 to 31 Jul 2022 (planned) 

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Table of Contents 
Protocol Synopsis ........................................................................................... 2 
Table of Contents ......................................................................................... 13 
List of In-text Tables ................................................................................... 19 
List of In-text Figures .................................................................................. 20 
List of Appendices........................................................................................ 21 
List of Abbreviations and Definitions of Terms ....................................... 22 
1 
Introduction .......................................................................................................24 
1.1 
Nonclinical Data .............................................................................................26 
1.2 
Clinical Data ...................................................................................................28 
1.2.1 
Clinical Data From Japanese Trials in Subjects With Schizophrenia .........28 
1.2.1.1 
Dose-finding Trial in Subjects With Schizophrenia (331-10-002) .........28 
1.2.1.2 
Long-term Trial in Subjects With Schizophrenia (331-10-003) .............29 
1.2.2 
Clinical Data From Overseas Trials in Subjects With Major 
Depressive Disorder ....................................................................................29 
1.2.2.1 
Confirmatory Trial in Subjects With Major Depressive Disorder 
(331-10-227) ............................................................................................29 
1.2.2.2 
Confirmatory Trial in Subjects With Major Depressive Disorder 
(331-10-228) ............................................................................................30 
1.2.2.3 
Confirmatory Trial in Subjects With Major Depressive Disorder 
(331-13-214) ............................................................................................31 
1.3 
Known and Potential Risks and Benefits........................................................32 
2 
Trial Rationale and Objectives ..........................................................................32 
2.1 
Trial Rationale ................................................................................................32 
2.2 
Rationale for CYP2D6 Genetic Testing and DNA Storage ............................34 
2.3 
 ...............................35 
2.4 
Rationale for Dosing and Regimen .................................................................35 
2.4.1 
Rational for Regimen ..................................................................................35 
2.4.2 
Rationale for Dosage ...................................................................................35 
2.4.2.1 
Rationale for Treatment Groups ..............................................................35 
2.4.2.2 
Rationale for a Starting Dose of 1 mg/day ..............................................36 
2.5 
Trial Objectives ..............................................................................................36 
3 
Trial Design .......................................................................................................37 

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3.1 
Type/Design of Trial .......................................................................................37 
3.2 
Trial Treatments ..............................................................................................38 
3.2.1 
Antidepressant Treatment Period (Phase A) ...............................................38 
3.2.2 
Double-blind Period (Phase B) ...................................................................39 
3.2.3 
Antidepressant-responder Treatment-continuation Period (Phase A+) ......40 
3.3 
Trial Population ..............................................................................................41 
3.3.1 
Number of Subjects and Trial Population ...................................................41 
3.3.2 
Subject Number Assignment ......................................................................42 
3.4 
Eligibility Criteria ...........................................................................................42 
3.4.1 
Informed Consent ........................................................................................42 
3.4.2 
Inclusion Criteria .........................................................................................43 
3.4.3 
Exclusion Criteria........................................................................................44 
3.5 
Endpoints ........................................................................................................47 
3.5.1 
Primary Endpoint(s) ....................................................................................47 
3.5.2 
Secondary Endpoint(s) ................................................................................48 
3.5.3 
Safety Endpoints .........................................................................................49 
3.5.4 
Pharmacokinetic Endpoint ..........................................................................49 
3.5.5 
Pharmacogenomic Endpoint .......................................................................49 
3.6 
Measures to Minimize/Avoid Bias .................................................................49 
3.7 
Trial Procedures ..............................................................................................50 
3.7.1 
Schedule of Assessments ............................................................................53 
3.7.1.1 
Informed Consent ....................................................................................54 
3.7.1.2 
Screening .................................................................................................54 
3.7.1.3 
Observations/Examinations at the Initiation of the Antidepressant 
Treatment Period (Phase A) ....................................................................55 
3.7.1.4 
Observations/Examinations During the Antidepressant Treatment 
Period (Phase A) ......................................................................................56 
3.7.1.5 
Observations/Examinations During the Double-blind Period (Phase 
B) .............................................................................................................56 
3.7.1.6 
Observations/Examinations During the Antidepressant-responder 
Treatment-continuation Period (Phase A+) .............................................57 
3.7.1.7 
Observations/Examinations in the Post-treatment Observation 
Period .......................................................................................................57 
3.7.1.8 
Examinations at Discontinuation .............................................................57 

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3.7.1.9 
Acceptable Window for Testing ..............................................................58 
3.7.2 
Efficacy Assessments ..................................................................................60 
3.7.2.1 
Montgomery Åsberg Depression Rating Scale .......................................60 
3.7.2.2 
Clinical Global Impression – Improvement ............................................60 
3.7.2.3 
Clinical Global Impression - Severity of Illness .....................................61 
3.7.2.4 
Hamilton Rating Scale for Depression ....................................................61 
3.7.2.5 
Sheehan Disability Scale .........................................................................62 
3.7.2.6 
Montgomery Åsberg Depression Rating Scale Self-assessment .............62 
3.7.3 
Safety Assessments .....................................................................................63 
3.7.3.1 
Adverse Events ........................................................................................63 
3.7.3.2 
Clinical Laboratory Assessments ............................................................63 
3.7.3.3 
Vital Signs and Physical Examination ....................................................64 
3.7.3.4 
12-lead Electrocardiography ...................................................................66 
3.7.3.5 
Pregnancy Test ........................................................................................67 
3.7.3.6 
Columbia-Suicide Severity Rating Scale ................................................68 
3.7.3.7 
Drug Induced Extra-Pyramidal Symptoms Scale ....................................69 
3.7.3.8 
Abnormal Involuntary Movement Scale .................................................69 
3.7.3.9 
Barnes Akathisia Rating Scale ................................................................69 
3.7.4 
Prior and Concomitant Medications and Therapies ....................................70 
3.7.5 
Investigational Medicinal Product ..............................................................70 
3.7.6 
Requisite Concomitant Medication .............................................................71 
3.7.7 
Pharmacokinetic Assessment, Pharmacogenomic Assessment
 ................................................................................71 
3.7.7.1 
Pharmacokinetic Assessment ..................................................................71 
3.7.7.1.1 
Blood Sampling Time Point ................................................................72 
3.7.7.1.2 
Plasma Samples for Pharmacokinetic Assessment ..............................72 
3.7.7.2 
Pharmacogenomic Assessment ...............................................................72 
3.7.7.2.1 
CYP2D6 Genetic Testing ....................................................................72 
3.7.7.2.1.1 
Blood Sampling Time Point ..............................................................73 
3.7.7.2.1.2 
Samples for CYP2D6 Genetic Testing ..............................................73 
3.7.7.2.2 
 ........................................................................................73 
3.7.7.2.2.1 
 ................................................................73 
3.7.7.2.2.2 
 .......................................................73 

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3.7.7.2.2.3 
Timing of Blood Sampling ................................................................73 
3.7.7.2.2.4 
Handling of Samples .........................................................................73 
3.7.7.2.2.5 
 ................................................................74 
3.7.7.2.2.6 
 ..................................................74 
3.7.7.2.2.7 
 ..........75 
3.7.7.3 
 ......................................75 
3.7.7.3.1 
Objective ..............................................................................................75 
3.7.7.3.2 
Target Population .................................................................................75 
3.7.7.3.3 
Blood Collection Time Points ..............................................................75 
3.7.7.3.4 
Handling of Samples ............................................................................75 
3.7.7.3.5 
.........................................................................76 
3.7.7.3.6 
...............................76 
3.7.7.3.7 
........................76 
3.7.8 
End of Trial .................................................................................................77 
3.8 
Stopping Rules, Withdrawal Criteria, and Procedures ...................................77 
3.8.1 
Entire Trial ..................................................................................................77 
3.8.2 
Individual Site .............................................................................................77 
3.8.3 
Individual Subject Discontinuation .............................................................77 
3.8.3.1 
Treatment Discontinuation ......................................................................77 
3.8.3.2 
Documenting Reasons for Discontinuation .............................................77 
3.8.3.3 
Withdrawal of Consent ............................................................................79 
3.8.3.4 
Procedures to Encourage Continued Trial Participation .........................80 
3.9 
Screen Failures ................................................................................................80 
3.10 
Definition of Completed Subjects ..................................................................81 
3.11 
Definition of Subjects Lost to Follow-up .......................................................81 
3.12 
Subject Compliance ........................................................................................81 
3.13 
Protocol Deviations ........................................................................................82 
4 
Restrictions ........................................................................................................82 
4.1 
Prohibited Concomitant Medications .............................................................82 
4.2 
Prohibited Concomitant Therapies .................................................................85 
4.3 
Restricted Concomitant Drugs ........................................................................85 
5 
Reporting of Adverse Events ............................................................................86 
5.1 
Definitions ......................................................................................................86 

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5.2 
Eliciting and Reporting Adverse Events .........................................................88 
5.3 
Immediately Reportable Events ......................................................................88 
5.4 
Potential Drug-induced Liver Injury ..............................................................89 
5.5 
Pregnancy .......................................................................................................89 
5.6 
Procedure for Breaking the Blind ...................................................................91 
5.7 
Follow-up of Adverse Events .........................................................................91 
5.7.1 
Follow-up of Nonserious Adverse Events ..................................................91 
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 and Immediately 
Reportable Events Occurring After the End of Trial Date (Final Day 
of Observation)............................................................................................92 
6 
Pharmacokinetic/Pharmacogenomic/ 
 ...........92 
6.1 
Pharmacokinetic Analysis Methods ...............................................................92 
6.2 
Pharmacogenomic Analysis Methods.............................................................92 
6.3 
 .....................................................................92 
7 
Statistical Analysis ............................................................................................92 
7.1 
Determination of Sample Size ........................................................................93 
7.2 
Datasets for Analysis ......................................................................................93 
7.2.1 
Pharmacokinetic Analysis Set .....................................................................93 
7.2.2 
Full Analysis Set .........................................................................................93 
7.2.3 
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.....................................................................95 
7.4.3 
Interim Analysis ..........................................................................................95 
7.5 
Analysis of Demographic and Baseline Characteristics .................................96 
7.6 
Safety Analysis ...............................................................................................96 
7.6.1 
Adverse Events............................................................................................96 
7.6.2 
Clinical Laboratory Data .............................................................................96 
7.6.3 
Physical Examination and Vital Signs Data................................................97 
7.6.4 
Electrocardiogram Data ..............................................................................97 

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7.6.5 
Other Safety Data ........................................................................................97 
8 
Management of Investigational Medicinal Product ..........................................98 
8.1 
Packaging and Labeling ..................................................................................98 
8.2 
Storage ............................................................................................................98 
8.3 
Accountability .................................................................................................99 
8.4 
Returns and Destruction .................................................................................99 
8.5 
Reporting of Product Quality Complaints ......................................................99 
8.5.1 
Eliciting and Reporting Product Quality Complaints .................................99 
8.5.2 
Information Required for Reporting Product Quality Complaints ...........100 
8.5.3 
Return Process for Product Quality Complaints .......................................100 
8.5.4 
Assessment/Evaluation .............................................................................100 
9 
Records Management ......................................................................................100 
9.1 
Source Documents ........................................................................................100 
9.2 
Data Collection .............................................................................................101 
9.3 
File Management at the Trial Site ................................................................101 
9.4 
Record Retention at the Trial Site ................................................................102 
10 
Quality Control and Quality Assurance ..........................................................102 
10.1 
Monitoring ....................................................................................................102 
10.2 
Auditing ........................................................................................................102 
11 
Ethics and Responsibility ................................................................................103 
12 
Confidentiality .................................................................................................103 
13 
Amendment Policy ..........................................................................................103 
14 
Publication Authorship Requirements.............................................................104 
15 
References .......................................................................................................105 
 

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List of In-text Tables 
Table 3.4.2-1 
Inclusion Criteria .......................................................................... 43 
Table 3.4.3-1 
Exclusion Criteria ......................................................................... 44 
Table 3.7-1 
Schedule of Assessments (Screening Period and 
Antidepressant Treatment Period [Phase A]) ............................... 51 
Table 3.7-2 
Schedule of Assessments (Double-blind Period [Phase B]) ......... 52 
Table 3.7-3 
Schedule of Assessments (Antidepressant-responder 
Treatment-continuation Period [Phase A+]) ................................. 53 
Table 3.7.1.9-1 
Acceptable Window for Examinations/Assessment Period .......... 58 
Table 3.7.3.2-1 
Clinical Laboratory Assessments .................................................. 64 
 
 

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List of In-text Figures 
Figure 3.1-1 
Trial Design .................................................................................. 38 
 
 

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List of Appendices 
Appendix 1 
Handling and Shipping of Bioanalytical Samples ...................... 107 
Appendix 2 
CYP2D6 Genotyping Table ........................................................ 110 
Appendix 3 
Criteria for Allowing Concomitant Use of Topical CYP2D6 
Inhibitors, CYP3A4 Inhibitors, and CYP3A4 Inducers.............. 114 
Appendix 4 
Protocol Amendments/Administrative Changes ......................... 117 
 
 

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List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
5-HT 
5-Hydroxytryptamine, serotonin 
AIMS 
Abnormal Involuntary Movement Scale 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BARS 
Barnes Akathisia Rating Scale 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CGI 
Clinical Global Impression 
CGI-I 
Clinical Global Impression - Improvement 
CGI-S 
Clinical Global Impression - Severity of Illness 
CK 
Creatine kinase 
CPK 
Creatine phosphokinase 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
Cytochrome P450 
D2 receptor 
Dopamine D2 receptor 
DIEPSS 
Drug Induced Extra-Pyramidal Symptoms Scale 
DILI 
Drug induced liver injury 
DNA 
Deoxyribonucleic acid 
DSM-5 
Diagnostic and statistical manual of mental disorders fifth edition 
EDTA 
Ethylenediaminetetraacetic acid 
EM 
Extensive metabolizer 
FAS 
Full analysis set 
FT4 
Free thyroxine 
GCP 
Good Clinical Practice  
GOT 
Glutamic-oxaloacetic transaminase 
GPT 
Glutamic-pyruvic transaminase 
HAM-D 
Hamilton Rating Scale for Depression 
HbA1c 
Glycosylated hemoglobin 
HDL 
High-density lipoprotein 
ICH 
The International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICMJE 
International Committee of Medical Journal Editors 
IRE 
Immediately reportable event 
IM 
Intermediate metabolizer 
IRB 
Institutional review board 
IWRS 
Interactive web response system 
JSMD 
Japanese Society of Mood Disorders 
LDH 
Lactate (lactic acid) dehydrogenase 
LDL 
Low-density lipoprotein 
LOCF 
Last observation carried forward 
LSMD 
Least square mean difference 
MADRS 
Montgomery Åsberg Depression Rating Scale 
MADRS-S 
The Montgomery Åsberg Depression Rating Scale Self-assessment 

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Abbreviation 
Definition 
MAO inhibitor 
Monoamine oxidase inhibitor 
MOR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHLW 
Ministry of Health, Labour and Welfare 
MMRM 
Mixed-model repeated measures 
MNOR 
Missing not at random 
NGSP 
The National Glycohemoglobin Standardization Program 
OC 
Observed Cases 
PANSS 
Positive and Negative Syndrome Scale 
PM 
Poor metabolizer 
PQC 
Product quality complaint 
PT 
Prothrombin time 
PT (INR) 
Prothrombin time (international normalized ratio) 
QTc 
QT corrected for heart rate 
QTcB 
QT corrected for heart rate by Bazett’s formula 
QTcF 
QT corrected for heart rate by Fridericia’s formula 
QTcN 
QT corrected for heart rate by FDA Neuropharmacological Division formula 
SDS 
Sheehan Disability Scale 
SIGH-D 
Structured Interview Guide for HAM-D 
SIGMA 
Structured Interview Guide for MADRS 
SNRI 
Serotonin-noradrenaline reuptake inhibitor 
SSRI 
Selective serotonin reuptake inhibitor 
T3/T4 
Triiodothyronine/levothyroxine 
TEAE 
Treatment-emergent adverse event; adverse event occurring after initiation of IMP 
administration in the double-blind period (Phase B) 
TSH 
Thyroid-stimulating hormone 
γ-GTP 
γ-glutamyl transpeptidase 
 

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1 
Introduction 
Depression is a condition that often takes a chronic course, causing significant suffering 
and imposing a burden on the patient. The disease interferes with the daily activities and 
social life of patients, who continue to suffer from decreased social functioning unless the 
disease remits.1 Moreover, depression is one of the major risk factors for suicide and, 
according to a psychological autopsy study, 60% to 70% of those who committed suicide 
had been diagnosed with depression.2 The number of suicides in Japan, even though a 
downward trend has been noted since 2012, was 21897 in 2016,3 which is still high 
compared with other developed countries. According to a published report by the 
Ministry of Health, Labour and Welfare (MHLW), the economic loss from depression 
resulting in leaves of absence from work, loss of employment, or suicide, etc, is estimated 
to be approximately 2.7 trillion yen in 2009.4 Decreased social functioning and increased 
suicide rate attributable to depression have become serious social problems. Under this 
circumstance, treatment of depression plays an important role in society. 
The lifetime and 12-month prevalence of major depressive disorder in Japan were 6.2% 
and 2.1%, respectively, according to “Study on Mental Health Epidemiological Survey,” 
a study supported by the Health and Labour Sciences Research Grants from fiscal year 
2004 to 2006.5 The Treatment Guidelines issued by the Japanese Society of Mood 
Disorders (JSMD) (hereinafter referred to as JSMD Treatment Guidelines)6 list 
pharmacotherapy with antidepressants as the mainstay in the treatment of major 
depressive disorder. As first-line agents, the guidelines recommend the following novel 
antidepressants: selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline 
reuptake inhibitors (SNRIs), and mirtazapine, a noradrenergic and specific serotonergic 
antidepressant. However, remission rates in patients treated with these antidepressants are 
as low as 30% to 40%.7 This difficulty in improving or achieving remission of major 
depressive disorder symptoms interferes with social functioning, causing various issues 
including loss of employment, withdrawal from education, and divorce. 
In the JSMD Treatment Guidelines,6 the following therapeutic methods are 
recommended for patients who fail to respond to the initial treatment with first-line 
agents such as SSRIs, SNRIs, and mirtazapine: Increase the dose to a sufficient level 
within the range in which adverse reactions are not clinically problematic; treat at the 
sufficiently increased dose for approximately 4 weeks; and then either change the drug if 
the patient does not respond to the treatment, or perform augmentation therapy if 
improvement is noted only in some of the symptoms of depression. Agents used for 
augmentation therapy include lithium, triiodothyronine/levothyroxine combination 

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(T3/T4), lamotrigine, valproic acid, carbamazepine, and atypical antipsychotics. While 
augmentation therapy with lithium has been reported to potentiate the antidepressant 
effects of drugs in many placebo-controlled studies,8 most of the drugs investigated in 
such studies were tricyclic antidepressants. Therefore, little data are available on 
augmentation of SSRIs or SNRIs at present. As a result of a meta-analysis on lithium 
toxicity profile,9 renal impairment, hypothyroidism, increased blood calcium level, and 
hyperparathyroidism were reported as adverse effects of particular concern. Special 
attention should be paid to the occurrence of these adverse effects during treatment with 
lithium. Concerning augmentation therapy with T3/T4, most of the available data are also 
from studies on tricyclic antidepressants. Furthermore, the efficacy of augmentation 
therapy with lamotrigine, valproic acid, or carbamazepine has not been sufficiently 
investigated. In addition, augmentation therapy with lithium, T3/T4, lamotrigine, valproic 
acid, or carbamazepine has not been approved for the indication of depression. 
Meanwhile, concerning augmentation therapy with atypical antipsychotics mediated by 
the dopaminergic system, aripiprazole is the only antipsychotic agent that has been 
approved in Japan for use as an adjunctive therapy for the treatment of major depressive 
disorder. The efficacy of aripiprazole was confirmed in a Japanese double-blind, placebo-
controlled trial (031-08-001)10 and 3 overseas double-blind trials of aripiprazole.11,12,13 
However, the results of these clinical trials suggest that a certain percentage of patients 
cannot tolerate long-term use of aripiprazole as adjunctive therapy due to adverse events 
(AEs) such as akathisia and insomnia. This drawback of aripiprazole as an adjunctive 
therapy remains a therapeutic issue. 
Brexpiprazole is a new chemical entity discovered by Otsuka Pharmaceutical Co., Ltd. 
Unlike aripiprazole, brexpiprazole, even at a low level of < 1 nM, exhibits serotonin (5-
HT)1A receptor partial agonist activity, 5-HT2A receptor antagonist activity, and 
dopamine D2 receptor (D2 receptor) partial agonist activity with optimal intrinsic activity. 
The pharmacology of brexpiprazole is believed to be mediated by a combination of high 
binding affinity and functional activities at multiple monoaminergic receptors. It 
modulates the serotonergic and dopaminergic systems with its partial agonist activity or 
antagonist activity. In addition, for adrenergic α1B/2C receptors, it also has similar 
subnanomolar binding affinity and antagonist activity. These 5-HT1A/D2 receptor partial 
agonist activities and 5-HT2A and α1B/2C receptor antagonist activities of brexpiprazole 
are thought to contribute to the antipsychotic, antidepressant, and impulse-control effects. 
Having the optimal intrinsic activity for D2 receptors and potent effects on the 
serotonergic system compared with aripiprazole, brexpiprazole is expected to contribute 

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to a reduction in the incidence and severity of adverse reactions, such as akathisia and 
insomnia, which are issues associated with treatment using aripiprazole. 
In Japan, brexpiprazole was investigated in a double-blind, placebo-controlled trial in 
patients with an acute relapse of schizophrenia (331-10-002)14 and in a long-term trial in 
outpatients with schizophrenia (331-10-003).15 Based on the results of these trials as well 
as overseas clinical trials, an application was filed for marketing authorization of 
brexpiprazole for the indication of schizophrenia, which was approved in January 2018.16 
Outside Japan, double-blind, placebo-controlled trials in patients with an acute relapse of 
schizophrenia (331-10-230 and 331-10-231) were performed, and the results confirmed 
the efficacy of brexpiprazole and demonstrated its safety.17,18 In addition, double-blind, 
placebo-controlled trials in patients with major depressive disorder who had insufficient 
responses to SSRIs or SNRIs (331-10-227 and 331-10-228) were performed, and the 
results confirmed the efficacy of brexpiprazole as adjunctive treatment and demonstrated 
its safety in this patient population.19,20 Based on the results of the above clinical trials, 
brexpiprazole was approved in the US not only for the indication of schizophrenia but 
also received approval as adjunctive treatment of major depressive disorder.21 
As shown above, outside Japan, the efficacy of brexpiprazole was demonstrated not only 
in treating schizophrenia but also as adjunctive treatment for major depressive disorder. 
Therefore, brexpiprazole as adjunctive therapy is also likely to be effective in Japanese 
patients with inadequate response to antidepressants. The results of overseas clinical trials 
show that there are no safety-related concerns associated with brexpiprazole as adjunctive 
therapy. Therefore, use of brexpiprazole as adjunctive therapy is expected to reduce the 
incidence of adverse reactions such as akathisia and insomnia, which are issues 
associated with augmentation therapy using aripiprazole, and to enhance treatment 
adherence. 
Based on the above, considering that it would be useful for the treatment of patients with 
major depressive disorder to investigate the efficacy and safety of brexpiprazole as 
adjunctive therapy in Japanese patients with inadequate response to antidepressants, we 
have planned to conduct this clinical trial. 
1.1 
Nonclinical Data 
 
 

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1.2 
Clinical Data 
1.2.1 
Clinical Data From Japanese Trials in Subjects With 
Schizophrenia 
1.2.1.1 
Dose-finding Trial in Subjects With Schizophrenia (331-10-002) 
A double-blind, placebo-controlled trial was conducted in Japan to assess the efficacy 
and safety of fixed-dose brexpiprazole in adult subjects with an acute relapse of 
schizophrenia. This trial had a total of 4 groups consisting of a placebo group and 3 
fixed-dose groups of brexpiprazole (1, 2, and 4 mg/day). The change from baseline to 
Week 6 in the Positive and Negative Syndrome Scale (PANSS) total score, the primary 
endpoint, showed significant improvement in the 2-mg group compared with the placebo 
group (least square 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 the 
PANSS total score was numerically greater in the 4-mg group than in the placebo group 
(LSMD: −3.86, p = 0.1959). There was no significant difference between the 1-mg group 
and the placebo group (LSMD = −0.63). 
The efficacy of brexpiprazole at a dose of 2 mg was demonstrated in subjects with an 
acute relapse of schizophrenia. 
The incidence of AEs 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. Most AEs reported in brexpiprazole groups were mild or moderate in 
severity. One subject in the 4-mg group died. The AE resulting in death was asphyxia. 
This event was considered unrelated to the investigational medicinal product (IMP). The 
incidence of serious adverse events (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 any 
treatment group, 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 in any treatment 
group. No marked changes were noted in laboratory test values, vital signs, body weight, 
or electrocardiogram (ECG) in brexpiprazole groups. 

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1.2.1.2 
Long-term Trial in Subjects With Schizophrenia (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. 
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. 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 body weight from 
baseline to the final assessment 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 
findings 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. 
All efficacy endpoints, including the PANSS total score and Clinical Global Impression - 
Severity of Illness (CGI-S) score, remained stable until Week 52. 
1.2.2 
Clinical Data From Overseas Trials in Subjects With Major 
Depressive Disorder 
1.2.2.1 
Confirmatory Trial in Subjects With Major Depressive Disorder 
(331-10-227) 
A double-blind, placebo-controlled trial was conducted outside Japan to evaluate the 
efficacy, safety, and tolerability of fixed doses of brexpiprazole in subjects with major 
depressive disorder who had an insufficient response to antidepressant therapy. All 
eligible subjects who passed the screening test entered an 8-week antidepressant 
treatment period (Phase A) in which SSRI/SNRI and placebo were administered in a 
single-blind manner. Subjects who responded to SSRI/SNRI and placebo in Phase A 

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entered a 6-week antidepressant-responder treatment-continuation period (Phase A+) in 
which SSRI/SNRI and placebo continued to be concomitantly administered for another 6 
weeks. Subjects who had an insufficient response to SSRI/SNRI and placebo in Phase A 
entered a double-blind period (Phase B) in which brexpiprazole or placebo was 
administered concomitantly with SSRI/SNRI for 6 weeks in a double-blind manner. This 
trial had a total of 3 treatment groups consisting of a placebo group and 2 fixed-dose 
groups of brexpiprazole (1 and 3 mg/day). The change from baseline to Week 6 in the 
Montgomery Åsberg Depression Rating Scale (MADRS) total score, the primary 
endpoint, showed numerical improvement in the 3-mg group compared with the placebo 
group (LSMD: −1.52, p = 0.0327). Improvement in the MADRS total score was 
numerically greater in the 1-mg group than in the placebo group (LSMD: −1.19, 
p = 0.0925). In the efficacy data from a subgroup meeting the inclusion criteria revised 
during the trial, the change from baseline to Week 6 in the MADRS total score showed 
improvement in the 3-mg group compared with the placebo group (LSMD: −1.95, 
p = 0.0079). Meanwhile, the change from baseline in the 1-mg group was −1.30 
(p = 0.0737). 
The incidence of AEs was 54.9% in the brexpiprazole 1-mg group, 63.3% in the 3-mg 
group, and 46.8% in the placebo group. The AEs reported in the brexpiprazole 3-mg 
group at an incidence of ≥ 5% and at more than double the incidence in the placebo group 
were akathisia (13.5% in the 3-mg group and 2.3% in the placebo group; hereinafter, the 
same order shall apply), somnolence (5.7%, 0.5%), and weight increased (5.7%, 0.9%). 
The AEs reported in the brexpiprazole 1-mg group at an incidence of ≥ 5% and at more 
than double the incidence in the placebo group were weight increased (6.6% in the 1-mg 
group and 0.9% in the placebo group; hereinafter, the same order shall apply) and 
nasopharyngitis (6.6%, 1.8%). Most AEs in either of the brexpiprazole groups were mild 
or moderate in severity. The incidence of SAEs was 0.4% in the 1-mg group, 0.4% in the 
3-mg group, and 0.0% in the placebo group. The incidence of AEs leading to 
discontinuation was 1.3% in the 1-mg group, 3.5% in the 3-mg group, and 1.4% in the 
placebo group. The incidences of both SAEs and AEs leading to discontinuation were 
low in the brexpiprazole groups as in the placebo group. No marked changes were noted 
in laboratory test values, vital signs, or ECGs in either of the brexpiprazole groups. 
1.2.2.2 
Confirmatory Trial in Subjects With Major Depressive Disorder 
(331-10-228) 
A double-blind, placebo-controlled trial was conducted outside Japan to evaluate the 
efficacy, safety, and tolerability of a fixed dose of brexpiprazole in subjects with major 
depressive disorder who had an insufficient response to antidepressant therapy. The trial 

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was designed similarly to Trial 331-10-227 and had 2 treatment groups consisting of a 
placebo group and a brexpiprazole 2-mg group. The change from baseline to Week 6 in 
the MADRS total score, the primary endpoint, showed significant improvement in the 2-
mg group compared with the placebo group (LSMD: −3.12, p = 0.0001). In the efficacy 
data from a subgroup meeting the inclusion criteria revised during the trial, the change 
from baseline to Week 6 in the MADRS total score showed improvement in the 2-mg 
group compared with the placebo group (LSMD: −3.21, p = 0.0002). 
The incidence of AEs was 59.0% in the brexpiprazole 2-mg group and 46.6% in the 
placebo group. The AEs reported in the brexpiprazole 2-mg group at an incidence of 
≥ 5% and at more than double the incidence in the placebo group were weight increased 
(8.0% in the 2-mg group and 3.1% in the placebo group; hereinafter, the same order shall 
apply) and akathisia (7.4%, 1.0%). Most AEs in the brexpiprazole group or the placebo 
group were mild or moderate in severity. The incidence of SAEs was 1.1% in the 2-mg 
group and 1.0% in the placebo group. The incidence of AEs leading to discontinuation 
was 3.2% in the 2-mg group and 0.0% in the placebo group. The incidences of both SAEs 
and AEs leading to discontinuation were low in the brexpiprazole group as in the placebo 
group. No marked changes were noted in laboratory test values, vital signs, or ECGs in 
the brexpiprazole group. 
1.2.2.3 
Confirmatory Trial in Subjects With Major Depressive Disorder 
(331-13-214) 
A double-blind, placebo-controlled trial was conducted outside Japan to evaluate the 
efficacy, safety, and tolerability of a fixed dose of brexpiprazole in subjects with major 
depressive disorder who had an inadequate response to antidepressant therapy. The trial 
was designed similarly to Trials 331-10-227 and 331-10-228 and had 2 treatment groups 
consisting of a placebo group and a brexpiprazole 2-mg group. The change from baseline 
to Week 6 in the MADRS total score, the primary endpoint, showed significant 
improvement in the 2-mg group compared with the placebo group (LSMD: −2.30, 
p = 0.0074). 
The incidence of AEs was 59.9% in the brexpiprazole 2-mg group and 49.5% in the 
placebo group. The AEs reported in the brexpiprazole 2-mg group at an incidence of 
≥ 5% and at more than double the incidence in the placebo group were restlessness (8.3% 
in the 2-mg group and 2.0% in the placebo group; hereinafter, the same order shall apply) 
and weight increased (5.2%, 0.5%). The AEs reported in the 2-mg group at an incidence 
of ≥ 5% and at a higher incidence than that in the placebo group were only akathisia 
(8.3%, 5.0%) and upper respiratory tract infection (5.2%, 5.0%). Most AEs in the 
brexpiprazole group were mild or moderate in severity. The incidence of SAEs was 0.5% 

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in the 2-mg group and 0.0% in the placebo group. The incidence of AEs leading to 
discontinuation was 2.1% in the 2-mg group and 0.5% in the placebo group. The 
incidences of both SAEs and AEs leading to discontinuation were low in the 
brexpiprazole group as in the placebo group. No marked changes were noted in 
laboratory test values, vital signs, or ECGs in the brexpiprazole group. 
1.3 
Known and Potential Risks and Benefits 
Extrapyramidal symptoms, seizures, suicidality, and dyslipidemia have been assessed as 
important risks associated with the administration of brexpiprazole. The potential 
mechanism of antipsychotics causing seizures is a class effect thought to be due to a 
reduction of the seizure threshold in susceptible individuals. The occurrence of suicidal 
behavior is inherent in psychotic illnesses and mood disorders. In the schizophrenia and 
major depressive disorder populations, short-term and long-term administration of 
brexpiprazole was associated with moderate weight gain; however, weight gain did not 
contribute significantly to IMP discontinuation, and only a few subjects with marked 
weight gain demonstrated metabolic syndrome. Although not clinically significant, an 
increase in triglycerides was observed in some trials. Due to this observation and 
considerations on potential clinical consequences related to weight gain, dyslipidemia is 
considered to be an important potential risk. 
With lower intrinsic activity at the D2 receptors and more potent effects on the 
serotonergic system, which is suggested to be involved in the improvement of depressive 
symptoms, extrapyramidal symptoms, and cognitive function, compared with 
aripiprazole, evidence suggests that brexpiprazole can reduce the incidence of AEs such 
as akathisia and other extrapyramidal symptoms, nausea, vomiting, excitement, and 
irritability, and also improve symptoms of depression. In clinical trials conducted 
overseas, the incidence of AEs, such as akathisia, which are considered risk factors for 
low adherence to treatment, was confirmed to be low in patients treated with 
brexpiprazole. Therefore, brexpiprazole is likely to become a useful treatment option for 
patients with major depressive disorder who need to receive treatment over a long period 
of time. 
2 
Trial Rationale and Objectives 
2.1 
Trial Rationale 
Considering the monoamine hypothesis, one of the assumptions of the underlying 
pathophysiologic bases of depression, use of drugs that act on the serotonergic, 
noradrenergic, or dopaminergic system is regarded as the most rational approach to the 

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treatment of major depressive disorder. SSRIs and SNRIs, which are commonly used to 
treat major depressive disorder, activate the serotonergic and noradrenergic systems. 
However, these drugs poorly activate the dopaminergic system with a response rate of 
50% to 60%. Aripiprazole is the only antipsychotic agent that has been approved in Japan 
as augmentation therapy acting directly on the dopaminergic system. However, the drug 
does have some therapeutic issues that need to be addressed, such as akathisia and 
insomnia caused by its high intrinsic activity at the D2 receptor. Unlike aripiprazole, 
brexpiprazole, even at a low level of < 1 nM, acts on 5-HT1A receptors and 5-HT2A 
receptors, and acts as an agonist at D2 receptors with optimal intrinsic activity. Adjunct 
administration of brexpiprazole with optimal intrinsic activity to SSRIs or SNRIs is likely 
to act on not only the serotonergic and noradrenergic systems but also the dopaminergic 
system. Therefore, this treatment is expected to be more effective in treating major 
depressive disorder patients with a safety profile that is superior to monotherapy with an 
antidepressant and thereby improve adherence to treatment. 
Phase 3, double-blind, placebo-controlled trials of fixed doses of brexpiprazole (331-10-
227, 331-10-228, and 331-13-214) conducted outside Japan demonstrated the efficacy of 
brexpiprazole as adjunctive therapy to SSRIs or SNRIs in patients with major depressive 
disorder and found no significant safety concerns. It is expected that brexpiprazole as 
adjunctive therapy will also be effective in Japanese patients with major depressive 
disorder. 
This trial has been designed to assess the doses and efficacy of brexpiprazole as 
adjunctive therapy in Japanese patients with major depressive disorder who have an 
inadequate response to antidepressants, and to confirm the drug’s safety. As was the case 
in the overseas trials, this trial has an antidepressant treatment period (Phase A), in which 
commercially available antidepressants and placebo will be administered in a single-blind 
manner, and a double-blind period (Phase B) in subjects with an inadequate response to 
antidepressants, in which brexpiprazole administered adjunctively with antidepressants 
will be compared with placebo. The antidepressant treatment period (Phase A) was set at 
8 weeks, which is considered sufficient based on the JSMD Treatment Guidelines.6 The 
antidepressant agent to be used will be an SSRI or SNRI, as in the overseas trials. The 
duration of the double-blind period (Phase B) for comparison with the placebo group was 
set at 6 weeks, the same duration used in the overseas trials. 
As in the overseas trials, the primary endpoint is the mean change in MADRS, which is 
used worldwide as a depression assessment scale. In order to assess the efficacy and 
doses of brexpiprazole, this trial will have a total of 3 treatment groups consisting of the 
brexpiprazole 1 mg/day group and 2 mg/day group and the placebo group. 

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The US package insert of brexpiprazole tablets21 contains warnings regarding 
antidepressant-related suicidal ideation or suicidal behavior, and also in the Japanese 
package insert of the drug for the indication of schizophrenia, patients with a history of 
suicidal ideation or suicide attempt come under Careful Administration. Considering the 
above, criteria that require the exclusion or discontinuation of patients at high risk of 
suicide have been established as exclusion or discontinuation criteria to minimize the risk 
of suicide during the trial and thereby to ensure the safety of subjects. 
Based on the above, we concluded that assessment of the efficacy and safety of 
brexpiprazole as adjunctive therapy in Japanese major depressive disorder patients 
receiving brexpiprazole or placebo once daily for 6 weeks in combination with an 
antidepressant (SSRI or SNRI) is scientifically and ethically justified. 
2.2 
Rationale for CYP2D6 Genetic Testing and DNA Storage 
The metabolism of brexpiprazole was shown to be mainly mediated by CYP3A4 and 
CYP2D6 based on in vitro metabolism studies, and CYP2D6 is known to have multiple 
genotypes with different enzyme activities. Therefore, in this trial, examination will be 
performed on CYP2D6 genotypes that affect the pharmacokinetics of brexpiprazole. 
 
 
 
 

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2.3 
 
 
 
2.4 
Rationale for Dosing and Regimen 
2.4.1 
Rational for Regimen 
All clinical trials of brexpiprazole in patients with major depressive disorder conducted 
outside Japan have employed once daily oral administration. This trial will likewise 
employ once daily oral administration of brexpiprazole, as the drug is approved in the US 
with this regimen and because it has been confirmed that there are no major differences 
in the pharmacokinetics of brexpiprazole between Japanese and non-Japanese 
populations. 
2.4.2 
Rationale for Dosage 
2.4.2.1 
Rationale for Treatment Groups 
Given that brexpiprazole was approved in the US at a dose of 2 mg/day as the 
recommended dose based on the results of overseas clinical trials, in which the efficacy 
of 2 mg/day of the drug was demonstrated in patients with major depressive disorder, and 
that the pharmacokinetics of the drug is similar between Japanese and non-Japanese 
populations, a dose level of 2 mg/day was considered to also be effective in Japanese 
patients with major depressive disorder and was selected for this trial. In a double-blind 

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trial conducted outside Japan (331-10-227), the brexpiprazole 1-mg group exhibited 
greater improvement compared with the placebo group (p < 0.05) at any time point 
during Weeks 1 through 5, and there were no marked differences between the 1-mg 
group and the 3-mg group in MADRS response rate (≥ 50% decrease in the MADRS 
total score from baseline) or MADRS remission rate (MADRS total score ≤ 10 and 
≥ 50% reduction in the MADRS total score from baseline) at Week 6. Although the 
efficacy of 1 mg/day of brexpiprazole was not confirmed in clinical trials conducted 
outside Japan in patients with major depressive disorder, the dose level of 1 mg/day was 
also selected in this trial to ascertain if this dose would be the minimal effective dose in 
Japanese patients. 
2.4.2.2 
Rationale for a Starting Dose of 1 mg/day 
Overseas clinical trials of brexpiprazole involving patients with major depressive disorder 
employed a starting dose of 0.5 or 1 mg/day, with no great differences in safety noted 
during the dose-escalation period at either of the starting doses; therefore, a starting dose 
of 1 mg/day was selected in order to attain an effective dose swiftly. 
2.5 
Trial Objectives 
The objective of the trial is to assess the dosage and efficacy of brexpiprazole as 
adjunctive therapy vs placebo in combination with antidepressants (SSRI or SNRI), in 
patients with major depressive disorder, and whose response to single-antidepressant 
therapy (SSRI or SNRI) was inadequate. The primary endpoint is mean changes from 
baseline (Week 8 of the antidepressant treatment period [Phase A]) in MADRS total 
scores at Week 6 of the double-blind period (Phase B), and the mean changes will be 
compared between antidepressant treatments and brexpiprazole as adjunctive therapy. 
The secondary endpoints are as follows: MADRS response rate: the proportion of 
subjects in whom MADRS total scores at Week 6 of the double-blind period (Phase B) 
have been reduced by at least 50% from baseline (Week 8 of the antidepressant treatment 
period [Phase A]); MADRS remission rate: the proportion of subjects in whom MADRS 
total scores at Week 6 of the double-blind period (Phase B) have been reduced by at least 
50% from baseline, with their MADRS total scores at Week 6 of the double-blind period 
(Phase B), being ≤ 10; Clinical Global Impression – Improvement (CGI-I) improvement 
rate: the proportion of subjects who score 1 or 2 on the CGI-I scale at Week 6 of the 
double-blind period (Phase B); mean changes from baseline in CGI-S scale at Week 6 of 
the double-blind period (Phase B); mean changes from baseline in Hamilton Rating Scale 
for Depression (HAM-D) 17-item total scores at Week 6 of the double-blind period 
(Phase B); mean changes from baseline in mean Sheehan Disability Scale (SDS) scores at 

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Week 6 of the double-blind period (Phase B); and mean changes from baseline in 
MADRS Self-assessment (MADRS-S) total scores at Week 6 of the double-blind period 
(Phase B). The dosage and efficacy of brexpiprazole as adjunctive therapy in 
combination with antidepressants (SSRI or SNRI) will be assessed in relation to these 
endpoints. 
The safety of brexpiprazole as adjunctive therapy vs placebo in combination with 
antidepressants (SSRI or SNRI) in patients with major depressive disorder whose 
response to single-antidepressant therapy (SSRI or SNRI) was inadequate will also be 
assessed. 
3 
Trial Design 
3.1 
Type/Design of Trial 
The trial is a multi-center, randomized, double-blind, placebo-controlled, parallel group-
comparison trial to assess the efficacy and safety of brexpiprazole as adjunctive therapy 
in patients with major depressive disorder, who have received 1 to 3 adequate 
antidepressant drug treatmentsa for the current major depressive episode and have shown 
an inadequate responseb to all of these treatments, and whose response during the 
antidepressant treatment period (Phase A) has also been inadequate. 
The trial design is shown in Figure 3.1-1. The trial comprises a screening period, 
antidepressant treatment period (Phase A), double-blind period (Phase B) or 
antidepressant-responder treatment-continuation period (Phase A+), and post-treatment 
observation period. 
a Definition of "adequate antidepressant drug treatment" is provided below. 
Treatment with an antidepressant at an approved dose for at least 6 weeks (for 
combination therapy, treatment for at least 3 weeks) 
b Definition of "inadequate response" is provided below. 
With complete recovery from depressive symptoms and not the slightest improvement 
considered as 100% and 0%, respectively, patients carry out self-evaluations for 
improvement by antidepressant drug treatments used to date, from among 4 grades 
(< 25% Improvement, 25% to 49% Improvement, 50% to < 75% Improvement, and 
≥ 75% Improvement), with the evaluations corresponding to < 25% Improvement or 
25% to 49% Improvement classified as inadequate response. 
Patients who, among 1 to 3 adequate antidepressant drug treatments, have received 

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treatment for ≥ 6 weeks at least once (receiving only combination therapies for ≥ 3 
weeks does not qualify) are eligible for selection. 
 
Figure 3.1-1 
Trial Design 
 
3.2 
Trial Treatments 
3.2.1 
Antidepressant Treatment Period (Phase A) 
(1) 
Drugs 
Among commercially available SSRIs (fluvoxamine maleate, paroxetine hydrochloride 
hydrate, sertraline hydrochloride, and escitalopram oxalate) and SNRIs (milnacipran 
hydrochloride, duloxetine hydrochloride, and venlafaxine hydrochloride), one 
antidepressant that is different from the prior medications of antidepressant*, plus the 
placebo tablet 
*Antidepressant that meets the definition for “adequate antidepressant drug treatment” and has been taken 
at the time of informed consent. 
Post-treatment
observation
period (30 days)
IMP
Starting dose
Required concomitant drug
1 mg/day
Randomization
Brexpiprazole 2 mg/day group: 240 subjects
Brexpiprazole 1 mg/day group: 240 subjects
Informed consent
Day -28 to -1
0
1
2
3
4
6
1
9
2
10
3
11
4
12
5
13
6
14
30 days after the final
IMP administration
Week
Week
Week
Post-
treatment
observation
period
2 mg/day
SSRI or SNRI
Trial period
Treatment period
Screening period
(maximum 28 days)
Antidepressant treatment period (Phase A)
(8 weeks)
Double-blind period (Phase B)
(6 weeks)
Placebo (single-blind)
Brexpiprazole 1 mg/day
SSRI or SNRI
SSRI or SNRI
Brexpiprazole
0
8
Post-treatment
observation
period
Post-treatment
observation
period
Treatment period
Antidepressant-responder treatment-
continuation period
 (Phase A+) (6 weeks)
Placebo (single-blind)
SSRI or SNRI
570 subjects (estimated)
Placebo
SSRI or SNRI
Placebo group: 240 subjects
Trial period
Not meeting the inclusion/exclusion criteria
→Proceed to the antidepressant-responder
treatment-continuation period (Phase A+)
Meeting the inclusion/exclusion criteria
→Proceed to the double-blind period (Phase B)
Gradual
dose reduction
of prior medications
R
No post-treatment 
observation for 
subjects starting 
treatment in the long-
term trial (331-102-
00059) treatment 
period
R

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(2) 
Dose and regimen 
In the antidepressant treatment period (Phase A), subjects will orally receive an 
antidepressant (SSRI or SNRI), which is different from the antidepressant prior 
medications, plus a placebo tablet once daily in a single-blind manner. The antidepressant 
(SSRI or SNRI) will be administered at the dose and regimen specified in the package 
insert, and the dose of the antidepressant will be progressively increased, within the 
approved dose range, to the maximum dose, as far as possible, in accordance with subject 
status; for the last 2 weeks of the 8-week period, dose and regimen will be fixed. A 
placebo tablet will be orally administered once daily. When an antidepressant cannot be 
administered at a fixed dose and regimen for the last 2 weeks of the 8-week 
antidepressant treatment period (Phase A) for tolerability-related reasons, the subject will 
be withdrawn from the trial. 
(3) 
Treatment period 
8 weeks 
[Rationale for Treatment Period] 
The JSMD Treatment Guidelines6 state that it is often difficult to determine whether the 
patient has responded to first-line drug after treatment for 3 to 4 weeks and that it often 
takes 4 to 6 weeks or even 8 weeks for the drug to show any antidepressant effect. Based 
on the above statement in the JSMD Treatment Guidelines, a duration of 8 weeks will be 
employed to assess the effects of SSRI or SNRI. 
3.2.2 
Double-blind Period (Phase B) 
At Week 8 of the antidepressant treatment period (Phase A), subjects who meet the 
criteria for proceeding to the double-blind period (Phase B) will proceed to the double-
blind period (Phase B). 
(1) 
Drugs 
• One commercially available antidepressant (SSRI or SNRI) used in the 
antidepressant treatment period (Phase A) 
• IMP: 
− 1 mg/day group: brexpiprazole 1 mg tablet 
− 2 mg/day group: brexpiprazole 1 mg tablet (until observations, examinations, 
and assessments at Week 1) and brexpiprazole 2 mg tablet (after observations, 
examinations, and assessments at Week 1) 
− Placebo group: placebo tablet 
 

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(2) 
Dose and regimen 
• Commercially available antidepressant (SSRI or SNRI): 
An antidepressant (SSRI or SNRI) used in the antidepressant treatment period 
(Phase A) will be continued with no changes from the final dose and regimen; no 
changes in dose, regimen, or drug will be allowed. 
• IMP: 
− 1 mg/day group: One brexpiprazole 1 mg tablet will be orally administered 
once daily. 
− 2 mg/day group: Treatment will be started with brexpiprazole at 1 mg/day. 
One brexpiprazole 1 mg tablet will be orally administered once daily until 
observations, examinations, and assessments at Week 1. After the 
observations, examinations, and assessments at Week 1, one brexpiprazole 
2 mg tablet will be orally administered once daily. 
− Placebo group: One placebo tablet will be orally administered once daily. 
 
(3) 
Treatment period 
6 weeks 
[Rationale for Treatment Period] 
Phase 3, double-blind, placebo-controlled trials conducted outside Japan in patients with 
major depressive disorder (331-10-227, 331-10-228, and 331-13-214) employed a 
duration of 6 weeks as the double-blind period and demonstrated the efficacy of 
brexpiprazole as adjunctive therapy vs placebo. Meanwhile, it has been confirmed that 
there are no major differences in the pharmacokinetics of brexpiprazole between 
Japanese and non-Japanese populations. Therefore, a duration of 6 weeks will also be 
employed in this trial, because the same treatment period as that in overseas phase 3, 
double-blind, placebo-controlled trials (331-10-227, 331-10-228, and 331-13-214) was 
considered necessary to assess the efficacy of adjunctive therapy. 
3.2.3 
Antidepressant-responder Treatment-continuation Period (Phase 
A+) 
Antidepressant responders who do not meet the criteria for proceeding to the double-
blind period (Phase B) based on the assessment at Week 8 of the antidepressant treatment 
period (Phase A) will proceed to the antidepressant-responder treatment-continuation 
period (Phase A+). 
(1) 
Drugs 
A commercially available antidepressant (SSRI or SNRI) used in the antidepressant 
treatment period (Phase A) plus the placebo tablet 

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(2) 
Dose and regimen 
Subjects will receive an antidepressant (SSRI or SNRI) used in the antidepressant 
treatment period (Phase A) with no changes from the final dose and regimen, plus oral 
placebo (1 tablet) once daily in a single-blind manner. 
(3) 
Treatment period 
6 weeks 
[Rationale for Treatment Period] 
To maintain single-blinding, it is necessary to set the duration to be the same as that of 
the double-blind period (Phase B). 
3.3 
Trial Population 
Adult patients with “major depressive disorder, single episode” or “major depressive 
disorder, recurrent episode” according to the Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5). 
3.3.1 
Number of Subjects and Trial Population 
The trial will be conducted in patients 20 to < 65 years of age who have major depressive 
disorder (major depressive disorder, single episode; major depressive disorder, recurrent 
episode) according to the DSM-5 classification. After provision of informed consent, 
subjects considered eligible at the screening examination and at the examination 
performed at the initiation of the antidepressant treatment period (Phase A) will 
commence the antidepressant treatment period (Phase A) in which they will receive 
antidepressants different from their prior antidepressant medications (SSRI or SNRI) and 
placebo tablets for 8 weeks in a single-blind manner. Subjects showing no response to the 
antidepressants during the antidepressant treatment period (Phase A) who meet the 
criteria for proceeding will proceed to the double-blind period (Phase B) to receive the 
IMP (brexpiprazole at 1 or 2 mg/day, or placebo) for 6 weeks in combination with the 
antidepressants used in the antidepressant treatment period (Phase A). The planned 
number of subjects proceeding to the double-blind period (Phase B) is set as follows: 
brexpiprazole 1 mg/day group: 240; brexpiprazole 2 mg/day group: 240; placebo group: 
240; total: 720. 
Subjects responding to antidepressants during the antidepressant treatment period (Phase 
A) and not meeting the criteria for proceeding to the double-blind period (Phase B) will 
not proceed to the double-blind period (Phase B) and will instead proceed to the 
antidepressant-responder treatment-continuation period (Phase A+), to receive 6-week 

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treatment with placebo tablets in addition to the antidepressants (SSRI or SNRI) used in 
the antidepressant treatment period (Phase A), in a single-blind manner. 
3.3.2 
Subject Number Assignment 
 
3.4 
Eligibility Criteria 
3.4.1 
Informed Consent 
Written informed consent will be obtained from all subjects on their voluntary decision. 
Consent will be documented on a written informed consent form (ICF) with the subject’s 
signature. The ICF will be approved by the same institutional review board (IRB) that 
approves this protocol. 
Each ICF will comply with the International Council for Harmonisation (ICH) Good 
Clinical Practice (GCP) Guideline22 and regulatory requirements. 
Investigators or subinvestigators may discuss the possibility for entry with a potential 
subject without first obtaining consent. However, informed consent must be obtained and 
documented before initiation of any procedures that are performed solely for the purpose 
of determining eligibility for this trial, including withdrawal from current medication(s). 
Potential subjects are free to refuse entry into the trial, or withdraw from the trial at any 
time, without justification, and there will be no consequences to their further care. 
Once appropriate essential information has been provided and fully explained in plain 
language to the potential subject by the investigator or subinvestigator, the IRB-approved 
written ICF will be signed and dated by both the potential subject and the person 
obtaining consent (investigator or subinvestigator). If a study collaborator has provided a 
supplemental explanation, the IRB-approved written ICF will be signed and dated by the 
study collaborator. The subject will receive a copy of the signed ICF; the original shall be 
kept on file by the investigator or subinvestigator. 
Subjects may be asked to sign additional ICFs if the protocol is amended to significantly 
add or change procedures. 
For CYP2D6 genetic testing, 
, a separate ICF 
will be used for explanation and written informed consent will be obtained from subjects 
on their voluntary decision in a similar manner. CYP2D6 genetic testing is mandatory, 

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and subjects who do not consent to CYP2D6 genetic testing cannot participate in the trial. 
 
 
3.4.2 
Inclusion Criteria 
Subjects must meet the inclusion criteria described in Table 3.4.2-1. 
Subjects who meet all of the following inclusion criteria at the initiation of the screening 
period, antidepressant treatment period (Phase A), and double-blind period (Phase B), are 
eligible for selection. 
Table 3.4.2-1 
Inclusion Criteria 
At screening 
1 
Outpatients, or inpatients at the time of informed consent whose treatment status can be successfully 
shifted to outpatient status before enrollment in the antidepressant treatment period (Phase A) 
2 
Male and female patients ≥ 20 to < 65 years of age (at the time of informed consent) 
3 
Patients who have a level of comprehension sufficient to allow them to give written informed 
consent to all of the observation/examination/evaluation items specified in the protocol, and who can 
understand the contents of the trial 
4 
Patients with a DSM-5 classification-based diagnosis of "major depressive disorder, single episode" 
or "major depressive disorder, recurrent episode" and whose current episode has persisted for at least 
8 weeks 
5 
Patients who have received 1 to 3 adequate antidepressant drug treatments for the current major 
depressive episode and whose response to all of the treatments has been inadequate. Definitions of 
"adequate antidepressant drug treatments" and "inadequate response" are provided below. 
 
Adequate antidepressant drug treatment 
Treatment with an antidepressant at an approved dose for at least 6 weeks (for combination therapy, 
treatment for at least 3 weeks) 
 
Inadequate response 
With complete recovery from depressive symptoms and not the slightest improvement considered as 
100% and 0%, respectively, patients carry out self-evaluations for improvement by antidepressant 
drug treatments used to date, from among 4 grades (< 25% Improvement, 25% to 49% Improvement, 
50% to < 75% Improvement, and ≥ 75% Improvement), with the evaluations corresponding to 
< 25% Improvement or 25% to 49% Improvement classified as inadequate response. 
Patients who, among 1 to 3 adequate antidepressant drug treatments, have received treatment for 
≥ 6 weeks at least once (receiving only combination therapies for ≥ 3 weeks does not qualify) are 
eligible for selection. 
6 
Patients with a HAM-D 17-item total score of ≥ 18 based on the evaluation conducted at screening 
At the initiation of the antidepressant treatment period (Phase A) 
7 
Outpatients 
8 
Subjects with a HAM-D 17-item total score of ≥ 18 based on the evaluation at the initiation of the 
antidepressant treatment period (Phase A) 
At the initiation of the double-blind period (Phase B) (criteria for proceeding) 
9 
Outpatients 
10 
Subjects with a HAM-D 17-item total score of ≥ 14 at Week 8 of the antidepressant treatment period 
(Phase A) 
11 
Subjects in whom the reduction rate for HAM-D 17-item total scores is < 50% at Week 8 of the 
antidepressant treatment period (Phase A), as compared with at the initiation of the antidepressant 
treatment period (Phase A). 

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Table 3.4.2-1 
Inclusion Criteria 
12 
Subjects in whom CGI-I scores have been consistently 3 (minimally improved) to 7 (very much 
worse) throughout the antidepressant treatment period (Phase A) 
 
[Rationale for inclusion criteria] 
Screening period 
1. 
This criterion is specified in view of subject safety, as treatment should be prioritized in subjects 
whose condition requires hospitalization. 
2. 
Patients younger than 65 years will be selected for appropriate assessment of safety of the drug, 
because the package insert of brexpiprazole tablet specifies, in Precautions, careful administration in 
the elderly, and because the elderly generally have decreased physiological functions. Furthermore, 
the lower age limit was determined to be 20 years for ethical considerations. 
3. 
This criterion is specified for ethical considerations. 
4 to 6. These criteria are specified for appropriate assessment of efficacy. 
 
At the initiation of the antidepressant treatment period (Phase A) 
7. 
This criterion is specified in view of subject safety, as treatment should be prioritized in subjects 
whose condition requires hospitalization. 
8. 
This criterion is specified for appropriate assessment of efficacy. 
 
At the initiation of the double-blind period (Phase B) 
9. 
This criterion is specified in view of subject safety, as treatment should be prioritized in subjects 
whose condition requires hospitalization. 
10 to 12. These criteria are specified for appropriate assessment of efficacy. 
 
3.4.3 
Exclusion Criteria 
Patients will be excluded if they fall under any of the exclusion criteria described in 
Table 3.4.3-1 during the screening period or at the initiation of the antidepressant 
treatment period (Phase A). 
Table 3.4.3-1 
Exclusion Criteria 
At screening 
1 
Women who are pregnant or breastfeeding or who have positive pregnancy test (urine) results at 
screening 
2 
Sexually active male subjects or sexually active female subjects of childbearing potential, who will 
not agree to practice 2 different methods of birth control or to remain abstinent during the trial and 
for 30 days after the final IMP administration. For birth control, 2 of the following methods must be 
used: vasectomy, tubal ligation, vaginal diaphragm, intra-uterine contraceptive device (IUD), oral 
contraceptives, or condom with spermicide. 
3 
Patients who have received at least 4 appropriate antidepressant drug treatments for the current major 
depressive episode but whose response was inadequate to all treatments 
4 
Patients receiving treatment with antipsychotics and psychostimulants for the current major 
depressive episode (excluding the use of sulpiride for depression/depressive state or gastric/duodenal 
ulcer) 
5 
Patients with a treatment history showing that all antidepressants (including those not used for the 
current major depressive episode) cannot be tolerated 
6 
Patients with a history of electroconvulsive therapy 

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Table 3.4.3-1 
Exclusion Criteria 
7 
Patients with a diagnosis of any of the following diseases according to DSM-5 
a) Neurocognitive disorders 
b) Schizophrenia spectrum and other psychotic disorders 
c) Bipolar and related disorders 
d) Feeding and eating disorders 
e) Obsessive-compulsive disorder 
f) 
Panic disorder 
g) Posttraumatic stress disorder 
8 
Patients with a diagnosis of any personality disorders (borderline personality disorder, antisocial 
personality disorder, paranoid personality disorder, schizoid personality disorder, schizotypal 
personality disorder, and histrionic personality disorder) according to DSM-5 
9 
Patients experiencing hallucinations or delusions, or showing mood-incongruent psychotic features, 
in the current major depressive episode 
10 
Patients receiving a new psychotherapy within 6 weeks prior to informed consent 
11 
Patients who have previously taken brexpiprazole 
12 
Patients who have participated in other clinical trials within 60 days prior to informed consent 
13 
Patients with a HAM-D score for suicide (No. 11) of ≥ 3 at screening, those answering "Yes" to 
question 4 or 5 of Columbia-Suicide Severity Rating Scale (C-SSRS), or those who are, based on 
current psychiatric symptoms or past medical history, at high risk of suicide during the trial in the 
opinion of the investigator or subinvestigator 
14 
Patients with clinically significant neurological, hepatic, renal, metabolic, hematological, 
immunological, cardiovascular, pulmonary, or gastrointestinal disorders; patients can be enrolled if 
the conditions are mild or well controlled and will not hamper assessment of safety and efficacy. 
15 
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 
(assessed based on results from the central laboratory) 
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 
16 
Patients with substance abuse or substance dependence, including alcohol and benzodiazepines, 
based on DSM-5 diagnostic criteria within 180 days prior to informed consent; caffeine and nicotine 
are not included 
17 
Patients with a complication of hypothyroidism or hyperthyroidism at informed consent (excluding 
those in a stable condition due to medications for the previous 90 days or longer at acquisition of 
informed consent), or abnormal thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels 
at screening (assessed based on results from the central laboratory) 
18 
Patients meeting any of the following criteria or showing symptoms at screening 
a) Poorly controlled hypertension (diastolic blood pressure of > 95 mmHg) 
b) Hypotension with symptoms 
c) Orthostatic hypotension in which blood pressure after 3 minutes of standing is 
≥ 30 mmHg lower for systolic blood pressure or ≥ 20 mmHg lower for diastolic blood 
pressure, compared with pressures in the supine position before standing 

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Table 3.4.3-1 
Exclusion Criteria 
19 
Patients with a complication of ischemic heart disease, myocardial infarction, or congestive heart 
failure (irrespective of well or poorly controlled), and patients with a history of angioplasty, stent 
placement, or coronary artery bypass 
20 
Patients with a history of neuroleptic malignant syndrome or serotonin syndrome 
21 
Patients with a history or complication of epilepsy or epileptic seizures, excluding pediatric febrile 
seizures, post-traumatic seizures, alcohol withdrawal seizures, and other seizures 
22 
Patients with the following clinical laboratory test values or ECG parameters at screening (assessed 
based on results from the central laboratory and central ECG measurement facility) 
a) Platelet count: ≤ 75,000/mm3 
b) Hemoglobin: ≤ 9 g/dL 
c) Absolute neutrophil count: ≤ 1000/mm3 
d) Aspartate aminotransferase (AST): > 2 times the upper limit of the reference range 
e) Alanine aminotransferase (ALT): > 2 times the upper limit of the reference range 
f) 
Creatine phosphokinase (CPK): > 3 times the upper limit of the reference range 
g) Creatinine: ≥ 2 mg/dL 
h) QT interval as corrected by Fridericia’s formula (QTcF): ≥ 450 msec 
23 
Patients with a history of hypersensitivity to antidepressants 
24 
Patients with a history or complication of allergy to more than one medication 
25 
The following patients falling under the contraindications in the package insert for brexpiprazole 
tablet 
a) Patients in a coma 
b) Patients under the strong influence of central nervous system depressants including 
barbiturate analogs/anesthetics 
c) Patients receiving adrenaline 
d) Patients with a history of hypersensitivity to components of brexpiprazole tablet 
26 
Patients who otherwise should not participate in the trial in the opinion of the investigator or 
subinvestigator 
At the initiation of the antidepressant treatment period (Phase A) 
27 
Pregnant or breastfeeding female subjects, or those with positive pregnancy test (urine) results at the 
initiation of the antidepressant treatment period (Phase A) 
28 
Subjects newly requiring hospitalization for the current major depressive episode during the 
screening period 
29 
Patients with a HAM-D score for suicide (No. 11) of ≥ 3 at the initiation of the antidepressant 
treatment period (Phase A), those answering "Yes" to question 4 or 5 of C-SSRS, or those who are, 
based on current psychiatric symptoms or past medical history, at high risk of suicide during the trial 
in the opinion of the investigator or subinvestigator 
30 
Patients meeting any of the following criteria or showing symptoms at the initiation of the 
antidepressant treatment period (Phase A) 
a) Poorly controlled hypertension (diastolic blood pressure of > 95 mmHg) 
b) Hypotension with symptoms 
c) Orthostatic hypotension in which blood pressure after 3 minutes of standing is 
≥ 30 mmHg lower for systolic blood pressure or ≥ 20 mmHg lower for diastolic blood 
pressure, compared with pressures in the supine position before standing 
31 
Subjects receiving treatment with monoamine oxidase (MAO) inhibitors within 2 weeks before the 
initiation of the antidepressant treatment period (Phase A) 
32 
Subjects using benzodiazepines (excluding ultrashort-acting sleep inducers) within 1 week before the 
initiation of the antidepressant treatment period (Phase A) 
33 
Subjects with urinary retention, if receiving milnacipran 

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Table 3.4.3-1 
Exclusion Criteria 
34 
Subjects with poorly controlled angle closure glaucoma, if receiving duloxetine 
35 
Subjects who otherwise should not participate in the trial in the opinion of the investigator or 
subinvestigator 
 
[Rationale for exclusion criteria] 
Screening period 
1, 2. These criteria are specified in view of safety, as safety of treatment with the drug is yet to be 
established in pregnant and breastfeeding women. 
3, 4. These criteria are specified for appropriate assessment of efficacy. 
5. 
This criterion is specified in view of safety. 
6. 
This criterion is specified in view of safety, as a combination of antidepressants and electroconvulsive 
therapy is likely to lower the convulsive threshold. 
7 to 10. These criteria are specified for appropriate assessment of efficacy. 
11. This criterion is specified because of the potential impact on blinding. 
12. This criterion is specified in view of safety. 
13. This criterion is specified to minimize the risk of suicide during the trial. 
14 to 16. These criteria are specified in view of safety. 
17. This criterion is specified for appropriate assessment of efficacy, as patients with thyroid disorders 
may have depressive symptoms. 
18 to 20. These criteria are specified in view of safety. 
21. This criterion is specified in view of safety, as the drug may lower the convulsive threshold. 
22 to 26. These criteria are specified in view of safety. 
 
At the initiation of the antidepressant treatment period (Phase A) 
27. This criterion is specified in view of safety, as safety of treatment with the drug is yet to be established 
in pregnant and breastfeeding women. 
28 to 30. These criteria are specified in view of safety. 
31. This criterion is specified in view of safety, as package inserts for antidepressants indicate that for 
patients receiving MAO inhibitors, the antidepressants should be administered after an interval of at 
least 2 weeks from discontinuation of MAO inhibitors. 
32. This criterion is specified for appropriate assessment of efficacy. 
33 to 35. These criteria are specified in view of safety. 
 
3.5 
Endpoints 
3.5.1 
Primary Endpoint(s) 
Mean changes from baseline (Week 8 of the antidepressant treatment period [Phase A]) 
in MADRS total scores at Week 6 of the double-blind period (Phase B) 
[Rationale] 
MADRS, used worldwide as a depression assessment scale, was created primarily to 
assess psychiatric symptoms of depression and exclude somatic symptoms; therefore, the 
scale is generally used in clinical trials that involve patients with major depressive 
disorder. As all placebo-controlled trials of fixed doses of brexpiprazole conducted 
outside Japan in patients with major depressive disorder have employed mean changes in 
MADRS scores as the primary endpoint, the same primary endpoint will be employed in 

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this trial also. As the high inter-rater reliability of MADRS has been confirmed by using 
the Structured Interview Guide for MADRS (SIGMA), SIGMA will be used in this trial 
also. 
3.5.2 
Secondary Endpoint(s) 
• MADRS response rate at Week 6 of the double-blind period (Phase B) 
The proportion of subjects in whom MADRS total scores at Week 6 of the double-
blind period (Phase B) have been reduced by at least 50% from baseline (Week 8 of 
the antidepressant treatment period [Phase A]) 
• MADRS remission rate at Week 6 of the double-blind period (Phase B) 
The proportion of subjects in whom MADRS total scores at Week 6 of the double-
blind period (Phase B) have been reduced by at least 50% from baseline (Week 8 of 
the antidepressant treatment period [Phase A]), with their MADRS total scores, at 
Week 6 of the double-blind period (Phase B), being ≤ 10 
• CGI-I improvement rate at Week 6 of the double-blind period (Phase B) 
The proportion of subjects who score 1 or 2 on the CGI-I scale at Week 6 of the 
double-blind period (Phase B) 
• Mean changes in CGI-S at Week 6 of the double-blind period (Phase B) 
Mean changes from baseline (Week 8 of the antidepressant treatment period 
[Phase A]) in CGI-S at Week 6 of the double-blind period (Phase B) 
• Mean changes in HAM-D 17-item total scores at Week 6 of the double-blind period 
(Phase B) 
Mean changes from baseline (Week 8 of the antidepressant treatment period 
[Phase A]) in HAM-D 17-item total scores at Week 6 of the double-blind period 
(Phase B) 
• Mean changes in mean SDS scores at Week 6 of the double-blind period (Phase B) 
Mean changes from baseline (Week 8 of the antidepressant treatment period 
[Phase A]) in mean SDS scores at Week 6 of the double-blind period (Phase B) 
• Mean changes in MADRS-S total scores at Week 6 of the double-blind period 
(Phase B) 
Mean changes from baseline (Week 8 of the antidepressant treatment period 
[Phase A]) in MADRS-S total scores at Week 6 of the double-blind period (Phase B) 
 
[Rationale] 
The MADRS response rate and MADRS remission rate were selected because they are 
useful for assessing the effects of antidepressants and are used in many clinical trials. 
CGI-I and CGI-S were selected because they are an overall assessment that enables 
comprehensive assessment of the subject’s clinical symptoms and are used in many 
clinical trials. 

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HAM-D was selected because it is useful for assessing a wide range of depressive 
symptoms including somatic and psychiatric symptoms and is used in many clinical trials. 
SDS was selected because it is a functional impairment assessment scale composed of 3 
daily living function-related items (work/school, social life, and communication and role 
within in family), and enables functional assessment through self-assessment. 
MADRS-S was created by modifying 9 subjective report-based assessment items among 
the 10 MADRS assessment items (excluding the objective assessment item, namely, 
“apparent sadness”) to allow self-assessment; it was selected to assess improvement in 
depressive symptoms based on the subject’s self-assessment. 
3.5.3 
Safety Endpoints 
Adverse events, laboratory tests, vital signs (body temperature, diastolic blood pressure 
and systolic blood pressure, and pulse rate [supine, sitting, and standing positions]), 
physical examinations, waist circumference, body weight, 12-lead ECG, pregnancy test, 
Columbia-Suicide Severity Rating Scale (C-SSRS), Drug-Induced Extrapyramidal 
Symptom Scale (DIEPSS), Abnormal Involuntary Movement Scale (AIMS), Barnes 
Akathisia Rating Scale (BARS) 
3.5.4 
Pharmacokinetic Endpoint 
Plasma brexpiprazole concentrations 
3.5.5 
Pharmacogenomic Endpoint 
CYP2D6 genetic testing 
3.6 
Measures to Minimize/Avoid Bias 
This trial has a double-blind design. In the double-blind period (Phase B), subjects will be 
randomly assigned to the brexpiprazole 1 mg/day group, the brexpiprazole 2 mg/day 
group, or placebo group at a 1:1:1 ratio. Details of the randomization method are 
provided in separately documented procedures. The treatment assignment code will be 
revealed to neither the subject nor the investigator. The sponsor’s staff involved in the 
trial, including contract research organizations (excluding the bioanalytical laboratory 
and the genetic analysis laboratory), will also remain blind to treatment assignment codes 
for the duration of the trial. 
Prior to the start of the trial, those who are involved in packaging the IMP and the 
sponsor will confirm that the IMP is not identifiable. 

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Documents providing treatment assignment codes will be strictly retained until 
unblinding is performed after finalization of all the case report forms (CRFs) and 
database. 
The emergency code break information will be managed by the interactive web response 
system (IWRS) until completion of the trial. In the event that a subject has a medical 
emergency and knowledge of the treatment assignment code is necessary for treatment, 
the blind will be broken in accordance with the instructions provided in Section 5.6, 
Procedure for Breaking the Blind. 
The results of plasma drug concentration measurements and CYP2D6 genetic testing 
should not be disclosed until unblinding after the end of the trial. These measurements 
should be performed respectively at the designated bioanalysis laboratory and genetic 
analysis laboratory, but not at laboratories of trial sites. 
3.7 
Trial Procedures 
Schedules of all examinations and assessment/observations in the screening period, 
antidepressant treatment period (Phase A), double-blind period (Phase B), antidepressant-
responder treatment-continuation period (Phase A+), and post-treatment observation 
period are provided in Table 3.7-1, Table 3.7-2, and Table 3.7-3, respectively. 
The investigator or subinvestigator should conduct observations, examinations, and 
evaluations in accordance with the schedules. For items that can be performed by a 
clinical trial associate, such as examination of subject demographics and laboratory tests, 
a clinical trial associate can perform them under the supervision of the investigator. 

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Table 3.7-1 
Schedule of Assessments (Screening Period and Antidepressant 
Treatment Period [Phase A]) 
Test Period 
(Acceptable 
Window) 
Items 
 
Screening 
Period 
Antidepressant Treatment Period (Phase A) 
At screening 
(Day −28 to 
−1) 
At 
initiation 
(Day 1) 
Week 1 
(± 2 
days) 
Week 2 
(± 2 
days) 
Week 3 
(± 2 
days) 
Week 4 
(± 2 
days) 
Week 6 
(± 2 
days) 
Week 8 
(± 2 
days) 
At 
discontin-
uation 
Acquisition of 
informed consent 
● 
 
 
 
 
 
 
 
 
Eligibility judgement 
● 
● 
 
 
 
 
 
 
 
Subject 
demographics 
● 
 
 
 
 
 
 
 
 
MADRS 
● 
● 
● 
● 
● 
● 
CGI-I 
● 
● 
● 
● 
● 
● 
● 
CGI-S 
● 
● 
● 
● 
● 
● 
● 
● 
● 
HAM-D 
● 
● 
● 
● 
SDS 
● 
● 
● 
MADRS-S 
questionnaire 
 
● 
 
● 
 
● 
● 
● 
● 
Laboratory tests 
● 
●d 
● 
Vital signs 
● 
● 
● 
● 
● 
● 
Physical 
examinations 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Waist circumference 
● 
● 
● 
Height 
● 
Body weight 
● 
● 
● 
12-lead ECG 
● 
● 
● 
Pregnancy test 
●b 
●b 
●b 
●b 
C-SSRS 
● 
● 
● 
● 
● 
● 
● 
● 
● 
DIEPSS 
● 
AIMS 
● 
BARS 
● 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
←------------------------------------------------------------------------------------------------------------→ 
IMP and requisite 
concomitant 
medicationa 
 
 
● 
● 
● 
● 
● 
● 
● 
Concomitant drugs/ 
therapies 
←------------------------------------------------------------------------------------------------------------→ 
a Treatment compliance regarding IMP and requisite concomitant medication will be recorded. 
b Pregnancy tests will be performed only in female subjects of childbearing potential. 
 
 
 
d For this item, subjects will be asked to visit the trial site in a fasting state (a fast for at least 8 hours 
[including drinks containing sugar, such as juice]) at Week 8 of the antidepressant treatment period 
(Phase A), and in a fasting state to the extent possible at other times, including at the discontinuation 
examination. 

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Table 3.7-2 
Schedule of Assessments (Double-blind Period [Phase B]) 
Test Period 
(Acceptable  
Window) 
Items 
Double-blind Period (Phase B)b 
Post-
treatment 
Observation 
Period 
Week 1 
(± 1 day) 
Week 2 
(± 2 days) 
Week 3 
(± 2 days) 
Week 4 
(± 2 days) 
Week 5 
(± 2 days) 
Week 6 
(± 2 days) 
At 
discontin-
uation 
After 30 
daysg 
(± 5 days) 
MADRS 
● 
● 
● 
● 
● 
● 
● 
CGI-I 
● 
● 
● 
● 
● 
● 
● 
CGI-S 
● 
● 
● 
● 
● 
● 
● 
HAM-D 
● 
● 
SDS 
● 
● 
● 
MADRS-S questionnaire 
● 
● 
● 
● 
● 
● 
● 
 
Laboratory tests 
● 
●d 
● 
Vital signs 
● 
● 
● 
● 
● 
● 
● 
Physical examinations 
● 
● 
● 
● 
● 
● 
● 
● 
Waist circumference 
● 
● 
Body weight 
● 
● 
12-lead ECG 
● 
● 
Pregnancy test 
●e 
●e 
C-SSRS 
● 
● 
● 
● 
● 
● 
● 
● 
DIEPSS 
● 
● 
● 
● 
● 
● 
● 
AIMS 
● 
● 
BARS 
● 
● 
Blood sampling for 
CYP2D6 genetic testing 
 
 
 
 
 
● 
● 
 
 
 
Adverse events 
←----------------------------------------------------------------------------------------→ 
←---→ 
IMP and requisite 
concomitant medicationa 
● 
● 
● 
● 
● 
● 
● 
 
Concomitant drugs/ 
therapies 
←----------------------------------------------------------------------------------------→ 
←---→ 
PK = pharmacokinetics 
a Treatment compliance regarding IMP and requisite concomitant medication will be recorded. 
b The starting point of the double-blind period (Phase B) is the day of assessment at Week 8 of the 
antidepressant treatment period (Phase A). 
 
 
d For this item, subjects will be asked to visit the trial site in a fasting state (a fast for at least 8 hours 
[including drinks containing sugar, such as juice]) at Week 6 of the double-blind period (Phase B), 
and in a fasting state to the extent possible at other times, including at the discontinuation 
examination. 
e Pregnancy tests will be performed only in female subjects of childbearing potential. 
 
 
g The starting point of the post-treatment observation period is the day of the final IMP administration. 
These items do not need to be performed for subjects who have commenced the treatment period of 
the long-term trial (331-102-00059). 
 

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Table 3.7-3 
Schedule of Assessments (Antidepressant-responder 
Treatment-continuation Period [Phase A+]) 
Test Period 
(Acceptable 
Window) 
Items 
 
Antidepressant-responder Treatment-continuation Period (Phase A+)b 
Week 1  
(± 1 day) 
Week 2  
(± 2 days) 
Week 3 
(± 2 days) 
Week 4  
(± 2 days) 
Week 5 
(± 2 days) 
Week 6 
(± 2 days) 
At 
discontin-
uation 
MADRS 
● 
● 
CGI-I 
● 
● 
CGI-S 
● 
● 
HAM-D 
● 
● 
SDS 
● 
● 
MADRS-S 
questionnaire 
 
 
 
 
 
● 
● 
Laboratory tests 
●c 
● 
Vital signs 
● 
● 
● 
● 
● 
● 
● 
Physical 
examinations 
● 
● 
● 
● 
● 
● 
● 
Waist 
circumference 
 
 
 
 
 
● 
● 
Body weight 
● 
● 
12-lead ECG 
● 
● 
Pregnancy test 
●d 
●d 
C-SSRS 
● 
● 
● 
● 
● 
● 
● 
DIEPSS 
● 
● 
AIMS 
● 
● 
BARS 
● 
● 
 
 
Adverse events 
←--------------------------------------------------------------------------------------------------------------→ 
IMP and requisite 
concomitant 
medicationa 
● 
● 
● 
● 
● 
● 
● 
Concomitant drugs/ 
therapies 
←--------------------------------------------------------------------------------------------------------------→ 
a Treatment compliance regarding IMP and requisite concomitant medication will be recorded. 
b The starting point of the antidepressant-responder treatment-continuation period (Phase A+) is the day 
of assessment at Week 8 of the antidepressant treatment period (Phase A). 
c For this item, subjects will be asked to visit the trial site in a fasting state (a fast for at least 8 hours 
[including drinks containing sugar, such as juice]) at Week 6 of the antidepressant-responder 
treatment-continuation period (Phase A+), and in a fasting state to the extent possible at the 
discontinuation examination. 
d Pregnancy tests will be performed only in female subjects of childbearing potential. 
 
 
3.7.1 
Schedule of Assessments 
The investigator or subinvestigator will conduct the trial in accordance with the schedules 
shown in Table 3.7-1 to Table 3.7-3. The methods of observation, examination, and 

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evaluation are prescribed in Section 3.7.2, Efficacy Assessments, to Section 3.7.3, Safety 
Assessments. 
3.7.1.1 
Informed Consent 
Before all screening examinations, written informed consent is to be obtained from 
subjects. After acquisition of informed consent followed by IWRS registration, a subject 
ID will be assigned to the subject and recorded. Management of IWRS after the first 
registration is separately specified in written procedures, as a management system 
particularly for subject enrollment status and IMP. The investigator or subinvestigator 
will record the subject ID and date on which signed inform consent was obtained in the 
subject screening log. The subject ID and date on which signed inform consent was 
obtained will also be recorded in the source documents and the CRF. 
3.7.1.2 
Screening 
After acquisition of informed consent and within 28 days before commencement of the 
antidepressant treatment period (Period A), the investigator or subinvestigator will 
perform the observations/examinations for the screening period, as specified in Table 3.7-
1 Schedule of Assessments (Screening Period and Antidepressant Treatment Period 
[Phase A]) and record the results in the source documents and the CRF. After subjects are 
judged eligible to participate in this trial, the dose of the antidepressant prior medication 
will be reduced gradually to a dose level that enables safe substitution. The investigator 
or subinvestigator will then record enrollment status, date of enrollment, and reasons for 
any failed enrollment in the subject screening log. 
The investigator or subinvestigator will examine the following subject demographics and 
record the results in the source documents and the CRF. Regarding the treatment history 
for the current major depressive episode, all antidepressant prior medications and their 
effectiveness, as well as psychotherapies/somatic therapies up until 6 weeks before 
informed consent, will be examined. To determine their effectiveness, the results of 
evaluation will be classified as < 25% Improvement, 25% to 49% Improvement, 50% to 
< 75% Improvement, and ≥ 75% Improvement (complete recovery from depressive 
symptoms and not the slightest improvement considered as 100% and 0%, respectively), 
based on the patient’s self-evaluations. 
• Date of visit 
• Subject demographics 
− Date of investigation 
− Date of birth 
− Sex 

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− For female subjects: whether the subject is a woman of childbearing potentiala (If 
not, the reason is to be recorded.) 
aWomen of childbearing potential are defined as female subjects for whom 
menstruation has started and who are not documented as sterile (ie, have had a 
bilateral oophorectomy and/or hysterectomy or who have been postmenopausal 
for at least 12 months). 
− Race 
− Ethnicity 
− Country where trial is performed 
− DSM-5-based diagnostic name and severity as well as specific terms (with 
anxious distress, with mixed features, with melancholic features, with atypical 
features, with mood-congruent psychotic features, with mood-incongruent 
psychotic features, with catatonia, with peripartum onset, and with seasonal 
pattern) 
− Date of first onset of major depressive disorder 
− Frequency of major depressive episodes 
− Date of onset of the current depressive episode 
− Prior medication used to treat the current major depressive episode (all 
antidepressants) 
− Prior therapy used to treat the current major depressive episode 
(psychotherapies/somatic therapies up until 6 weeks before informed consent) 
− Frequency of appropriate antidepressant drug treatments of the current major 
depressive episode (treatment for at least 6 weeks at the approved dose for the 
antidepressant, or treatment for at least 3 weeks with combination therapy) 
− All prior medications and therapies used within 30 days before acquisition of 
informed consent 
− Medical history (within 2 years before acquisition of informed consent, although 
matters pertaining to the inclusion or exclusion criteria are not limited to 2 years) 
and complications 
• Results of eligibility criteria assessment 
 
3.7.1.3 
Observations/Examinations at the Initiation of the 
Antidepressant Treatment Period (Phase A) 
After gradual dose reduction of prior medications, the investigator or subinvestigator will 
perform observations/examinations at the initiation of the antidepressant treatment period 
(Phase A), as specified in Table 3.7-1 Schedule of Assessments (Screening Period and 
Antidepressant Treatment Period [Phase A]), and record the results and findings as well 
as the date of visit in the source documents and the CRF. Subject eligibility will be 
assessed, and the results of the assessment will be registered in the IWRS and recorded in 

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the source documents and the CRF. For subjects assessed as eligible, date of enrollment 
in the antidepressant treatment period (Phase A) will be recorded in the source documents 
and the CRF. 
3.7.1.4 
Observations/Examinations During the Antidepressant 
Treatment Period (Phase A) 
Subjects meeting the eligibility criteria based on observations/examinations at the 
initiation of the antidepressant treatment period (Phase A) will proceed to the 8-week 
antidepressant treatment period (Phase A) to receive an antidepressant (SSRI or SNRI), 
which is different from the antidepressants they had been taking previously, and placebo 
tablets in a single-blind manner. After proceeding to the antidepressant treatment period 
(Phase A), the investigator or subinvestigator will perform the observations/examinations 
required in the antidepressant treatment period (Phase A) as specified in Table 3.7-1 
Schedule of Assessments (Screening Period and Antidepressant Treatment Period [Phase 
A]) and record the results and findings as well as the date of visit in the source documents 
and the CRF. Furthermore, whether or not subjects can proceed to the double-blind 
period (Phase B) will be determined based on the results of observations/examinations at 
Week 8 of the antidepressant treatment period (Phase A), and the results of assessment 
will be registered in the IWRS and recorded in the source documents and the CRF. Based 
on an assessment at Week 8 of the antidepressant treatment period (Phase A), if the 
investigator or subinvestigator confirms that the subject is eligible to proceed, the subject 
will proceed to the double-blind period (Phase B); and if the investigator or 
subinvestigator determines that the subject is not eligible to proceed, the subject will be 
entered in the antidepressant-responder treatment-continuation period (Phase A+). 
Subjects meeting the criteria for proceeding to Phase B based on an assessment at Week 
8 of the antidepressant treatment period (Phase A) will be randomly assigned to the 
brexpiprazole 1 mg/day group, the brexpiprazole 2 mg/day group, or the placebo group at 
a 1:1:1 ratio. Date of assignment and assignment number will be recorded in the source 
documents and the CRF. For subjects who do not meet the criteria for proceeding to 
Phase B, date of enrollment in the antidepressant-responder treatment-continuation period 
(Phase A+) will be recorded in the source documents and the CRF. 
3.7.1.5 
Observations/Examinations During the Double-blind Period 
(Phase B) 
Subjects meeting the criteria for proceeding to Phase B based on an assessment at Week 
8 of the antidepressant treatment period (Phase A) will continue to receive the same 
antidepressant (SSRI or SNRI) as in the antidepressant treatment period (Phase A) with 
no changes in the dose and regimen, and will receive the IMP (brexpiprazole 1 mg/day, 

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brexpiprazole 2 mg/day [1 mg/day until observations/examinations/assessments at Week 
1], or placebo) for 6 weeks. After proceeding to the double-blind period (Phase B), the 
investigator or subinvestigator will perform the observations/examinations required in the 
double-blind period (Phase B) as specified in Table 3.7-2 Schedule of Assessments 
(Double-blind Period [Phase B]) and record the results and findings as well as the date of 
visit in the source documents and the CRF. 
The investigator or subinvestigator will register the required items in the IWRS after each 
subject has completed the 6-week treatment. 
3.7.1.6 
Observations/Examinations During the Antidepressant-
responder Treatment-continuation Period (Phase A+) 
Subjects not meeting the criteria for proceeding to Phase B based on an assessment at 
Week 8 of the antidepressant treatment period (Phase A) will continue to receive the 
same antidepressant (SSRI or SNRI) as in the antidepressant treatment period (Phase A) 
with no changes in the dose and regimen, and will receive placebo for 6 weeks in a 
single-blind manner. The investigator or subinvestigator will perform the 
observations/examinations specified in Table 3.7-3 Schedule of Assessments 
(Antidepressant-responder Treatment-continuation Period [Phase A+]) and record the 
results and findings as well as the date of visit in the source documents and the CRF. 
The investigator or subinvestigator will register the required items in the IWRS after each 
subject has completed the 6-week treatment. 
3.7.1.7 
Observations/Examinations in the Post-treatment Observation 
Period 
In all subjects who proceed to the double-blind period (Phase B) but not to the long-term 
trial (331-102-00059), the investigator or subinvestigator will perform the 
observations/examinations specified in Table 3.7-2 Schedule of Assessments (Double-
blind Period [Phase B]) at a site visit made 30 days (± 5 days) after final IMP 
administration and record the results and findings as well as the date of visit in the source 
documents and the CRF. The investigator or subinvestigator will register the required 
items in the IWRS after each subject has completed the post-treatment observation period. 
3.7.1.8 
Examinations at Discontinuation 
If a subject is withdrawn from the trial during the antidepressant treatment period (Phase 
A), the double-blind period (Phase B), or the antidepressant-responder treatment-
continuation period (Phase A+), the investigator or subinvestigator will perform the 
required examinations at discontinuation, as specified in Table 3.7-1 Schedule of 
Assessments (Screening Period and Antidepressant Treatment Period [Phase A]), Table 

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3.7-2 Schedule of Assessments (Double-blind Period [Phase B]), and Table 3.7-3 
Schedule of Assessments (Antidepressant-responder Treatment-continuation Period 
[Phase A+]), and record the results along with the date of visit in the source documents 
and the CRF. 
The investigator or subinvestigator will register the required items in IWRS at the time of 
each subject’s withdrawal. 
3.7.1.9 
Acceptable Window for Testing 
Observations/examinations and other procedures are to be performed within an 
acceptable window for testing, as specified in Table 3.7.1.9-1, with consideration of the 
availability of each subject for site visits, etc. 
Table 3.7.1.9-1 
Acceptable Window for Examinations/Assessment Period 
The starting point of the antidepressant treatment period (Phase A) is the day of 
assessment at the initiation of the antidepressant treatment period (Phase A). 
Examination Point 
Reference Day 
Acceptable Window 
(From the Reference 
Day) 
At screening 
Day of assessment 
at the initiation of 
the antidepressant 
treatment period 
(Phase A) 
Day −28 to −1 
Day of assessment at the initiation of the antidepressant 
treatment period (Phase A) 
Day 1 
− 
Week 1 of the antidepressant treatment period (Phase A) 
Day 8 
± 2 days 
Week 2 of the antidepressant treatment period (Phase A) 
Day 15 
± 2 days 
Week 3 of the antidepressant treatment period (Phase A) 
Day 22 
± 2 days 
Week 4 of the antidepressant treatment period (Phase A) 
Day 29 
± 2 days 
Week 6 of the antidepressant treatment period (Phase A) 
Day 43 
± 2 days 
Week 8 of the antidepressant treatment period (Phase A) 
Day 57 
± 2 days 
At discontinuation 
− 
− 
At discontinuation: Performed within a possible window at a feasible time point. 
 

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Table 3.7.1.9-1 
Acceptable Window for Examinations/Assessment Period 
The starting point of the double-blind period (Phase B) is the day of assessment at 
Week 8 of the antidepressant treatment period (Phase A). 
Examination Point 
Reference Day 
Acceptable Window 
(From the Reference 
Day) 
Day of assessment at Week 8 of the antidepressant 
treatment period (Phase A) 
Day 1 
− 
Week 1 of the double-blind period (Phase B) 
Day 8 
± 1 day 
Week 2 of the double-blind period (Phase B) 
Day 15 
± 2 days 
Week 3 of the double-blind period (Phase B) 
Day 22 
± 2 days 
Week 4 of the double-blind period (Phase B) 
Day 29 
± 2 days 
Week 5 of the double-blind period (Phase B) 
Day 36 
± 2 days 
Week 6 of the double-blind period (Phase B) 
Day 43 
± 2 days 
At discontinuation 
− 
− 
At discontinuation: Performed within a possible window at a feasible time point. 
 
The starting point of the antidepressant-responder treatment-continuation period (Phase 
A+) is the day of assessment at Week 8 of the antidepressant treatment period (Phase A). 
Examination Point 
Reference Day 
Acceptable Window 
(From the Reference 
Day) 
Day of assessment at Week 8 of the antidepressant 
treatment period (Phase A) 
Day 1 
− 
Week 1 of the antidepressant-responder treatment-
continuation period (Phase A+) 
Day 8 
± 1 day 
Week 2 of the antidepressant-responder treatment-
continuation period (Phase A+) 
Day 15 
± 2 days 
Week 3 of the antidepressant-responder treatment-
continuation period (Phase A+) 
Day 22 
± 2 days 
Week 4 of the antidepressant-responder treatment-
continuation period (Phase A+) 
Day 29 
± 2 days 
Week 5 of the antidepressant-responder treatment-
continuation period (Phase A+) 
Day 36 
± 2 days 
Week 6 of the antidepressant-responder treatment-
continuation period (Phase A+) 
Day 43 
± 2 days 
At discontinuation 
− 
− 
At discontinuation: Performed within a possible window at a feasible time point. 
 
The starting point of the post-treatment observation period is the day of the final IMP 
administration. 
Period 
Reference Day 
Acceptable Window 
(From the Reference 
Day) 
Day of final IMP administration 
Day 1 
− 
Post-treatment observation period 
Day 31 
± 5 days 
 

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3.7.2 
Efficacy Assessments 
3.7.2.1 
Montgomery Åsberg Depression Rating Scale 
(1) 
Time points 
At the initiation and Weeks 2, 4, 6, and 8 (or discontinuation) of the antidepressant 
treatment period (Phase A), Weeks 1, 2, 3, 4, 5, and 6 (or discontinuation) of the double-
blind period (Phase B), and Week 6 (or discontinuation) of the antidepressant-responder 
treatment-continuation period (Phase A+) 
(2) 
Methods 
A trained and qualified investigator or subinvestigator will assess the following 10 
symptoms of depression in the subject on a 7-point scale (0 to 6) using SIGMA at the 
specified assessment time points, and record the date, time, and results of assessment in 
the source documents and the CRF. 
1. Apparent sadness 
2. Reported sadness 
3. Inner tension 
4. Reduced sleep 
5. Reduced appetite 
6. Concentration difficulties 
7. Lassitude 
8. Inability to feel 
9. Pessimistic thoughts 
10. Suicidal thoughts 
 
 
 
3.7.2.2 
Clinical Global Impression – Improvement 
(1) 
Time points 
At Weeks 1, 2, 3, 4, 6, and 8 (or discontinuation) of the antidepressant treatment period 
(Phase A), Weeks 1, 2, 3, 4, 5, and 6 (or discontinuation) of the double-blind period 
(Phase B), and Week 6 (or discontinuation) of the antidepressant-responder treatment-
continuation period (Phase A+) 
(2) 
Methods 
The investigator or subinvestigator will assess the improvement of depressive symptoms 
in the subject on the following 8-point scale using CGI-I at the specified assessment time 
points. Improvement relative to the subject’s condition at the initiation of the 
antidepressant treatment period (Phase A) will be assessed during the antidepressant 
treatment period (Phase A), and the improvement relative to the subject’s condition at 
Week 8 of the antidepressant treatment period (Phase A) will be assessed during the 
double-blind period (Phase B) and the antidepressant-responder treatment-continuation 
period (Phase A+). The date, time, and results of assessment will be recorded in the 
source documents and the CRF. 

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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 
 
3.7.2.3 
Clinical Global Impression - Severity of Illness 
(1) 
Time points 
At screening, the initiation and Weeks 1, 2, 3, 4, 6, and 8 (or discontinuation) of the 
antidepressant treatment period (Phase A), Weeks 1, 2, 3, 4, 5, and 6 (or discontinuation) 
of the double-blind period (Phase B), and Week 6 (or discontinuation) of the 
antidepressant-responder treatment-continuation period (Phase A+) 
(2) 
Methods 
The investigator or subinvestigator will assess the severity of the subject’s depressive 
symptoms on the following 8-point scale using CGI-S at the specified assessment time 
points, and record the date, time, and results of assessment in the source documents and 
the CRF. 
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 
 
 
 
3.7.2.4 
Hamilton Rating Scale for Depression 
(1) 
Time points 
At screening, the initiation and Week 8 (or discontinuation) of the antidepressant 
treatment period (Phase A), Week 6 (or discontinuation) of the double-blind period 
(Phase B), and Week 6 (or discontinuation) of the antidepressant-responder treatment-
continuation period (Phase A+) 
(2) 
Methods 
A trained and qualified investigator or subinvestigator will assess the following 21 
symptoms of depression in the subject on a 5-point scale (0 to 4) for Items No. 1, 2, 10 to 
14, 16 to17, and 19, on a 4-point scale (0 to 3) for Items No. 5 and 20, and on a 3-point 
scale (0 to 2) for Items No. 3, 4, 6 to 9, 15, 18, and 21 using the Structured Interview 
Guide for HAM-D (SIGH-D) at the specified assessment time points, and calculate the 
total score for Items No. 1 to 17, and record the date, time, and results of assessment in 
the source documents and the CRF. 

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1. Depressed mood 
2. Work and activities 
3. Genital symptoms 
 
4. Somatic symptoms gastrointestinal 
5. Loss of weight 
6. Early (initial) insomnia 
7. Middle insomnia 
8. Late (terminal) insomnia 
9. Somatic symptoms general 
10. Feelings of guilt 
11. Suicide 
12. Anxiety psychic 
13. Anxiety somatic 
14. Hypochondriasis 
15. Insight 
16. Retardation 
17. Agitation 
18. Diurnal variation 
19. Depersonalization and derealization  
20. Paranoid symptoms 
21. Obsessional and compulsive symptoms 
 
 
 
3.7.2.5 
Sheehan Disability Scale 
(1) 
Time Points 
At the initiation and Week 8 (or discontinuation) of the antidepressant treatment period 
(Phase A), Weeks 3 and 6 (or discontinuation) of the double-blind period (Phase B), and 
Week 6 (or discontinuation) of the antidepressant-responder treatment-continuation 
period (Phase A+) 
(2) 
Methods 
The investigator or subinvestigator will use SDS at the specified assessment time points 
and ask subjects to self-rate the degree of impairment for each of 3 items (“work/school,” 
“social life,” and “family life/home responsibilities”) on an 11-point scale ranging from 0 
(not at all) to 10 (extremely) and the number of “days lost” and “days unproductive” 
caused by symptoms in the past week. The investigator or subinvestigator will record the 
date, time, and results of assessment in the source documents and the CRF. 
3.7.2.6 
Montgomery Åsberg Depression Rating Scale Self-assessment 
(1) 
Time points 
At the initiation and Weeks 2, 4, 6, and 8 (or discontinuation) of the antidepressant 
treatment period (Phase A), Weeks 1, 2, 3, 4, 5, and 6 (or discontinuation) of the double-
blind period (Phase B), and Week 6 (or discontinuation) of the antidepressant-responder 
treatment-continuation period (Phase A+) 
(2) 
Methods 
All subjects will self-assess each of the following 10 MADRS-S items, selecting the 
applicable level on a scale from 0 to 3 at the specified assessment time points. The 
investigator or subinvestigator will record the date, time, and results of assessment in the 
source documents and the CRF. 

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Staying power 
1. Mood 
2. Feelings of unease 
3. Sleep 
4. Appetite 
5. Ability to concentrate 
6. Initiative 
7. Emotional involvement 
8. Pessimism 9. Zest for life 
 
3.7.3 
Safety Assessments 
3.7.3.1 
Adverse Events 
Refer to Section 5, Reporting of Adverse Events. 
3.7.3.2 
Clinical Laboratory Assessments 
(1) 
Time Points 
At screening (in the fasting state to the extent possible), Week 8 (in the fasting state) or at 
discontinuation (in the fasting state to the extent possible) of the antidepressant treatment 
period (Phase A), Week 3 (in the fasting state to the extent possible) and Week 6 (in the 
fasting state) or at discontinuation (preferably in the fasting state) of the double-blind 
period (Phase B), and Week 6 (in the fasting state) or at discontinuation (in the fasting 
state to the extent possible) of the antidepressant-responder treatment-continuation period 
(Phase A+) 
(2) 
Methods 
Subjects will be asked to visit the trial site in the fasting state (a fast for at least 8 hours 
[including drinks containing sugar, such as juice]) at Week 8 of the antidepressant 
treatment period (Phase A) and Week 6 of the double-blind period (Phase B) or the 
antidepressant-responder treatment-continuation period (Phase A+) and in the fasting 
state to the extent possible at other time points including examinations at discontinuation. 
Blood and urine samples will be collected from each subject at the time of clinical 
laboratory tests as specified in the assessment schedules shown in Table 3.7-1 through 
Table 3.7-3, and the date and time of blood sampling and the date of urine sampling as 
well as the fasting or fed state during blood sampling will be recorded in the source 
documents and the CRF. In this trial, the central laboratory selected by the sponsor will 
be used. Clinical laboratory test values determined at the central laboratory will be used 
for eligibility assessment. For appropriate procedures for the collection, handling, and 
shipment of samples, separately documented procedures will be prepared and provided 
prior to the start of the trial. The central laboratory will report the results of tests to the 
investigator or subinvestigator. The investigator or subinvestigator will confirm the 
results of tests and date and sign the clinical laboratory test report to make it an official 
document. The results of laboratory tests, which will be reported directly from the central 

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laboratory to the sponsor as an electronic file, do not need to be recorded in the source 
documents or the CRF. 
Table 3.7.3.2-1 
Clinical Laboratory Assessments 
Hematology: 
Red Blood Cell count 
White blood cell count 
Differential count of white blood cells (neutrophils, 
eosinophils, basophils, monocytes, and lymphocytes) 
Platelet count 
Hemoglobin 
Hematocrit 
 
Urinalysis: 
pH 
Protein 
Glucose 
Occult blood 
Urobilinogen 
Specific gravity 
Ketone body 
Serum chemistry: 
AST (Glutamic oxaloacetic transaminase [GOT]) 
ALT (Glutamic pyruvic transaminase [GPT]) 
Alkaline Phosphatase (ALP) 
Lactic Dehydrogenase (LDH) 
Gamma-glutamyl transpeptidase (γ-GTP) 
Total protein 
Albumin 
Total bilirubin 
Cholesterol 
(total 
cholesterol, 
low-density 
lipoprotein [LDL] cholesterol, and high-density 
lipoprotein [HDL] cholesterol) 
Triglycerides 
Blood urea nitrogen (BUN) 
Creatinine 
Uric acid 
Creatine kinase (CK) (CPK) 
Serum electrolytes (Na, K, Cl, Ca, Mg, P, 
bicarbonate) 
Blood glucose 
HbA1c (NGSP value) 
Prothrombin time (PT) 
Activated partial thromboplastin time (APTT) 
PT (international normalized ratio [INR]) 
 
Endocrinology: 
Serum prolactin 
Insulin 
FT4 
TSH 
 
To be performed in subjects in the fasting state (a fast for at least 8 hours [including drinks containing 
sugar, such as juice]) at Week 8 of the antidepressant treatment period (Phase A) and Week 6 of the 
double-blind period (Phase B) or the antidepressant-responder treatment-continuation period (Phase 
A+) and in the fasting state to the extent possible at other time points including examinations at 
discontinuation 
 
3.7.3.3 
Vital Signs and Physical Examination 
(1) 
Vital signs 
(a) Time points 
At screening, the initiation and Weeks 1, 4, and 8 (or discontinuation) of the 
antidepressant treatment period (Phase A), Weeks 1, 2, 3, 4, 5, and 6 (or 
discontinuation) of the double-blind period (Phase B), and Weeks 1, 2, 3, 4, 5, and 6 
(or discontinuation) of the antidepressant-responder treatment-continuation period 
(Phase A+) 

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(b) Methods 
After keeping the subject in a relaxed state, body temperature will be measured and 
then blood pressure (systolic and diastolic) and pulse rate will be measured in the 
supine, sitting, and standing positions in accordance with the measurement methods 
specified by the trial site. For body temperature, the date and result of measurement 
will be recorded in the source documents and the CRF. Blood pressure and pulse rate 
will be measured in the supine, sitting, and standing positions, in this order, after 
maintaining each position for at least 3 minutes. The date, time, positions, and results 
of measurement will be recorded in the source documents and the CRF. 
(2) 
Physical examination 
(a) Time points 
At screening, the initiation and Weeks 1, 2, 3, 4, 6, and 8 (or discontinuation) of the 
antidepressant treatment period (Phase A), Weeks 1, 2, 3, 4, 5, and 6 (or 
discontinuation) of the double-blind period (Phase B), post-treatment observation 
period, and Weeks 1, 2, 3, 4, 5, and 6 (or discontinuation) of the antidepressant-
responder treatment-continuation period (Phase A+) 
(b) Methods 
The investigator or subinvestigator will perform a physical examination that includes 
the assessment items shown below through subject interview and other relevant 
methods and record the physical findings in the source documents. The date and results 
of examinations at screening and only the dates of examinations after the initiation of 
the antidepressant treatment period (Phase A) will be recorded in the source documents 
and the CRF. Any clinically significant physical findings compared with findings at 
screening are to be recorded as AEs. 
Assessment items: HEENT (head, eyes, ears, nose, and throat), chest, abdomen, 
urogenital organs, limbs, nerves, and skin mucosa 
(3) 
Waist circumference 
(a) Time points 
At the initiation and Week 8 (or discontinuation) of the antidepressant treatment period 
(Phase A), Week 6 (or discontinuation) of the double-blind period (Phase B), and 
Week 6 (or discontinuation) of the antidepressant-responder treatment-continuation 
period (Phase A+) 

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(b) Methods 
Measurement will be performed while the subject is minimally clothed (lightly clothed, 
removing heavy outer garments). The top of the hip bone and the upper edge of the 
right iliac crest will be located, and then a measuring tape will be placed horizontally 
all the way around the abdomen at the height of the iliac crest. Prior to measurement, 
the person engaged in measurement should ensure that the measuring tape is snug 
without indenting the subject’s skin and is parallel to the floor. At the end of a normal 
expiration, waist circumference will be measured in centimeters (rounded off to the 
nearest whole number) and the date and result of measurement will be recorded in the 
source documents and the CRF. 
(4) 
Height and body weight 
(a) Time points 
At screening, Week 8 (or discontinuation) of the antidepressant treatment period (Phase 
A), Week 6 (or discontinuation) of the double-blind period (Phase B), and Week 6 (or 
discontinuation) of the antidepressant-responder treatment-continuation period (Phase 
A+) 
However, height will be measured only at screening. 
(b) Methods 
Body weight and height will be measured at the specified time points, and the date and 
results of measurement will be recorded in the source documents and the CRF (body 
weight in increments of 0.1 kg, height in increments of 0.1 cm). Body weight will be 
measured by the standard measurement method (fully clothed but without shoes) using 
a reliable, calibrated scale (the same scale should always be used to measure a 
particular subject). 
3.7.3.4 
12-lead Electrocardiography 
(1) 
Time points 
At screening, Week 8 (or discontinuation) of the antidepressant treatment period (Phase 
A), Week 6 (or discontinuation) of the double-blind period (Phase B), and Week 6 (or 
discontinuation) of the antidepressant-responder treatment-continuation period (Phase 
A+) 
(2) 
Methods 
The investigator or subinvestigator will record the subject’s ECG using a 12-lead 
electrocardiograph supplied by the central ECG laboratory, assess whether the ECG 

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result is normal or abnormal, and record the date and time of ECG, normal/abnormal 
judgement, and abnormal findings in the source documents and the CRF. The original of 
the 12-lead ECG chart will be kept in the medical record or the investigator’s file. The 
central ECG laboratory will collect 12-lead ECG data and measure heart rate, PR interval, 
RR interval, QRS interval, QT interval, and QT corrected for heart rate (QTc) [QTcB = 
QT interval/(RR interval)1/2, QTcF = QT interval/(RR interval)1/3, QTcN = QT 
interval/(RR interval)0.37], and the physician of the central ECG laboratory will assess the 
data. The central ECG laboratory will report the results of analysis to the investigator or 
subinvestigator. The investigator or subinvestigator will confirm the results of analysis 
and date and sign the analysis result report to make it an official document. The 
investigator or subinvestigator will reconfirm the normal/abnormal judgement with 
reference to the analysis result report sent from the central ECG laboratory. The results of 
analysis, which will be reported directly from the central ECG laboratory to the sponsor 
as an electronic file, do not need to be recorded in the source documents or the CRF. 
3.7.3.5 
Pregnancy Test 
(1) 
Time points 
At screening, the initiation and Week 8 (or discontinuation) of the antidepressant 
treatment period (Phase A), Week 6 (or discontinuation) of the double-blind period 
(Phase B), and Week 6 (or discontinuation) of the antidepressant-responder treatment-
continuation period (Phase A+) 
(2) 
Methods 
A urine pregnancy test will be performed in women of childbearing potentiala and the 
date of urine sampling and the result of the test will be recorded in the source documents 
and the CRF. If the urine test is positive, another pregnancy test will be performed using 
serum [excluding the time of screening and the initiation of the antidepressant treatment 
period (Phase A)] and the date of blood sampling will be recorded in the source 
documents and the CRF. A serum pregnancy test will be performed by the central 
laboratory selected by the sponsor. For appropriate procedures for the collection, 
handling, and shipment of samples, separately documented procedures will be prepared 
and provided prior to the start of the trial. The central laboratory will report the results of 
tests to the investigator or subinvestigator. The investigator or subinvestigator will 
confirm the results of tests and date and sign the clinical laboratory test report to make it 
an official document. The results of serum tests, which will be reported directly from the 
central laboratory to the sponsor as an electronic file, do not need to be recorded in the 
source documents or the CRF. 

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a: Women of childbearing potential are defined as female subjects for whom 
menstruation has started and who are not documented as sterile (ie, have had a 
bilateral oophorectomy and/or hysterectomy or who have been postmenopausal for 
at least 12 months). 
3.7.3.6 
Columbia-Suicide Severity Rating Scale 
(1) 
Time points 
At screening, the initiation and Weeks 1, 2, 3, 4, 6, and 8 (or discontinuation) of the 
antidepressant treatment period (Phase A), Weeks 1, 2, 3, 4, 5, and 6 (or discontinuation) 
of the double-blind period (Phase B), post-treatment observation period, and Weeks 1, 2, 
3, 4, 5, and 6 (or discontinuation) of the antidepressant-responder treatment-continuation 
period (Phase A+) 
(2) 
Methods 
This scale consists of the "Baseline Version," which assesses the lifetime history of 
suicide-related events and suicidal ideation and the "Since Last Visit Version," which 
focuses on suicidality since the last assessment in the trial. The "Baseline Version" will 
be used at screening and the "Since Last Visit Version" will be used at subsequent time 
points for C-SSRS assessment. The date, time, and results of assessment will be recorded 
in the source documents and the CRF. 
The presence of suicidal ideation 1 or 2 will be assessed with “yes” or “no,” and if the 
answer to 2 is “yes,” suicidal ideation 3 to 5 will be assessed. If the answer to suicidal 
ideation 1 or 2 is “yes,” the intensity of ideation will also be rated. Intensity of ideation 
will be rated on a 5-point scale for “frequency” and “duration” and a 6-point scale for 
“controllability,” “deterrents,” and “reasons for ideation.” The following suicidal 
behavior will also be assessed with “yes” or “no,” and 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 injury 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 Version") 
 
 
 
 

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3.7.3.7 
Drug Induced Extra-Pyramidal Symptoms Scale 
(1) 
Time points 
At Week 8 of the antidepressant treatment period (Phase A), Weeks 1, 2, 3, 4, 5, and 6 (or 
discontinuation) of the double-blind period (Phase B), and Week 6 (or discontinuation) of 
the antidepressant-responder treatment-continuation period (Phase A+) 
(2) 
Methods 
The investigator or subinvestigator will assess the following 9 items related to extra-
pyramidal symptoms on a 5-point scale ranging from 0 (none, normal) to 4 (severe) using 
DIEPSS at specified time points. The date, time, and results of assessment will be 
recorded in the source documents and the CRF. 
1. Gait 
2. Bradykinesia 
3. Sialorrhea 
4. Muscle rigidity 
5. Tremor 
6. Akathisia 
7. Dystonia 
8. Dyskinesia 
9. Global severity 
 
 
3.7.3.8 
Abnormal Involuntary Movement Scale 
(1) 
Time points 
At Week 8 of the antidepressant treatment period (Phase A), Week 6 (or discontinuation) 
of the double-blind period (Phase B), and Week 6 (or discontinuation) of the 
antidepressant-responder treatment-continuation period (Phase A+) 
(2) 
Methods 
Using AIMS, the investigator or subinvestigator will assess the severity of abnormal 
involuntary movement at 7 sites (“muscles of facial expression,” “lips and perioral area,” 
“jaw,” “tongue,” “upper extremities [arms, wrists, hands, and fingers],” “lower 
extremities [legs, knees, ankles, and toes],” and “neck, shoulders, and hips”) and 3 global 
judgment items on a 5-point scale ranging from 0 (none) to 4 (severe) and assess the 
dental status items “current problems with teeth and/or dentures” and “Dose patient 
usually wear dentures” as either “yes” or “no,” at the specified time points. The date, time, 
and results of assessment will be recorded in the source documents and the CRF. 
3.7.3.9 
Barnes Akathisia Rating Scale 
(1) 
Time points 
At Week 8 of the antidepressant treatment period (Phase A), Week 6 (or discontinuation) 
of the double-blind period (Phase B), and Week 6 (or discontinuation) of the 
antidepressant-responder treatment-continuation period (Phase A+) 

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(2) 
Methods 
Using BARS, the investigator or subinvestigator will assess “objective,” “subjective—
awareness of restlessness,” and “subjective—distress related to restlessness” for akathisia 
on a 4-point scale and a “global clinical assessment of akathisia” on a 6-point scale at the 
specified time points. The date, time, and results of assessment will be recorded in the 
source documents and the CRF. 
3.7.4 
Prior and Concomitant Medications and Therapies 
The investigator or subinvestigator will examine the use of the following prior and 
concomitant medications and therapies. For prior and concomitant medications, the name 
of the drug, purpose of use (excluding prior medications used to treat the current major 
depressive episode), dose, frequency, route of administration, start and end dates of 
treatment, and treatment response (for prior medications used to treat the current major 
depressive episode) will be examined and recorded in the source documents and the CRF. 
For prior and concomitant therapies, the name of the therapy, purpose of use (excluding 
prior therapies used to treat the current major depressive episode), and the start and end 
dates of treatment will be examined and recorded in the source documents and the CRF. 
• Prior medications and therapies 
− Prior medications used to treat the current major depressive episode (all 
antidepressants)  
− Prior therapies used to treat the current major depressive episode 
(psychotherapies/somatic therapies up until 6 weeks before informed consent) 
− All prior medications and therapies used within 30 days before acquisition of 
informed consent 
• Concomitant medications and therapies 
− Concomitant medications and therapies used during the trial period (including 
treatments for AEs) 
 
3.7.5 
Investigational Medicinal Product 
(1) 
Treatment compliance 
The investigator or subinvestigator will confirm the subject’s IMP compliance during the 
interval between 2 consecutive scheduled visits after proceeding to the antidepressant 
treatment period (Phase A) and record the consumed daily dose and the start and end 
dates of IMP administration in the source documents and the CRF. 

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(2) 
Compliance rate 
Compliance rate (%) = 
Doses consumed between 2 consecutive scheduled visits (number of tablets) 
× 100 
“Number of prescribed days between 2 consecutive scheduled visits” (number of 
days) × 1 tablet 
 
(3) 
Compliance instruction 
The investigator, subinvestigator, or IMP manager will provide subjects with compliance 
instructions with particular attention to the following points: 
• The subject should take the IMP once daily, removing only the prescribed daily 
amount of the IMP from the sheet. 
• The subject must bring any missed/unused doses (IMP tablets) to the trial site at the 
next visit. 
• Contact information for any questions about taking the IMP 
• The subject must not discard any empty IMP sheets but should bring them to the trial 
site at the next visit. 
• The subject should be withdrawn from the trial if the subject’s IMP compliance 
during an interval between 2 consecutive scheduled visits is less than 65%. 
 
3.7.6 
Requisite Concomitant Medication 
The investigator or subinvestigator will confirm the subject’s compliance with the 
requisite concomitant medication, a commercially available antidepressant (SSRI or 
SNRI), during the interval between 2 consecutive scheduled visits after proceeding to the 
antidepressant treatment period (Phase A) and record the name of the drug, prescribed 
daily dose, consumed daily dose, and start and end dates of administration in the source 
documents and the CRF. 
3.7.7 
Pharmacokinetic Assessment, Pharmacogenomic Assessment, 
and 
 
3.7.7.1 
Pharmacokinetic Assessment 
Plasma brexpiprazole concentrations will be measured by validated high performance 
liquid chromatography/tandem mass spectrometry. Metabolites that are not presented in 
the protocol may be measured based on newly obtained information. 
The bioanalytical laboratory will measure drug concentrations only for samples collected 
from subjects in the brexpiprazole 1 mg/day group or the brexpiprazole 2 mg/day group 
after recording the use of the documents providing treatment assignment codes. Access to 
the documents containing treatment assignment codes will be strictly controlled and not 

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disclosed to anyone other than those who need them to carry out trial-related activities in 
the opinion of the person responsible for drug concentration measurements. The 
bioanalytical laboratory will hold the results of drug concentration measurements in strict 
confidence and submit an electronic file containing these results to the sponsor after 
unblinding. 
3.7.7.1.1 
Blood Sampling Time Point 
 
3.7.7.1.2 
Plasma Samples for Pharmacokinetic Assessment 
All plasma samples will be shipped to the bioanalytical laboratory. The date and time of 
IMP administration immediately before blood sampling and the date and time of blood 
sampling will be recorded in the source documents and the CRF. The results of 
measurements, which will be reported directly from the bioanalytical laboratory to the 
sponsor as an electronic file after unblinding, do not need to be recorded in the source 
documents or the CRF. Detailed handling and shipping methods of samples are provided 
in Appendix 1. 
3.7.7.2 
Pharmacogenomic Assessment 
3.7.7.2.1 
CYP2D6 Genetic Testing 
CYP2D6 genotypes and phenotypes will be analyzed. CYP2D6 genetic testing is 
mandatory. 
The CYP2D6 genotype will be determined for each subject 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 be disclosed to subjects. 
The genetic analysis laboratory will select blood samples collected from subjects in the 
brexpiprazole 1 mg/day group and the brexpiprazole 2 mg/day group and extract DNA 
after recording the use of the documents providing treatment assignment codes. Blood 
samples collected from subjects in the placebo group will be discarded in accordance 
with the procedure specified by the genetic analysis laboratory. Access to the documents 
containing treatment assignment codes will be strictly controlled and not be disclosed to 
anyone except for those who need them to carry out trial-related activities in the opinion 
of the person responsible for genetic testing. The genetic analysis laboratory will hold the 

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results of CYP2D6 genetic testing in strict confidence and submit an electronic file 
containing these results to the sponsor after unblinding. 
3.7.7.2.1.1 
Blood Sampling Time Point 
Blood sampling will be performed at Week 6 of the double-blind period (Phase B) or at 
discontinuation. If resampling of blood is necessary, it will be performed by the end of 
the trial date. 
3.7.7.2.1.2 
Samples for CYP2D6 Genetic Testing 
All blood samples will be shipped to the genetic analysis laboratory. The date and time of 
blood sampling will be recorded in the source documents and the CRF. The results of 
measurements, which will be reported directly from the genetic analysis laboratory to the 
sponsor as an electronic file after unblinding, do not need to be recorded in the source 
documents or the CRF. Detailed handling and shipping methods of samples are provided 
in Appendix 1. 
3.7.7.2.2 
 
3.7.7.2.2.1 
 
 
3.7.7.2.2.2 
 
 
 
3.7.7.2.2.3 
Timing of Blood Sampling 
 
 
3.7.7.2.2.4 
Handling of Samples 
 

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3.7.7.2.2.5 
 
 
 
 
 
 
 
 
 
 
 
 
3.7.7.2.2.6 
 
 
 
 

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3.7.7.2.2.7 
 
 
3.7.7.3 
 
3.7.7.3.1 
Objective 
 
3.7.7.3.2 
Target Population 
 
 
3.7.7.3.3 
Blood Collection Time Points 
 
3.7.7.3.4 
Handling of Samples 

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3.7.7.3.5 
 
 
 
 
 
 
3.7.7.3.6 
 
 
 
 
 
3.7.7.3.7 
 

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3.7.8 
End of Trial 
The end of trial date is defined as the date of completion or discontinuation of the trial as 
recorded on the trial completion page or the date of last visit or contact or date of final 
contact attempt as recorded on the follow-up page of the CRF prepared for the last 
subject completing or withdrawing from the trial. 
3.8 
Stopping Rules, Withdrawal Criteria, and Procedures 
3.8.1 
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. 
3.8.2 
Individual Site 
Individual trial site participation may be discontinued by the sponsor, the investigator, or 
the IRB for medical, safety, regulatory, ethical, or other reasons consistent with 
applicable laws, regulations, and GCP. The head of the trial site will notify the sponsor 
promptly if the trial is terminated by the investigator or the IRB at the site. 
3.8.3 
Individual Subject Discontinuation 
3.8.3.1 
Treatment Discontinuation 
After commencement of the treatment period, a subject may stop treatment permanently 
for a variety of reasons. Treatment discontinuations may be initiated by a subject who is 
no satisfied with treatment or may become medically necessary due to AEs, required 
treatment with a disallowed medication or therapy, or other issues, as determined by the 
investigator or subinvestigator. However, for subjects who have undergone 
randomization, each investigator or subinvestigator must comprehensively review the 
circumstances and offer the subject options for continued treatment to the degree possible 
as described in Section 3.8.3.4 Procedures to Encourage Continued Trial Participation. 
3.8.3.2 
Documenting Reasons for Discontinuation 
All subjects have the right to withdraw and the investigator or subinvestigator can 
discontinue a subject’s participation in the trial at any time if medically necessary. In 
addition, subjects meeting the following criteria must be withdrawn from the trial. Only 

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one reason for discontinuation (the main reason) can be recorded in the source documents 
and CRF, along with the date of discontinuation. 
1) Adverse event: 
a) Death 
b) Subjects experiences exacerbation of symptoms of the underlying disease, and 
the investigator or subinvestigator judges that continued participation in the 
trial is inappropriate 
c) Subject experiences a change to the manic state 
d) Based on clinical symptoms, subject is considered to be at high risk of suicide 
in the opinion of the investigator or subinvestigator or has an MADRS score 
for Suicidal Thought (No. 10) of ≥ 5 or HAM-D suicide score (No. 11) of ≥ 3, 
or those answering "Yes" to question 4 or 5 of C-SSRS. 
e) Subject decides to discontinue because of annoyance or discomfort due to a 
nonserious AE which is not otherwise determined to be an undue hazard 
f) Continuation of IMP would place the subject at undue risk as determined by 
the investigator or subinvestigator (eg, there is a safety concern possibly, 
probably, or likely related to IMP) 
i) SAE 
ii) Other safety concern or AE possibly, probably, or likely related to IMP 
2) Subject’s withdrawal of informed consent 
a) Reasons unrelated to medical condition (issues regarding subject’s 
convenience, such as a change of residence or other commitments: provide 
detail and review AE history with subject) 
b) Withdrawal of informed consent (complete written withdrawal of consent 
form) 
3) Marked noncompliance with the IMP regimen 
a) Compliance rate of < 65% during the interval between 2 consecutive 
scheduled visits 
4) Protocol deviation 
a) Subject is discovered to have not been in accord with inclusion/exclusion 
criteria 
b) Subject has received any prohibited concomitant drugs or therapies, or is 
judged to be in need of such 
c) Dose of antidepressant (SSRI or SNRI) cannot be fixed from Week 7 of the 
antidepressant treatment period [Phase A]) 
5) Lost to follow-up 
6) Pregnancy (see Section 5.5 Pregnancy) 
7) Termination of all or part of the trial by the sponsor 
8) Discontinuation of the trial site by the sponsor 
9) Lack of efficacy 

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10) Impossibility of protocol compliance or judgement by the investigator or 
subinvestigator that discontinuation is necessary for any reason other than the 
above 
If the subject discontinues IMP due to an AE, the investigator, subinvestigator, or other 
trial personnel will make every effort to follow the event until the event is resolved or 
stabilized, or the subject is lost to follow up or has died. Follow-up procedures in Section 
3.8.3.1 Treatment Discontinuation must be followed. 
3.8.3.3 
Withdrawal of Consent 
All subjects have the right to withdraw their consent from further participation in the trial 
at any time without prejudice. Subjects cannot withdraw consent for use of data already 
collected as part of the trial, but only for future participation. The investigator or 
subinvestigator can also discontinue a subject’s participation in the trial at any time if 
medically necessary. Unless the subject provides their written withdrawal of consent or 
there is other written documentation by the investigator or subinvestigator confirming the 
subject’s verbal intent to completely withdraw from the trial, subjects should be followed 
for all protocol-specified evaluations and assessments, if possible. 
Complete withdrawal of consent requires refusal by a subject of ALL of the following 
methods of follow up (these methods of follow up will also be noted in the trial ICF): 
• Participation in all follow-up procedures specified in the protocol (whether in-clinic, 
by telephone, or by an in-home visit). 
• Participation in a subset of protocol specified follow-up procedures (by a frequency 
schedule and method, as agreed by subject and staff). 
• Contact of the subject by trial personnel, even if only by telephone, to assess current 
medical condition, and obtain necessary medical or laboratory reports relevant to the 
trial’s objectives. 
• Contact of alternative person(s) who have been designated in source documents as 
being available to discuss the subject’s medical condition, even if only by telephone, 
mail, or e-mail (eg, family, spouse, partner, legal representative, friend, neighbor, or 
physician). 
• Access to medical information from alternative sources (eg, hospital/clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, social media sources). 
Withdrawal of consent is a critical trial event and therefore should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent. 
The reasons of a subject for an intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial. 
A subject may initially express their desire to discontinue IMP administration, which is 
not equivalent to a complete withdrawal of consent for further participation (see Section 

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3.8.3.1 Treatment Discontinuation). A subject may, however, indicate that further trial 
participation is creating a burden on their work or social schedule. Therefore, the 
investigator or subinvestigator should follow the procedures outlined in Section 3.8.3.2 
Documenting Reasons for Discontinuation to determine if the subject can continue 
participation in the trial if modifications to his/her treatment and/or schedule of 
assessments can be accommodated. Only subjects who withdraw their permission for all 
of the above degrees of follow-up are considered to have completely withdrawn their 
consent to participate in the trial. 
3.8.3.4 
Procedures to Encourage Continued Trial Participation 
In all cases of impending IMP discontinuation or consent withdrawal for subjects who 
have undergone randomization, investigators or subinvestigators will be given 
instructions to meet and discuss with the subject their options of continuing in the trial, 
preferably on therapy. The investigator or subinvestigator should ensure understanding 
and documentation of the reasons why the subject wishes to withdraw consent. 
3.9 
Screen Failures 
A screen failure subject is one from whom informed consent is obtained and is 
documented in writing (ie, subject has signed an ICF), but who is not enrolled in the 
antidepressant treatment period (Phase A). For screen failures, the following information 
will be recorded in the source documents and the CRF: 
• Date of visit 
• Date of informed consent 
• Subject demographics 
− Date of investigation 
− Date of birth 
− Sex 
− Race 
− Ethnicity 
− Country where trial is performed 
• Results of eligibility criteria assessment 
• Date of assessment as screen failure 
• Reason for screening failure 
Subjects who participate in this trial but who are categorized as screening failures are 
permitted to be rescreened. Prior to rescreening, if performed, informed consent must be 
newly obtained and a new subject ID must be assigned. 

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3.10 
Definition of Completed Subjects 
The treatment period is defined as the time period during which subjects are evaluated for 
safety and efficacy irrespective of whether the subject actually receives all doses of the 
IMP. Subjects who are evaluated at the last scheduled visit during the treatment period 
will be defined as trial completers. For the purposes of this trial, subjects who are 
evaluated at Week 6 of the double-blind period (Phase B) or antidepressant-responder 
treatment-continuation period (Phase A+) will be defined as trial completers. 
3.11 
Definition of Subjects Lost to Follow-up 
Subjects who cannot be contacted on or before the examinations at Week 6 of the double-
blind period (Phase B) or antidepressant-responder treatment-continuation period (Phase 
A+) during the treatment period, who do not have a known reason for discontinuation (eg, 
withdrew consent or AE), and for whom a survival status at the end of the trial cannot be 
determined will be classified as “lost to follow-up.” Subjects who did not commence the 
treatment period of the long-term trial (331-102-00059) and did not undergo post-
treatment observation after completing the examinations at Week 6 of the double-blind 
period (Phase B) will also be classified as “lost to follow-up.” Survival status can be 
determined from a variety of sources, either by obtaining acceptable documentation for 
death (ie, death certificate, medical records, public records, statement by a family 
member or primary care physician) or acceptable documentation for life (ie, direct 
contact with the subject, medical records, successful telephone contact with the subject, 
statement by a family member or primary care physician, or public records). 
The investigator, subinvestigator, or designee will make 3 documented attempts to 
contact the subject by telephone and in the event 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, and will 
make a record of the inability to contact the subject, recording the dates of the 3 attempts 
at contact and the method(s) of contact in the source documents and the date and method 
of the last attempt at contact in the CRF. 
3.12 
Subject Compliance 
The investigator or subinvestigator will give subjects the following instructions to ensure 
compliance with the protocol: 
1) Site visits are to be made on the scheduled visit days as specified in the protocol 
(see Section 3.7.1.9). 
2) No prohibited concomitant drugs are to be taken during the period from informed 
consent to Week 6 (or discontinuation) of the double-blind period (Phase B) or to 

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Week 6 (or discontinuation) of the antidepressant-responder treatment-
continuation period (Phase A+). 
3) No commercially available brexpiprazole is to be taken during the period from 
Week 6 (or discontinuation) of the double-blind period (Phase B) to the post-
treatment observation period. 
4) The requirements regarding the method, duration, and frequency of administration 
of a commercially available antidepressant and the IMP are to be complied with 
(see Section 3.2). If IMP compliance during the interval between 2 consecutive 
scheduled visits is less than 65%, the subject will be withdrawn from the trial (see 
Section 3.8.3). 
5) Subjects must take appropriate contraceptive methods as instructed (see Section 
5.5). 
 
3.13 
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. For major deviations, 
the date on which the deviation occurred and the details of the deviation will be recorded 
in the source documents and the CRF. 
4 
Restrictions 
The use of the following drugs, etc., and therapies will be prohibited or restricted. 
4.1 
Prohibited Concomitant Medications 
For appropriate assessment of the efficacy and safety of brexpiprazole, use of the drugs 
shown below will be prohibited. Discontinuation of these drugs following gradual dose 
reduction in the screening period but before the start of the prohibition period shown 
below may be allowed, if deemed necessary by the investigator or subinvestigator. 
• One week prior to the initiation of the antidepressant treatment period (Phase A) to 
the treatment period (the antidepressant treatment period [Phase A], and the double-
blind period [Phase B] or the antidepressant-responder treatment-continuation period 
[Phase A+]) 
− Benzodiazepines (excluding ultrashort-acting sedative-hypnotic drugs) 
*Necessary washout period: 7 days 

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• Two weeks prior to the initiation of the antidepressant treatment period (Phase A) to 
the treatment period (the antidepressant treatment period [Phase A], and the double-
blind period [Phase B] or the antidepressant-responder treatment-continuation period 
[Phase A+]) 
− MAO inhibitors 
*Necessary washout period: 14 days 
• Twenty-four hours before the initiation of the antidepressant treatment period (Phase 
A) to the treatment period (the antidepressant treatment period [Phase A], and the 
double-blind period [Phase B] or the antidepressant-responder treatment-continuation 
period [Phase A+]) 
− Central nervous system drugs (excluding ultrashort-acting sedative-hypnotic 
drugs, anticholinergic drugs for Parkinson’s disease, antipyretic analgesic anti-
inflammatory drugs, and general cold drugs) 
Note: Concomitant use of CYP2D6 inhibitors, CYP3A4 inhibitors, and CYP3A4 
inducers specified in this section is prohibited (eg, chlorpheniramine, 
diphenhydramine, clemastine, and celecoxib). 
− Chinese medicine (drugs indicated for neurosis, anxiety neurosis, neurasthenia, 
insomnia, and other disorders) 
− Over-the-counter drugs used as hypnotics 
− Supplements used for improvement of depressive symptoms (St. John's wort, S-
adenosylmethionine [SAM-e], ω-3 fatty acids, Kava extracts, and gamma-
aminobutyric acid [GABA]) 
− Varenicline 
− Adrenaline 
− CYP2D6 inhibitors (excluding topical agents in the dosage forms permitted for 
concomitant use as specified in Appendix 3): 
Drug category 
Nonproprietary name 
Antihistamines 
clemastine, chlorpheniramine, 
diphenhydramine 
Antiallergic minor tranquilizers 
hydroxyzine 
Antiinflammatory agents 
celecoxib 
Analgesics 
methadone 
Antifungal agents 
terbinafine 
Antiarrhythmic agents 
quinidine 
Acid suppressants 
cimetidine 
Overactive bladder treatments 
mirabegron 
Antidepressants 
clomipramine 
Hyperthyroidism treatments 
cinacalcet 
Erythematosus treatments 
hydroxychloroquine 

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− CYP3A4 inhibitors (excluding topical agents in the dosage forms permitted for 
concomitant use as specified in Appendix 3): 
Drug category 
Nonproprietary name 
Antibiotics 
erythromycin, quinupristin/dalfopristin 
(injection), clarithromycin, chloramphenicol, 
ciprofloxacin 
Antifungal agents 
itraconazole, clotrimazole, fluconazole, 
voriconazole 
Calcium antagonists 
diltiazem, verapamil 
Antiarrhythmic agents 
amiodarone 
Acid suppressants 
cimetidine 
Antiemetics 
aprepitant 
Antineoplastic agents 
imatinib, crizotinib 
Immunosuppressants 
ciclosporin 
Anti-HIV agents 
atazanavir, indinavir, cobicistat 
(combination), saquinavir, nelfinavir, 
fosamprenavir, ritonavir, lopinavir/ritonavir 
(combination) 
Hepatitis C treatments 
telaprevir, ombitasvir/paritaprevir/ritonavir 
(combination) 
− CYP3A4 inducers (excluding topical agents in the dosage forms permitted for 
concomitant use as specified in Appendix 3): 
Drug category 
Nonproprietary name 
Corticosteroids 
cortisone, dexamethasone, triamcinolone, 
hydrocortisone, fludrocortisone, 
prednisolone, betamethasone, 
methylprednisolone 
Antihormones 
enzalutamide, mitotane 
Cervical ripening agents 
prasterone 
Central nervous system 
stimulants 
modafinil 
Antiepileptics 
oxcarbazepine, carbamazepine, phenytoin, 
fosphenytoin, phenobarbital, primidone 
Pulmonary hypertension 
treatments 
bosentan 
Antituberculous agents 
rifampicin (rifampin) 
Anti-HIV agents 
etravirine, efavirenz, nevirapine 
− Drugs not approved in Japan 
− Foods: Food products containing St. John's wort, and grapefruit, starfruit, Seville 
orange, and their juice and other processed products 
• Post-treatment observation period 
− Commercially available brexpiprazole 
 

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4.2 
Prohibited Concomitant Therapies 
For appropriate assessment of the efficacy and safety of brexpiprazole, the following 
therapies are prohibited during the treatment period (antidepressant treatment period 
[Phase A], and double-blind period [Phase B] or antidepressant-responder treatment-
continuation period [Phase A+]). 
• Somatic therapy (electroconvulsive therapy, high-intensity phototherapy, sleep 
deprivation, transcranial magnetic stimulation) 
• Psychotherapy (excluding supportive psychotherapies used in general clinical 
practice) 
 
4.3 
Restricted Concomitant Drugs 
• Ultrashort-acting sedative-hypnotic drugs 
Ultrashort-acting sedative-hypnotic drugs that can be used in this trial are restricted to 
zolpidem, zopiclone, eszopiclone, and triazolam. During the treatment period 
(antidepressant treatment period [Phase A], and double-blind period [Phase B] or 
antidepressant-responder treatment-continuation period [Phase A+]), the concomitant 
use of only one of the aforementioned drugs is allowed; 2 or more drugs are not to be 
coadministered simultaneously. Change in the types of the aforementioned drugs is 
allowed. Regarding ultrashort-acting sedative-hypnotic drugs, the concomitant use in 
the double-blind period (Phase B) or the antidepressant-responder treatment-
continuation period (Phase A+) is allowed but only when the drugs have been used 
concomitantly in the antidepressant treatment period (Phase A). 
• Anticholinergic drugs for Parkinson's disease 
Concomitant use of anticholinergic drugs for Parkinson's disease is allowed only in 
the double-blind period (Phase B). Anticholinergic drugs for Parkinson's disease, for 
which concomitant use is allowed, are biperiden, trihexyphenidyl, profenamine, 
piroheptine, and mazaticol. In the case where extrapyramidal symptoms occur and 
use is necessary in the opinion of the investigator or subinvestigator, only one drug 
can be coadministered with no prophylactic use allowed. Change in the types of the 
aforementioned drugs is allowed. 
• Antipyretic analgesic anti-inflammatory drugs, antihistamines 
The concomitant use during the treatment period (antidepressant treatment period 
[Phase A], and double-blind period [Phase B] or the antidepressant-responder 
treatment-continuation period [Phase A+]) is allowed if the drugs were being used to 
treat complications at the time of informed consent; however, no changes in dose and 
regimen are allowed unless AEs occur or the use of these drugs is considered 
unnecessary because of remission of symptoms. Furthermore, short-term concomitant 
use, including use such as a medication for colds, is also allowed. The topical external 
use of these drugs is allowed. 
Note: Concomitant use of CYP2D6 inhibitors, CYP3A4 inhibitors, and CYP3A4 
inducers specified in Section 4.1 Prohibited Concomitant Medications is prohibited 

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(eg, chlorpheniramine, diphenhydramine, clemastine, and celecoxib). “Short-term” is 
defined as 1 week in principle. If antipyretic analgesic anti-inflammatory drugs or 
antihistamines that were not in use at the time of informed consent have been used for 
more than 2 weeks or if the use of these drugs for more than 2 weeks is judged to be 
necessary, the subject will be withdrawn from the trial under the reason for 
discontinuation “Subject has received any prohibited concomitant drugs or therapies, 
or is judged to be in need of such.” 
• β-Blockers 
During the treatment period (antidepressant treatment period [Phase A], and double-
blind period [Phase B] or the antidepressant-responder treatment-continuation period 
[Phase A+]), use is allowed only for treatment of cardiovascular diseases, with no 
changes in the dose and regimen employed at the time of informed consent. The 
topical external use of these drugs is allowed. 
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. 

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• Other medically significant events that, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above, eg, allergic bronchospasm requiring 
intensive treatment in an emergency room or home, blood dyscrasias or convulsions 
that do not result in hospitalization, or the development of drug dependency or drug 
abuse. 
Nonserious AEs are all AEs that do not meet the criteria for a “serious” AE. 
 
Immediately Reportable Event (IRE): 
• Any SAE 
• Any AE related to occupational exposure. 
• Potential drug-induced liver injury (DILI) (see Section 5.4). 
• Pregnancies are also defined as IREs. Although normal pregnancy is not an AE, it 
will mandate IMP discontinuation and must be reported on an IRE form to the 
sponsor. Pregnancy will only be recorded in the source documents and the AE section 
of the CRF if there is an abnormality or complication. This applies both to 
pregnancies of subjects and pregnancies of subjects’ partners. 
 
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 
medically relevant by the investigator or subinvestigator (subject is symptomatic, 
requiring corrective treatment or further evaluation), or if the laboratory value leads to 
discontinuation or meets the criteria for an SAE, this is considered an AE. 
 
Severity: Adverse events will be graded on a 3-point scale and reported. 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. 

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IMP Causality: Assessment of causal relationship between an AE and the IMP: 
Related:  
There is a reasonable possibility of a temporal and causal relationship 
between the IMP and the AE. 
Not related:  There is no temporal or reasonable relationship between the IMP and the 
AE. 
5.2 
Eliciting and Reporting Adverse Events 
The investigator or subinvestigator will periodically assess subjects for the occurrence of 
AEs. To avoid bias in eliciting AEs, subjects should be asked the nonleading question: 
“How have you felt since your last visit?” For all AEs (serious and nonserious) reported 
by the subject, the event name, start and stop dates, severity, seriousness, relationship to 
IMP, actions taken regarding IMP administration, and outcome thereof must be recorded 
in the source documents and CRFs provided by the sponsor. Adverse event and SAE 
collection is to begin after a subject has signed the ICF. In this trial, AEs occurring during 
the screening period and the antidepressant treatment period (Phase A) will be assessed in 
comparison to the subject's condition at screening, and AEs occurring during the double-
blind period (Phase B) and the antidepressant-responder treatment-continuation period 
(Phase A+) will be assessed in comparison to the subject’s condition at Week 8 of the 
antidepressant treatment period (Phase A). 
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. If a reported 
AE has worsened in severity or seriousness, it should be reported as a new AE on the 
CRF. 
In addition, the sponsor must be notified immediately by e-mail, in principle, 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 SAE, potential DILI, or confirmed 
pregnancy to the sponsor by e-mail (using the contact information on the title page of this 
protocol) immediately after either the investigator, subinvestigator, or designee becomes 
aware of the event. The IRE form and so on should be completed and sent by e-mail, in 

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principle, to the sponsor. Please note that the IRE form is NOT the AE section of the 
CRF. Due consideration must be given to privacy when the IRE form and so on is sent by 
mail or other means of communication. 
For subjects experiencing SAEs or IREs, such AEs should be followed until the events 
are resolved or stabilized, or the subject is lost to follow-up or has died. Resolved means 
that the subject has returned to the baseline state of health, and stabilized means that the 
investigator or subinvestigator does not expect any further improvement or worsening of 
the subject’s condition. It is expected that the investigator or subinvestigator will provide 
or arrange appropriate supportive care for the subject and will provide prompt updates on 
the subject’s status to the sponsor. 
5.4 
Potential Drug-induced Liver Injury 
For a subject who experiences an elevation in aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) that is ≥ 3 times the upper limit of normal (ULN), total 
bilirubin level should also be evaluated. If the total bilirubin is ≥ 2 times the ULN, 
complete the IRE form and so on with all values listed and also report as an AE in the 
source documents and CRF. 
5.5 
Pregnancy 
Women of childbearing potential (WOCBP) 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, vaginal diaphragm, intrauterine device, oral contraceptives, or 
condom with spermicide. Any single method of birth control, including vasectomy and 
tubal ligation, may fail, leading to pregnancy. The contraceptive method will be 
documented at each trial visit. 

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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. 
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 pregnancy tests are available. If the pregnancy is 
confirmed, the subject must not receive the IMP and must not be enrolled in the trial. If 
pregnancy is suspected while the subject is taking IMP, the IMP must be withheld 
immediately (if reasonable, taking into consideration any potential withdrawal risks) until 
the result of the serum pregnancy test is known. If pregnancy is confirmed, the IMP will 
be permanently discontinued in an appropriate manner (eg, dose tapering if necessary for 
subject safety) and the subject will be withdrawn from the trial. 
The investigator or subinvestigator must immediately notify the sponsor of any 
pregnancy associated with IMP exposure during the trial and for 30 days after the last 
dose of IMP, and record the event on the IRE form, and forward it to the sponsor. The 
sponsor will forward Pregnancy Surveillance Form(s) for monitoring the outcome of the 
pregnancy. 
Protocol-required procedures for trial discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered, if indicated. In addition, the 
investigator or subinvestigator must report to the sponsor, on appropriate Pregnancy 
Surveillance Form(s), follow-up information regarding the course of the pregnancy, 

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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 
In an emergency situation, such as when a subject experiences an SAE, if breaking the 
treatment assignment code is considered necessary by the investigator or subinvestigator 
to ensure the subject’s safety, the investigator or subinvestigator will be able to obtain the 
emergency code break information through IWRS in accordance with the separately 
specified procedures. The investigator or subinvestigator must contact the sponsor within 
24 hours of opening the code, and prepare a document containing the reason and process 
of opening the code and submit it to the sponsor. If the blind is broken, the Department of 
Pharmacovigilance must be notified immediately (see the cover page of this protocol for 
contact information). Documentation of breaking the blind should be recorded in the 
subject’s medical record with the date and time the blind was broken and the names of 
the personnel involved. Once the blind is broken for a subject, the IMP may not be 
reinitiated for that subject. 
5.7 
Follow-up of Adverse Events 
5.7.1 
Follow-up of Nonserious Adverse Events 
Nonserious AEs that are identified at any time during the trial must be recorded in the 
source documents and the AE section of the CRF, with the current status (ongoing or 
resolved/recovered) noted. All nonserious events (other than immediately reportable 
events) that are ongoing at the end of trial date (final day of observation) will be recorded 
as ongoing in the source documents and CRF. For any AE having been identified 
throughout the trial, during data analysis, additional relevant medical history information 
may be requested by the sponsor to further ascertain causality (including, but not limited 
to, information such as risk-related behavior, family history and occupation). The follow-
up information after the end of trial date (final day of observation) will be recorded in the 
subject’s medical record. 
5.7.2 
Follow-up of Serious Adverse Events and Immediately 
Reportable Events 
This trial requires that subjects be actively monitored for SAEs and IREs up to 30 days 
(±5 days) after the final day of IMP administration (end of trial date [final day of 
observation]). 
Serious AEs and IREs that are identified or ongoing at the end of trial date must be 
recorded in the source documents and the AE section of the CRF. Between the end of 

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trial date for the individual subject and the end of trial date for the last subject, if any new 
information regarding an SAE or IRE becomes available (eg, the event is resolved), this 
must be reported to the sponsor using the IRE form and so on, and the information must 
be recorded in the source documents and the AE section of the CRF. The investigator or 
subinvestigator will follow SAEs and IREs, and will continue to report any significant 
information to the sponsor until the events are resolved or stabilized, or the subject is lost 
to follow-up or has died, using the IRE form and so on. 
5.7.3 
Follow-up and Reporting of Serious Adverse Events and 
Immediately Reportable Events Occurring After the End of Trial 
Date (Final Day of Observation) 
Any new SAEs or IREs reported to the investigator or subinvestigator, which occur after 
the end of trial date (final day of observation) and are determined by the investigator or 
subinvestigator to be associated with the use of the IMP, should be reported to the 
sponsor. This includes SAEs and IREs that are captured on follow-up telephone contact 
or at any other time point after the defined trial period. The investigator or 
subinvestigator will follow SAEs and IREs identified after the defined trial period and 
continue to report any significant follow-up information to the sponsor until the events 
are resolved or stabilized, or the subject is lost to follow-up or has died, using the IRE 
form and so on. 
6 
Pharmacokinetic/Pharmacogenomic/ 
 
Analysis 
6.1 
Pharmacokinetic Analysis Methods 
Descriptive statistics of plasma brexpiprazole concentrations will be determined for each 
treatment group. 
6.2 
Pharmacogenomic Analysis Methods 
A list of data obtained from CYP2D6 genetic assessment will be provided without 
summarization. 
 
6.3 
 
 
7 
Statistical Analysis 
For the double-blind period (Phase B), the definitions of the datasets for analysis and the 
analysis methods for the specified endpoints are described below. 

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The detailed statistical analysis plan for the double-blind period (Phase B) and the 
analysis plans for the antidepressant treatment period (Phase A) and the antidepressant-
responder treatment-continuation period (Phase A+) are described in a separate Statistical 
Analysis Plan. The Statistical Analysis Plan will be finalized prior to data lock. 
7.1 
Determination of Sample Size 
In phase 3, double-blind, placebo-controlled, fixed dose trials of brexpiprazole (331-10-
227, 331-10-228, and 331-13-214) conducted outside Japan, changes from baseline in 
MADRS total scores at Week 6 of the double-blind period (Phase B) have been analyzed 
by the Mixed-model Repeated Measure (MMRM) method (for 331-10-227 and 331-10-
228, based on the results for efficacy from an analysis of subgroups meeting the inclusion 
criteria that had been revised in the middle of the trials), which demonstrated that the 
differences between the brexpiprazole groups (the 3 mg group in 331-10-227, and the 
2 mg group in 331-10-228 and 331-13-214) and the placebo group were −1.9, −3.2, and 
−2.3, respectively, and that the standard deviations obtained from standard errors and 
numbers of subjects at Week 6 of the double-blind period (Phase B) were 7.2, 7.7 and 8.2, 
respectively. On the assumption that the difference in changes from baseline in MADRS 
total scores at Week 6 of the double-blind period (Phase B) is −2.4 for the brexpiprazole 
group compared with the placebo group with a standard deviation of 7.7, this trial will 
require 218 subjects per group to ensure a power of 90% in a two-sided test with a 
significance level of 0.05. We have decided that the planned number of subjects for 
randomization will be 240 per group, assuming that 7% of subjects will discontinue the 
trial during the double-blind period (Phase B) and some subjects will be excluded from 
analysis. 
7.2 
Datasets for Analysis 
7.2.1 
Pharmacokinetic Analysis Set 
The pharmacokinetic analysis set will comprise subjects who have been treated with 
brexpiprazole and for whom plasma drug concentration data have been obtained. 
7.2.2 
Full Analysis Set 
The full analysis set (FAS) will comprise subjects who, after randomization, have 
received at least 1 dose of the IMP in the double-blind period (Phase B), and from whom 
MADRS total scores have been obtained at baseline and at least 1 time point after 
initiation of the treatment. 

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7.2.3 
Safety Analysis Set 
The safety analysis set will comprise subjects who, after randomization, have received at 
least 1 dose of the IMP in the double-blind period (Phase B). 
7.3 
Handling of Missing Data 
The primary analysis of the primary endpoint will be performed in the observed cases 
(OC) dataset by MMRM without data imputation for missing data under the missing at 
random (MAR) assumption. As a sensitivity analysis for the handling of missing data, 
placebo multiple imputation and tipping point analysis will be performed under the 
missing not at random (MNAR) assumption. Details are described in the statistical 
analysis plan. 
For efficacy and safety analyses, the last observation carried forward (LOCF) method (in 
which missing post-dose data are imputed by the last observed data after initiation of IMP 
treatment) will be used as needed. 
For pharmacokinetic analysis, no imputation will be performed for missing data. 
7.4 
Primary and Secondary Endpoint Analyses 
7.4.1 
Primary Endpoint Analyses 
The primary endpoint is mean changes from baseline (Week 8 of the antidepressant 
treatment period [Phase A]) in MADRS total scores at Week 6 of the double-blind period 
(Phase B). 
For the primary analysis, MMRM analysis will be performed using the OC data set in the 
FAS. The statistical hypotheses will be tested, based on differences in least square means 
between each brexpiprazole group and the placebo group, which are calculated by 
MMRM. To adjust for multiplicity of tests, due to there being 2 comparisons with the 
placebo group for each of the brexpiprazole groups, a fixed-sequence approach will be 
used to control overall type 1 error rates. Comparison between the brexpiprazole 
2 mg/day group and placebo group will be performed first; only when significance is 
observed at a two-sided significance level of 5%, will comparison between the 
brexpiprazole 1 mg/day group and placebo group be performed at a two-sided 
significance level of 5%. 
The MMRM will include treatment group (brexpiprazole 1 mg/day group, brexpiprazole 
2 mg/day group, and placebo group), time point (double-blind period [Phase B] Weeks 1, 
2, 3, 4, 5, and 6), and interaction between treatment group and time point as factors, and 
baseline and interaction between baseline and time point as covariates. Unstructured error 

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variance-covariance structure will be assumed. For a degree-of-freedom approximation, 
the Kenward-Roger method will be used. If any problems in convergence status arise in 
the estimation of variance components, heterogeneous Toeplitz, heterogeneous 
autoregressive of order 1, and heterogeneous compound symmetry, which are error 
variance-covariance structures, will be applied in this order, and the first structure that 
achieves convergence will be used in the primary analysis. If anything other than an 
unstructured variance-covariance structure is selected, a sandwich estimator for standard 
errors will be used. 
For each time point, least square means of each treatment group and differences in least 
square means between each brexpiprazole group and the placebo group, as well as the 
two-sided 95% confidence intervals (CIs) will be determined. 
7.4.2 
Secondary Endpoint Analyses 
• MADRS response rate at Week 6 of the double-blind period (Phase B) 
• MADRS remission rate at Week 6 of the double-blind period (Phase B) 
• CGI-I improvement rate at Week 6 of the double-blind period (Phase B) 
For the MADRS response rate, a χ2 test will be performed for between-treatment-group 
comparison using the LOCF data set. Differences in the response rates between each of 
the brexpiprazole groups and the placebo group, and the two-sided 95% CIs will be 
determined. For MADRS remission rate and CGI-I improvement rate, the same analysis 
employed for the MADRS response rate will be used. 
• Mean changes from baseline (Week 8 of the antidepressant treatment period [Phase 
A]) in HAM-D 17-item total scores at Week 6 of the double-blind period (Phase B) 
Using the LOCF data set, analysis will be performed by ANCOVA model with treatment 
group as a factor and baseline as a covariate. Least square means of each treatment group 
and differences in least square means between each brexpiprazole group and the placebo 
group, as well as the two-sided 95% CIs will be determined. 
• Mean changes from baseline (Week 8 of the antidepressant treatment period [Phase 
A]) in CGI-S at Week 6 of the double-blind period (Phase B) 
• Mean changes from baseline (Week 8 of the antidepressant treatment period [Phase 
A]) in mean SDS scores at Week 6 of the double-blind period (Phase B) 
• Mean changes from baseline (Week 8 of the antidepressant treatment period [Phase 
A]) in MADRS-S total scores at Week 6 of the double-blind period (Phase B) 
As performed for the primary endpoint, MMRM analysis will be performed. 
7.4.3 
Interim Analysis 
No interim analyses are planned. 

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7.5 
Analysis of Demographic and Baseline Characteristics 
Descriptive statistics or frequency distribution of demographic and other baseline 
characteristics will be determined for each treatment group and for the overall 
brexpiprazole group in each analysis dataset. 
7.6 
Safety Analysis 
Safety analysis for the double-blind period (Phase B) will be performed using the safety 
analysis set. Baseline is defined as Week 8 of the antidepressant treatment period (Phase 
A). 
7.6.1 
Adverse Events 
All AEs will be coded by system organ class and Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term. The incidence of the following events will be 
summarized by treatment group and by the overall brexpiprazole group: 
• Adverse events occurring after initiation of IMP administration in the double-blind 
period (Phase B) (treatment-emergent adverse events [TEAEs]) 
• TEAEs by severity 
• TEAEs with an outcome of death 
• Serious TEAEs 
• TEAEs leading to discontinuation of the IMP 
 
TEAEs potentially causally related to the IMP will also be summarized in the same 
manner. 
7.6.2 
Clinical Laboratory Data 
For each quantitative laboratory parameter, descriptive statistics of actual measurements 
and changes from baseline at each time point will be calculated for each treatment group 
and for the overall brexpiprazole group. 
For each laboratory parameter (excluding qualitative parameters), actual measurements 
will be classified as “lower than the lower limit of the reference range,” “within the 
reference range,” and “higher than the upper limit of the reference range” using the 
reference range specified by the central laboratory, and a shift table from baseline will be 
produced for each treatment group and for the overall brexpiprazole group. 
For each qualitative laboratory parameter, a shift table from baseline will be produced for 
each treatment group and for the overall brexpiprazole group. 

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Numbers and proportions of subjects with potentially clinically significant laboratory test 
values will be determined for each treatment group and for the overall brexpiprazole 
group. 
7.6.3 
Physical Examination and Vital Signs Data 
Physical examination data will be provided in a listing. 
For each vital sign parameter, descriptive statistics of actual measurements and changes 
from baseline at each time point will be calculated for each treatment group and for the 
overall brexpiprazole group. 
Numbers and proportions of subjects with potentially clinically significant vital signs will 
be determined for each treatment group and for the overall brexpiprazole group. 
7.6.4 
Electrocardiogram Data 
For heart rate, PR interval, RR interval, QRS interval, QT interval, and QTc, descriptive 
statistics of actual measurements and changes from baseline at each time point will be 
calculated for each treatment group and for the overall brexpiprazole group. 
A shift table from baseline for normal/abnormal 12-lead ECG will be produced for each 
treatment group and for the overall brexpiprazole group. 
Numbers and proportions of subjects with actual measurements of corrected QT interval 
(QTcF, QTcB, QTcN) at each time point of > 450 msec, > 480 msec, and > 500 msec 
will be determined for each treatment group and for the overall brexpiprazole group. 
Numbers and proportions of subjects with changes from baseline of > 30 msec and 
> 60 msec will be determined for each treatment group and for the overall brexpiprazole 
group. 
Numbers and proportions of subjects with ECG results meeting the criteria for potentially 
clinically significant ECG data will be determined for each treatment group and for the 
overall brexpiprazole group. 
7.6.5 
Other Safety Data 
• Body weight, body mass index (BMI), and waist circumference 
For body weight, BMI, and waist circumference, descriptive statistics of actual 
measurements and changes from baseline at each time point will be calculated for 
each treatment group and for the overall brexpiprazole group. 
In addition, using the LOCF data set, analysis will be performed by the ANCOVA 
model with treatment group as a factor and baseline as a covariate. Least square 
means of each treatment group and differences in least square means between each 
brexpiprazole group and the placebo group, as well as the two-sided 95% CIs will be 
determined. 

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Numbers and proportions of subjects with results meeting the criteria for potentially 
clinically significant body weight gain or loss will be determined for each treatment 
group and for the overall brexpiprazole group. 
• DIEPSS, AIMS, and BARS 
For DIEPSS total score (total of scores for items 1 through 8) and score for each 
DIEPSS item, AIMS total score (total of scores for items 1 through 7) and score for 
each of the items 8 through 10, and BARS, descriptive statistics of actual 
measurements and changes from baseline at each time point will be calculated for 
each treatment group and for the overall brexpiprazole group. 
In addition, using the LOCF data set, analysis will be performed by the ANCOVA 
model with treatment group as a factor and baseline as a covariate. Least square 
means of each treatment group and differences in least square means between each 
brexpiprazole group and the placebo group, as well as the two-sided 95% CIs will be 
determined. 
• C-SSRS 
Numbers and proportions of subjects for 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 for each treatment group 
and for the overall brexpiprazole group. 
 
8 
Management of Investigational Medicinal Product 
Refer to the investigator’s brochure on brexpiprazole and the separately-specified manual 
for details regarding IMP management. 
8.1 
Packaging and Labeling 
 
 
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 is to be stored at room temperature. 
The clinical site staff will maintain a temperature log in the drug storage area recording 
the temperature at least once each working day. 

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8.3 
Accountability 
The IMP manager must maintain an inventory record of IMP 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. 
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) regarding the IMP is any written, electronic, or 
verbal communication by a healthcare professional, consumer, subject, medical 
representative, Competent Authority, regulatory agency, partner, affiliate, or other third 
party that alleges deficiencies or dissatisfaction related to identity, quality, labeling, 
packaging, reliability, safety, durability, tampering, counterfeiting, theft, effectiveness, or 
performance of a drug product or medical device after it is released for distribution. 
Examples include, but are not limited to, communications involving: 
• Failure/malfunction of a product to meet any of its specifications 
• Incorrect or missing labeling 
• Packaging issues (eg, damaged, dirty, crushed, missing product) 
• Blister defects (eg, missing, empty blisters) 
• Bottle defects (eg, under/over-fill, no safety seal) 
• Vial defects 
• 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 (or sponsor’s designee) 
via e-mail immediately after becoming aware of the PQC according to the procedure 

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outlined in Section 8.5.2 Information Required for Reporting Product Quality Complaints. 
(E-mail address
) 
Identification of a PQC by the subject should be reported to the investigator or 
subinvestigator, who should then follow the reporting mechanisms listed above. 
8.5.2 
Information Required for Reporting Product Quality Complaints 
• Description of complaint 
• Reporter identification (eg, subject, investigator or subinvestigator, site information, 
etc) 
• Reporter contact information (eg, address, phone number, e-mail address) 
• ID of material (product/compound name, drug number) 
• Clinical protocol reference (protocol number or trial name) 
• Dosage form/strength (if known) 
• Pictures (if available) 
• Complaint sample availability for return 
 
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 

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ICF. In all cases, subject confidentiality must be maintained in accordance with 
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 
investigator's or subinvestigator’s assessment of relationship to IMP must also be 
recorded; 
• Any changes in concomitant medications or dosages; 
• A general reference to the procedures completed; 
• The signature (or initials) and date of each clinician (or designee) who made an entry 
in the medical records. 
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the medical records as 
described above. Any changes to information in the medical records and other source 
documents will be initialed and dated on the day the change is made by a trial site staff 
member authorized to make the change. Changes will be made by striking a single line 
through erroneous data (so as not to obliterate the original data), and clearly entering the 
correct data (eg, wrong data right data). If the reason for the change is not apparent, a 
brief explanation for the change will be written in the source documentation by the 
investigator or subinvestigator. If electronic data systems are being utilized, a full audit 
trail of changes must be maintained. 
Information from the medical records and other source documents will be entered by trial 
site personnel directly onto electronic CRFs in the sponsor’s electronic data capture 
(EDC) system. Changes to the data will be captured by an automatic audit trail. 
9.3 
File Management at the Trial Site 
The head of the trial site will ensure that the trial site file is maintained in accordance 
with Section 8 of the ICH GCP Guideline E6 and as required by applicable local 

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regulations. The trial site will take measures to 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 whichever is the 
longer of the four periods indicated below. However, if the sponsor requires a longer 
period of archiving, the head of the trial site will consult with the sponsor on the period 
and procedures of record retention. 
• Until the date 2 years after manufacturing and marketing approval date; however, if 
the head of the trial site receives notification from the sponsor that development has 
been terminated or that results of the trial will not be submitted with the approval 
application, until the date 3 years after receipt of such notification. 
• Until the date 3 years after termination or completion of the trial. 
• Until the date on which it is decided to end DNA storage 
• Until the date on which it is decided to end biomarker sample storage 
 
The trial site must not dispose of any records relevant to this trial without either 
(1) written permission from the sponsor or (2) providing an opportunity for the sponsor to 
collect such records. The trial site will be responsible to maintain adequate and accurate 
electronic or hard copy source documents of all observations and data generated during 
the trial. Such documentation is subject to inspection by the sponsor and relevant 
regulatory authorities. 
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 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 Quality Assurance Unit (or representative) may conduct trial site audits. 
Audits will include, but are not limited to, IMP supply, presence of required documents, 

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the informed consent process, and comparison of CRFs with source documents. The 
investigator agrees to participate with audits. 
Regulatory authorities may inspect the trial site during or after the trial. The investigator 
will cooperate with such inspections and will contact the sponsor immediately if such an 
inspection occurs. 
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. Each trial site will seek approval/favorable opinion by an IRB 
according to the requirements of each region, and the trial site will provide that 
documentation to the sponsor. The IRB will evaluate the ethical, scientific, and medical 
appropriateness of the trial. Further, in preparing and handling source documents, CRFs, 
and the IRE form and so on, the investigator or subinvestigator and their staff will take 
measures to ensure adequate care in protecting subject privacy. To this end, a subject ID 
will be used to identify each subject. Financial aspects, subject insurance, and publication 
policy for the trial will be documented in the agreement between the sponsor and the trial 
site. 
12 
Confidentiality 
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission. Subject confidentiality requirements of the region where the trial is 
conducted will be met. However, authorized regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy the records, 
consistent with local requirements. All IMPs, subject bodily fluids, and other materials 
collected shall be used solely in accordance with this protocol, unless otherwise agreed to 
in writing by the sponsor. 
Subjects will be identified only by a unique subject ID in the source documents and CRFs. 
If further subject identification is required, subjects’ full names may be made known to a 
regulatory agency or other authorized officials if necessary, subject to local regulations. 
13 
Amendment Policy 
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval/favorable opinion by the IRB. Any permanent 
change to the protocol, whether an overall change or a change for specific trial site(s), 

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must be handled as a protocol amendment. Any amendment will be written by the 
sponsor. Each amendment will be submitted to the IRB, as required by local regulations. 
Except for “administrative” or “nonsubstantial” amendments, investigators or 
subinvestigators will wait for IRB approval/favorable opinion of the amended protocol 
before implementing the change(s). Administrative amendments are defined as having no 
effect on the safety of subjects, conduct or management of the trial, trial design, or the 
quality or safety of IMP(s) used in the trial. A protocol change intended to eliminate an 
apparent immediate hazard to subjects should be implemented immediately, followed by 
IRB notification within local applicable timelines. The sponsor will submit protocol 
amendments to the applicable regulatory agency within local applicable timelines. 
When the IRB, investigators, or the sponsor concludes that the protocol amendment 
substantially alters the trial design or increases the potential risk to the subject, the 
currently approved written ICF will require similar modification. In such cases, after 
approval/favorable opinion of the new ICF by the IRB, repeat written informed consent 
will be obtained from subjects enrolled in the trial before expecting continued 
participation and before the amendment-specified changes in the trial are implemented. 
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: 
1) Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND 
2) Drafting the work or revising it critically for important intellectual content; AND 
3) Final approval of the version to be published; AND 
4) Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved. 
 
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors. 
Investigators or other trial participants who do not qualify for authorship may be 
acknowledged in publications resulting from the trial. By agreeing to participate in the 
trial, investigators or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct. 

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15 
References 
1 
Lecrubier Y. How do you define remission? Acta Psychiatr Scand 
2002;106(Suppl.415):7-11. 
2 
Takahashi Y. Mood disorder and suicide. Japanese Journal of Clinical Psychiatry. 
2000;29:877-84. 
3 
Office for Policy of Suicide Prevention, Ministry of Health, Labour and Welfare, and 
Community Safety Planning Division, National Police Agency. 2016 Situation of 
suicide [Internet]: March 23, 2017 [accessed on 2018 Jan 9]. Available from:  
http://www.npa.go.jp/safetylife/seianki/jisatsu/H28/H28_jisatunojoukyou_01.pdf 
4 
Ministry of Health, Labour and Welfare. Economic benefits of prevention of 
suicide/depression (social loss from suicide/depression). [Internet]: September 7, 
2010 [accessed on 2018 Jan 9]. Available from: 
http://www.mhlw.go.jp/stf/houdou/2r9852000000qvsy.html 
5 
Kawakami N. Study on mental health epidemiological survey. A research project 
supported by the FY 2004 to 2006 Health and Labour Sciences Research Grants 
(Research project for mental health science). Study report for “Study on mental health 
epidemiological survey.” 2007. 
6 
Committee for Treatment Guidelines of Mood Disorders of the Japanese Society of 
Mood Disorders. Guidelines for Treatment of Depression. Edition 2. Tokyo: Igaku-
Shoin Ltd.; 2017. 
7 
Inoue T, Kitaichi Y, Honda M, Tanaka T, Suzuki K, Nakagawa S, et al. Research on 
treatment for depressive patients resistant to SSRIs and SNRIs. Psychiatria et 
Neurologia Japonica. 2003;105:1318. 
8 
Crossley NA, Bauer M. Acceleration and augmentation of antidepressants with 
lithium for depressive disorders: Two meta-analyses of randomized, placebo-
controlled trials. J Clin Psychiatry. 2007;68(6):935-40. 
9 
McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM, Geddes JR. Lithium 
toxicity profile: a systematic review and meta-analysis. Lancet. 2012;379:721–8. 
10 Kamijima K, Higuchi T, Ishigooka J, Ohmori T, Ozaki N, Kanba S, et al. 
Aripiprazole augmentation to antidepressant therapy in Japanese patients with major 
depressive disorder: A randomized, double-blind, placebo-controlled study 
(ADMIRE study). Journal of Affective Disorders. 2013;151:899-905. 
11 Berman RM, Marcus RN, Swanink R, McQuade RD, Carson WH, Corey-Lisle PK, et 
al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive 
disorder: A multicenter, randomized, double-blind, placebo-controlled study. J Clin 
Psychiatry. 2007;68(6):843-53. 
12 Marcus RN, McQuade RD, Carson WH, Hennicken D, Fava M, Simon JS, et al. The 
efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder 
a second multicenter, randomized, double-blind, placebo-controlled study. Journal of 
Clinical Psychopharmacology. 2008;28(2):156-65. 
13 Berman RM, Fava M, Those ME, Trivedi MH, Swanink R, McQuade RD, et al. 
Aripiprazole augmentation in major depressive disorder: a double-blind, placebo-

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controlled study in patients with inadequate response to antidepressants. CNS Spectr. 
2009;14(4):197-206. 
14 Otsuka Pharmaceutical Co, Ltd. A dose-finding trial of OPC-34712 in patients with 
schizophrenia. Clinical Study Report for Protocol 331-10-002, issued 18 Dec 2015. 
15 Otsuka Pharmaceutical Co, Ltd. A long-term trial of OPC-34712 in patients with 
schizophrenia. Clinical Study Report for Protocol 331-10-003, issued 18 Dec 2015. 
16 Otsuka Pharmaceutical Co, Ltd. Package insert for Rexulti (brexpiprazole). April 
2018. 
17 Kane JM, Skuban A, Ouyang J, Hobart M, Pfister S, McQuade RD, et al. A 
multicenter, randomized, double-blind, controlled phase 3 trial of fixed-dose 
brexpiprazole for the treatment of adults with acute schizophrenia. Schizophrenia 
Research. 2015;164:127-35. 
18 Correll CU, Skuban A, Ouyang J, Hobart M, Pfister S, McQuade RD, et al. Efficacy 
and safety of brexpiprazole for the treatment of acute schizophrenia: a 6-week 
randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 
2015;172(9):870-80. 
19 Thase ME, Youakim JM, Skuban A, Hobart M, Zhang P, McQuade RD, et al. 
Adjunctive brexpiprazole 1 and 3 mg for patients with major depressive disorder 
following inadequate response to antidepressants: A phase 3, randomized, double-
blind study. J Clin Psychiatry. 2015;76(9):1232-40. 
20 Thase ME, Youakim JM, Skuban A, Hobart M, Augustine C, Zhang P, et al. Efficacy 
and safety adjunctive brexpiprazole 2 mg in major depressive disorder: A phase 3, 
randomized, placebo-controlled study in patients with inadequate response to 
antidepressants. J Clin Psychiatry. 2015;76(9):1224-31.  
21 Otsuka Pharmaceutical Co, Ltd. Package insert for Rexulti (brexpiprazole). USA. 
February 2017.  
22 International Conference on Harmonization (ICH) [homepage on the Internet]. E6: 
Good Clinical Practice: Consolidated Guideline [finalized 1996 May, corrected 1996 
Jun 1996; cited 2014 Dec 5]. Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E
6/E6_R1_Guideline.pdf. 
 
 

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Appendix 1 
Handling and Shipping of Bioanalytical Samples 
(1) 
 
(2) 
 
 
 
. 
(3) 
 

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(4) 
 
 
 
rocedure. 
(5) 
 
 
 
 
 
 

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Appendix 2 
CYP2D6 Genotyping Table 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 3 
Criteria for Allowing Concomitant Use of Topical CYP2D6 
Inhibitors, CYP3A4 Inhibitors, and CYP3A4 Inducers 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 4 
Protocol Amendments/Administrative Changes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Agreement 
I, the undersigned principal investigator, have read and understand the protocol 
(including the Investigator's Brochure) and agree that it contains all the ethical, legal and 
scientific information necessary to conduct this trial in accordance with the principles of 
Good Clinical Practices and as described herein and in the sponsor's (or designee's) 
Clinical Trial Agreement. 
I will provide copies of the protocol to all physicians, nurses, and other professional 
personnel to whom I delegate trial responsibilities. I will discuss the protocol with them 
to ensure that they are sufficiently informed regarding the investigational new drug, 
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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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.