Conditions: Major Depressive Disorder
Keywords: MDD Depression Brexpiprazole
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 122
Healthy volunteers: no

Brief summary:
The clinical trial will investigate the effect of brexpiprazole on the concept of life engagement in participants with Major Depressive Disorder (MDD) with a current depressive episode.

Detailed description:
This is a phase 4, multicenter, open-label, flexible dose trial designed to assess the effects of brexpiprazole (flexible dose; 0.5 to 2 milligrams \[mg\], once daily \[QD\]) as adjunctive therapy to antidepressant therapy (ADT) on life engagement in participants with MDD. This trial is being conducted in line with the Canadian Product Monograph.

Arms:
arm 1: Participants received brexpiprazole as a flexible dose; 0.5 mg to 2 mg, orally (PO), QD, and continued on the stable dose of ADT up to 8 weeks.

Interventions: intervention 1: Brexpiprazole
Intervention descriptions: intervention 1: Oral brexpiprazole tablets as adjunctive therapy to ADT

Protocol document:
Prot_000.pdf: 
Otsuka Pharmaceutical
Development & Commercialization, Inc.
Investigational Medicinal Product
REXULTI® (brexpiprazole, OPC-34712, OPC-331, Lu AF41156)
REVISED CLINICAL PROTOCOL
A Phase 4, Multicenter, Open-label, Interventional Trial to Assess the Effects on 
Engagement of Flexible-dose Brexpiprazole (OPC-34712) as Adjunctive Therapy for the 
Treatment of Adults With Major Depressive Disorder
A Phase 4, Canadian Interventional Trial to Assess Brexpiprazole (OPC-34712) as 
Adjunctive Therapy in Adults With Major Depressive Disorder
Protocol No. 331-201-00289
CONFIDENTIAL  PROPRIETARY INFORMATION
Drug Development Phase:
4
Sponsor:
Otsuka Pharmaceutical Development &
Commercialization, Inc.
2440 Research Boulevard
Rockville, Maryland 20850, United States
Sponsor Representatives:
Associate Director,
Global Clinical Development
Senior Manager,
Clinical Management
Director,
Clinical Management
Immediately Reportable Event 
Amendment 1 Approval:
18 Mar 2021
Original Approval:
15 Oct 2020
Clinical Study Report 331-201-00289
16.1.1 Protocol and Protocol Amendments
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Table of Contents
Table of Contents ..........................................................................................2
List of In-text Tables.....................................................................................7
List of In-text Figures ...................................................................................8
List of Abbreviations.....................................................................................9
1
Protocol Summary..............................................................................11
1.1
Synopsis ............................................................................................................11
1.2
Trial Schematic..................................................................................................18
1.3
Schedule of Assessments ..................................................................................19
2
Introduction........................................................................................22
2.1
Nonclinical Data................................................................................................23
2.1.1
Efficacy Pharmacology...................................................................................23
2.1.2
Safety Pharmacology......................................................................................23
2.2
Clinical Data......................................................................................................23
2.2.1
Pharmacokinetics/Pharmacodynamics ...........................................................24
2.2.2
Major Depressive Disorder.............................................................................25
2.3
Known and Potential Risks and Benefits ..........................................................25
2.4
Trial Rationale...................................................................................................26
3
Objectives............................................................................................26
4
Trial Design.........................................................................................27
4.1
Type/Design of Trial .........................................................................................27
4.2
Scientific Rationale for Trial Design.................................................................27
4.3
Dosing Rationale...............................................................................................28
4.4
End of Trial Definition......................................................................................28
4.5
Definition of Completed Patients......................................................................28
5
Trial Population..................................................................................28
5.1
Patient Selection and Numbering......................................................................29
5.2
Eligibility Criteria .............................................................................................29
5.2.1
Inclusion Criteria ............................................................................................29
5.2.2
Exclusion Criteria...........................................................................................30
5.3
Lifestyle Considerations....................................................................................31
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5.3.1
Meals and Dietary Restrictions.......................................................................31
5.3.2
Caffeine and Alcohol......................................................................................31
5.4
Screen Failures ..................................................................................................31
6
Trial Treatments ................................................................................32
6.1
Trial Treatments Administered .........................................................................32
6.2
Management of Investigational Medicinal Product ..........................................32
6.2.1
Packaging and Labeling..................................................................................33
6.2.2
Storage............................................................................................................33
6.2.3
Accountability.................................................................................................33
6.2.4
Returns and Destruction .................................................................................33
6.2.5
Reporting of Product Quality Complaints......................................................33
6.2.5.1
Eliciting and Reporting Product Quality Complaints .................................34
6.2.5.2
Information Required for Reporting Purposes............................................34
6.2.5.3
Return Process.............................................................................................34
6.2.5.4
Assessment/Evaluation ...............................................................................34
6.3
Measures to Minimize/Avoid Bias....................................................................34
6.4
Patient Compliance ...........................................................................................34
6.5
Concomitant Medications or Therapies ............................................................35
6.5.1
Prohibited Medications or Therapies..............................................................35
7
Stopping Rules, Withdrawal Criteria, and Procedures..................35
7.1
Entire Trial or Treatment...................................................................................35
7.2
Individual Site ...................................................................................................35
7.3
Individual Patient Discontinuation....................................................................36
7.3.1
Treatment Discontinuation .............................................................................36
7.3.2
Documenting Reasons for Treatment Interruption or Discontinuation ..........36
7.3.3
Withdrawal of Consent...................................................................................37
7.4
Definition of Patients Lost to Follow-up...........................................................38
8
Trial Procedures.................................................................................38
8.1
Efficacy Assessments........................................................................................38
8.1.1
Inventory of Depressive Symptomatology Self-Report (IDS-SR).................39
8.1.1.1
IDS-SR-10-Engagement .............................................................................39
8.1.2
Patient Health Questionnaire-9 (PHQ-9)........................................................39
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8.1.3
Generalized Anxiety Disorder-7 (GAD-7) .....................................................39
8.1.4
World Health Organization Disability Assessment Schedule 2.0 
(WHODAS) Short Form Questionnaire .........................................................39
8.1.5
Sheehan Disability Scale (SDS) .....................................................................40
8.1.6
Clinical Global Impression - Severity of Illness (CGI-S) ..............................40
8.1.7
Clinical Global Impression - Improvement (CGI-I).......................................40
8.1.8
Word of the Day .............................................................................................40
8.1.9
Patient Global Impression - Severity (PGI-S) ................................................41
8.1.10
Patient Global Impression - Improvement (PGI-I).........................................41
8.2
Safety Assessments ...........................................................................................41
8.2.1
Physical Examination .....................................................................................41
8.2.2
Vital Signs ......................................................................................................42
8.2.3
Suicidality Monitoring....................................................................................42
8.3
Adverse Events..................................................................................................42
8.3.1
Definitions ......................................................................................................42
8.3.2
Eliciting and Reporting Adverse Events.........................................................44
8.3.3
Immediately Reportable Events......................................................................45
8.3.4
Procedure for Breaking the Blind...................................................................45
8.3.5
Follow-up of Adverse Events.........................................................................45
8.3.5.1
Follow-up of Nonserious Adverse Events ..................................................45
8.3.5.2
Follow-up of Immediately Reportable Events............................................45
8.3.5.3
Follow-up and Reporting of Immediately Reportable Events 
Occurring After Last Scheduled Contact....................................................46
9
Statistical Considerations ..................................................................46
9.1
Sample Size.......................................................................................................46
9.2
Datasets for Analysis.........................................................................................47
9.3
Handling of Missing Data .................................................................................47
9.4
Statistical Analyses ...........................................................................................48
9.4.1
Efficacy Analyses...........................................................................................48
9.4.1.1
Primary Efficacy Endpoint Analysis...........................................................48
9.4.1.2
Control of Experiment-wise Type I Error...................................................49
9.4.1.3
Other Efficacy Endpoint Analysis ..............................................................49
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9.4.2
Analysis of Demographic and Baseline Characteristics.................................50
9.4.3
Safety Analysis...............................................................................................51
9.4.3.1
Adverse Events ...........................................................................................51
9.4.3.2
Physical Examination and Vital Signs Data ...............................................51
10
Supporting Documentation and Operational Considerations .......52
10.1
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations.............52
10.1.1
Ethics and Responsibility ...............................................................................52
10.1.2
Informed Consent ...........................................................................................52
10.1.3
Confidentiality................................................................................................53
10.1.4
Quality Control and Quality Assurance..........................................................53
10.1.4.1
Monitoring ..................................................................................................53
10.1.4.2
Auditing ......................................................................................................54
10.1.5
Protocol Deviations ........................................................................................54
10.1.6
Records Management .....................................................................................54
10.1.6.1
Source Documents ......................................................................................54
10.1.6.2
Data Collection ...........................................................................................55
10.1.6.3
File Management at the Trial Site...............................................................55
10.1.6.4
Records Retention at the Trial Site .............................................................56
10.1.6.5
Publication Authorship Requirements ........................................................56
10.2
Appendix 2: Contraceptive Guidance and Collection of Pregnancy 
Information........................................................................................................58
10.3
Appendix 3: Criteria for Identifying Vital Signs of Potential Clinical 
Relevance ..........................................................................................................60
10.5
Appendix 5: Trial Continuity Plan....................................................................63
10.5.1
Trial Continuity Plan Appendix......................................................................63
10.5.1.1
Trial Design Schematic - Trial Continuity..................................................64
10.5.1.2
Schedule of Assessments - Trial Continuity...............................................65
10.5.2
General Considerations...................................................................................68
10.5.2.1
Telemedicine...............................................................................................68
10.5.2.2
Reconsent....................................................................................................68
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10.5.2.3
Protocol Deviations.....................................................................................68
10.5.2.4
Guidance to Record Adverse Events and Discontinuations Due to 
Extenuating Circumstances.........................................................................68
10.5.2.4.1
Novel Coronavirus 19 (COVID-19)........................................................69
10.5.2.5
Statistical Analyses .....................................................................................69
10.5.2.6
Clinical Outcomes.......................................................................................69
10.5.3
Trial Procedures..............................................................................................69
10.5.3.1
Safety Assessments.....................................................................................69
10.5.3.1.1
Vital Signs ...............................................................................................69
10.5.3.1.2
Pregnancy ................................................................................................70
11
References ...........................................................................................71
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List of In-text Tables
Table 1.3-1
Schedule of Assessments...............................................................19
Table 6.1-1
Brexpiprazole Dosing Schedule ....................................................32
Table 10.5.1.2-1
Schedule of Assessments - Trial Continuity..................................65
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List of In-text Figures
Figure 1.2-1
Trial Design Schematic..................................................................18
Figure 10.5.1.1-1
Trial Design Schematic - Trial Continuity ....................................64
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List of Abbreviations
Abbreviation
Definition
AAD
Agitation associated with dementia
ADHD
Attention deficit hyperactivity disorder
ADT
Antidepressant therapy
AE
Adverse event
AUCt
Area under the concentration-time curve calculated to the last 
observable concentration at time t
BMI
Body mass index
bpm
Beats per minute
CANMAT
Canadian Network for Mood and Anxiety Treatments
CBC
Complete blood count
CGI-I
Clinical Global Impression - Improvement
CGI-S
Clinical Global Impression - Severity
CIOMS
Council for International Organizations of Medical Science
Cmax
Maximum (peak) plasma concentration
CRF
Case report form
CYP
Cytochrome P450
D
dopamine
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
ET
Early termination
FOCBP
Females of childbearing potential
GAD-7
Generalized Anxiety Disorder 7-item
GCP
Good Clinical Practice
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
ICMJE
International Committee of Medical Journal Editors
ID
Identification
IDS-SR
Inventory of Depressive Symptomatology Self-Report
IEC
Independent ethics committee
IND
Investigational New Drug
IRB
Institutional review board
IRE
Immediately reportable event
Ki
Inhibition constant
LAI
Long-acting injectable
LOCF
Last observation carried forward
MAR
Missing at random
MDD
Major Depressive Disorder
MDE
Major depressive episode
mmHg
Millimeter of mercury
MMRM
Mixed model repeated measure
MNAR
Missing not at random
N
Number of patients
OC
Observed cases
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Abbreviation
Definition
OCD
Obsessive-compulsive disorder
PD
Pharmacodynamic
PGI-I
Patient Global Impression – Improvement
PGI-S
Patient Global Impression – Severity
PHQ-9
Patient Health Questionnaire 9-item scale
PK
Pharmacokinetic
PQC
Product quality complaint
PTSD
Post-traumatic stress disorder
QD
Once daily
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
SDS
Sheehan Disability Scale
SOP
Standard operating procedure
TEAE
Treatment-emergent adverse event
UFIE
Unusual failure in efficacy
US or USA
United States or United States of America
WHODAS
World Health Organization Disability Assessment Schedule
5-HT
5-hydroxytryptamine
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1
Protocol Summary
1.1
Synopsis
Name of Sponsor:
Otsuka Pharmaceutical Development & Commercialization, Inc.
Name of Investigational Medicinal Product:
REXULTI® (brexpiprazole, OPC-34712, OPC-331, Lu AF41156)
Protocol No.:
331-201-00289
Protocol Title:
A Phase 4, Multicenter, Open-label, Interventional Trial to Assess the Effects on 
Engagement of Flexible-dose Brexpiprazole (OPC-34712) as Adjunctive Therapy for the 
Treatment of Adults With Major Depressive Disorder
Protocol Lay Person Short Title:
A Phase 4, Canadian Interventional Trial to Assess Brexpiprazole (OPC-34712) as 
Adjunctive Therapy in Adults With Major Depressive Disorder
Clinical Phase:
4
Treatment/Indication:
Major Depressive Disorder (MDD)
Objectives:
The primary objective of the trial is:

To prospectively characterize the effect of brexpiprazole on the concept of 
engagement, by evaluating Inventory of Depressive Symptomatology Self-Report 
(IDS-SR)-10-engagement, and the IDS-SR Total score, in patients with MDD with a 
current depressive episode.
The secondary objectives of the trial are:

To evaluate patients’ impression of improvement of their depression symptoms over 
time.

To explore the relationship between engagement and other clinical effects of 
brexpiprazole, such as improvement in depressive symptoms and functioning.
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
To evaluate the safety and tolerability of brexpiprazole (flexible dose; 0.5 to 2 mg 
once daily [QD]) as adjunctive therapy to antidepressant therapy (ADT) in the 
proposed patient population with MDD.
Trial Design:
This is a phase 4, multicenter, open-label, flexible dose trial designed to assess the effects 
of brexpiprazole (flexible dose; 0.5 to 2 mg QD) as adjunctive therapy to ADT in patients 
with MDD. This trial is being conducted in line with the Canadian Product Monograph.
The trial will be organized as follows:
Screening Phase: The screening period of up to 14 days (Days -14 to -1) will begin when 
the informed consent form (ICF) is signed. The purpose of the screening period is to 
assess eligibility criteria at 1 or more visits (as necessary to complete screening 
assessments) and to washout prohibited concomitant pharmacotherapy, if applicable.
Open-Label Treatment Phase: Patients meeting all of the inclusion and none of the 
exclusion criteria will be enrolled at the baseline visit into an 8-week open-label 
treatment phase. The screening and baseline visits can occur on the same day if the 
patient meets all required enrollment criteria. During the open-label treatment phase, all 
patients will receive brexpiprazole (that is, adjunctive brexpiprazole as a flexible dose; 
0.5 to 2 mg/day) and will continue on the stable dose of ADT that they were taking at 
screening. Patients will attend visits at Weeks 2, 4, and 8 during the open-label treatment 
phase. If any patient discontinues the trial early, every effort should be made to complete 
the Week 8/early termination (ET) evaluations.
Following the completion of all scheduled visits, patients will be asked if they are 
interested in taking part in an exit interview, which will be separate from trial 
assessments and should occur within 30 days of the Week 8/ET visit. This also applies to 
patients withdrawn prematurely from the trial.
Trial Population:
The trial population will include male and female outpatients between the regional age of 
majority (18 or 19 years of age) and 65 years of age, inclusive, with a Diagnostic and 
Statistical Manual of Mental Disorders, 5th Edition (DSM-5) diagnosis of a single or 
recurrent, non-psychotic episode of MDD with or without symptoms of anxiety. 
Additionally, patients must have a treatment history for the current major depressive 
episode (MDE) of an inadequate response (assessment of inadequate response is per 
investigator judgment) to at least 1 and no more than 2 adequate antidepressant 
treatments (including the antidepressant that the patient is taking at screening).
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Patients with a historical diagnosis of any concurrent condition that is exclusionary may 
be permitted if the investigator determines and documents this prior diagnosis was not 
appropriate based on current and historical presentation.
Patients with attention deficit hyperactivity disorder (ADHD), obsessive compulsive 
disorder (OCD), panic disorders, or generalized anxiety disorder can be included under 
the following conditions:

These disorders are not the primary focus of treatment at the screening visit

Changes in any treatment for these disorders (permitted medication and/or 
psychotherapy) would not likely be required for the duration of the trial

All other concurrent psychiatric or neurological diagnoses must be discussed with the 
medical monitor.
It is anticipated that approximately 210 patients will be screened and approximately 
134 enrolled into the open-label treatment phase from approximately 15 sites (to 
complete 100 patients).
Inclusion/Exclusion Criteria:
Patients are required to meet the following inclusion criteria:
1) Patients who are able to provide informed consent, understand the nature of the 
trial, follow protocol requirements, and read and understand English or French.
2) Male and female patients (outpatients) between the regional age of majority (18 or 
19 years of age) to 65 years of age, inclusive, at the time of informed consent.
3) Primary diagnosis of MDD and in a current non-psychotic MDE as defined by 
DSM-5 criteria, who have been outpatients for at least 4 weeks, and have an 
inadequate response, per investigator judgment, to 1 or 2 adequate treatments of 
ADTs in their current MDE, including current ADT.
4) Patients with a Patient Health Questionnaire 9-item scale (PHQ-9) ≥ 15 at the 
screening and baseline visits, if separate.
Patients will be excluded if they meet any of the following exclusion criteria:
1) Females who are breast-feeding and/or who are pregnant at the time of trial 
enrollment, or who plan to become pregnant during the trial.
2) Patients currently or previously treated with brexpiprazole including patients who 
received brexpiprazole in any prior clinical trial.
3) Patients with a concurrent DSM-5 diagnosis of the following will be excluded:
a) Schizophrenia or schizoaffective disorder
b) Bipolar I or bipolar II disorder
c) Post-traumatic stress disorder
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d) Dementia
e) Eating disorder
f)
Borderline personality disorder
g) Antisocial personality disorder
4) Patients with a suicidality score of 3 based on IDS-SR suicidality item 18 or 
patients who, in the opinion of the investigator, presents a serious risk of suicide.
5) Psychotherapy administered at baseline that is not expected to remain stable 
throughout the trial.
6) Patients who have received neurostimulation when used for treatment resistant 
depression.
7) Current, prior (lifetime treatment history), or planned use (during trial 
participation) of ketamine and/or esketamine for treatment of depression.
8) Current use of oral, immediate release intramuscular, or long-acting injectable 
(LAI) antipsychotics at Baseline and within 7 days prior to trial participation (one 
treatment cycle for LAIs).
9) Subjects who are currently participating in another clinical trial.
10) Any patient who does not have baseline blood glucose and complete blood count 
(CBC) including white blood cell counts as required prior to initiating treatment 
with brexpiprazole as per the Canadian Product Monograph. Has a medical 
condition (eg, moderate or severe substance use disorder) that would expose them 
to undue risk or interfere with the trial endpoints, or any other reason that, in the 
opinion of the sponsor, investigator, or medical monitor, should not participate in 
the trial. Please review the contraindications and warnings and precautions of the 
Canadian Product Monograph..
Trial Site(s):
Approximately 15 trial sites in Canada.
Investigational Medicinal Product(s), Dose, Dosage Regimen, Treatment Duration, 
Formulation, Mode of Administration:
During the open-label treatment phase, all patients will receive brexpiprazole (that is, 
adjunctive brexpiprazole as a flexible dose; 0.5 to 2 mg/day) and will continue on the 
stable dose of ADT that they were taking at screening. Brexpiprazole should be taken at 
approximately the same time each day and can be taken at the same time as the ADT. 
Antidepressant therapy is not considered trial drug in this trial.
Patients will take the first dose of brexpiprazole with or without food on the day after 
they are enrolled in the trial (Day 1). In accordance with the Canadian Product 
Monograph, the starting dose will be 0.5 mg or 1 mg QD. Up-titration will occur at 
weekly intervals to reach a dose of at least 1 mg QD by the Week 2 visit. After the 
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Week 2 visit, the dose may be decreased to a minimum of 0.5 mg QD or increased to a 
maximum of 2 mg QD based on the investigator’s clinical judgment. Dose increases may 
occur at weekly intervals based on the patient’s clinical response and tolerability. Dose 
decreases can occur at unscheduled trial visits. This dosing regimen is consistent with the 
Canadian Product Monograph and with clinical practice in Canada.
Allowable brexpiprazole doses that may be given starting the day after the Week 2 visit 
will be 
. The dose of 2 mg QD is the recommended 
target dose and is also the maximum recommended dose.
The trial drug will not be provided by the sponsor to the investigators. Instead, the trial 
drug will be supplied directly to enrolled patients by their retail pharmacists through a 
trial cards system.
Trial Assessments:
Assessments for Efficacy: IDS-SR, Patient Health Questionnaire 9-item (PHQ-9), 
Generalized Anxiety Disorder 7-item scale (GAD-7), World Health Organization 
Disability Assessment Schedule (WHODAS) 2.0 short, Sheehan Disability Scale (SDS), 
Clinical Global Impression - Severity (CGI-S), Clinical Global Impression - 
Improvement (CGI-I), Patient Global Impression – Severity (PGI-S), and Patient Global 
Impression – Improvement (PGI-I) scales.
Assessments for Safety: adverse events (AEs), vital signs, and physical examination 
findings.
Screening/Other: Demographic information, medical and psychiatric history, medication 
history, and urine pregnancy test.
Patient diary: Word of the day. Patients will be provided a list of words and will select 
one each day as their “word of the day”. The meaningful word list was generated based 
on interviews with MDD patients.
Criteria for Evaluation:
The co-primary efficacy endpoints are as follows:
1) Change from baseline to Week 8 in IDS-SR-10-engagement.
2) Change from baseline to Week 8 in IDS-SR Total score.
The other efficacy endpoints are as follows:
1) Change from baseline to Weeks 2 and 4 in IDS-SR-10-engagement.
2) Change from baseline to Weeks 2 and 4 in IDS-SR Total score.
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Sample Size: This is a single-arm trial to assess the effect of brexpiprazole on patient 
engagement in MDD patients through the following co-primary endpoints: 1) change 
from baseline to Week 8 in IDS-SR-10-engagement 2) change from baseline to Week 8 
in IDS-SR Total score. A sample size of 100 completers (ie, patients who have an 
evaluation on IDS-SR Total score and IDS-SR-10-engagement at Week 8) will yield 95% 
power to show a difference from baseline in IDS-SR Total score and at least 95% power 
to show a difference from baseline in IDS-SR-10-engagement at a two-sided significance 
level of 0.05, respectively. It will ensure the overall power is at least 90%. After 
considering an ET rate of 25%, a total of 134 patients need to be enrolled in this trial.
Efficacy: The primary efficacy analysis is to evaluate if changes from baseline to Week 8 
in both co-primary endpoints will differ from 0, separately. Each of the endpoints will be 
tested by fitting a mixed model repeated measure (MMRM) analysis with an unstructured 
variance covariance structure at a two-sided significance level of 0.05 on observed cases 
(OC) dataset on Efficacy Sample. The model will include fixed effect terms for visit, 
baseline value, an interaction term of baseline value by visit, and trial center. The trial 
will be claimed positive if both p-values are less than 0.05. Therefore, the overall type I 
error is controlled at 0.05 level.
Safety: Adverse events and vital signs will be summarized by descriptive statistics. 
Descriptive statistics will be also used to summarize body weight and BMI at screening, 
baseline, and Weeks 2, 4, and 8/ET. The incidence of potentially clinically significant 
changes in body weight will be tabulated in incidence tables.
Trial Duration:
Each patient in this trial is expected to participate in the following periods of the trial 
(approximate durations listed):

Screening period (14 days [Day -14 to Day -1])

Outpatient treatment period (8 weeks; including assessments at baseline and Weeks 2, 
4, and 8)

End of Trial (Week 8 visit/ET)
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1.3
Schedule of Assessments
Table 1.3-1
Schedule of Assessments
Visit
Baselinea 
(Day -1)
Week 2
Week 4
Week 8
/ETb
Assessment
Screeninga
(Days -14 to -2)
± 5 days
ENTRANCE/HISTORY
Informed consent
X
Inclusion/exclusion criteria
X
X
Demography
X
Medical history
X
Psychiatric history
X
Prohibited medication washoutc
X
Urine pregnancy test
X
X
EFFICACYd
IDS-SR (patient reported)
X
X
X
X
PHQ-9 (patient reported)e
X
X
X
X
X
GAD-7 (patient reported)
X
X
X
X
WHODAS 2.0 short (patient reported)
X
X
X
SDS (patient reported)
X
X
X
CGI-S
X
X
X
X
CGI-I
X
X
X
SAFETY
Brief physical examinationf
X
X
Height and body weightg
X
X
X
X
X
Vital signsh
X
X
X
X
Adverse events
X
X
X
X
X
Concomitant medicationsi
X
X
X
X
X
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Table 1.3-1
Schedule of Assessments
Visit
Baselinea 
(Day -1)
Week 2
Week 4
Week 8
/ETb
Assessment
Screeninga
(Days -14 to -2)
± 5 days
Clinical evaluation for suicidalitye
X
X
X
X
X
OTHER
Trial drug prescribedj
X
X
X
Trial drug accountability (patient reported)
X
X
X
Review of Patient Diary (word of the day, 
PGI-S, and PGI-I)k
X
X
X
X
ADT = antidepressant therapy; CGI-I = Clinical Global Impression - Improvement; CGI-S = Clinical Global Impression - Severity; ET = early termination; 
GAD-7 = Generalized Anxiety Disorder 7-item scale; ICF = informed consent form; IDS-SR = Inventory of Depressive Symptomatology Self-Report; 
PGI-I = Patient Global Impression – Improvement; PGI-S = Patient Global Impression – Severity; PHQ-9 = Patient Health Questionnaire 9-item scale; 
SDS = Sheehan Disability Scale; WHODAS = World Health Organization Disability Assessment Schedule.
aBrexpiprazole dosing will take place on Day 1 of Week 1. The screening visit can comprise 1 or more visits as needed. Screening and baseline visits can 
occur the same day if the patient meets all required enrollment criteria. Where screening and baseline visits occur on the same day, assessments will not be 
duplicated.
bIf a patient discontinues prematurely before Week 8, every effort should be made to complete the “Week 8/ET” evaluations.
cWashout of prohibited medications begins after signing the ICF and must comply with the required washout periods.
dWhere possible, sites should follow the order of efficacy assessments and patient reported outcomes as listed.
eIf the PHQ-9 indicates suicidal ideation (eg, a patient has suicidality on item 9 of the PHQ-9 scale [≥ 1] and/or IDS item 18 ≥ 3), then clinical evaluation of 
suicidality is essential on that particular visit and the investigator will conduct a more in-depth clinical assessment of the patient per the site’s standard 
protocol.
fThe extent of the physical examination will be at the discretion of the investigator.
gHeight and body weight at screening and body weight at baseline and at Weeks 2, 4, and 8/ET. When screening and baseline visits occur on the same day, 
assessments will not be duplicated.
hVital signs include systolic and diastolic blood pressure and heart rate.
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iAll medications taken within 30 days prior to informed consent will be recorded. In addition, all prescription and non-prescription medications taken during 
the trial will be recorded as concomitant medications. All ADTs taken within 12 months prior to informed consent will be recorded.
jTrial drug will not be prescribed at the Week 8 visit. The ADT regimen will be left to the discretion of the investigator.
kPatient diary entries will be reduced in frequency from daily to twice weekly from Week 5 to Week 8 (word of the day and PGI-S). The PGI-I will be 
administered weekly throughout the trial.
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2
Introduction
Major depressive disorder (MDD) is a serious medical illness associated with significant 
suicide risk and marked disability. Symptoms are heterogenous, spanning emotional, 
physical and cognitive domains, and lead to impairments in personal and social 
functioning, as well as diminished quality of life. Importantly, patients want a treatment 
that will help them to regain optimism and self-confidence, feel like their usual selves, 
and regain their pre-morbid level of functioning1 and feelings of well-being. The return to 
premorbid levels of functioning are often rated by patients as more important than 
symptom relief.2 Given that full symptomatic and functional recovery is the goal of MDD 
treatment, early identification of treatments that can address a broad range of symptoms 
of the illness are needed in order to effectively treat the consequences on overall 
functioning and well-being, and help the patient return to their premorbid state.
Canadian clinical practice guidelines emphasize the importance of adequate treatment for 
MDD, including a timely change in treatment (ie, medication switch or addition of 
adjunct therapy) if improvement is not observed within 2-4 weeks of dose-optimized 
therapy.3 Second-generation antipsychotics such as aripiprazole, brexpiprazole, 
olanzapine, quetiapine, and risperidone are recommended by the Canadian Network for 
Mood and Anxiety Treatments (CANMAT) as adjunct treatments with Level 1 evidence 
for patients who have not experienced an adequate response to prior antidepressant 
medications; however not all of these treatments are approved by Health Canada as 
adjunctive MDD treatments, and patients respond differently in terms of efficacy and 
tolerability to different medications. Consequently, there is an ongoing medical need to 
identify adjunctive strategies that offer a broad efficacy to enable patients to regain their 
premorbid functioning and personal well-being, and ultimately to return to their 
premorbid state. 
Brexpiprazole (OPC-34712 and Lu AF41156) is an atypical antipsychotic synthesized by 
Otsuka that is being codeveloped by Otsuka and Lundbeck. Brexpiprazole is currently 
approved in Canada, the United States (US), Mexico, United Arab Emirates, and other 
countries as monotherapy for the treatment of schizophrenia and in the US and Canada 
for use as an adjunctive therapy to antidepressants for the treatment of MDD. 
Brexpiprazole is a serotonin (5-hydroxytryptamine [5-HT]) –dopamine (D) activity 
modulator which is a partial agonist at serotonin 5-HT1A and dopamine D2 receptors, and 
an antagonist at serotonin 5-HT2A and noradrenaline α1B/2C receptors, all with 
subnanomolar affinities.
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2.1
Nonclinical Data
Efficacy and safety pharmacology of brexpiprazole are summarized in Section 2.1.1 and 
Section 2.1.2. A complete description of the available data from nonclinical studies, 
including pharmacokinetic and toxicology studies in different animal species can be 
found in the Investigator’s Brochure (IB).4
2.1.1
Efficacy Pharmacology
While the precise mechanism of action of brexpiprazole in treating psychiatric conditions 
is unknown, the pharmacology of brexpiprazole is believed to be mediated by a 
combination of high binding affinity and functional activities at multiple monoaminergic 
receptors. It has modulatory activity at the serotonin and dopamine systems that 
combines partial agonist activity at serotonergic 5-HT1A and at dopaminergic D2 
receptors with antagonist activity at serotonergic 5-HT2A receptors, with similar high 
affinities at all of these receptors (inhibition constant [Ki]: 0.1 - 0.5 nM). Brexpiprazole 
also shows antagonist activity at noradrenergic α1B/2C with affinity in the same 
subnanomolar Ki range (Ki: 0.2 - 0.6 nM). The 5 HT1A/D2 receptor partial agonist 
activity in combination with 5-HT2A and α1B/2C receptors antagonism of brexpiprazole 
may correlate with antipsychotic and antidepressant efficacy. These mechanisms of 
actions have previously shown activity in preclinical models for MDD.
Please refer to the IB4 for more detailed information.
2.1.2
Safety Pharmacology
Please refer to the IB4 for information.
2.2
Clinical Data
As of 17 Apr 2020, the brexpiprazole clinical development program consisted of a total 
of 96 clinical trials conducted in North America, Latin America, Europe, and Asia 
(74 completed and 22 ongoing). This total includes 77 trials conducted under US 
Investigational New Drug (IND) Applications (65 completed and 12 ongoing) for healthy 
subjects, schizophrenia, adjunctive treatment of MDD, adjunctive treatment of attention 
deficit hyperactivity disorder (ADHD), agitation associated with dementia (AAD) of the 
Alzheimer’s type, post-traumatic stress disorder (PTSD), bipolar disorder, or autism 
spectrum disorder; and 19 non-US IND trials (9 completed and 10 ongoing in China, 
South Korea, and Japan) conducted in healthy subjects, subjects with schizophrenia, 
subjects with MDD, and subjects with AAD.
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Please refer to the IB4 for more detailed information.
2.2.1
Pharmacokinetics/Pharmacodynamics
The pharmacokinetics (PK) of single and multiple doses of brexpiprazole was studied in 
healthy subjects and in subjects with MDD, ADHD, and schizophrenia or schizoaffective 
disorder. Based on preclinical data and human clinical trials, brexpiprazole and 
1 metabolite, DM-3411, were identified as the major analytes that are present in human 
plasma. In vitro, the activity of DM-3411 is 17 times lower than that of brexpiprazole and 
thus is considered a minimally active metabolite. Both brexpiprazole and DM-3411 
pharmacokinetics were linear in healthy subjects following single oral doses of 
brexpiprazole 0.2 to 6.0 mg. In healthy subjects, administration of single-dose 
brexpiprazole with a high-fat meal did not affect its rate and extent of absorption.
Steady state PK was linear following multiple daily doses of brexpiprazole in the range of 
0.5 to 2.0 mg to healthy subjects. The accumulation factor based on maximum (peak) 
plasma concentration (Cmax) and area under the concentration-time curve calculated to 
the last observable concentration at time t (AUCt) was approximately 4 times. After 
multiple dose administration of brexpiprazole (1.0 to 12.0 mg/day) to subjects with 
schizophrenia or schizoaffective disorder, brexpiprazole and DM-3411 mean terminal 
elimination half-life at steady state was 95.4 and 89.3 hours, respectively; median time to 
maximum (peak) plasma concentration was 3.0 and 8.0 hours, respectively.
In drug interaction trials in healthy subjects, brexpiprazole was shown to be metabolized 
by cytochrome P450 (CYP) 3A4 and CYP2D6 isozymes and was not an inhibitor of 
CYP3A4, CYP2B6, CYP2D6, or P-glycoprotein. Coadministration of potent CYP3A4 or 
CYP2D6 inhibitors with brexpiprazole resulted in about a 2-fold higher exposure and 
about a 1.5-fold increase in the terminal elimination half-life of brexpiprazole. Of note, 
administration of brexpiprazole with fluoxetine, paroxetine, and duloxetine (medications 
for treatment of MDD coadministered in this trial) may potentially increase brexpiprazole 
plasma concentrations by up to 2-fold.
In a single-dose trial in healthy subjects, approximately 46.0% and 24.6% of 
administered radioactivity following an oral dose of 14C-brexpiprazole was excreted in 
feces and urine, respectively. In this same trial, brexpiprazole did not preferentially bind 
to red blood cells. Brexpiprazole showed high protein binding in human serum (≥ 99.8%) 
in vitro.
The binding of brexpiprazole to dopamine receptors was assessed using positron 
emission tomography. The mean D2/D3 receptor occupancies at 4 and 24 hours postdose 
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after 0.25, 0.5, 1.0, 2.0, 4.0, 5.0, and 6.0 mg single-dose administration of brexpiprazole 
to healthy subjects were 11.4% to 17.4%, 36.5% to 46.3%, 45.6% to 60.2%, 52.7% to 
68.6%, 67.9% to 79.5%, 71.9% to 88.2%, and 69.5% to 92.6%, respectively (Trial 
331-07-202). Based on the single-dose D2/D3 receptor occupancy data and steady state 
PK/pharmacodynamic (PD) modeling, it was predicted that the D2/D3 receptor occupancy 
after multiple daily dose administration of 1.0 to 2.0 mg and higher doses of 
brexpiprazole will result in at least 80% to 90% D2/D3 receptor occupancy.
Population PK analysis of phase 1 through phase 3 trials demonstrated no differences in 
the PK of brexpiprazole between healthy subjects, subjects with MDD, and subjects with 
either schizophrenia or schizoaffective disorder (in phase 1 trials).
Please refer to the IB4 for more detailed information.
2.2.2
Major Depressive Disorder
The data derived from 6 adequate and well-controlled short-term trials provides evidence 
that brexpiprazole 2 mg/day and 3 mg/day is efficacious as adjunctive treatment in adults 
with MDD who had a persistent inadequate response to antidepressant therapy (ADT). 
The maximum dose approved in Canada is 2 mg/day.
Please refer to the IB4 for more detailed information.
2.3
Known and Potential Risks and Benefits
Phase 1 data indicated that brexpiprazole demonstrated good safety and tolerability when 
administered to healthy volunteers at single doses of 0.2 to 6 mg and at a repeated dose of 
2 mg/day. Data from completed repeated dosing trials indicate that brexpiprazole 
demonstrated good tolerability when administered to subjects with schizophrenia or 
schizoaffective disorder at doses of up to 12 mg/day; when administered to subjects with 
MDD at doses of up to 4 mg/day in combination with a marketed antidepressant 
(brexpiprazole in MDD is approved only to 2 mg/day); up to 3 mg/day as adjunctive 
therapy in elderly subjects (70 - 85 years of age) with MDD; and when administered to 
subjects with ADHD at doses of up to 4 mg/day in combination with a marketed 
stimulant (brexpiprazole is approved for doses of up to 2 mg for the adjunct treatment of 
MDD in Canada). Please refer to the Canadian Product Monograph5 for details of known 
and potential risks and benefits of brexpiprazole.
Please refer to the current brexpiprazole IB4 for a summary of available nonclinical and 
clinical safety data.
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2.4
Trial Rationale
Currently, brexpiprazole is approved in Canada for use in adult patients for the treatment 
of schizophrenia and for the use as an adjunctive therapy to antidepressants for the 
treatment of MDD.
Post-marketing reports from various sources have revealed a clinical observation of 
brexpiprazole-treated patients, initially described as an increase or improvement in 
“engagement,” “positivity,” or “brightening.” This unique effect was reported by 
physicians from multiple countries, and was also observed in reports received by the 
company call centers. Based on this spontaneous feedback, a post-hoc analysis of specific 
“engagement items” of the Inventory of Depressive Symptomatology Self-Report 
(IDS-SR) from the brexpiprazole pivotal trial data was conducted to explore patient 
ratings of this so-called “engagement effect,” and patient interviews from previous MDD 
exploratory studies were analyzed for spontaneous use of “engagement” lexicon. Briefly, 
results indicated that MDD patients treated with adjunctive brexpiprazole demonstrated 
improvements vs adjunctive placebo on items that represented patient well-being and 
engagement.6 Furthermore, a majority of patients (~89%) that consented to participate in 
exit interviews after exploratory studies used language reflecting an improvement in at 
least one of four engagement domains (social, emotional, physical or cognitive).7 
Canadian healthcare providers confirmed that improvement in engagement has been 
observed in Canadian MDD patients, with reports of patients experiencing “increased 
motivation,” “improved anhedonia,” “clarity of mind,” and being “more engaged” 
indicating that further prospective investigation of this effect is warranted. Furthermore, 
interviews recently conducted with MDD patients support the relevance of the 
previously-identified IDS-SR items in the measurement of patient engagement.
3
Objectives
The primary objective of this trial is:

To prospectively characterize the effect of brexpiprazole on the concept of 
engagement, by evaluating IDS-SR-10-engagement, and the IDS-SR Total score, in 
patients with MDD with a current depressive episode.
The secondary objectives of this trial are:

To evaluate patients’ impression of improvement of their depression symptoms over 
time.

To explore the relationship between engagement and other clinical effects of 
brexpiprazole, such as improvement in depressive symptoms and functioning.
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
To evaluate the safety and tolerability of brexpiprazole (flexible dose; 0.5 to 2 mg 
once daily [QD]) as adjunctive therapy to ADT in the proposed patient population 
with MDD.
4
Trial Design
4.1
Type/Design of Trial
This is a phase 4, multicenter, open-label, flexible dose trial designed to assess the effects 
of brexpiprazole (flexible dose; 0.5 to 2 mg QD) as adjunctive therapy to ADT in patients 
with MDD. This trial is being conducted in line with the Canadian Product Monograph.5
The trial will be organized as follows:
Screening Phase: The screening period of up to 14 days (Days -14 to -1) will begin when 
the informed consent form (ICF) is signed. The purpose of the screening period is to 
assess eligibility criteria at 1 or more visits (as necessary to complete screening 
assessments) and to washout prohibited concomitant pharmacotherapy, if applicable. 
Open-Label Treatment Phase: Patients meeting all of the inclusion and none of the 
exclusion criteria will be enrolled at the baseline visit into an 8-week open-label 
treatment phase. The screening and baseline visits can occur on the same day if the 
patient meets all required enrollment criteria. During the open-label treatment phase, all 
patients will receive brexpiprazole (that is, adjunctive brexpiprazole as a flexible dose; 
0.5 to 2 mg/day) and will continue on the stable dose of ADT that they were taking at 
screening. Patients will attend visits at Weeks 2, 4, and 8 during the open-label treatment 
phase. If any patient discontinues the trial early, every effort should be made to complete 
the Week 8/early termination (ET) evaluations.
Following the completion of all scheduled visits, patients will be asked if they are 
interested in taking part in an exit interview, which will be separate from trial 
assessments and should occur within 30 days of the Week 8/ET visit. This also applies to 
patients withdrawn prematurely from the trial.
A schematic of the trial design is presented in Figure 1.2-1.
4.2
Scientific Rationale for Trial Design
The current clinical trial will be the first prospective investigation to further characterize 
the effect of brexpiprazole on patient engagement.
The engagement items of the IDS-SR (which were previously identified by clinicians and 
subsequently confirmed by MDD patients) will serve as one of the co-primary outcome 
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measures. The relationship between engagement and other outcomes of interest (such as 
functioning, and depressive symptoms) will be explored in order to further characterize 
this engagement effect. The majority of the clinical assessments to be used in this trial are 
patient-reported, which is aligned with current views that patient-reported outcomes are 
imperative to demonstrating the clinical effectiveness of MDD treatments.8
While the current trial is interventional, the trial design is intended to assess the effect of 
adjunctive brexpiprazole on MDD patients when administered in a real-world setting. 
The open-label nature of the trial, as well as the patient population, the timing of the 
visits, the clinical assessments used, and the dosing parameters are intended to mimic 
Canadian clinical practice as closely as possible. Patient diaries will assess the patient’s 
clinical experience in a manner that is as non-invasive as possible.
4.3
Dosing Rationale
Dosing is in line with the instructions for use in the Canadian Product Monograph5 while 
providing flexibility to adjust based on tolerability and treatment response.
The dosing regimen for brexpiprazole in this trial is presented in Section 6.1.
4.4
End of Trial Definition
The end of trial date is defined as the last date of contact or the date of final contact 
attempt from the post-treatment follow-up case report form (CRF) page for the last 
patient completing or withdrawing from the trial.
4.5
Definition of Completed Patients
The treatment period is defined as the time period during which patients are evaluated for 
primary and/or secondary objectives of the trial irrespective of whether or not the patient 
actually consumes all doses of the trial drug. Patients who are evaluated at the last 
scheduled visit during the treatment period will be defined as trial completers. For 
purposes of this trial, patients who complete the Week 8 visit will be defined as trial 
completers.
5
Trial Population
The trial population will include male and female outpatients between the regional age of 
majority (18 or 19 years of age) and 65 years of age, inclusive, with a Diagnostic and 
Statistical Manual of Mental Disorders, 5th Edition (DSM-5) diagnosis of a single or 
recurrent, non-psychotic episode of MDD with or without symptoms of anxiety. 
Additionally, patients must have a treatment history for the current major depressive 
episode (MDE) of an inadequate response (assessment of inadequate response is per 
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investigator judgment) to at least 1 and no more than 2 adequate antidepressant 
treatments (including the antidepressant that the patient is taking at screening).
Patients with a historical diagnosis of any concurrent condition that is exclusionary may 
be permitted if the investigator determines and documents this prior diagnosis was not 
appropriate based on current and historical presentation.
Patients with ADHD, obsessive compulsive disorder (OCD), panic disorders, or 
generalized anxiety disorder can be included under the following conditions:

These disorders are not the primary focus of treatment at the screening visit

Changes in any treatment for these disorders (permitted medication and/or 
psychotherapy) would not likely be required for the duration of the trial

All other concurrent psychiatric or neurological diagnoses must be discussed with the 
medical monitor.
It is anticipated that approximately 210 patients will be screened and approximately 
134 enrolled into the open-label treatment phase from approximately 15 sites (to 
complete 100 patients).
5.1
Patient Selection and Numbering
All patients will be given a unique identification (ID; site number [3 digits] + patient 
number [‘S’ + 5 digits] upon providing consent [or assent if applicable]). The site number 
will be designated by the sponsor. For each site, the patient number will be given 
sequentially from S00001.
Demographic information (collection date, date of birth, sex, gender identity, 
childbearing potential, race, ethnicity, native language, years of education) and medical 
history will be recorded in the CRF at the screening visit.
5.2
Eligibility Criteria
Exceptions for eligibility criteria will not be permitted during the trial, either by the 
investigator or by the medical monitor.
5.2.1
Inclusion Criteria
Patients are required to meet the following inclusion criteria:
1) Patients who are able to provide informed consent, understand the nature of the 
trial, follow protocol requirements, and read and understand English or French.
2) Male and female patients (outpatients) between the regional age of majority (18 or 
19 years of age) to 65 years of age, inclusive, at the time of informed consent.
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3) Primary diagnosis of MDD and in a current non-psychotic MDE as defined by 
DSM-5 criteria, who have been outpatients for at least 4 weeks, and have an 
inadequate response, per investigator judgment, to 1 or 2 adequate treatments of 
ADTs in their current MDE, including current ADT.
4) Patients with a Patient Health Questionnaire 9-item scale (PHQ-9) ≥ 15 at the 
screening and baseline visits, if separate.
5.2.2
Exclusion Criteria
Patients will be excluded if they meet any of the following exclusion criteria:
1) Females who are breast-feeding and/or who are pregnant at the time of trial 
enrollment, or who plan to become pregnant during the trial (see Section 10.2).
2) Patients currently or previously treated with brexpiprazole including patients who 
received brexpiprazole in any prior clinical trial.
3) Patients with a concurrent DSM-5 diagnosis of the following will be excluded:
a) Schizophrenia or schizoaffective disorder
b) Bipolar I or bipolar II disorder
c) PTSD
d) Dementia
e) Eating disorder
f)
Borderline personality disorder
g) Antisocial personality disorder
4) Patients with a suicidality score of 3 based on IDS-SR suicidality item 18 or 
patients who, in the opinion of the investigator, presents a serious risk of suicide.
5) Psychotherapy administered at baseline that is not expected to remain stable 
throughout the trial.
6) Patients who have received neurostimulation when used for treatment resistant 
depression.
7) Current, prior (lifetime treatment history), or planned use (during trial 
participation) of ketamine and/or esketamine for treatment of depression.
8) Current use of oral, immediate release intramuscular, or long-acting injectable 
(LAI) antipsychotics at Baseline and within 7 days prior to trial participation (one 
treatment cycle for LAIs).
9) Subjects who are currently participating in another clinical trial.
10) Any patient who does not have baseline blood glucose and CBC including white 
blood cell counts as required prior to initiating treatment with brexpiprazole as per 
the Canadian Product Monograph. Has a medical condition (eg, moderate or 
severe substance use disorder) that would expose them to undue risk or interfere 
with the trial endpoints, or any other reason that, in the opinion of the sponsor, 
investigator, or medical monitor, should not participate in the trial. Please review 
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the contraindications and warnings and precautions of the Canadian Product 
Monograph.  
Full requirements for contraception along with a definition of females of childbearing 
potential (FOCBP) are described in Section 10.2.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Brexpiprazole dosing is in line with the instructions for use and restrictions indicated in 
the Canadian Product Monograph.5 There are no other restrictions on food or water 
intake prior to or after administration of brexpiprazole.
5.3.2
Caffeine and Alcohol
Alcohol may interact with brexpiprazole. Patients will be informed of the risks of 
interaction between alcohol and brexpiprazole.
5.4
Screen Failures
Patients who sign an ICF but who are not started on treatment will be considered screen 
failures and are permitted to be re-screened with consent of the medical monitor. In the 
event that the patient is re-screened for trial participation, and the re-screening was not 
completed within the original screening window, a new ICF must be signed, a new 
screening number assigned, and all screening procedures repeated.
A screen failure is a patient from whom informed consent is obtained and is documented 
in writing (ie, patient signs an ICF), but who is not assigned trial treatment. All adverse 
events (AEs) must be reported after patient informed consent has been obtained, 
including screening failures due to AEs, irrespectively of trial drug administration.
If the patient meets the definition of a screen failure in this trial, the following 
information will be recorded in the CRF:

Date of informed consent

Visit date (screening visit)

Demographics (collection date, birth date, sex, race, ethnicity)

Result of eligibility assessment

Screen failure date

Reason for screen failure
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6.2.1
Packaging and Labeling
The trial drug will not be provided by the sponsor to the investigators. Instead, the trial 
drug will be supplied directly to enrolled patients by their retail pharmacists through a 
trial cards system.
6.2.2
Storage
The trial drug will be labeled at the patient’s retail pharmacy and storage instructions 
should be provided to the patient by their retail pharmacist at the time that the patient fills 
the prescription. The trial drug will also be labeled with appropriate storage conditions. 
Patients will be instructed by their retail pharmacist to adhere to trial drug storage 
requirements for the duration of the trial.
6.2.3
Accountability
For the entire duration of trial participation, the trial drug will be dispensed to patients by 
retail pharmacists through a trial cards system (Section 6.2.1).
6.2.4
Returns and Destruction
Patients will be instructed that upon completion or termination of the trial, all unused trial 
drug and partially used trial drug must be returned to the patient’s retail pharmacy for 
proper disposal.
6.2.5
Reporting of Product Quality Complaints
A Product Quality Complaint (PQC) is any written, electronic, or oral communication 
provided by a healthcare professional, patient, medical representative, regulatory agency, 
Partner, or other third party that alleges deficiencies related to the identity, quality, 
durability, reliability, safety, or performance of a Medical Device or Medicinal Product 
after it is released for distribution to a clinical trial.
Examples include, but are not limited to, communications involving:

Incorrect or missing labeling

Packaging issues (eg, damaged, dirty, crushed, missing product)

Bottle defects (eg, under-fill, over-fill, no safety seal)

Product defect (eg, odor, chipped, broken, embossing illegible)

Loss or theft of product
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6.2.5.1
Eliciting and Reporting Product Quality Complaints
The investigator or designee must notify the sponsor (or sponsor’s designee) by telephone 
or email within 24 hours of becoming aware of the PQC according to the procedure 
outlined below.

Report all PQCs by calling 1-877-341-9245 or by sending PQC reporting information 
to the OPCI Medical Information mailbox email: OCPI-MedInfo@otsuka-ca.com.

Also indicate whether or not the complaint sample is available for return.
6.2.5.2
Information Required for Reporting Purposes

Description of complaint

Reporter identification (eg, patient, investigator, site, etc.)

Reporter contact information (eg, address, phone number, e-mail address)

ID of material (product/compound name, coding)

Clinical protocol reference (number and/or trial name)

Dosage form/strength (if known)

Pictures of complaint sample (if available)

Availability of complaint sample for return

Was any patient at risk due to the identified issue?
6.2.5.3
Return Process
Indicate during the report of the PQC if the complaint sample is available for return. If 
the complaint sample is available for return, the sponsor will provide return instructions, 
when applicable.
6.2.5.4
Assessment/Evaluation
Assessment and evaluation of PQCs will be handled by the sponsor.
6.3
Measures to Minimize/Avoid Bias
This is an open-label trial.
6.4
Patient Compliance
There will be a question in the patient’s daily diary asking the patient if they have taken 
their daily medication. Sites and investigators will assess compliance with patients at the 
scheduled visits. The actual start and finish dates for each dose strength of trial drug 
administered will be recorded on the CRF. Information regarding any inappropriately 
administered dose will also be documented on the CRF.
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Patients will be required to comply with medication restrictions outlined in Section 6.5.
6.5
Concomitant Medications or Therapies
The investigator will record all medications (including prescription medications, 
over-the-counter medications, herbal remedies, etc.) and therapies taken by the patient 
from the time of signing the ICF through the end of the evaluation period (defined as the 
time period during which patients are evaluated for primary and/or secondary objectives) 
in the CRF. The investigator will also record all medications and therapies taken by the 
patient for treatment of an AE or which caused an AE until the end of the trial (defined as 
the last date of contact or date of final contact attempt) in the CRF.
The clinical site will record all concomitant medications taken 30 days prior to baseline 
in the CRF, including the ADT for the patient’s current MDE.
For concomitant medications, the following will be recorded in the CRF: medication, 
indication, dose, frequency, route, start date and end date. For concomitant therapy, the 
following will be recorded in the CRF: therapy, indication, start date and end date.
6.5.1
Prohibited Medications or Therapies
Concomitant medications that are contraindicated in the Canadian Product Monograph5 
are prohibited in this trial. In addition, benzodiazepines and/or hypnotics (including non-
benzodiazepine sleep aids) should not be ingested within 8 hours prior to a scheduled 
visit due to the possibility of impacting efficacy assessments.
7
Stopping Rules, Withdrawal Criteria, and Procedures
7.1
Entire Trial or Treatment
If the sponsor terminates or suspends the trial for any reason, prompt notification will be 
given to investigators, Institutional Review Boards (IRBs) and Independent Ethics 
Committees (IECs), and regulatory authorities in accordance with regulatory 
requirements.
7.2
Individual Site
Individual trial site participation may be discontinued by the sponsor, the investigator, or 
the IRB/IEC if judged to be necessary for medical, safety, regulatory, ethical or other 
reasons consistent with applicable laws, regulations, and Good Clinical Practice (GCP). 
The investigator will notify the sponsor promptly if the trial is terminated by the 
investigator or the IRB/IEC at the site.
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7.3
Individual Patient Discontinuation
7.3.1
Treatment Discontinuation
After the baseline visit, a patient may stop treatment permanently for a variety of reasons. 
Treatment discontinuations may be initiated by a patient for any reason or may become 
medically necessary due to AEs, required treatment with a disallowed medication or 
therapy, or other issues, as determined by the investigator. If a patient discontinues 
treatment, their participation in the trial will be discontinued. Discontinued patients 
should be encouraged to complete all ET and follow-up assessments with ET assessments 
conducted as soon as possible after the patient is withdrawn.
7.3.2
Documenting Reasons for Treatment Interruption or 
Discontinuation
Brief treatment interruptions/periods of non-adherence will be allowed and managed 
according to the clinical judgment of the investigators.
A patient may discontinue trial drug for the reasons listed below:

Adverse event

Patient decides to discontinue because of annoyance or discomfort due to a 
nonserious AE which is not otherwise determined to be an undue hazard

Continuing trial drug places the patient at undue risk as determined by the 
investigator (eg, a safety concern that is possibly, probably, or likely related to 
trial drug)

Serious adverse event (SAE)

Other potentially trial drug-related safety concerns or AEs

Death

Failure to meet continuation criteria

Lack of efficacy

Lost to follow-up

Noncompliance with trial drug

Physician decision

Pregnancy (see Section 10.2)

Protocol deviation

Protocol-specific withdrawal criterion met

Site terminated by sponsor

Trial terminated by sponsor

Technical problems

Withdrawal by patient
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
Other
If the patient discontinues trial drug due to an AE, the investigator, or other trial 
personnel, will make every effort to follow the event until it has resolved or stabilized. 
Follow-up procedures in Section 7.3.1 must be followed.
7.3.3
Withdrawal of Consent
Each patient has the right to withdraw their consent from further participation in the trial 
at any time without prejudice. Patients can withdraw consent for use of data which has 
not previously been anonymously transferred into trial data sets collected as part of the 
trial and can only withdraw consent for future participation. The investigator can also 
discontinue a patient’s participation in the trial at any time if medically necessary. Unless 
the patient provides their written withdrawal of consent or there is other written 
documentation by the investigator confirming the patient’s verbal intent to completely 
withdraw from the trial, patients should be followed for all protocol-specified evaluations 
and assessments, if possible.
Complete withdrawal of consent requires a patient’s refusal of ALL of the following 
methods of follow-up:

Participation in all follow-up procedures specified in the protocol (whether in-clinic, 
by telephone, or by a home visit).

Participation in a subset of protocol specified follow-up procedures (by a frequency 
schedule and method, as agreed by patient and trial site staff).

Contact of the patient by trial personnel, even if only by telephone, to assess current 
medical condition, and obtain necessary medical reports relevant to the trial’s 
objectives.

Contact of alternative person(s) who have been designated in source records as being 
available to discuss the patient’s medical condition, even if only by telephone, mail, 
or e-mail (eg, family, spouse, partner, legal representative, friend, neighbor, or 
physician).

Access to medical information from alternative sources (eg, hospital/clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, social media sources).
Withdrawal of consent is a critical trial event and, therefore, should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent. 
The reasons for a patient’s intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the patient and the integrity of the trial. 
A patient may initially express their desire to discontinue trial drug administration, which 
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is not equivalent to a complete withdrawal of consent for further participation (see 
Section 7.3.1). A patient may, however, indicate that further trial participation is creating 
a burden on their work, school, or social schedule. Therefore, the investigator should 
follow the procedures outlined in Section 7.3.2 to determine if the patient can continue 
participation in the trial if modifications to his/her treatment and/or schedule of 
assessments can be accommodated (Section 6.1). Only patients who withdraw their 
permission for all of the above methods of follow-up are considered to have completely 
withdrawn their consent to participate in the trial.
7.4
Definition of Patients Lost to Follow-up
Patients who cannot be contacted on or before the Week 8 visit 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”. 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 patient, 
medical records, successful telephone contact with the patient, statement by a family 
member or primary care physician, or public records).
The site will make 3 documented attempts to contact the patient by telephone and in the 
event the site is unable to reach the patient by telephone, the site will attempt to contact 
the patient via certified mail or an alternative similar method, where appropriate, before 
assigning a “lost to follow-up” status.
If the patient was classified as “lost to follow-up”, “Were you able to contact the 
patient?”, “Date of contact/Date of final contact attempt” and “Contact method” will be 
recorded in the source system.
8
Trial Procedures
Individual participation for patients who complete the trial without early withdrawal will 
consist of a 14-day screening period and an 8-week outpatient treatment period.
The assessments to be conducted during the trial are summarized in Table 1.3-1.
8.1
Efficacy Assessments
Where possible, sites should follow the order of efficacy assessments and patient reported 
outcomes as listed below and in Table 1.3-1.
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8.1.1
Inventory of Depressive Symptomatology Self-Report (IDS-SR)
The IDS-SR9 is a 30-item self-report measure used to assess core diagnostic depressive 
symptoms as well as atypical and melancholic symptom features of MDD (see 
Section 9.3 for more details). Symptom severity is rated using the following scale: 0-13: 
None, 14-25: Mild, 26-38: Moderate, 39-48: Severe, and 49-84: Very severe. The 
investigator or designated trial personnel should encourage patients to complete this 
instrument completely and legibly.
8.1.1.1
IDS-SR-10-Engagement
The IDS-SR-10-engagement consists of selected 10 item scores, including the following 
10 items for the co-primary endpoint (clinician-selected): item 8 - Response of your 
mood to good or desired events, item 15 - Concentration/decision making, item 16 - View 
of myself, item 17 - View of my future, item 19 - General interest, item 20 - Energy level, 
item 21 - Capacity for pleasure or enjoyment (excluding sex), item 22 - Interest in sex 
(please rate interest, not activity), item 23 - Feeling slowed down, and item 29 - 
Interpersonal sensitivity. The IDS-SR-10-engagement will be determined based on these 
10 items as described in Section 9.3.
IDS-SR patient-selected engagement items will be included in the other efficacy endpoint 
analysis and the exploratory endpoint analysis. Details will be provided in the statistical 
analysis plan (SAP).
8.1.2
Patient Health Questionnaire-9 (PHQ-9)
The PHQ-9 is a standardized, self-administered rating scale that assesses the severity of 
depressive symptoms. The scale consists of 9 items, representing the 9 criteria upon 
which the diagnosis of DSM-5 depressive disorders is based. A higher score on the 
PHQ-9 represents a higher severity of depressive symptoms.
8.1.3
Generalized Anxiety Disorder-7 (GAD-7)
The Generalized Anxiety Disorder 7-item (GAD-7) scale is designed to assess anxiety in 
patients. The scale contains 7 items and each item is rated from 0 (not at all) to 3 (nearly 
every day). The score ranges from 0 to 21. A higher score on the GAD-7 represents 
greater anxiety symptomatology.
8.1.4
World Health Organization Disability Assessment Schedule 2.0 
(WHODAS) Short Form Questionnaire
The World Health Organization Disability Assessment Schedule (WHODAS) 2.0 short 
form10 is a 12-item self-assessment questionnaire to assess a patient’s activity limitations 
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and participation restrictions (ie, disability) across 6 domains of life: cognition 
(understanding and communicating), mobility (moving and getting around), self-care 
(hygiene, dressing, eating, staying alone), getting along (interacting with others), life 
activities (domestic responsibilities, leisure, work and school), and participation 
(community and society).
8.1.5
Sheehan Disability Scale (SDS)
The Sheehan Disability Scale (SDS)11,12 is a self-rated instrument used to measure the 
effect of the patient’s symptoms on work/school, social life, and family/home 
responsibilities. For each of the three items, scores range from 0 through 10. The number 
most representative of how much each area was disrupted by symptoms is marked along 
the line from 0 = not at all, to 10 = extremely. For the work/school item, no response was 
to be entered if the patient did not work or go to school for reasons unrelated to the 
disorder and a response therefore not being applicable. The Mean SDS Score will be 
calculated over the three item scores. All three item scores need to be available with the 
exception of the work/school item score when this item is not applicable.
8.1.6
Clinical Global Impression - Severity of Illness (CGI-S)
The severity of illness for each patient will be rated using the Clinical Global Impression 
- Severity (CGI-S) scale.13 To perform this assessment, the rater or investigator will 
answer the following question: “Considering your total clinical experience with this 
particular population, how mentally ill is the patient at this time?” Response choices 
include: 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; and 7 = among the most 
extremely ill patients.
8.1.7
Clinical Global Impression - Improvement (CGI-I)
The efficacy of trial treatment will be rated for each patient using the Clinical Global 
Impression - Improvement (CGI-I) scale.14 The rater or investigator will rate the patient’s 
total improvement whether or not it is due entirely to drug treatment. Response choices 
include: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally 
improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much 
worse.
8.1.8
Word of the Day
The ''Word of the Day'' is a word contained in a previously-generated list of meaningful 
words that has been developed through patient interviews. Words in this list have been 
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assigned a valence (ie, positive, negative, or neutral) and will be selected by patients to 
best describe how the patient has felt that day.
8.1.9
Patient Global Impression - Severity (PGI-S)
The Patient Global Impression – Severity (PGI-S) scale is a 7-point single-item 
self-report scale for the patient to rate the severity of symptoms of MDD. Patients answer 
the following question: “Taking into account all of your symptoms, how severe is your 
Major Depressive Disorder at this time?” Scores range from 1 “no symptoms” to 7 “very 
severe.”
8.1.10
Patient Global Impression - Improvement (PGI-I)
The Patient Global Impression – Improvement (PGI-I) scale is a 7-point single-item 
self-report scale depicting a patient’s rating of overall improvement in their condition 
since starting trial medication. Patients answer the following question: “Since starting 
trial medication, how much have your symptoms of Major Depressive Disorder 
changed?” Scores range from 1 “very much improved” to 7 “very much worse.”
8.2
Safety Assessments
Details pertaining to the definitions, collection, reporting, and follow-up of AEs are 
described in Section 8.3.
8.2.1
Physical Examination
Physical examinations will be performed at the time points described in the schedule of 
assessments (Table 1.3-1).
The investigator or designee is primarily responsible for performing the physical 
examination and the extent of the physical examination will be at the discretion of the 
investigator. Whenever possible, the same individual should perform all physical 
examinations for any individual patient. Any clinically significant condition present at a 
post treatment physical examination that was not present at the baseline physical 
examination should be documented as an AE and followed to a satisfactory conclusion.
Body height and weight will also be measured during screening for calculation of body 
mass index (BMI) and weight will be measured at baseline and at Weeks 2, 4, and 8/ET. 
Where screening and baseline visits occur on the same day, assessments will not be 
duplicated.
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8.2.2
Vital Signs
Vital signs will be collected at the time points described in the schedule of assessments 
(Table 1.3-1). Patients should be monitored for potentially clinically significant vital 
signs values (Section 10.3).
Vital signs will include systolic and diastolic blood pressure and heart rate. At each time 
point for vital signs, blood pressure (systolic and diastolic) and heart rate will be taken 
after patients have been in the seated position for at least 5 minutes. If the patient has any 
symptoms suggestive of orthostatic hypotension, the sitting and standing vital signs can 
be performed at the investigator's discretion.
8.2.3
Suicidality Monitoring
A suicidality assessment will be conducted using the PHQ-9 suicidality item and/or as 
per the trial site's standard operating procedures (SOPs). If the PHQ-9 indicates suicidal 
ideation (eg, a patient has suicidality on item 9 of the PHQ-9 scale [≥ 1] and/or IDS item 
18 ≥ 3), then clinical evaluation of suicidality is essential on that particular visit and the 
investigator will conduct a more in-depth clinical assessment of the patient per the site’s 
SOPs.
8.3
Adverse Events
8.3.1
Definitions
An AE is defined as any untoward medical occurrence in a clinical trial patient 
administered a trial drug and which does not necessarily have a causal relationship with 
this treatment. Adverse events would not include information recorded as medical history 
at screening for pre-planned procedures for which the underlying condition was known 
and no worsening occurred. An adverse reaction is any untoward and unintended 
response to a trial drug related to any dose administered.
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
trial drug caused the AE. For the purpose of IND safety reporting, “reasonable 
possibility” means there is evidence to suggest a causal relationship between the trial 
drug and the AE. Suspected adverse reaction implies a lesser degree of certainty about 
causality.
Treatment-emergent AEs (TEAEs) are defined as AEs with an onset date on or after the 
start of open-label treatment. In more detail, TEAEs are all AEs which started after the 
start of open-label trial drug treatment; or if the event was continuous from baseline and 
was worsening, serious, trial drug related, or resulted in death, discontinuation, 
interruption, or reduction of trial drug.
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A serious AE (SAE) includes any event that results in any of the following outcomes:

Death

Life-threatening; ie, the patient was, in the opinion of the investigator, at immediate 
risk of death from the event as it occurred. It does not include an event that, had it 
occurred in a more severe form, might have caused death.

Persistent or significant incapacity/disability or substantial disruption of the ability to 
conduct normal life functions.

Requires inpatient hospitalization or prolongs hospitalization.

Hospitalization itself should not be reported as an SAE; whenever possible the 
reason for the hospitalization should be reported.

Hospitalizations or prolonged hospitalizations for social admissions (ie, those 
required for reasons of convenience or other nonmedical need) are not considered 
SAEs.

Prescheduled hospitalization to address a condition that has existed prior to the 
signing of the ICF should not be considered an SAE.

Congenital anomaly/birth defect.

Other medically significant events that, based upon appropriate medical judgment, 
may jeopardize the patient 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.

Lack of efficacy cases should be evaluated for unusual failure in efficacy (UFIE) and 
must be reported in an expedited fashion.

Pregnancies are also defined as IREs. Although normal pregnancy is not an AE, it 
will mandate trial drug discontinuation and must be reported on an IRE form and the 
Pregnancy Surveillance Form(s) to the sponsor. This includes pregnancy of the 
patient or the partner of the patient. Pregnancy will only be documented on the AE 
CRF if the pregnancy occurs in a female patient and there is an abnormality or 
complication. Please refer to Section 10.2 for contraceptive guidance and collection 
of pregnancy information.
Clinical Laboratory Test Value Changes: Clinical laboratory assessments will be 
conducted at the investigator’s discretion to ensure safety of the patient. However, aside 
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from the urine pregnancy test at screening, ongoing clinical laboratory assessments are 
not required for this trial. In the event that the investigator orders a laboratory test in the 
interest of patient safety, it is the investigator’s responsibility to review the results of all 
laboratory tests as they become available. This review will be documented by the 
investigator’s dated signature on the laboratory report. For each abnormal laboratory test 
result, the investigator needs to ascertain if this is abnormal (eg, clinically significant) for 
that individual patient. This determination, however, does not necessarily need to be 
made the first time an abnormal value is observed. The investigator may repeat the 
laboratory test or request additional tests to verify the results of the original laboratory 
tests.
Severity: Adverse events will be graded on a 3-point scale and reported as indicated in 
the CRF. The severity 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.
Trial Drug Causality: Assessment of causal relationship of an AE to the use of the trial 
drug is defined as follows:
Related: 
There is a reasonable possibility of a temporal and causal 
relationship between the trial drug and the AE.
Not Related: 
There is no temporal or causal relationship between the trial drug 
and the AE.
8.3.2
Eliciting and Reporting Adverse Events
The investigator will regularly assess patients for the occurrence of AEs. To avoid bias in 
eliciting AEs, patients should be asked the nonleading question: “How have you felt since 
your last visit?” All AEs (serious and nonserious) reported by the patient must be 
recorded on the source documents and CRF provided by the sponsor. Adverse event 
collection will begin after a patient signs the ICF, and will continue until the Week 8/ET 
visit. All AEs must be reported after patient informed consent has been obtained, 
including screening failures due to AEs, irrespective of trial drug administration.
Medical terminology should be used for AE reporting. Adverse events should be reported 
as a single unifying diagnosis whenever possible or, in the absence of a unifying 
diagnosis, as individual signs or symptoms.
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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.
In addition, the sponsor must be notified immediately by telephone, fax, or e-mail of any 
IREs according to the procedure outlined below, in Section 8.3.3. Special attention 
should be paid to recording hospitalization and concomitant medications.
The adverse event, start date and time, end date and time, seriousness, severity, 
relationship to trial treatment (trial drug causality), action taken with trial treatment, and 
outcome will be recorded on the source documents and in the CRF.
8.3.3
Immediately Reportable Events
The investigator must immediately report (within 24 hours), using an IRE form, after 
he/she or site personnel become aware of any IRE (SAE, AE related to occupational 
exposure, UFIE, or confirmed pregnancy), by telephone, fax, or e-mail to the sponsor or 
designee using the contact information on the cover page of this protocol (please note that 
the IRE form is NOT the AE CRF). Patient confidentiality must be protected and contact 
information such as name, address, phone number or any other protected health 
information as determined by applicable local regulation must be redacted when 
forwarding Safety Information and supporting documentation. Details regarding the 
follow-up of IREs are included in Section 8.3.5.2.
8.3.4
Procedure for Breaking the Blind
This trial does not use blinding procedures.
8.3.5
Follow-up of Adverse Events
8.3.5.1
Follow-up of Nonserious Adverse Events
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE CRF with the current status (ongoing or resolved/recovered) noted. All nonserious 
events (that are not IREs) that are ongoing at the last scheduled contact will be recorded 
as ongoing in the CRF. For any AE having been identified throughout the trial, during 
analysis, additional relevant medical history information may be requested by the sponsor 
to further ascertain causality (including, but not limited to, information such as risk-
related behavior, family history, and occupation).
8.3.5.2
Follow-up of Immediately Reportable Events
This trial requires that patients be actively monitored for IREs up to the Week 8/ET visit.
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Immediately reportable events that are identified or ongoing at the last scheduled 
contact must be recorded as such on the AE CRF page and the IRE form. If updated 
information (eg, resolved status) on IRE status becomes available after a patient’s last 
scheduled contact (up to last in-clinic visit for the entire trial), this must be reported to the 
sponsor and recorded on the AE CRF page and the IRE form, according to the 
appropriate reporting procedures described in Section 8.3.3.
It is expected that the investigator will provide or arrange appropriate supportive care for 
the patient and will provide prompt updates on the patient’s status to the sponsor. The 
investigator will follow IREs until the events are:

Resolved,

Stabilized,

The patient is lost to follow-up, or

Has died.
Resolution means that the patient has returned to the baseline state of health and 
stabilized means that the investigator does not expect any further improvement or 
worsening of the patient’s condition. The investigator will continue to report any 
significant follow-up information to the sponsor up to the point the event has resolved or 
stabilized, or the patient is lost to follow-up, or has died.
Refer to Section 10.2 for additional information regarding the follow-up period for 
patients that become pregnant or for pregnant partners of male patients.
8.3.5.3
Follow-up and Reporting of Immediately Reportable Events 
Occurring After Last Scheduled Contact
Any new IREs reported to the investigator which occur after the last scheduled contact 
and are determined by the investigator to be reasonably associated with the use of the 
trial drug, should be reported to the sponsor according to the procedures outlined in 
Section 8.3.3. This may include IREs that are captured on follow-up telephone contact or 
at any other time point after the defined trial period and continue to report any significant 
follow-up information to the sponsor until the events are resolved or stabilized, or the 
patient is lost to follow-up or has died.
9
Statistical Considerations
9.1
Sample Size
This is a single-arm trial to assess the effect of brexpiprazole on patient engagement in 
MDD patients through the following co-primary endpoints: 1) change from baseline to 
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Week 8 in IDS-SR-10-engagement; 2) change from baseline to Week 8 in IDS-SR Total 
score.
Based on the results of the appropriate brexpiprazole-plus-ADT arms from four previous 
Phase 2/3 brexpiprazole MDD trials, it is reasonable to expect a mean change of -2.5 
(standard deviation = 6.5) in IDS-SR-10-engagement and a mean change of -5 (standard 
deviation = 13.5) in IDS-SR Total score from baseline to Week 8. A sample size of 
100 completers (ie, patients who have an evaluation on IDS-SR Total score and 
IDS-SR-10-engagement at Week 8) will yield 95% power to show a difference from 
baseline in IDS-SR Total score and at least 95% power to show a difference from 
baseline in IDS-SR-10-engagement at a two-sided significance level of 0.05, 
respectively. It will ensure the overall power is at least 90%. After considering an ET rate 
of 25%, a total of 134 patients need to be enrolled in this trial.
9.2
Datasets for Analysis
The following analysis samples are defined for this trial:
Enrolled Sample: comprises all patients who signed an ICF for the trial and enrolled into 
the open-label treatment phase.
Safety Sample: comprises all enrolled patients who received at least one dose of 
open-label brexpiprazole.
Efficacy Sample: the Full Analysis Set comprises all patients in the Safety Sample who 
have a baseline value and at least one post-baseline efficacy evaluation for IDS-SR Total 
score and IDS-SR-10-engagement during the open-label treatment phase.
9.3
Handling of Missing Data
IDS-SR is utilized as the primary efficacy measurement to assess core diagnostic 
depressive symptoms as well as the atypical and melancholic symptom features of MDD. 
The IDS-SR consists of 30 items, all rated on a 0 to 3 scale with 0 being the “best” rating 
and 3 being the “worse” rating. Besides item 9, two sub-items 9A and 9B exist, with 
possible scores of 1, 2 or 3 for item 9A, and 0 or 1 for item 9B. The scores for these two 
sub-items are not included in the calculation of the total score. Item 11 or item 12 should 
be completed but not both, and similarly, item 13 or item 14 should be completed but not 
both. Should items 11 and 12 be rated both, then the maximum of the two scores will be 
used. The same approach will be used for handling items 13 and 14. 
The IDS-SR Total Score is the sum of ratings of 28 item scores. The possible IDS-SR 
Total Score ranges from 0 to 84.
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The IDS-SR-10-engagement is the sum of ratings of the selected 10 item scores, 
including item 8 - Response of your mood to good or desired events, item 15 - 
Concentration/decision making, item 16 - View of myself, item 17 - View of my future, 
item 19 - General interest, item 20 - Energy level, item 21 - Capacity for pleasure or 
enjoyment (excluding sex), item 22 - Interest in sex (please rate interest, not activity), 
item 23 - Feeling slowed down, and item 29 - Interpersonal sensitivity. The possible 
IDS-SR-10-engagement ranges from 0 to 30.
The mixed model repeated measure (MMRM) method assumes data are missing at 
random (MAR), which is a reasonable assumption in longitudinal clinical trials in 
MDD.15 However, the possibility of “missing not at random” (MNAR) data can never be 
ruled out. Sensitivity analyses based on MNAR will be performed and details will be 
provided in the SAP.
The observed cases (OC) data set will consist of actual observations recorded at each 
scheduled visit during the open-label treatment phase, and no missing data will be 
imputed. MMRM and sensitivity analyses based on MNAR will be performed on the OC 
dataset. The last observation carried forward (LOCF) approach will also be used to 
impute missing data for continuous and categorical efficacy endpoints. The LOCF data 
set will include data recorded at a scheduled visit during the open-label treatment phase 
or, if no observation is recorded at that visit, data carried forward from the previous 
scheduled visit at the open-label treatment phase. Baseline data will not be carried 
forward to impute missing values for the LOCF data set.
9.4
Statistical Analyses
9.4.1
Efficacy Analyses
9.4.1.1
Primary Efficacy Endpoint Analysis
The co-primary efficacy endpoints are as follows:
1) Change from baseline to Week 8 in IDS-SR-10-engagement.
2) Change from baseline to Week 8 in IDS-SR Total score.
The primary hypothesis is that the mean changes from baseline to Week 8 in both 
co-primary endpoints will differ from 0, separately. Each of the endpoints will be tested 
by fitting a MMRM analysis with an unstructured variance covariance structure at a 
two-sided significance level of 0.05 on OC dataset on Efficacy Sample. The model will 
include fixed effect terms for visit, baseline value, an interaction term of baseline value 
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by visit, and trial center. The trial will be claimed positive if both p-values are less than 
0.05. Therefore, the overall type I error is controlled at 0.05 level.
In case there is a convergence problem with MMRM model with the unstructured 
variance covariance matrix, the following structures other than unstructured will be used 
in order of 1) heterogeneous Toeplitz, 2) heterogeneous autoregressive of order 1, and 3) 
heterogeneous compound symmetry and the first (co)variance structure converging to the 
best fit will be used as the primary analysis. If a structured covariance has to be used, the 
“sandwich” estimator of the standard error of the fixed effects parameters will be used in 
order to deal with possible model misspecification of the covariance matrix. Details will 
be provided in SAP.
One-sample Wilcoxon signed rank test will also be performed for each endpoint in case 
that the normality assumptions are violated.
9.4.1.2
Control of Experiment-wise Type I Error
Each of the co-primary endpoints will be tested by fitting a MMRM analysis at a 
two-sided significance level of 0.05 on OC dataset on Efficacy Sample, and the trial will 
be claimed positive if both p-values are less than 0.05. Therefore, the overall type I error 
is controlled at 0.05 level.
9.4.1.3
Other Efficacy Endpoint Analysis
The other efficacy endpoints are as follows. All of them will be evaluated at a nominal 
0.05 level (2-sided) without adjusting for multiplicity on Efficacy Sample:
1) Change from baseline to Weeks 2 and 4 in IDS-SR-10-engagement.
2) Change from baseline to Weeks 2 and 4 in IDS-SR Total score.
3) Change from baseline to Weeks 2, 4, and 8 in IDS-SR patient-selected 
engagement items.
4) Change from baseline to Weeks 2, 4, and 8 in IDS-SR engagement items selected 
by both clinicians and patients.
5) Change from baseline to Weeks 2, 4, and 8 in CGI-S score.
6) CGI-I score at Weeks 2, 4, and 8.
7) Change from baseline to Weeks 4 and 8 in SDS Mean score and SDS individual 
item scores.
8) Change from baseline to Weeks 4 and 8 in WHODAS 2.0 short form score.
9) Change from baseline to Weeks 2, 4, and 8 in PHQ-9 score.
10) Change from baseline to Weeks 2, 4, and 8 in GAD-7 score.
11) Change from baseline to each timepoint (ie, being measured weekly at home) in 
depression as measured by PGI-I score.
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mean, median, standard deviation (SD), maximum, minimum, and percentage when 
applicable).
9.4.3
Safety Analysis
Safety analysis will be performed on the Safety Sample. Safety variables of interest 
mainly include AEs, body weight, BMI, and vital signs.
9.4.3.1
Adverse Events
All AEs will be coded by system organ class and Medical Dictionary for Regulatory 
Activities preferred term. The incidence of the following events will be summarized by 
descriptive statistics:

TEAEs

TEAEs by severity

TEAEs potentially causally related to the trial drug

TEAEs with an outcome of death

Serious TEAEs

TEAEs leading to discontinuation of the trial drug 
Adverse event data will also be presented in listings.
9.4.3.2
Physical Examination and Vital Signs Data
Physical examination data will be presented in a listing.
Descriptive statistics will be used to summarize body weight and BMI at screening, 
baseline, and Weeks 2, 4, and 8/ET. The incidence of potentially clinically significant 
changes in body weight will be tabulated in incidence tables.
Descriptive statistics for changes from baseline in vital signs will also be provided. 
Potentially clinically significant results in vital signs will be summarized.
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10
Supporting Documentation and Operational Considerations
10.1
Appendix 1: Regulatory, Ethical, and Trial Oversight 
Considerations
10.1.1
Ethics and Responsibility
This trial must be conducted in compliance with the protocol, applicable ICH GCP 
guidance, international ethical principles derived from the Declaration of Helsinki and 
Council for International Organizations of Medical Science (CIOMS) guidelines, and 
applicable local laws and regulations. Each trial site will seek approval/favorable opinion 
by an IRB or IEC according to regional requirements, and the investigator will provide 
that documentation to the sponsor. The IRB/IEC will evaluate the ethical, scientific, and 
medical appropriateness of the trial. Further, in preparing and handling the CRF, IRE and 
any safety information, the investigator, subinvestigator, and their staff will take 
measures to ensure adequate care in protecting patient privacy. To this end, a patient ID 
will be used to identify each patient.
Financial aspects, patient insurance, and the publication policy for the trial will be 
documented in the agreement between the sponsor and the investigator.
10.1.2
Informed Consent
Informed consent will be freely obtained from all patients (or legally acceptable 
representative, as applicable for local laws). The ICF will be approved by the same 
IRB/IEC that approves this protocol.
Each ICF will comply with the International Council for Harmonisation (ICH) GCP 
Guidelines, and local regulatory requirements. The investigator will ensure that the 
sponsor reviews and authorizes any site-specific ICF used in the trial before submission 
to the IRB/IEC. Trial sites will have patients review and sign the ICF prior to starting any 
trial procedures.
Investigators may discuss trial availability and the possibility for entry with a potential 
patient 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 patients 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.
Prospective trial patients will be provided with study protocol information by the trial site 
staff. When the trial site staff and the patient agree that the patient has enough 
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information to make an informed decision to participate, the patient will sign the ICF. 
The patient will be given a printed, signed copy of the ICF. Any other parties required by 
the IRB/IEC (trial site staff, witnesses, or legally authorized representative) are also 
required to sign the ICF in accordance with the ICH GCP Guideline and local regulatory 
requirements/guidelines. These signatures cannot be altered, removed, or copied.
Once appropriate essential information has been provided and fully explained in 
layman’s language to the patient by the investigator (or a qualified designee), and it has 
been documented that the patient has had the opportunity to ask questions, the 
IRB/IEC-approved ICF will be signed and dated by both the patient and the person 
obtaining consent (investigator or designee), as well as by any other parties required by 
the IRB/IEC. The patient will receive a copy of the signed ICF; the original shall be kept 
on file by the investigator.
Patients may be asked to sign additional ICFs if the protocol is amended and the changes 
to the protocol result in additional information that needs to be provided to the patients, 
so that they can make a knowledgeable and voluntary decision on continued trial 
participation. Female partners of male patients who become pregnant during the course of 
the trial may be asked to sign additional ICFs in order to collect additional information 
regarding the nonpatient partner and fetus.
10.1.3
Confidentiality
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission. Patient confidentiality requirements of Canada 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 and/or other materials collected shall be 
used solely in accordance with this protocol, unless otherwise agreed to in writing by the 
sponsor.
Patients will be identified only by unique patient ID in the CRF. If further patient 
identification is required, patients’ full names may be made known to a regulatory agency 
or other authorized officials if necessary, patient to local regulations.
10.1.4
Quality Control and Quality Assurance
10.1.4.1
Monitoring
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, the applicable ICH GCP guidance, and applicable 
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regulatory requirements and local laws. As part of a concerted effort to fulfill these 
obligations (maintain current personal knowledge of the progress of the trial), the 
sponsor’s monitors will visit the site during the trial, as well as communicate frequently 
via telephone, e-mail, and written communications. In addition, all investigators and trial 
site personnel will undergo initial and ongoing training for this particular trial, and this 
training will be clearly documented.
10.1.4.2
Auditing
The sponsor’s Quality Assurance Unit (or representative) may conduct trial site audits. 
Audits will include, but are not limited to, trial drug supply, presence of required 
documents, the informed consent process, site operations, delegation of authority and 
training, and a review of the CRF with source documents, as applicable. The investigator 
will agree to cooperate and participate with audits.
Regulatory authorities may inspect the investigator site during or after the trial. The 
investigator will cooperate with such inspections and will contact the sponsor 
immediately if such an inspection occurs.
10.1.5
Protocol Deviations
In the event of a significant deviation from the protocol due to an emergency, accident, or 
mistake (eg, violation of informed consent process, patient dosing error, patient enrolled 
in violation of eligibility criteria or concomitant medication criteria), the investigator or 
designee will contact the sponsor or designee at the earliest possible time by telephone or 
via e-mail. The investigator and sponsor (or designee) will come as quickly as possible to 
a joint decision regarding the patient’s continuation in the trial. This decision will be 
documented by the investigator and the sponsor (or designee) and reviewed by the site 
monitor.
Any major protocol deviation will be recorded in the CRF along with the start date and 
details of the deviation.
10.1.6
Records Management
10.1.6.1
Source Documents
Source documents are defined as the results of original observations and activities of a 
clinical investigation. Source documents will include but are not limited to medical 
records, electronic data, logs, and recorded data from automated instruments or 
applications. All source documents pertaining to this trial will be maintained by the 
investigators and made available for direct inspection by authorized persons.
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Investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, 
and regulatory inspection(s) by providing direct access to source data/documents by 
authorized persons as defined in the ICF. In all cases, patient confidentiality must be 
maintained in accordance with local regulatory requirements.
10.1.6.2
Data Collection
Source data will be captured electronically in this trial, and will meet the same 
fundamental elements of data quality (eg, attributable, legible, contemporaneous, 
original, and accurate). This data will be collected into a system that is fully validated. 
Changes to the data will be captured by an automatic audit trail.
Designated trial site staff will not be given access to the system until they have been 
appropriately trained. Information to be originally captured and reviewed electronically 
shall include details of the patient visit and the protocol-required assessments performed 
as a part of these visits, medical history, AEs, and concomitant medications.
Source data will be source data verified by the trial clinical research associate, and the 
location of the source data (ie, paper, or a local electronic system) will be documented 
before the trial start. Any changes to information in paper 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, 
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 clinician.
Remote monitoring and on-site monitoring will take place in order to review data entry 
source documentation directly captured on paper and transcribed into the system, to 
ensure protocol adherence, to assess site operational capabilities and to perform other 
monitoring activities that cannot be performed remotely.
At the end of the trial, the investigator must certify that the data entered into the source 
system are complete and accurate. After database lock, the investigator will receive an 
electronic copy of the patient data. Additional details for data collection will be provided 
in the Operations Manual.
10.1.6.3
File Management at the Trial Site
The investigator will ensure that the trial site file is maintained in accordance with 
applicable ICH GCP guidance and as required by applicable local regulations. The 
investigator/institution will take measures to prevent accidental or premature destruction 
of these documents.
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10.1.6.4
Records Retention at the Trial Site
Regulatory requirements for the archival of records for this trial necessitate that 
participating investigators maintain detailed clinical data for the longest of the following 
3 periods:

A period of at least 2 years after the date on which approval to market the drug is 
obtained (or if trial drug development is discontinued, the date regulatory authorities 
were notified of discontinuation); OR

A period of at least 3 years after the sponsor notifies the investigator that the final 
report has been filed with regulatory authorities.

Longer, region-specific storage requirements, if applicable.
The investigator must not dispose of any records relevant to this trial without either 
(1) written permission from the sponsor or (2) provision of an opportunity for the sponsor 
to collect such records. The investigator will be responsible to maintain adequate and 
accurate electronic or hard copy source documents of all observations and data generated 
during this trial including any data clarification forms received from the sponsor. Such 
documentation is patient to inspection by the sponsor and relevant regulatory authorities. 
If the investigator withdraws from the trial (eg, due to relocation or retirement), all 
trial-related records should be transferred to a mutually agreed-upon designee within a 
sponsor-specified timeframe. Notice of such transfer will be given to the sponsor in 
writing.
10.1.6.5
Publication Authorship Requirements
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 
criteria (http://www.icmje.org/recommendations). According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met:
1) Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors.
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Investigators or other trial patients 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 patients consent to such acknowledgement in any 
publications resulting from its conduct.
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10.2
Appendix 2: Contraceptive Guidance and Collection of Pregnancy 
Information
Females of childbearing potential are females whose menstruation has started and who 
are not documented as sterile (eg, have had a bilateral oophorectomy, or hysterectomy, or 
who have been postmenopausal for at least 12 months). Females of nonchildbearing 
potential do not meet definition of FOCBP.
For males and FOCBP, or their partners, who are sexually active, there must be a 
documented agreement that the patient and their partner will take effective measures 
(ie, 2 different approved methods of birth control or remains abstinent) to prevent 
pregnancy during the course of the trial and for 30 days after the last dose of trial drug. 
Unless the patient is sterile (ie, females who have had a bilateral oophorectomy, have had 
a hysterectomy, or have been postmenopausal for at least 12 consecutive months; or 
males who have had a bilateral orchiectomy) or remains abstinent during the trial and for 
30 days after the last dose of trial drug, 2 of the following approved methods of birth 
control must be used: vasectomy, tubal ligation, intrauterine device, birth control pill, 
birth control implant, birth control depot injection, birth control patch, condom with 
spermicide, sponge with spermicide, or occlusive cap (vaginal diaphragm or 
cervical/vault cap) with spermicide. Any single method of birth control, including 
vasectomy and tubal ligation, may fail, leading to pregnancy. The contraceptive method 
will be documented in the CRF or source document. Male patients must also agree not to 
donate sperm from trial screening through 30 days after the last dose of trial drug.
Before enrolling males and females in this clinical trial, investigators must review the 
below information about trial participation as part of the ICF process. The topics should 
generally include:

General information

ICF

Pregnancy prevention information

Drug interactions with hormonal contraceptives

Contraceptives in current use

Follow-up of a reported pregnancy
Before trial enrollment, males and FOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy. Patients must sign the ICF confirming that the above-mentioned risk factors 
and the consequences were discussed.
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A urine pregnancy test for human chorionic gonadotropin will be performed at screening 
and baseline on all FOCBP.
During the trial, all FOCBP should be instructed to contact the investigator immediately 
if they suspect they might be pregnant (eg, missed or late menstrual cycle). Male patients 
must be instructed to contact the investigator immediately, during the trial, if their partner 
suspects that they might be pregnant (eg, missed or late menstrual cycle).
If a patient is suspected to be pregnant before she receives trial drug, the trial drug 
administration must be withheld. If the pregnancy is confirmed, the patient must not 
receive the trial drug and must not be enrolled in the trial. If pregnancy is suspected while 
the patient is taking trial drug, the trial drug must be withheld immediately (if reasonable, 
taking into consideration any potential withdrawal risks) until the result of the pregnancy 
test is known. If pregnancy is confirmed, the trial drug will be permanently discontinued 
in an appropriate manner (eg, dose tapering if necessary for patient safety) and the patient 
will be withdrawn from the trial. Exceptions to trial discontinuation may be considered 
for life-threatening conditions only after consultations with the IRE contact (see the title 
page of this protocol for contact information).
The investigator must immediately notify the sponsor (within 24 hours) of any pregnancy 
associated with trial drug exposure during the trial and for at least 30 days after the last 
dose of trial drug, and record the event on the IRE form and forward it to the sponsor. 
The sponsor will forward the Pregnancy Surveillance Form(s) to the investigator for 
monitoring the outcome of the pregnancy.
Protocol required procedures for trial discontinuation and follow-up must be performed 
on the patient unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated. In addition, the 
investigator must report to the sponsor, on the Pregnancy Surveillance Form(s), follow-
up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome. Infants will be followed for a minimum of 6 months from the date of birth.
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10.3
Appendix 3: Criteria for Identifying Vital Signs of Potential Clinical 
Relevance
Variable
Criterion Valuea
Change Relative to 
Baselinea
Heart rateb
> 100 bpm
< 50 bpm
 10 bpm increase
 10 bpm decrease
Systolic blood pressureb
≥ 140 mmHg
< 90 mmHg
 20 mmHg increase
 20 mmHg decrease
Diastolic blood pressureb
≥ 90 mmHg
< 60 mmHg
 10 mmHg increase
 10 mmHg decrease
Weight
−
 7% increase
 7% decrease
bpm = beats per minute; mmHg = millimeter of mercury.
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the patient’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column.
bAs defined in “Supplementary Suggestions for Preparing an Integrated Summary of Safety Information in 
an Original New Drug Application Submission and for Organizing Information in Periodic Safety 
Updates,” Food and Drug Administration Division of Neuropharmacological Drug Products draft (2/27/87).
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10.4
Appendix 4: Protocol Amendments
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/IEC. Any 
permanent change to the protocol, whether an overall change or a change for specific trial 
site(s), must be handled as a protocol amendment. Any amendment will be written by the 
sponsor. Each amendment will be submitted to the IRB/IEC, as required by local 
regulations. Except for “administrative” or “nonsubstantial” amendments, investigators 
will wait for IRB/IEC approval/favorable opinion of the amended protocol before 
implementing the change(s). Administrative amendments are defined as having no effect 
on the safety of patients, conduct or management of the trial, trial design, or the quality or 
safety of trial drug(s) used in the trial. A protocol change intended to eliminate an 
apparent immediate hazard to patients should be implemented immediately after 
agreement by the sponsor and investigator, followed by IRB/IEC notification within local 
applicable timelines. The sponsor will submit protocol amendments to the applicable 
regulatory agencies within local applicable timelines.
When the IRB/IEC, investigators, and/or the sponsor conclude that the protocol 
amendment substantially alters the trial design and/or increases the potential risk to the 
patient, the currently approved ICF will require similar modification. In such cases, after 
approval/favorable opinion of the new ICF by the IRB/IEC, repeat informed consent will 
be obtained from patients enrolled in the trial before expecting continued participation 
and before the amendment-specified changes in the trial are implemented.
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10.5
Appendix 5: Trial Continuity Plan
10.5.1
Trial Continuity Plan Appendix
All procedures and assessments in the main body of the protocol are to be followed to the 
fullest extent possible. In the event that the ability to conduct the trial (ie, perform 
specified procedures and assessments) is impacted by extenuating circumstances (eg, 
pandemic, natural disaster, national or international conflict), the sponsor, in coordination 
with the site, investigator(s), and medical monitor, may implement the trial continuity 
measures provided in this appendix.
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10.5.1.2
Schedule of Assessments - Trial Continuity
Table 10.5.1.2-1
Schedule of Assessments - Trial Continuity
Visit
Baselinea 
(Day -1)
Week 2
Week 4
Week 8
/ETb
Assessment
Screeninga
(Days -14 to -2)
(in-person visit)
virtual visits (± 5 days)
ENTRANCE/HISTORY
Informed consent
X
Inclusion/exclusion criteria
X
X
Demography
X
Medical history
X
Psychiatric history
X
Prohibited medication washoutc
X
Urine pregnancy test
X
X
EFFICACYd
IDS-SR (patient reported)
X
X
X
X
PHQ-9 (patient reported)e
X
X
X
X
X
GAD-7 (patient reported)
X
X
X
X
WHODAS 2.0 short (patient reported)
X
X
X
SDS (patient reported)
X
X
X
CGI-S
X
X
X
X
CGI-I
X
X
X
SAFETY
Brief physical examinationf
X
X
Height and body weightg
X
X
X
X
X
Vital signsh
X
X
X
X
Adverse events
X
X
X
X
X
Concomitant medicationsi
X
X
X
X
X
Clinical evaluation for suicidalitye
X
X
X
X
X
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Table 10.5.1.2-1
Schedule of Assessments - Trial Continuity
Visit
Baselinea 
(Day -1)
Week 2
Week 4
Week 8
/ETb
Assessment
Screeninga
(Days -14 to -2)
(in-person visit)
virtual visits (± 5 days)
OTHER
Trial drug prescribedj
X
X
X
Trial drug accountability (patient reported)
X
X
X
Review of Patient Diary (word of the day, 
PGI-S, and PGI-I)k
X
X
X
X
ADT = antidepressant therapy; CGI-I = Clinical Global Impression - Improvement; CGI-S = Clinical Global Impression - Severity; ET = early termination; 
GAD-7 = Generalized Anxiety Disorder 7-item scale; ICF = informed consent form; IDS-SR = Inventory of Depressive Symptomatology Self-Report; 
PGI-I = Patient Global Impression – Improvement; PGI-S = Patient Global Impression – Severity; PHQ-9 = Patient Health Questionnaire 9-item scale; 
SDS = Sheehan Disability Scale; WHODAS = World Health Organization Disability Assessment Schedule.
aBrexpiprazole dosing will take place on Day 1 of Week 1. The screening visit can comprise 1 or more visits as needed. Screening and baseline visits can 
occur the same day if the patient meets all required enrollment criteria. Where screening and baseline visits occur on the same day, assessments will not be 
duplicated. The Screening Visit will be an in-person visit at the clinic. All other visits will be virtual.
bIf a patient discontinues prematurely before Week 8, every effort should be made to complete the “Week 8/ET” evaluations.
cWashout of prohibited medications begins after signing the ICF and must comply with the required washout periods.
dWhere possible, sites should follow the order of efficacy assessments and patient reported outcomes as listed.
eIf the PHQ-9 indicates suicidal ideation (eg, a patient has suicidality on item 9 of the PHQ-9 scale [≥ 1]), then clinical evaluation of suicidality is essential on 
that particular visit and the investigator will conduct a more in-depth clinical assessment of the patient per the site’s standard protocol.
fThe extent of the physical examination will be at the discretion of the investigator.
gHeight and body weight at screening and body weight at baseline and at Weeks 2, 4, and 8/ET. When screening and baseline visits occur on the same day, 
assessments will not be duplicated.
hVital signs include systolic and diastolic blood pressure and heart rate.
iAll medications taken within 30 days of informed consent will be recorded. In addition, all prescription and non-prescription medications taken during the 
trial will be recorded as concomitant medications. All ADTs taken within 12 months of informed consent will be recorded.
jTrial drug will not be prescribed at the Week 8 visit. The ADT regimen will be left to the discretion of the investigator.
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kPatient diary entries will be reduced in frequency from daily to twice weekly from Week 5 to Week 8 (word of the day and PGI-S). The PGI-I will be 
administered weekly throughout the trial.
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10.5.2
General Considerations
10.5.2.1
Telemedicine
Sites should collect information from subjects via phone or video in a standardized 
approach to minimize confusion and risk of errors that could occur from utilizing varying 
collection strategies. All applicable guidances and local regulations will be followed 
when implementing telemedicine options.
10.5.2.2
Reconsent
If there is an immediate need to reconsent subjects to maintain trial continuity, a paper 
reconsent process may be followed and sites are encouraged to contact the CRO and 
sponsor with questions. In regions where remote capacity exists to collect remote 
consent, information will be provided by the CRO and sponsor.
10.5.2.3
Protocol Deviations
Deviations from this Trial Continuity Plan, once implemented, must be recorded by the 
site in the source system separately from other protocol deviations as soon as they are 
identified and will be recorded as “Other” in the source system for data capture purposes. 
Sites will be instructed to indicate “Trial Continuity:” at the start of the description field 
for the “Other” protocol deviation. Examples of the types of trial continuity-related 
deviations to be reported include: missed visits, missed assessments, assessments 
performed remotely (completed outside of protocol procedure), missed IMP dose, IMP 
dispensed/returned via courier, IMP not returned to site/site unable to verify medication 
compliance, out of window visits, changes in rater, and prohibited concomitant 
medication. All other deviations will follow the normal deviation process described in the 
protocol and should not be entered proactively by sites.
10.5.2.4
Guidance to Record Adverse Events and Discontinuations Due 
to Extenuating Circumstances
If a subject experiences an AE as a direct result of the extenuating circumstances, the 
reason will be recorded in the source system. Subjects who experience an AE as a direct 
result of the extenuating circumstances must be reviewed with the medical monitor and 
approval must be received for the subject to continue in the trial with remote visits. 
Experiencing such an AE is not automatically an SAE, unless an SAE criterion is met 
(eg, hospitalization). If the event meets the criterion for an SAE, then the subject will be 
discontinued from the trial.
Upon implementation of this appendix, the criteria that require consideration for the 
appropriateness of subject continuation in the trial will be determined by the sponsor in 
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coordination with the sites, investigator(s), and medical monitor. The medical monitor 
will be consulted for consideration of individual subjects that meet those criteria.
10.5.2.4.1
Novel Coronavirus 19 (COVID-19)
An AE of “Coronavirus Infection” OR “Coronavirus Positive Test Result” must be 
recorded on the AE page in the source system if a subject tests positive OR is presumed 
positive with COVID-19. The subject may continue in the trial with remote visits only as 
long as they remain asymptomatic for COVID-19. Subjects who are symptomatic for 
COVID-19 must be reviewed with the medical monitor and approval must be received 
for the subject to continue in the trial with remote visits. A positive test result or a 
presumed positive subject is not automatically an SAE, unless an SAE criterion is met 
(eg, hospitalization). If the event meets the criterion for an SAE, then the subject will be 
discontinued from the trial.
10.5.2.5
Statistical Analyses
Any impact of changes made to maintain trial continuity on the planned statistical 
analyses for the trial will be described in the final SAP.
10.5.2.6
Clinical Outcomes
To decrease variability, sites should attempt to standardize the method of administering a 
scale to an individual subject and across all subjects in the trial. Assessments should be 
administered by the same qualified/trained rater who previously rated the subject; if this 
is not possible due to staff availability and/or technological limitations, discuss relevant 
information with previous raters to obtain clinical context (note that per protocol raters 
must be trained/qualified to conduct assessments in all cases). Raters should conduct all 
assessments for that visit during the same remote session, where possible.
Please refer to guidance provided to clinical sites regarding the administration methods 
for remote visits.
10.5.3
Trial Procedures
10.5.3.1
Safety Assessments
10.5.3.1.1
Vital Signs
Blood pressure, heart rate, and weight will all be measured as described in the protocol at 
the time points defined in this Schedule of Assessments - Trial Continuity 
(Table 10.5.1.2-1) with the following changes, if remote visits are necessary:

Subjects will be asked to use their own collection device, if available, until devices 
can be provided to subjects;
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
Site staff will remotely supervise the collection of measurements via video or 
guide by telephone, if video is not possible.

All remote measurements should be performed at a consistent time of day.

Site staff will be instructed to record the measurement in the source system, and if 
there are believed to be any errors, inconsistencies, or safety concerns with the 
home measurement, the medical monitor should be notified.

Site staff will instruct the subjects to follow the procedures in the protocol for blood 
pressure and heart rate collection.
10.5.3.1.2
Pregnancy
Pregnancy tests will be performed as described in the protocol at the time points defined 
in this Schedule of Assessments - Trial Continuity (Table 10.5.1.2-1) with the following 
changes: 

For the baseline visit that requires a pregnancy test for FOCBP, the site will provide 
the necessary tests and instructions so the test may be performed at home;

Applicable subjects will perform a pregnancy test prior to dosing with IMP, ensuring 
a date and time-stamped picture or video of the result is taken, followed by 
notification to the site staff of the results via telephone, or other means, on the 
appropriate visits. Subjects will also provide the site staff with the date- and time 
stamped picture/video.

If negative, site to inform subject to proceed with dosing.

If positive, the site must instruct the subject to immediately stop taking IMP, and 
the site will refer to the Pregnancy section of the protocol for appropriate IRE 
reporting.

Further instruction must be agreed upon in consultation with the sponsor.
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11
References
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15 Siddiqui O, Hung JH, O'Neill R. MMRM vs. LOCF:  A comprehensive comparison 
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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) or receive a favorable opinion 
by the Independent Ethics Committee (IEC) 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/IEC-approved protocol will be submitted to the appropriate regulatory 
authority/ies by the sponsor. I agree that clinical data entered on CRF by me and my staff will be 
utilized by the sponsor in various ways, such as for submission to governmental regulatory authorities 
and/or in combination with clinical data gathered from other research sites, whenever applicable. I 
agree to allow sponsor and designee monitors and auditors full access to all medical records at the 
research facility for patients screened or enrolled in the trial.
I agree to await IRB/IEC approval before implementation of any substantial amendments to this 
protocol. If, however, there is an immediate hazard to patients, I will implement the amendment 
immediately, and provide the information to the IRB/IEC within the required local applicable 
timelines. Administrative changes to the protocol will be transmitted to the IRB/IEC for informational 
purposes only, if required by local regulations.
I agree to provide all patients with informed consent forms, as required by the applicable regulations 
and by ICH guidelines. I agree to report to the sponsor any adverse experiences in accordance with the 
terms of the sponsor’s Clinical Trial Agreement and the relevant regional regulation(s) and 
guideline(s). I further agree to provide all required information regarding financial certification or 
disclosure to the sponsor for all investigators and subinvestigators in accordance with the terms of the 
relevant regional regulation(s). I understand that participation in the protocol involves a commitment 
to publish the data from this trial in a cooperative publication before publication of efficacy and safety 
results on an individual basis may occur, and I consent to be acknowledged in any such cooperative 
publications that result.
____________________________
_____________________________
___________
Principal Investigator Print Name
Signature
Date
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SIGNATURE PAGE
Document Name: 331-201-00289 Protocol Amendment 1
Document Number: 
Document Version: 4.0
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:min) -
UTC timezone
Clinical Approval
19-Mar-2021
13:59:19
Biostatistics Approval
18-Mar-2021
21:34:08
Clinical Approval
18-Mar-2021
20:40:42
Clinical Study Report 331-201-00289
16.1.1 Protocol and Protocol Amendments
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SAP 331-201-00289 
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Otsuka Pharmaceutical Development & Commercialization, Inc. 
 
 
Investigational New Drug  
REXULTI® (brexpiprazole, OPC-34712, OPC-331, Lu AF41156) 
 
Protocol No. 331-201-00289 
 
A Phase 4, Multicenter, Open-label, Interventional Trial to Assess the Effects on Engagement 
of Flexible-dose Brexpiprazole (OPC-34712) as Adjunctive Therapy for the Treatment of 
Adults With Major Depressive Disorder 
A Phase 4, Canadian Interventional Trial to Assess Brexpiprazole (OPC-34712) as Adjunctive 
Therapy in Adults With Major Depressive Disorder 
 
 
Statistical Analysis Plan 
 
Phase 4 
Version: 3.0 
Date: 6/29/2022 
 
 
 
Protocol Amendment 1:  Mar 18, 2021 
 
 
 
 
 
 
 
 
 
 
 
Confidential 
May not be used, divulged, published, or otherwise disclosed without the prior written 
consent of Otsuka Pharmaceutical Development & Commercialization, Inc. 
 
Clinical Study Report 331-201-00289
16.1.9 Documentation of Statistical Methods
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Table of Contents 
Table of Contents ................................................................................................. 2 
List of In-text Tables ............................................................................................ 4 
List of In-text Figures .......................................................................................... 4 
List of Appendices ................................................................................................ 4 
1 
Introduction ................................................................................................. 5 
2 
Trial Objectives ........................................................................................... 5 
3 
Trial Design ................................................................................................. 5 
3.1 
Type/Design of Trial ................................................................................................. 5 
3.2 
Trial Treatments ........................................................................................................ 8 
3.3 
Trial Population ......................................................................................................... 8 
4 
Sample Size .................................................................................................. 9 
5 
Statistical Analysis Datasets .....................................................................10 
5.1 
Datasets for Analysis ............................................................................................... 10 
5.2 
Handling of Missing Data........................................................................................ 10 
5.3 
Definition of Baseline and Last Visit ...................................................................... 11 
6 
Outcome Variables ...................................................................................11 
6.1 
Efficacy Variables ................................................................................................... 11 
6.2 
Safety Variables ....................................................................................................... 12 
7 
Disposition and Demographic Analysis ..................................................12 
7.1 
Subject Disposition .................................................................................................. 12 
7.2 
Demographic and Baseline Characteristics ............................................................. 12 
7.3 
Medical and Psychiatric History ............................................................................. 12 
7.4 
Treatment Compliance ............................................................................................ 12 
7.5 
Concomitant Medications ........................................................................................ 13 
7.6 
Protocol Deviations ................................................................................................. 13 
8 
Efficacy Analysis .......................................................................................13 
8.1 
Primary Efficacy Endpoint ...................................................................................... 13 
8.1.1 
Technical Computation Details for Primary Efficacy Analysis ........................... 13 
8.2 
Other Efficacy Endpoint Analysis ........................................................................... 14 
Clinical Study Report 331-201-00289
16.1.9 Documentation of Statistical Methods
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8.4 
Sensitivity analysis .................................................................................................. 16 
9 
Safety Analyses ..........................................................................................16 
9.1 
Extent of Exposure .................................................................................................. 16 
9.2 
Adverse Events ........................................................................................................ 17 
9.3 
Clinical Laboratory Data ......................................................................................... 17 
9.4 
Vital Sign Data ........................................................................................................ 17 
9.5 
Physical Examination Data ...................................................................................... 18 
10 
Changes in the Planned Analyses ............................................................18 
11 
Conventions ...............................................................................................18 
11.1 
Trial Visit Windows ................................................................................................ 18 
11.2 
Scales: Rules for Scoring and Handling of Missing Data ....................................... 19 
11.2.1 
Inventory of Depressive Symptomatology Self-Report (IDS-SR) ....................... 19 
11.2.2 
IDS-SR-10-Engagement ....................................................................................... 20 
11.2.3 
IDS-SR Patient-Selected Engagement Items ........................................................ 20 
11.2.4 
Patient Health Questionnaire-9 (PHQ-9) .............................................................. 21 
11.2.5 
Generalized Anxiety Disorder-7 (GAD-7) ........................................................... 21 
11.2.6 
World Health Organization Disability Assessment Schedule 2.0 (WHODAS 
2.0) Short Form Questionnaire ............................................................................. 21 
11.2.7 
Sheehan Disability Scale (SDS)............................................................................ 22 
11.2.8 
Clinical Global Impression - Severity of Illness Scale (CGI-S) ........................... 22 
11.2.9 
Clinical Global Impression - Improvement (CGI-I) ............................................. 22 
11.2.10 
Word of the Day.................................................................................................... 23 
11.2.11 
Patient Global Impression - Severity (PGI-S) ...................................................... 23 
11.2.12 
Patient Global Impression - Improvement (PGI-I) ............................................... 23 
12 
Reference ...................................................................................................24 
13 
Appendix ....................................................................................................25 
Appendix 1  
Criteria for Potentially Clinically Relevant Vital Sign   Abnormalities ........ 25 
  
 
14 
History of SAP Amendment ....................................................................29 
Clinical Study Report 331-201-00289
16.1.9 Documentation of Statistical Methods
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List of In-text Tables 
Table 3.2-1                 Brexpiprazole Dosing Schedule ............................................................. 8 
Table 11.1-1 Study Day and Visit Windows for Efficacy Scales (IDS-SR, PHQ-9, 
GAD-7, WHODAS2.0, SDS, CGI-S, and CGI-I) ................................ 18 
Table 11.1-2 Study Day and Visit Windows for Patient Diary Entries (PGI-I, PGI-S and 
‘Word of the Day’) ............................................................................... 19 
Table 11.2.2-1 Weights for Calculating the weighted IDS-SR-10 Engagement ..................... 20 
List of In-text Figures 
Figure 3.1-1 
Trial Design Schematic .......................................................................... 7 
List of Appendices 
Appendix 1  
Criteria for Potentially Clinically Relevant Vital Sign   
Abnormalities ....................................................................................... 25 
Appendix 2  
Proposed List of Summary Tables ....................................................... 25 
Clinical Study Report 331-201-00289
16.1.9 Documentation of Statistical Methods
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screening and baseline visits can occur on the same day if the patient meets all required 
enrollment criteria. During the open-label treatment phase, all patients will receive 
brexpiprazole (that is, adjunctive brexpiprazole as a flexible dose; 0.5 to 2 mg/day) and will 
continue on the stable dose of ADT that they were taking at screening. Patients will attend 
visits at Weeks 2, 4, and 8 during the open-label treatment phase. If any patient discontinues 
the trial early, every effort should be made to complete the Week 8/early termination (ET) 
evaluations. 
A schematic of the trial design is presented in Figure 3.1-1.
Clinical Study Report 331-201-00289
16.1.9 Documentation of Statistical Methods
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Protocol 331-201-00289 
 
Statistical Analysis Plan  
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Statistical Manual of Mental Disorders, 5th Edition (DSM-5) diagnosis of a single or 
recurrent, non-psychotic episode of MDD with or without symptoms of anxiety. 
Additionally, patients must have a treatment history for the current major depressive 
episode (MDE) of an inadequate response (assessment of inadequate response is per 
investigator judgment) to at least 1 and no more than 2 adequate antidepressant 
treatments (including the antidepressant that the patient is taking at screening). 
Patients with a historical diagnosis of any concurrent condition that is exclusionary may 
be permitted if the investigator determines and documents this prior diagnosis was not 
appropriate based on current and historical presentation. 
Patients with ADHD, obsessive compulsive disorder (OCD), panic disorders, or 
generalized anxiety disorder can be included under the following conditions: 
• These disorders are not the primary focus of treatment at the screening visit 
• Changes in any treatment for these disorders (permitted medication and/or 
psychotherapy) would not likely be required for the duration of the trial 
• All other concurrent psychiatric or neurological diagnoses must be discussed with the 
medical monitor. 
•  
4 
Sample Size  
This is a single-arm trial to assess the effect of brexpiprazole on patient engagement in 
MDD patients through the following co-primary endpoints: 1) change from baseline to 
Week 8 in IDS-SR-10-engagement; 2) change from baseline to Week 8 in IDS-SR Total 
score. 
Based on the results of the appropriate brexpiprazole-plus-ADT arms from four previous 
Phase 2/3 brexpiprazole MDD trials, it is reasonable to expect a mean change of -2.5 
(standard deviation = 6.5) in IDS-SR-10-engagement and a mean change of -5 (standard 
deviation = 13.5) in IDS-SR Total score from baseline to Week 8. A sample size of 
100 completers (ie, patients who have an evaluation on IDS-SR Total score and 
IDS-SR-10-engagement at Week 8) will yield 95% power to show a difference from 
baseline in IDS-SR Total score and at least 95% power to show a difference from 
baseline in IDS-SR-10-engagement at a two-sided significance level of 0.05, 
respectively. It will ensure the overall power is at least 90%. After considering an ET rate 
of 25%, a total of 134 patients needs to be enrolled in this trial. 
It is anticipated that approximately 210 patients will be screened in order to enroll 134 
subjects from approximately 15 sites (to complete 100 patients). 
Clinical Study Report 331-201-00289
16.1.9 Documentation of Statistical Methods
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Protocol 331-201-00289 
 
 
Statistical Analysis Plan  
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5 
Statistical Analysis Datasets 
5.1 
Datasets for Analysis 
The following analysis samples are defined for this trial: 
Enrolled Sample: comprises all patients who signed an ICF for the trial and enrolled into 
the open-label treatment phase. 
Safety Sample: comprises all enrolled patients who received at least one dose of 
open-label brexpiprazole. 
Efficacy Sample: the Full Analysis Set comprises all patients in the Safety Sample who 
have a baseline value and at least one post-baseline efficacy evaluation for IDS-SR Total 
score and IDS-SR-10-engagement during the open-label treatment phase. 
Per-Protocol Sample: Comprises all patients in the Efficacy Sample which excludes 
major protocol deviation subjects. 
 
5.2 
Handling of Missing Data 
IDS-SR is utilized as the primary efficacy measurement to assess core diagnostic 
depressive symptoms as well as the atypical and melancholic symptom features of MDD. 
The IDS-SR consists of 30 items, all rated on a 0 to 3 scale with 0 being the “best” rating 
and 3 being the “worse” rating. Besides item 9, two sub-items 9A and 9B exist, with 
possible scores of 1, 2 or 3 for item 9A, and 0 or 1 for item 9B. The scores for these two 
sub-items are not included in the calculation of the total score. Item 11 or item 12 should 
be completed but not both, and similarly, item 13 or item 14 should be completed but not 
both. Should items 11 and 12 be rated both, then the maximum of the two scores will be 
used. The same approach will be used for handling items 13 and 14.  
The IDS-SR Total Score is the sum of ratings of 28 item scores. The possible IDS-SR 
Total Score ranges from 0 to 84. The IDS-SR Total Score will be un-evaluable if less 
than 23 of the 28 items are recorded. If the number of items recorded is at least 23 and at 
most 27, the IDS-SR Total Score will be the mean of the recorded items multiplied by 28 
and then rounded to the first decimal place. 
The IDS-SR-10-engagement is the sum of ratings of the selected 10 item scores, 
including item 8 - Response of your mood to good or desired events, item 15 - 
Concentration/decision making, item 16 - View of myself, item 17 - View of my future, 
item 19 - General interest, item 20 - Energy level, item 21 - Capacity for pleasure or 
enjoyment (excluding sex), item 22 - Interest in sex (please rate interest, not activity), 
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16.1.9 Documentation of Statistical Methods
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item 23 - Feeling slowed down, and item 29 - Interpersonal sensitivity. The possible 
IDS-SR-10-engagement ranges from 0 to 30. The IDS-SR engagement score will be un-
evaluable if less than 8 of the 10 items are recorded. If 8 or 9 of the10 items are recorded, 
the IDS-SR engagement score will be the mean of the recorded items multiplied by 10 
and then rounded to the first decimal place. 
The observed-cases (OC) data set will consist of actual observations recorded at each 
scheduled visit during the open-label treatment phase, and no missing data will be 
imputed. MMRM analysis will be performed on the OC dataset.  
The last observation carried forward (LOCF) approach will also be used to impute 
missing data for continuous and categorical efficacy endpoints. The LOCF data set will 
include data recorded at a scheduled visit during the open-label treatment phase or, if no 
observation is recorded at that visit, data carried forward from the previous scheduled 
visit at the open-label treatment phase. Baseline data will not be carried forward to 
impute missing values for the LOCF data set. 
5.3 
Definition of Baseline and Last Visit 
Baseline is defined as the last available measurement prior to the first dose of open-label 
brexpiprazole, while last visit is defined as the last available measurement upon 
completion or early termination of the open-label treatment phase. 
6 
Outcome Variables  
6.1 
Efficacy Variables 
The efficacy of open-label brexpiprazole is assessed by IDS-SR, Patient Health 
Questionnaire 9-item (PHQ-9), Generalized Anxiety Disorder 7-item scale (GAD-7), 
World Health Organization Disability Assessment Schedule (WHODAS) 2.0 short form 
questionnaire, Sheehan Disability Scale (SDS), Clinical Global Impression - Severity 
(CGI-S), Clinical Global Impression - Improvement (CGI-I), Patient Global Impression – 
Severity (PGI-S),  Patient Global Impression – Improvement (PGI-I) scales, and ‘Word 
of the Day’. 
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6.2 
Safety Variables 
The safety of the open-label brexpiprazole is assessed based on reported adverse events 
(AEs), vital signs, body weight, BMI, and physical examination,  
7 
Disposition and Demographic Analysis  
7.1 
Subject Disposition 
Subject disposition, subject completion rate and reasons for discontinuation will be 
summarized for the Enrolled Sample. 
7.2 
Demographic and Baseline Characteristics 
Baseline demographic characteristics, including age, race, ethnicity, gender, weight, 
height, and BMI for the Enrolled Sample, will be summarized. Summary statistics will 
consist of mean, median, minimum, maximum, and standard deviation for continuous 
variables and tabulations of frequency distributions for categorical variables.  
Baseline disease characteristics will also be summarized for the Enrolled Sample by 
summary statistics. They include IDS-SR related assessments, PHQ-9 total score, GAD-7 
total score, WHODAS 2.0 short form score, SDS score, CGI-S score, PGI-S score. and  
‘Word of the Day’.  
7.3 
Medical and Psychiatric History 
A summary of medical and psychiatric history will be presented for the Enrolled Sample. 
Listings of medical and psychiatric history will also be provided.  
7.4 
Treatment Compliance 
Based on the Study Medication Log of the CRF, compliance in taking study medication 
is calculated by the dividing total dose taken by the total dose prescribed for subjects 
during the open-label treatment period. A listing of treatment compliance by subject will 
be provided on the Safety Sample. 
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7.5 
Concomitant Medications 
Number and proportion of subjects taking concomitant medications prior to, during, and 
post the open-label treatment period will be tabulated by drug classification using the 
World Health Organization (WHO) drug dictionary on the Safety Sample. In addition, 
listings of concomitant mediations will be provided. 
7.6 
Protocol Deviations 
Protocol deviation data will be summarized by type of deviations and center. In addition, 
listing will be provided describing the deviations by subject. 
8 
Efficacy Analysis 
All efficacy analyses pertaining to open-label treatment period will performed on the 
Efficacy Sample. Statistical comparisons are based on 2-sided, 0.05 significance levels. 
8.1 
Primary Efficacy Endpoint 
The co-primary efficacy endpoints are as follows: 
1) Change from baseline to Week 8 in IDS-SR-10-engagement 
2) Change from baseline to Week 8 in IDS-SR Total score 
8.1.1 
Technical Computation Details for Primary Efficacy Analysis 
The primary hypothesis is that the mean changes from baseline to Week 8 in both co-
primary endpoints will differ from 0, separately. Each of the endpoints will be tested by 
fitting a MMRM analysis with an unstructured variance covariance structure at a two-
sided significance level of 0.05 on OC dataset on Efficacy Sample. The model will 
include fixed effect terms for visit, baseline value, an interaction term of baseline value 
by visit, and trial center. The trial will be claimed positive if both p-values are less than 
0.05. Therefore, the overall type I error is controlled at 0.05 level. 
In case there is a convergence problem with MMRM model with the unstructured 
variance covariance matrix, the following structures other than unstructured will be used 
in order of 1) heterogeneous Toeplitz, 2) heterogeneous autoregressive of order 1, and 3) 
heterogeneous compound symmetry and the first (co)variance structure converging to the 
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Statistical Analysis Plan  
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best fit will be used as the primary analysis. If a structured covariance has to be used, the 
“sandwich” estimator of the standard error of the fixed effects parameters will be used in 
order to deal with possible model misspecification of the covariance matrix.  
The SAS code for the PROC MIXED procedure to carry out the above MMRM analysis 
with an unstructured variance covariance structure is illustrated as follows: 
    
where baseline is the last IDS-SR assessment total score at baseline. 
8.2 
Other Efficacy Endpoint Analysis 
The other efficacy endpoints are as follows. All of them will be evaluated at a nominal 
0.05 level (2-sided) without adjusting for multiplicity on Efficacy Sample: 
1) Change from baseline to Weeks 2 and 4 in IDS-SR-10-engagement 
2) Change from baseline to Weeks 2 and 4 in IDS-SR Total score 
3) Change from baseline to Weeks 2, 4, and 8 in IDS-SR patient-selected 
engagement items  
4) Change from baseline to Weeks 2, 4, and 8 in IDS-SR engagement items selected 
by both clinicians and patients. 
5) Change from baseline to Weeks 2, 4, and 8 in CGI-S score 
6) CGI-I score at Weeks 2, 4, and 8 
7) Change from baseline to Weeks 4 and 8 in SDS Mean score and SDS individual 
item scores 
8) Change from baseline to Weeks 4 and 8 in WHODAS 2.0 short form score. 
9) Change from baseline to Weeks 2, 4, and 8 in PHQ-9 score 
10)  Change from baseline to Weeks 2, 4, and 8 in GAD-7 score 
11)  PGI-I score at each timepoint (ie, being measured weekly at home) 
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16.1.9 Documentation of Statistical Methods
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12)  PGI-I response rate at each timepoint (ie, being measured weekly at home), 
where response is defined as a PGI-I score of 1 or 2 (very much improved or 
much improved) 
13)  Time to first PGI-S response, where response is defined as a reduction of 2 points 
in PGI-S score from baseline. 
Endpoint (1) - (5), (7) - (10) will be analyzed by fitting the same MMRM model 
described in the primary analysis on OC dataset. Endpoints (6) and (11) will be analyzed 
using one-sample t-test on LOCF dataset, with the null hypothesis of no change in each 
of the endpoints. The point estimate with 95% CI will be provided for endpoint (12) 
using normal approximation on LOCF dataset. Endpoint (13) will be evaluated by time-
to-event analysis with Kaplan-Meier curve on OC dataset. The time origin for measuring 
this event time is the date of the first dose of open-label brexpiprazole. The event date 
will be the date when a reduction of 2 points in PGI-S score from baseline is achieved. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Clinical Study Report 331-201-00289
16.1.9 Documentation of Statistical Methods
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8.4 
Sensitivity analysis 
The primary endpoint will be analyzed by Per-Protocol sample. This analyses will be 
conducted using the same MMRM analysis for the primary efficacy analysis. 
9 
Safety Analyses 
All safety analyses will be conducted based upon the Safety Sample. Safety variables to 
be analyzed include Adverse Events (AEs), body weights, BMI, vital signs, and physical 
examinations. In general, baseline of a safety variable is defined as the last observation of 
the variable before taking the first open-label brexpiprazole unless specified otherwise. 
Prospectively defined criteria will be used to identify potentially clinically relevant 
abnormal values for vital signs and body weight. 
9.1 
Extent of Exposure  
Duration of exposure is defined as the last day of open-label brexpiprazole - the first day 
of open-label brexpiprazole +1. The number and percentage of subject who receive open-
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Statistical Analysis Plan  
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label brexpiprazole will be presented biweekly: i.e., Day 1-14 in Week 1-2, Day 15-28 in 
Week 3-4, etc. The overall exposure will also be provided by summary statistics.  
The mean daily dosage will be summarized biweekly using descriptive statistics. The 
mean daily dosage per patient biweekly will be determined for every two weeks of the 
study: ie,  Day 1-14 in Week 1-2, Day 15-28 in Week 3-4, etc. This will be calculated by 
dividing the sum of individual total doses by the number of days in the biweekly interval.  
The summary will contain the number of patients receiving receive open-label 
brexpiprazole and the mean and range of the mean daily dose for every two weeks. 
9.2 
Adverse Events  
All AEs will be coded by system organ class and Medical Dictionary for Regulatory 
Activities preferred term. A treatment-emergent AE (TEAE) is defined as an AE which 
starts after start of the first open-labelbrexpiprazole, or an AE continues from baseline 
and is worsening, serious, trial drug-related, or results in death, discontinuation, 
interruption or reduction of trial medication. The incidence of the following events will 
be summarized by descriptive statistics: 
• TEAEs 
• TEAEs by severity 
• TEAEs potentially causally related to the trial drug 
• TEAEs with an outcome of death 
• Serious TEAEs 
• TEAEs leading to discontinuation of the trial drug 
All TEAEs will be presented in listings. The listings of death due to AEs, serious AEs, 
AEs leading to discontinuation of the trial drug, will also be provided.  
9.3 
Clinical Laboratory Data 
Listings of pregnancy test results by subject will be provided. 
9.4 
Vital Sign Data 
Vital signs are taken at screening, baseline, Week 4, and Week8/End of Treatment of. 
Assessments will include blood pressure, heart rate, respiratory rate, and temperature.  In 
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Protocol 331-201-00289 
 
 
Statistical Analysis Plan  
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a Relative to the date of 1st use of open-label brexpiprazole; If more than one observation falls within a 
particular study day interval, then the last observation within that interval is used. 
b Evaluations occurring more than seven days after the last open-label brexpiprazole date will be excluded. 
 
Table 11.1-2 Study Day and Visit Windows for Patient Diary Entries (PGI-I, PGI-S and 
‘Word of the Day’) 
Week 
Target Daya 
Study Day Interval a 
 1 
2 
                                2-7 
 2 
9 
                               8-14 
 3 
16 
 15-21 
 4 
23 
 22-28 
 5 
30 
 29-35 
 6 
37 
36-42 
 7 
44 
 43-49 
 8 
51 
 50-70b 
a Relative to the date of 1st use of open-label brexpiprazole. 
b Evaluations occurring more than seven days after the last open-label brexpiprazole date will be excluded. 
 
 
11.2 
Scales: Rules for Scoring and Handling of Missing Data 
11.2.1 
Inventory of Depressive Symptomatology Self-Report (IDS-SR) 
IDS-SR is utilized to assess core diagnostic depressive symptoms as well as the atypical 
and melancholic symptom features of MDD. The IDS-SR consists of 30 items, all rated 
on a 0 to 3 scale with 0 being the “best” rating and 3 being the “worse” rating. Besides 
item 9, two sub-items 9A and 9B exist, with possible scores of 1, 2 or 3 for item 9A, and 
0 or 1 for item 9B. The scores for these two sub-items are not included in the calculation 
of the total score. Item 11 or item 12 should be completed but not both, and similarly, 
item 13 or item 14 should be completed but not both. Should items 11 and 12 be rated 
both, then the maximum of the two scores will be used. The same approach will be used 
for handling items 13 and 14.  
The IDS-SR Total Score is the sum of ratings of 28 item scores. The possible IDS-SR 
Total Score ranges from 0 to 84. The IDS-SR Total Score will be un-evaluable if less 
than 23 of the 28 items are recorded. If the number of items recorded is at least 23 and at 
most 27, the IDS-SR Total Score will be the mean of the recorded items multiplied by 28 
and then rounded to the first decimal place. 
The IDS-SR symptom severity is rate using the following categories based on IDS-SR 
total Score: 0-13: None, 14-25: Mild, 26-38: Moderate, 39-48: Severe, and 49-84: Very 
severe. 
The IDS-SR related scales are assessed at each scheduled visit. 
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11.2.7 
Sheehan Disability Scale (SDS) 
The Sheehan Disability Scale (SDS) is a self-rated instrument used to measure the effect 
of the patient’s symptoms on work/school, social life, and family/home responsibilities. 
For each of the three items, scores range from 0 through 10. The number most 
representative of how much each area was disrupted by symptoms is marked along the 
line from 0 = not at all, to 10 = extremely. For the work/school item, no response was to 
be entered if the patient did not work or go to school for reasons unrelated to the disorder 
and a response therefore not being applicable. The Mean SDS Score will be calculated 
over the three item scores. All three item scores need to be available with the exception 
of the work/school item score when this item is not applicable. The SDS is assessed at 
baseline, Weeks 4 and 8. 
11.2.8 
Clinical Global Impression - Severity of Illness Scale (CGI-S) 
The severity of agitation for each subject will be rated using the Clinical Global 
Impression- Severity of Illness Scale (CGI-S). To perform this assessment, the 
investigator (or designee) will answer the following question: “Considering your total 
clinical experience with this particular population, how mentally ill (as related to 
agitation) is the subject at this time?” Response choices are 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; and 7 = among the most extremely ill subjects. The score 0 (not 
assessed) will be set to missing. The CGI-S is therefore a 7-point scale from 1 through 7. 
The CGI-S is assessed at each scheduled visit. 
11.2.9 
Clinical Global Impression - Improvement (CGI-I) 
The efficacy of trial treatment will be rated for each patient using the Clinical Global 
Impression - Improvement (CGI-I) scale. The rater or investigator will rate the patient’s 
total improvement whether or not it is due entirely to drug treatment. Response choices 
include: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally 
improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much 
worse. The score 0 (not assessed) will be set to missing. The CGI-I is therefore a 7-point 
scale from 1 through 7. The CGI-I is assessed at Weeks 2, 4, and 6. 
Clinical Study Report 331-201-00289
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11.2.10 
Word of the Day 
The ''Word of the Day'' is a word contained in a previously-generated list of meaningful 
words that has been developed through patient interviews. Words in this list have been 
assigned a valence (ie, positive, negative, or neutral) and will be selected by patients to 
best describe how the patient has felt that day. The ‘Word of the Day’ will be reduced in 
frequency from daily to twice weekly from Week 5 to Week 8.  
11.2.11 
Patient Global Impression - Severity (PGI-S) 
The Patient Global Impression – Severity (PGI-S) scale is a 7-point single-item self-
report scale for the patient to rate the severity of symptoms of MDD. Patients answer the 
following question: “Taking into account all of your symptoms, how severe is your Major 
Depressive Disorder at this time?” Scores range from 1 “no symptoms” to 7 “very 
severe.” The PGI-S will be reduced in frequency from daily to twice weekly from Week 
5 to Week 8. 
11.2.12 
Patient Global Impression - Improvement (PGI-I) 
The Patient Global Impression – Improvement (PGI-I) scale is a 7-point single-item self 
report scale depicting a patient’s rating of overall improvement in their condition since 
starting trial medication. Patients answer the following question: “Since starting trial 
medication, how much have your symptoms of Major Depressive Disorder changed?” 
Scores range from 1 “very much improved” to 7 “very much worse.” The PGI-I will be 
administered weekly throughout the trial. 
Clinical Study Report 331-201-00289
16.1.9 Documentation of Statistical Methods
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12 
Reference 
1       REXULTI (brexpiprazole tablets) Canadian Product Monograph. Otsuka Canada 
Pharmaceutical Inc., Saint-Laurent, Quebec, Canada; Otsuka Pharmaceutical Co., 
Ltd., Tokyo, Japan; Feb 2017. 
2      Üstün TB, Kostanjsek N, Chatterji S, Rehm J, editors. Measuring Health and 
Disability: Manual for WHO Disability Assessment Schedule (WHODAS 2.0) Malta: 
World Health Organization; 2010. 
Clinical Study Report 331-201-00289
16.1.9 Documentation of Statistical Methods
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13 
Appendix 
Appendix 1  
Criteria for Potentially Clinically Relevant Vital Sign   
Abnormalities 
Variable 
Criterion Valuea 
Change Relative to Baselinea 
Heart rateb 
> 100 bpm 
< 50 bpm 
 10 bpm increase 
 10 bpm decrease 
Systolic blood pressureb 
≥ 140 mmHg 
< 90 mmHg 
 20 mmHg increase 
 20 mmHg decrease 
Diastolic blood 
pressureb 
≥ 90 mmHg 
< 60 mmHg 
 10 mmHg increase 
 10 mmHg decrease 
Weight 
− 
 7% increase 
 7% decrease 
bpm = beats per minute; mmHg = millimeter of mercury 
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column. 
bAs defined in “Supplementary Suggestions for Preparing an Integrated Summary of Safety Information 
in an Original NDA Submission and for Organizing Information in Periodic Safety Updates,” FDA 
Division of Neuropharmacological Drug Products draft (2/27/87). 
 
 
 
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Clinical Study Report 331-201-00289
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Statistical Analysis Plan  
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Clinical Study Report 331-201-00289
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Clinical Study Report 331-201-00289
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Statistical Analysis Plan  
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Clinical Study Report 331-201-00289
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Medical Affairs Approval
11-Jul-2022
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Biostatistics Approval
07-Jul-2022
23:26:31
Clinical Approval
11-Jul-2022
14:12:48
Clinical Study Report 331-201-00289
16.1.9 Documentation of Statistical Methods
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