Clinical trial NCT04100096
Conditions: Borderline Personality Disorder
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Start date: 2019-10-17; Completion date: 2021-06-27
Enrollment: 332 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
There are currently no pharmacological treatments approved to treat borderline personality disorder (BPD). This trial will be conducted to evaluate the efficacy and safety of brexpiprazole for the treatment of participants diagnosed with BPD to provide a pharmacological treatment for BPD.

Detailed description:

Arms: arm 1: Participants received brexpiprazole, 2-3 milligrams per day (mg/day) tablets, orally, up to Week 12 during the treatment phase. arm 2: Participants received brexpiprazole-matching placebo tablets, orally, up to Week 12 during the treatment phase.
Interventions: intervention 1: Brexpiprazole intervention 2: Placebo
Intervention descriptions: intervention 1: Tablet intervention 2: Tablet

Protocol documents:
Prot_000.pdf: 


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Trial Conduct for COVID-19
All procedures and assessments in this protocol are to be followed to the fullest 
extent possible. The sponsor, in coordination with the site, investigator(s), and 
medical monitor, will continuously monitor and evaluate the benefits and risks to 
subject participation in the clinical trial as it related to COVID-19. If any protocol-
specified activities were not able to be performed, or cannot be performed due to 
COVID-19 considerations, refer to the COVID-19 Addendum for the appropriate 
measures to be followed. Appropriate measures may include replacing in-person 
visits with remote or virtual visits (phone or video) as deemed necessary by the 
investigator to ensure subject safety and maintain protocol requirements.


Table of Contents
Table of Contents...........................................................................................3
List of In-text Tables .....................................................................................9
List of In-text Figures..................................................................................10
1
Protocol Summary..............................................................................11
1.1
Synopsis.............................................................................................................11
1.2
Schema ..............................................................................................................16
1.3
Schedule of Assessments...................................................................................17
2
Introduction ........................................................................................22
2.1
Trial Rationale...................................................................................................22
2.2
Background .......................................................................................................23
2.3
Known and Potential Risks and Benefits ..........................................................24
3
Objectives and Endpoints..................................................................25
4
Trial Design.........................................................................................26
4.1
Type/Design of Trial .........................................................................................26
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 Subjects.....................................................................28
5
Trial Population..................................................................................29
5.1
Subject 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....................................................................................34
5.3.1
Meals and Dietary Restrictions.......................................................................34
5.3.2
Caffeine, Alcohol, and Tobacco .....................................................................34
5.3.3
Activity ...........................................................................................................34
5.4
Screen Failures ..................................................................................................34
6
Trial Treatments.................................................................................35


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6.1
Trial Treatments Administered .........................................................................35
6.1.1
Medical Devices .............................................................................................36
6.2
Management of Investigational Medicinal Product ..........................................36
6.2.1
Packaging and Labeling..................................................................................36
6.2.2
Storage ............................................................................................................36
6.2.3
Accountability.................................................................................................36
6.2.4
Returns and Destruction .................................................................................37
6.2.5
Reporting of Product Quality Complaints......................................................37
6.2.5.1
Eliciting and Reporting Product Quality Complaints .................................37
6.2.5.2
Information Required for Reporting Purposes............................................38
6.2.5.3
Return Process.............................................................................................38
6.2.5.4
Assessment/Evaluation ...............................................................................38
6.3
Measures to Minimize/Avoid Bias....................................................................38
6.4
Subject Compliance...........................................................................................39
6.5
Concomitant Medications or Therapies ............................................................39
6.5.1
Prohibited Medications...................................................................................39
6.5.2
Benzodiazepine Use During the Trial.............................................................42
6.5.3
Permitted Medications....................................................................................42
6.5.4
Rescue Medications........................................................................................42
6.6
Intervention after the End of the Trial...............................................................43
7
Stopping Rules, Withdrawal Criteria, and Procedures..................43
7.1
Entire Trial or Treatment...................................................................................43
7.2
Individual Site ...................................................................................................43
7.3
Individual Subject Discontinuation...................................................................43
7.3.1
Treatment Interruption....................................................................................43
7.3.2
Treatment Discontinuation .............................................................................43
7.3.3
Documenting Reasons for Treatment Interruption or Discontinuation..........44
7.3.4
Withdrawal of Consent...................................................................................44
7.3.5
Procedures to Encourage Continued Trial Participation ................................45
7.4
Definition of Subjects Lost to Follow-up..........................................................46
8
Trial Procedures .................................................................................46
8.1
Efficacy Assessments........................................................................................46


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8.1.1
Clinician Administered...................................................................................46
8.1.1.1
Zanarini Rating Scale for Borderline Personality Disorder........................46
8.1.1.2
Clinical Global Impression-Severity of Illness Scale .................................47
8.1.1.3
Clinical Global Impression-Improvement Scale.........................................47
8.1.2
Patient Completed...........................................................................................48
8.1.2.1
Patient’s Global Impression - Severity .......................................................48
8.1.2.2
Patient’s Global Impression - Change ........................................................48
8.1.3
Screening Assessments...................................................................................48
8.1.3.1
Structured Clinical Interview for DSM-5 Personality Disorders................48
8.1.3.2
Mini International Neuropsychiatric Interview for Psychotic 
Disorders .....................................................................................................49
8.2
Pharmacokinetic Assessments...........................................................................49
8.2.1
Pharmacokinetic Blood Samples....................................................................49
8.3
Pharmacodynamic Assessments........................................................................49
8.5
Biomarker Assessments ....................................................................................50
8.7
Safety Assessments ...........................................................................................51
8.7.1
Clinical Laboratory Assessments ...................................................................51
8.7.2
Physical Examination .....................................................................................52
8.7.3
Vital Signs ......................................................................................................53
8.7.4
Electrocardiogram...........................................................................................54
8.7.5
Suicidality Monitoring - Columbia-Suicide Severity Rating Scale................55
8.7.6
Other Safety Variables....................................................................................55
8.7.6.1
Simpson Angus Scale..................................................................................55
8.7.6.2
Abnormal Involuntary Movement Scale.....................................................56
8.7.6.3
Barnes Akathisia Rating Scale....................................................................56


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8.8
Adverse Events..................................................................................................57
8.8.1
Definitions ......................................................................................................57
8.8.2
Eliciting and Reporting Adverse Events.........................................................59
8.8.3
Immediately Reportable Events......................................................................59
8.8.4
Medical Device Incidents (Including Malfunctions)......................................60
8.8.5
Adverse Events of Special Interest.................................................................60
8.8.6
Potential Serious Hepatotoxicity ....................................................................60
8.8.7
Procedure for Breaking the Blind...................................................................60
8.8.8
Follow-up of Adverse Events .........................................................................60
8.8.8.1
Follow-up of Nonserious Adverse Events ..................................................60
8.8.8.2
Follow-up of Immediately Reportable Events ............................................61
8.8.8.3
Follow-up and Reporting of Immediately Reportable Events
Occurring After Last Scheduled Contact....................................................61
8.9
Treatment of Overdose......................................................................................62
8.10
Subject Assessment Recording .........................................................................62
8.11
Other Assessments ............................................................................................62
9
Statistical Considerations ..................................................................62
9.1
Sample Size.......................................................................................................62
9.2
Datasets for Analysis.........................................................................................62
9.3
Handling of Missing Data for Primary and Key Secondary Endpoint 
Analysis.............................................................................................................62
9.4
Statistical Analyses............................................................................................63
9.4.1
Efficacy Analyses ...........................................................................................63
9.4.1.1
Primary Efficacy Endpoint Analysis...........................................................63
9.4.1.2
Key Secondary Efficacy Endpoint Analysis...............................................63
9.4.1.3
Secondary Efficacy Endpoint Analysis.......................................................63
9.4.1.4
Control of Experiment-wise Type 1 Error ..................................................63
9.4.2
Safety Analysis ...............................................................................................63
9.4.2.1
Adverse Events............................................................................................64
9.4.2.2
Clinical Laboratory Data.............................................................................64
9.4.2.3
Physical Examination and Vital Signs Data................................................64
9.4.2.4
Electrocardiogram Data ..............................................................................64


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9.4.2.5
Other Safety Data........................................................................................65
9.4.3.1
Analysis of Demographic and Baseline Characteristics .............................65
9.4.3.2
Pharmacokinetic Analysis...........................................................................65
9.4.3.3
Pharmacodynamic Analysis........................................................................65
9.4.3.4
Pharmacokinetic/Pharmacodynamic Analysis............................................65
9.5
Interim Analysis and Adaptive Design .............................................................66
9.5.1
Data Monitoring Committee...........................................................................66
10
Supporting Documentation and Operational Considerations .......67
10.1
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations.............67
10.1.1
Ethics and Responsibility ...............................................................................67
10.1.2
Informed Consent ...........................................................................................67
10.1.3
Confidentiality................................................................................................68
10.1.4
Quality Control and Quality Assurance..........................................................69
10.1.4.1
Monitoring ..................................................................................................69
10.1.4.2
Auditing ......................................................................................................69
10.1.5
Protocol Deviations ........................................................................................69
10.1.6
Records Management .....................................................................................70
10.1.6.1
Source Documents ......................................................................................70
10.1.6.2
Data Collection............................................................................................70
10.1.6.3
File Management at the Trial Site...............................................................71
10.1.6.4
Records Retention at the Trial Site .............................................................72
10.1.6.5
Publication Authorship Requirements ........................................................72
10.2
Appendix 2: Clinical Laboratory Tests .............................................................74
10.3
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information........................................................................................................75
10.4
Appendix 4: Abbreviations ...............................................................................77
10.5
Appendix 5: Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance.............................................................................................80
10.6
Appendix 6: Criteria for Identifying Vital Signs of Potential Clinical 
Relevance ..........................................................................................................81


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10.7
Appendix 7: Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance.............................................................................................82
10.8
Appendix 8: Protocol Amendments ..................................................................83
11
References............................................................................................86


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List of In-text Tables
Table 1.3-1
Schedule of Assessments.............................................................. 17
Table 3-1
Trial Objectives and Endpoints..................................................... 25
Table 6.5-1
List of Medications Prohibited Before the Trial........................... 40
Table 6.5-2
List of Medications Prohibited During the Trial........................... 41


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List of In-text Figures
Figure 1.2-1
Trial Design Schematic................................................................. 16


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1
Protocol Summary
1.1
Synopsis
Name of Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Name of Investigational Medicinal Product: Brexpiprazole (OPC-34712)
Protocol No.: 331-201-00242
IND No.: 141091
Protocol Title: A Multicenter, Randomized, Flexible-dose, Double-blind Trial of 
Brexpiprazole Versus Placebo for the Treatment of Adults With Borderline Personality 
Disorder
Protocol Lay Person Short Title:
A Trial of Brexpiprazole in the Treatment of Borderline Personality Disorder
Clinical Phase/Trial Type: Phase 2 / Therapeutic confirmatory
Treatment/Indication: For the treatment of borderline personality disorder (BPD)
Objectives and Endpoints:
Trial Objectives and Endpoints
Objectives
Endpoints
Primary: To compare the efficacy of 
brexpiprazole versus placebo for the 
treatment of subjects with a diagnosis of 
BPD
Primary efficacy: Change from baseline 
in the ZAN-BPD total score
Key secondary efficacy: Change from 
baseline in the CGI-S score
Secondary efficacy:

Change from baseline in the PGI-S
for each trial visit during the double-
blind treatment period

PGI-C score

CGI-I score




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The trial will consist of a screening period (up to 21 days), a 12-week, double-blind 
treatment period, and safety follow-up (21 [±2] days after the last dose of investigational 
medicinal product [IMP]).
Trial Population:
Approximately 350 subjects will be screened to have 240 subjects randomized into the 
trial. 
Key Inclusion Criteria:
The trial population will consist of male and female outpatients, aged 18 to 65 years, 
inclusive. Subjects will have a BPD diagnosis according to Diagnostic and Statistical 
Manual of Mental Disorders, 5th edition (DSM-5) and confirmed by a valid diagnostic 
instrument (Structured Clinical Interview for DSM-5 Personality Disorders 
[SCID-5-PD]) and a total score of ≥12 on the Zanarini Rating Scale for Borderline 
Personality Disorder (ZAN-BPD) at the screening visit and at Day 0. In addition, a score 
of ≥2 in at least 2 of the following 4 ZAN-BPD subscale items will be required at 
screening and Day 0: 1) “inappropriate, intense anger or difficulty controlling anger” 
(hereafter referred to as inappropriate anger), 2) “transient stress-related paranoid 
ideation or severe dissociative symptoms” (paranoid ideation), 3) “affective instability 
due to a marked reactivity of mood” (affective instability), and 4) “impulsivity in at least 
other two areas that are potentially self-damaging” (impulsivity).
Trial Sites:
This trial will be conducted in the United States (US) and Europe.
Investigational Medicinal Product, Dose, Dosage Regimen, Treatment Duration, 
Formulation, Mode of Administration:
During the double-blind treatment period, subjects will receive IMP, consisting of up to 
3 mg/day brexpiprazole or placebo, depending on the subject’s treatment assignment.
All doses of IMP should be taken at the same time each day, if possible. All doses of IMP 
can be taken without regard to meals. If tolerability issues arise, the timing of 
administration of the IMP may be adjusted at the investigator’s discretion in order to 
achieve optimum tolerability and compliance.
Trial Assessments:
Assessments for Efficacy: ZAN-BPD, Clinical Global Impression-Severity (CGI-S), 
Clinical Global Impression-Improvement (CGI-I), Patient’s Global Impression of Change 
(PGI-C), Patient’s Global Impression of Severity (PGI-S), 


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Assessments for Pharmacokinetics: blood sampling for IMP plasma concentrations.
 
 
 
.
Assessments for Safety: AE, clinical laboratory tests (hematology, serum chemistry 
[including glycosylated hemoglobin (HbA1c), thyroid-stimulating hormone (TSH), and 
blinded prolactin], and urinalysis), electrocardiogram (ECG), vital signs, physical 
examination findings, Columbia-Suicide Severity Rating Scale (C-SSRS), Simpson 
Angus Scale (SAS), Abnormal Involuntary Movement Scale (AIMS), and Barnes 
Akathisia Rating Scale (BARS).
Screening/Other: SCID-5-PD, Mini International Neuropsychiatric Interview (MINI) for 
Psychotic Disorders, medical history, psychiatric history (including BPD history and 
BPD therapy), urine drug screen/blood alcohol test, and urine pregnancy test.
Data Monitoring Committee: None
Statistical Methods:
In general, descriptive statistics will be provided for all efficacy and safety endpoints. 
Continuous variables will be summarized by tabulations of mean, median, range, and 
standard deviation (SD). Tabulations of frequency distributions will be provided for 
categorical variables. The change from baseline in the ZAN-BPD total score will be 
analyzed using a mixed-effect model repeated measures (MMRM) methodology with the 
unstructured variance covariance matrix. The model will include fixed class-effect terms 
for treatment, trial center, visit week, and an interaction term of treatment by visit week 
and include the interaction term of baseline values of ZAN-BPD total score by visit week 
as a covariate. Other continuous efficacy endpoints will also be analyzed using MMRM 
methodology. 
 


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Trial Duration:
Each subject in this trial is expected to participate in the following periods of the trial 
(approximate durations listed):

Eligibility screening period (up to 21 days)

Double-blind randomized treatment period (12 weeks)

Post-treatment safety follow-up period (21 days; for subjects who do not enroll in the 
open-label extension trial)
Overall, the trial duration from first informed consent form signed to the final subject 
assessment is expected to be approximately 15.5 months.


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1.2
Schema
ADT = antidepressant therapy; BPD = borderline personality disorder; ZAN-BPD = Zanarini Rating Scale for Borderline Personality Disorder.
aFor subjects who do not enroll in the open-label extension trial.
bRandomization will be stratified by site and the status of background ADT therapy (with or without background ADT).
cExtension of screening may be requested and discussed with the medical monitor prior to the expiration of the screening period.
dSubjects who complete all trial visits through Week 12 with no major protocol deviations may be offered entry into an open-label extension trial.
Figure 1.2-1
Trial Design Schematic


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1.3
Schedule of Assessments
Table 1.3-1
Schedule of Assessments
Assessment
Visit
Screeninga
(Day -21 to 
Day -1)
Double-Blind Treatment Period
Post-
treatment 
Follow-up
(21 ± 2 
days)d
12 weeks
Day 0
Week 1b
Week 2
Week 4
Week 6
Week 8
Week 10
End of 
treatment 
(Week 12) 
or ETc
± 2 days
ENTRANCE and HISTORY
Informed consent
X
Inclusion and exclusion criteria
X
X
Confirmation of eligibility
Xe
Demography
X
Medical history
X
Psychiatric history, including 
BPD history
X
Confirm use/no use of ADTs
X
SCID-5-PDf
X
Diagnostic for concurrent 
excluded diseases (MINI for 
Psychotic Disorders)
X
Prior medication washoutg
X
HIV, HBsAg, and anti-HCV
X
EFFICACY
ZAN-BPD
X
X
X
X
X
X
X
X
X
CGI-S
X
X
X
X
X
X
X
X
CGI-I
X
X
X
X
X
X
X
PGI-S
X
X
X
X
X
X
X
X
PGI-C
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Table 1.3-1
Schedule of Assessments
Assessment
Visit
Screeninga
(Day -21 to 
Day -1)
Double-Blind Treatment Period
Post-
treatment 
Follow-up
(21 ± 2 
days)d
12 weeks
Day 0
Week 1b
Week 2
Week 4
Week 6
Week 8
Week 10
End of 
treatment 
(Week 12) 
or ETc
± 2 days
X
X
X
X
X
X
X
X
SAFETY
Physical examinationh
X
X
Vital signsi
X
X
X
X
X
X
X
X
X
Clinical laboratory tests 
(hematology, serum chemistry, 
and urinalysis)
Xj
X
X
Prolactin (blinded)
X
X
TSH with reflex to free T4 if 
abnormal
X
HbA1c
X
X
ECGk
X
X
Urine pregnancy test (FOCBP 
only)l
X
X
X
X
X
Urine drug screen and blood 
alcohol testm
X
X
X
C-SSRSn
X
X
X
X
X
X
X
X
X
Extrapyramidal symptoms scales 
(SAS, AIMS, and BARS)
X
X
X
Adverse eventso
X
X
X
X
X
X
X
X
X
X
Concomitant therapyp
X
X
X
X
X
X
X
X
X
X


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Table 1.3-1
Schedule of Assessments
Assessment
Visit
Screeninga
(Day -21 to 
Day -1)
Double-Blind Treatment Period
Post-
treatment 
Follow-up
(21 ± 2 
days)d
12 weeks
Day 0
Week 1b
Week 2
Week 4
Week 6
Week 8
Week 10
End of 
treatment 
(Week 12) 
or ETc
± 2 days
PHARMACOKINETIC AND PHARMACOGENOMIC SAMPLING
Pharmacokinetic samplingq
X
X
 
X
X
OTHER PROCEDURES
IMP dispensings
Xt
X
X
X
X
X
X
IMP accountability
X
X
X
X
X
X
X
Schedule optional phone 
contact/other communication
Xu
Xu
Xu
Xu
Xu
anti-HCV = antibodies to hepatitis C virus; 
; ET = Early Termination; 
; 
FOCBP = females of childbearing potential; HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; IRE = immediately reported 
events; PGI-C = Patient’s Global Impression of Change; PGI-S = Patient’s Global Impression of Severity; 
; PK = pharmacokinetic; 
T4 = thyroxine.
aExtension of screening may be requested and discussed with the medical monitor prior to the expiration of the screening period. Screening visit may be split 
over two days.
bWeek designations correspond to the end of the week (eg, Week 4 visit occurs at the end of week 4 of the trial).
cIf a subject discontinues early, every effort should be made to complete the “Week 12/End of treatment/ET” evaluations as soon as possible and, whenever 
possible, prior to starting any new medication or treatment.
dTelephone contact or clinic visit (investigator’s discretion) for evaluation of safety (AEs) for all subjects who do not enroll in the open-label extension trial.
eAn assessment of all inclusion and exclusion criteria will be made to determine the subject’s eligibility for the trial 
. Subjects cannot be enrolled 
until site personnel have received the final 
 notification from the Medical Monitor or Clinical Scientist.
CCI
CCI
CCI


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fThe BPD and antisocial personality disorder modules must be conducted as part of screening in order to meet inclusion/exclusion criteria; however, per 
investigator discretion other PD modules may be administered at baseline in order to decrease the length of the screening visit. The investigator is 
responsible for determining that BPD is the primary personality disorder diagnosis at screening.
gWashout of prohibited medications begins after completion of the consent process and must comply with the required washout periods (see Section 6.5).
hTo include measurement of height (at screening only) and waist circumference.
iVital sign measurements include body weight, body temperature, systolic and diastolic blood pressure, and heart rate. Blood pressure and heart rate will be 
measured in the following order: supine and standing after the subject has been in each position for at least 3 minutes. Vital signs scheduled for the same 
visit as blood samples are to be completed before blood is drawn.
jBlood samples for clinical laboratory tests should be drawn after a minimum 8-hour fast at screening, if possible. If the Screening Visit laboratory samples 
were not obtained under fasting conditions, clinical laboratory tests (hematology, serum chemistry [including blinded prolactin], HbA1c, TSH with reflex 
to free T4 if the result for TSH is abnormal, and urinalysis) need to be obtained under fasting conditions at the Day 0 Visit. Vital sign and ECG assessments 
should be completed before any blood samples are collected.
kStandard ECGs will be performed after the subject has been supine and at rest for 5 minutes prior to the ECG. Any screening ECG with abnormal result(s) 
considered to be clinically significant should be repeated to ensure reproducibility of the abnormality before excluding a subject. For ECG, perform 3 
consecutive recordings. If 2 of the 3 remain exclusionary then the subject must be excluded. 
lAll positive urine pregnancy test results must be confirmed by a serum test. Pregnancy tests can be performed at any point during the trial if pregnancy is 
suspected.
mA urine drug screen and a blood alcohol test are required at the designated times, but either or both can be conducted at any time during the trial at the 
discretion of the investigator. See the exclusion criteria for exclusions based on urine drug screen and blood alcohol tests at screening.
nThe “Baseline/Screening” C-SSRS form will be completed for all subjects at screening to determine eligibility and the “Since Last Visit” C-SSRS form will 
be completed at the Day 0 Visit to ensure that the subject continues to qualify for the trial. The “Since Last Visit” C-SSRS form will also be completed at 
all visits after the Day 0 Visit.
oAdverse events will be recorded starting after the subject completes the consent process and through the last scheduled trial visit (IREs will be collected 
through the last trial contact).
pAll prescription and non-prescription therapy (pharmacological or other therapy) taken during the trial will be recorded. Details of prohibited therapies are 
provided in Section 6.5.1.
qA PK sample will be collected at the same time of collection of clinical laboratory assessments, where applicable. Time of last 3 doses will be recorded at the 
time of PK sampling.
 
.




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2
Introduction
Borderline personality disorder (BPD) is a mental disorder consisting of a pervasive 
pattern of instability in regulation of emotions, impulse control, interpersonal 
relationships, and self image.1,2 Patients with BPD are prone to self-harm (including 
suicidal behavior/ideation), other dangerous behaviors, substance abuse, depression and 
eating disorders.3 The prevalence of BPD has been reported to be as high as 5.9% in the 
general population4 but represents 15% to 29% of patients in psychiatric clinics and 
hospitals.5,6 Because the personality of children and adolescents is developing, the 
features of BPD do not become recognizable until late adolescence or early adulthood.7,8
There is a high comorbidity of BPD with other psychiatric disorders (approximately 
85%), including anxiety disorders, mood disorders, impulse-control disorders, and 
substance-use disorders.9
Brexpiprazole (REXULTI®) is an atypical antipsychotic that is a serotonin-dopamine 
activity modulator and is indicated in the United States (US) as monotherapy for the 
treatment of schizophrenia in adult patients (2 - 4 mg/day) and as an adjunctive therapy to 
antidepressants for the treatment of major depressive disorder (MDD) (2 - 3 mg/day).10
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 receptors with affinity in the same 
sub-nanomolar 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, reduced impulsive 
behavior, and cognitive improvement.10
Please refer to the Brexpiprazole Investigator’s Brochure for more detailed information.
2.1
Trial Rationale
There are currently no pharmacological treatments approved for BPD. The first-line of 
treatment is psychotherapy, including dialectic behavior therapy to manage emotions, 


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help with tolerating distress, and managing relationships.7 Pharmacotherapy is used to 
treat targeted symptoms that fall within the following categories: 1) affective 
dysregulation, mood lability, and anger, 2) impulsive and self-harming behavior, and 3)
cognitive perceptual symptoms. Based on off-label prescribing practices and on clinical 
trial data, there is evidence that atypical antipsychotics may be efficacious at treating 
patients with BPD, especially symptoms of mood, self-harm, impulsivity, and aggression. 
Reductions in overall BPD symptomatology have been demonstrated in clinical trials of 
quetiapine11 olanzapine12,13,14 clozapine15,16 and aripiprazole.17,18
This receptor activity profile may allow for effective pharmacotherapy for the treatment 
of BPD. More specifically, the serotonergic and dopaminergic stabilization and 
modulation provided by brexpiprazole may directly address the pathways implicated in 
the BPD features of impulse aggression (serotonergic) and emotional dysregulation and 
impulsivity (dopaminergic).
The proposed 12-week, double-blind, placebo-controlled trial will be conducted to 
evaluate the efficacy and safety of brexpiprazole for the treatment of subjects diagnosed 
with BPD.
2.2
Background
A complete description of the available efficacy and safety pharmacology data from 
nonclinical studies, including pharmacokinetic (PK) and toxicology studies in different 
animal species can be found in the current IB.10
Currently, brexpiprazole is approved in multiple countries 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. Additionally, the current clinical development program is 
designed to show safety and efficacy of brexpiprazole for the treatment of the following 
indications: treatment of adult post-traumatic stress disorder (PTSD), bipolar mania, 
adolescent schizophrenia, and the treatment of agitation in Alzheimer’s disease (AAD).10
As of 17 Apr 2018, the brexpiprazole clinical development program consisted of a total 
of 74 clinical trials conducted in North America, Latin America, Europe, and Asia 
(66 completed and 8 ongoing). This includes 67 trials conducted under US 
Investigational New Drug (IND) Applications (59 completed and 8 ongoing) for 
schizophrenia, adjunctive treatment of MDD, adjunctive treatment of 
attention-deficit/hyperactivity disorder (ADHD), AAD, PTSD, or bipolar; and 7 non-US 
IND trials (7 completed and 0 ongoing) in either South Korea or Japan conducted in 
healthy subjects and subjects with schizophrenia.10


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Please refer to the IB for a detailed summary of available clinical data.10
2.3
Known and Potential Risks and Benefits
As of 17 Apr 2018, a total of 9153 unique subjects were exposed to single or multiple 
doses of brexpiprazole (either alone or with another marketed drug) in US IND trials. 
This total includes 877 subjects in the collective phase 1 clinical pharmacology trials
(593 healthy subjects or subjects in special populations and 284 subjects diagnosed with 
either schizophrenia or schizoaffective disorder [N = 236], MDD [N = 36], or ADHD 
[N = 12]) and 8276 subjects diagnosed with either schizophrenia or schizoaffective 
disorder (N = 2404), MDD (N = 5265), AAD (N = 429), ADHD (N = 155), or PTSD 
(N = 23) in the collective phase 2 and phase 3/3b trials. 
Overall, the total number of subject years of exposure (SYE) in the completed phase 1 
clinical pharmacology trials (N = 877) and all phase 2 and phase 3/3b trials combined 
(N = 8276) was 28.5 and 3590.3 SYEs, respectively. Exposure to brexpiprazole in the 
completed phase 2 and phase 3/3b US IND trials is summarized by duration of exposure 
and indication in the current IB.10 The majority of subjects within each of the 5 
indications have received at least 6 weeks of brexpiprazole, including 3139 subjects with 
at least 26 weeks of exposure and 1612 subjects with at least 52 weeks of exposure.
Completed phase 2 and phase 3 clinical trials have evaluated multiple oral doses up to 
6 mg/day in subjects with schizophrenia, up to 3 mg/day when coadministered with 
marketed antidepressant therapy in subjects with MDD, up to 3 mg/day in subjects with 
PTSD, up to 2 mg/day when coadministered with marketed stimulant therapy in subjects 
with ADHD, and up to 2 mg/day in subjects with AAD. Dose selection for the ongoing 
multiple-dose trials was derived from the collective safety, efficacy, and receptor 
occupancy data from completed phase 1, phase 1b, phase 2, and phase 3 trials of 
brexpiprazole.
Overall, 9062 subjects received brexpiprazole either alone or coadministered with 
another marketed medication from the 59 completed brexpiprazole trials conducted under 
US INDs. Overall, 6403/9062 subjects (70.7%) reported at least 1 treatment-emergent 
adverse event (TEAE) compared with 1498/2781 subjects (53.9%) who received placebo 
either alone or coadministered with another marketed medication. The most frequently 
reported TEAEs (incidence ≥ 5% of the total brexpiprazole group and more than total 
placebo) in all subjects who received brexpiprazole were increased weight (12.1%), 
headache (9.1%), insomnia (7.8%), akathisia (7.2%), somnolence (6.2%), and dizziness 
(5.3%). In the total placebo group, headache (8.2%) was the most frequently reported 
TEAE (incidence ≥ 5% of subjects).




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Secondary: To evaluate the safety and 
tolerability of brexpiprazole for the 
treatment of subjects with a diagnosis of 
BPD

Frequency and severity of AEs

Changes in ECGs, vital signs, 
clinical laboratory tests including 
blinded prolactin, changes in body 
weight, and physical examinations

EPS: SAS, the AIMS, and the 
BARS

Suicidal ideation and behavior will 
be assessed using the C-SSRS
AE = adverse event; AIMS = Abnormal Involuntary Movement Scale; BARS = CGI-I = Clinical Global 
Impression-Improvement of Illness; CGI-S = Clinical Global Impression-Severity of Illness; 
 
 C-SSRS = Columbia-Suicide Severity Rating 
Scale; Barnes Akathisia Rating Scale; ECG = electrocardiogram; 
 
PGI-C = Patient’s Global Impression of Change; PGI-S = Patient’s Global 
Impression of Severity; SAS = Simpson Angus Scale; 
 
 ZAN-BPD = Zanarini Rating Scale for Borderline Personality
Disorder.
Section 9.4 describes the statistical analysis of the endpoints.
4
Trial Design
4.1
Type/Design of Trial
This will be a 12-week, multicenter, randomized, double-blind, placebo-controlled trial of 
brexpiprazole in subjects diagnosed with BPD according to the Diagnostic and Statistical 
Manual of Mental Disorders, 5th edition (DSM-5) and confirmed by a valid diagnostic 
instrument (Structured Clinical Interview for DSM-5 Personality Disorders 
[SCID-5-PD]). 
The trial will be organized as follows:
Screening Period: The screening period will begin after written informed consent has 
been obtained and will take place between Day −21 and Day −1 prior to enrollment. 
Eligible subjects are required to meet all inclusion criteria at both screening and Day 0, 
including a total score of ≥12 on the Zanarini Rating Scale for Borderline Personality 
Disorder (ZAN-BPD). In addition, a score of ≥2 in at least 2 of the following 
4 ZAN-BPD subscale items will be required at screening and Day 0: 1) “inappropriate, 
intense anger or difficulty controlling anger” (hereafter referred to as inappropriate 
anger), 2) “transient stress-related paranoid ideation or severe dissociative symptoms” 
(paranoid ideation), 3) “affective instability due to a marked reactivity of mood” 
(affective instability), and 4) “impulsivity in at least other two areas that are potentially 
self-damaging” (impulsivity). Following screening, eligible subjects will enter the trial 


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and be randomly assigned to brexpiprazole 2 to 3 mg/day or placebo in a 1:1 fashion. 
Randomization will be stratified by site and the status of background antidepressant
therapy (ADT) use (with background ADT or without background ADT).
Treatment Period: Subjects will receive their assigned treatment during a 12-week, 
double-blind treatment period. The primary endpoint and the key secondary endpoint will 
be the change from baseline in the ZAN-BPD total score and Clinical Global Impression 
Scale - Severity of Illness (CGI-S) score, respectively. Visits will occur at Day 0 and at 
the end of Weeks 1, 2, 4, 6, 8, 10, and 12, with phone contact to check on subject status 
on the weeks the subject does not visit the clinic.
Safety Follow-up: Subjects who do not continue treatment in the open-label extension
trial will be followed up for safety reasons via telephone contact or in clinic visit 21 (± 2) 
days after the last dose of investigational medicinal product (IMP). This contact also 
applies to subjects who are withdrawn prematurely from the trial.
See Figure 1.2-1 for a schematic of the trial.
4.2
Scientific Rationale for Trial Design
Given its clinical efficacy in treating both schizophrenia and MDD as well as its 
multimodal mechanism of action, brexpiprazole may offer added benefit to patients 
suffering from BPD. Like other psychological disorders, BPD has been linked to 
aberrations in monoaminergic neurotransmission. While dysfunctions related to 
dopamine and serotonin have been historically cited, recent evidence has also implicated 
noradrenergic dysfunction in BPD as well.19,20,21,22 Since brexpiprazole possesses a 
multi-modal mechanism of drug action, pharmacologically, it may improve defects in 
monoamine circuitry that have gone awry in this psychiatric disorder. Notably, 
brexpiprazole is a partial agonist at dopamine D2/D3 and serotonin 5-HT1A receptors. It is 
also an antagonist at serotonin 5-HT2A and adrenergic α1B and α2C receptors. Its 
pharmacological effects at each receptor subtype may be beneficial in treating the diverse 
symptomology present in patients diagnosed with BPD. For example, as a partial 
dopamine D2/D3 receptor agonist, brexpiprazole may quell the hyperresponsiveness in 
the dopaminergic circuitry purported to exist in patients with BPD.23 By dampening 
dopaminergic tone in overactivated circuits, brexpiprazole may improve impulsivity and 
cognitive and emotional processing. Conversely, brexpiprazole may also improve 
dopaminergic tone in those circuits that are understimulated to improve mood. Likewise, 
brexpiprazole may normalize aberrations that are believed to exist in a heightened 
adrenergic system.23 Since the noradrenergic system is one of the effectors of the stress 


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response and likely activated with childhood trauma, it is postulated that noradrenergic 
genetic variants may confer BPD risk.22 Furthermore, 5-HT2A receptors are expressed on 
locus coeruleus noradrenergic neurons.24 In this regard, brexpiprazole may improve BPD 
symptomology like affective dysregulation, anxiety and impulsive-aggression by 
modulating noradrenergic drive.25 Impulsive-aggressive behavior is a core feature of 
BPD that may also result from hyperactivation of the amygdala. The amygdala is part of 
the limbic system that controls negative emotions. In BPD, loss of inhibitory regulation 
of the amygdala may occur from alterations in the 5-HT1A receptor gene, HTR1A, in 
some individuals.21 In these individuals, serotonergic function is reduced. Low levels of 
serotonin may lead to anger, suicidality, impulsivity, and aggressive behavior. Given its 
agonistic effects on both pre- and post-synaptic 5-HT1A receptors, brexpiprazole may 
help negatively modulate these behaviors, respectively, by normalizing serotonin 
neurotransmission. 
This phase 2, 2-arm trial is intended to provide preliminary evidence that treatment of 
subjects with BPD with brexpiprazole is superior to placebo.  
4.3
Dosing Rationale
The dosing paradigm of brexpiprazole to be used in Trial 331-201-00242 has been 
determined based on the dosing ranges investigated in other related psychiatric 
indications (bipolar I disorder, MDD, PTSD, and schizophrenia).10
In other psychiatric indications, brexpiprazole has been shown to be safe and well 
tolerated within the proposed dose range to be investigated in this trial (ie, 2 to
3 mg/day). In addition, the effective dose range for approved indications (MDD and 
schizophrenia) is 2 to 4 mg/day; the 1 mg/day dose has not been shown to be effective. 
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 safety follow-up eSource page for the last subject 
completing or withdrawing from the trial.
4.5
Definition of Completed Subjects
The treatment period is defined as the time period during which subjects are evaluated for 
primary and/or secondary objectives of the trial irrespective of whether or not the subject 
actually consumed all doses of the IMP. Subjects who are evaluated at the last scheduled 
visit during the treatment period will be defined as trial completers. For purposes of this 
trial, subjects who complete Week 12 will be defined as trial completers.


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5
Trial Population
It is planned that approximately 240 subjects will be enrolled at approximately 65 trial 
sites in the US and Europe.
 
 
 
 
The sponsor reserves the right to utilize external quality oversight methods to ensure the 
validity of diagnosis, severity of illness, and other factors determining appropriateness of 
subject selection.
Decisions regarding inclusion of subjects at time of enrollment and assessment of subject 
safety throughout the trial primarily remain at the discretion of the investigator; however, 
the medical monitor may recommend exclusion or discontinuation of a subject based on 
individual subject data.
5.1
Subject Selection and Numbering
All subjects will be given a unique subject identifier (ID; site number [3 digits] + subject 
number [‘S’ + 5 digits] upon providing consent [or assent if applicable]). Site number 
will be designated by the sponsor. The subject number will be given sequentially from 
S00001 as the serial numbers in the trial sites.
Demographic information (collection date, date of birth, sex, childbearing potential, race, 
ethnicity) and medical history will be recorded in eSource at screening visit.
Eligible subjects who are enrolled in the trial will be assigned a unique subject 
randomization number for treatment sequence assignment. Results of the eligibility 
assessment, date of randomization (or date of treatment assignment) and subject ID (or 
treatment group) will be recorded in eSource.
5.2
Eligibility Criteria
5.2.1
Inclusion Criteria
Subjects are required to meet the following inclusion criteria at the time points described 
in the schedule of assessments (Table 1.3-1).
1) Male or female subjects, ages 18 to 65 years, inclusive, at the time of informed 
consent.
2) Subjects who are able to complete the consent process and/or consent obtained from 
a legally acceptable representative (as required by Institutional Review Board 
[IRB]/Independent Ethics Committee [IEC]) prior to the initiation of any protocol-
required procedures.
CCI


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3) Ability, in the opinion of the principal investigator, to understand the nature of the 
trial and follow protocol requirements, including the prescribed dosage regimens, 
tablet ingestion, and discontinuation of prohibited medication, and to read and 
understand the written word in order to be reliably rated on assessment scales.
4) Subjects with a primary DSM-5 diagnosis of BPD confirmed by the SCID-5-PD at 
screening.
5) At screening and Day 0, subjects must have a total score of ≥ 12 on the ZAN-BPD
scale. In addition, a score of ≥2 in at least 2 of the following 4 ZAN-BPD subscale 
items will be required at screening and Day 0: 1) inappropriate anger, 2) paranoid 
ideation, 3) affective instability, and 4) impulsivity.
6) Subjects who, in the investigator’s judgment, require treatment with a medication 
for BPD.
7) Subjects willing to discontinue all prohibited medications to meet protocol-required 
washouts prior to and during the trial period.
5.2.2
Exclusion Criteria
Subjects will be excluded if they meet any of the following exclusion criteria at the time 
points described in the schedule of assessments (Table 1.3-1).
Sex and Reproductive Status
1) Sexually active males or females of childbearing potential (FOCBP) who do not 
agree to practice 2 different methods of birth control or remain abstinent during the 
trial and for 30 days after the last dose of IMP. If employing birth control, 2 of the 
following precautions must be used: vasectomy, tubal ligation, vaginal diaphragm, 
intrauterine device, birth control pill, birth control implant, birth control depot 
injection, condom with spermicide, or sponge with spermicide.
Consensual sexual activity that cannot biologically result in pregnancy may not be 
subject to required birth control methods, following discussion with the medical 
monitor.
Male subjects must also agree not to donate sperm from trial screening through 30 
days after the last dose of IMP.
2) Women who are breastfeeding and/or who have a positive pregnancy test result 
prior to receiving IMP.
Target Disease
3) Subjects with a concurrent DSM-5 diagnosis of schizophrenia or schizoaffective 
disorder are excluded. Subjects with a historical diagnosis of schizophrenia or 
schizoaffective disorder may be permitted if the investigator determines and 
documents that this prior diagnosis was not appropriate based on current and 
historical presentation. Also, subjects with a concurrent diagnosis of bipolar I 
disorder, bipolar II disorder, delirium, dementia, amnesia, eating disorder, antisocial 
personality disorder, or other cognitive disorders are excluded. Subjects with MDD, 
PTSD, ADHD, panic disorder, or generalized anxiety disorder can be included 
under the following conditions: symptoms have been stable for at least 60 days prior 


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to screening, these disorders are not the primary focus of treatment, and 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) Subjects who are currently in psychotherapy specifically used to target BPD 
symptoms at the time of screening (eg, dialectical behavior therapy, 
mentalization-based therapy) or who have participated in BPD-targeted 
psychotherapy within 60 days of screening are excluded. Individual or group 
supportive talk therapy, or other non-pharmacological interventions, may be 
permitted provided the treatment has not been initiated or a changed within 60 days 
prior to the screening visit, and if is not anticipated that that the subject will require 
changes in this treatment during the trial.
5) Subjects who have had electroconvulsive treatment or transcranial magnetic 
stimulation within 90 days prior to the screening visit.
Medical History and Concurrent Diseases
6) Subjects who have a current diagnosis of substance or alcohol use disorder 
(excluding nicotine) (DSM-5 criteria) within 90 days prior to the screening visit.
7) Subjects who fulfill the following criteria related to suicide and/or suicidal ideation 
are excluded:

Subjects who have a significant risk of committing violent acts, serious self-harm, 
or suicide based on history or routine psychiatric status examination, or those who 
are homicidal or considered to be a high risk to others, or subjects with a response 
of “yes” on the C-SSRS Suicidal Ideation Item 5 (Active Suicidal Ideation with 
Specific Plan and Intent) within the 90 days prior to screening or at Day 0, OR

Subjects with a response of “yes” on the C-SSRS Suicidal Behavior Items Actual 
Attempt, Interrupted Attempt, or Aborted Attempt within the 90 days prior to 
screening or at Day 0, OR

Subjects who have had 3 suicide attempts within 2 years prior to screening, OR

Subjects who have had 3 or more hospitalizations due to suicidal behavior within 
12 months prior to screening. 
Note that subjects who have engaged in non-suicidal self-injurious behavior within 
the 90 days prior to screening or at Day 0 are eligible, unless the behavior is better 
described as an actual attempt, interrupted attempt, or aborted attempt according to 
C-SSRS definition and/or investigator judgment and therefore exclusionary.
Subjects with a response of “yes” on the C-SSRS Suicidal Ideation Item 4 (Active 
Suicidal Ideation with Some Intent to Act, without Specific Plan and Intent) within 
the 90 days prior to screening or at Day 0 may be included following discussion 
with the medical monitor.
8) Subjects with hypothyroidism or hyperthyroidism (unless condition has been 
stabilized with medications for at least 90 days prior to screening) or an abnormal 
result for free T4 at screening.


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9) Subjects who currently have clinically significant neurological, hepatic, renal, 
metabolic, hematological, immunological, cardiovascular, pulmonary, or 
gastrointestinal disorders such as the following:

Any history of myocardial infarction or congestive heart failure (whether 
controlled or uncontrolled)

Human immunodeficiency virus (HIV) seropositive status or acquired 
immunodeficiency syndrome

Chronic hepatitis B or C (defined as positive serology and aspartate 
aminotransferase [AST] or alanine aminotransferase [ALT] elevated to > 2 × 
upper limit of normal [ULN])
Medical conditions that are minor or well-controlled may be considered acceptable 
if the condition does not expose the subject to an undue risk of a significant AE or 
interfere with assessments of safety or efficacy during the course of the trial. The 
medical monitor should be contacted in any instance where the investigator is 
uncertain regarding the stability of a subject’s medical condition(s) and the potential 
impact of the condition(s) on trial participation. Subjects who are severely obese, as 
confirmed by a correspondingly high body mass index (BMI), need to be reviewed 
and discussed with the medical monitor.
10) Subjects with diabetes mellitus (both insulin-dependent and non-insulin-dependent) 
may be eligible for the trial if their condition is stable and well-controlled as 
determined by satisfying ALL of the following criteria:
a) Glycosylated hemoglobin (HbA1c) < 8.0%, AND
b) Screening glucose must be 125 mg/dL (fasting) or < 200 mg/dL 
(non-fasting). If the non-fasting screening glucose is 200 mg/dL, subjects 
must be retested in a fasted state and the retest value must be 125 mg/dL, 
AND
c) Subject has not had any hospitalizations within the 12 months prior to 
screening due to diabetes or complications related to diabetes.
Subjects with non-insulin-dependent diabetes mellitus (ie, any subjects not using 
insulin) must also satisfy the below criterion:
a) Subject has been maintained on a stable regimen of antidiabetic medication(s) 
for at least 28 days prior to screening or diabetes has been well-controlled by 
diet for at least 28 days prior to screening.
Subjects with newly diagnosed diabetes during screening are excluded.
11) Subjects with uncontrolled hypertension, symptomatic hypotension, or orthostatic 
hypotension (see Section 8.7.3).
NOTE: Blood pressure measurements may be repeated once to ensure 
reproducibility of the exclusionary result(s) before excluding a subject based on the 
criteria noted above.
12) Subjects with epilepsy or a history of seizures, except for a single seizure episode; 
for instance childhood febrile, post traumatic, or alcohol withdrawal seizure.
Physical and Laboratory Results


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13) Subjects with abnormal laboratory tests results, vital signs results, or ECG findings, 
unless, based on the investigator’s judgment, the findings are not medically 
significant and would not impact the safety of the subject or the interpretation of the 
trial results. The medical monitor should be contacted to discuss individual cases, as 
needed. 
In addition, subjects with the following laboratory test and ECG results at screening 
must be excluded from the trial:

Platelets ≤ 75000/mm3

Hemoglobin ≤ 9 g/dL

Neutrophils, absolute ≤ 1000/mm3

AST > 2 × ULN

ALT > 2 × ULN

Creatine phosphokinase (CPK) > 3 × ULN, unless discussed with and 
approved by the medical monitor

Creatinine ≥ 2 mg/dL

QTcF ≥ 450 msec in men and ≥ 470 msec in women, unless due to ventricular 
pacing.
Tests with exclusionary results should be repeated to ensure reproducibility of the 
abnormality before excluding a subject based on the criteria noted above. For 
ECG, perform 3 consecutive recordings. If 2 of the 3 remain exclusionary then the 
subject must be excluded.
14) Subjects with a positive drug screen for cocaine or other illicit drugs are excluded 
and may not be retested or rescreened. Subjects with a positive urine drug screen 
resulting from use of cannabis, or prescription or over-the counter medications, or 
products that, in the investigator’s documented opinion, do not signal a clinical 
condition that would impact the safety of the subject or interpretation of the trial 
results may continue evaluation for the trial following consultation and approval by 
the medical monitor. Subjects with positive results for alcohol use will require 
consultation and approval by the medical monitor in order to verify use does not 
indicate a substance-use disorder.
Disallowed and Concomitant Medication
15) Recent treatment with a prohibited therapy (a table of prohibited therapies along
with required wash-out periods is provided in Section 6.5.1)
16) Subjects who would be likely to require prohibited concomitant therapy during the 
trial (see Section 6.5). 
17) Subjects who received brexpiprazole in any prior clinical trial or subjects who have 
taken or are currently taking commercially available brexpiprazole (Rexulti®).
Allergies and Adverse Drug Reactions
18) Subjects with a history of neuroleptic malignant syndrome, serotonin syndrome, or 
clinically significant tardive dyskinesia.


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19) Subjects with a history of true allergic response (ie, not intolerance) to more than 1 
class of medications.
20) Subjects who are known to be allergic or hypersensitive to brexpiprazole or other 
quinolinones.
Other
21) Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for 
treatment of either a psychiatric or physical (eg, infectious disease) illness must not 
be enrolled into this trial.
22) Subjects who are currently either inpatient or partially hospitalized should not 
participate in the trial.
23) Subjects who participated in a clinical trial within 90 days prior to screening or who 
participated in more than 2 clinical trials within a year prior to screening.
24) Any subject who, in the opinion of the sponsor, investigator, or medical monitor, 
should not participate in the trial.
A definition of childbearing potential can be found in Section 10.3.
Subjects must agree to restrictions to medications described in Section 6.5. No 
restrictions to activity, food, caffeine, alcohol or tobacco or any other lifestyle 
considerations are needed during this trial.
5.3
Lifestyle Considerations
Not applicable.
5.3.1
Meals and Dietary Restrictions
Not applicable.
5.3.2
Caffeine, Alcohol, and Tobacco
Not applicable.
5.3.3
Activity
Not applicable.
5.4
Screen Failures
A screen failure is a subject from whom informed consent is obtained and is documented 
in writing (ie, subject signs an informed consent form [ICF]), but who is not enrolled or 
assigned trial treatment.
Subjects who sign an ICF but who are not started on treatment are permitted to be 
re-screened. In the event that the subject is re-screened for trial participation, and the 






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6.2.4
Returns and Destruction
The IMP will be destroyed by the clinical trial site. The IMP may only be destroyed by 
the trial site(s), if approved by the sponsor and if the IMP destruction meets all local 
regulations. Accountability of the IMP must be completed and verified by the assigned 
trial monitor prior to destruction. The trial site(s) may utilize qualified third-party 
vendors for IMP destruction.
6.2.5
Reporting of Product Quality Complaints
A Product Quality Complaint (PQC) is any written, electronic, or verbal communication 
by a healthcare professional, consumer, subject, medical representative, Competent 
Authority, regulatory agency, partner, affiliate or other third party that alleges 
deficiencies or dissatisfaction related to identity, quality, labeling, packaging, reliability, 
safety, durability, tampering, counterfeiting, theft, effectiveness, or performance of a drug 
product or medical device after it is released for distribution. Examples include, but are 
not limited to, communications involving the following:

Failure/malfunction of a product to meet any of its specifications

Incorrect or missing labeling

Packaging issues (eg, damaged, dirty, crushed, missing product)

Blister defects (eg, missing, empty blisters)

Bottle defects (eg, under/over-fill, no safety seal)

Vial defects

Product defect (eg, odor, chipped, broken, embossing illegible)

Loss or theft of product
6.2.5.1
Eliciting and Reporting Product Quality Complaints
The investigator or designee must record all PQCs identified through any means from the 
receipt of the IMP from the sponsor or sponsor’s designee, through and including 
reconciliation and up to destruction, including subject dosing. The investigator or 
designee must notify the sponsor (or sponsor’s designee) by e-mail within 24 hours of 
becoming aware of the PQC according to the procedure outlined below.

Send information required for reporting purposes (listed below) to
It should also be indicated if the complaint sample is available or not available for 
return.


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Identification of a PQC by the subject should be reported to the site investigator, who 
should then follow one of the reporting mechanisms above.
6.2.5.2
Information Required for Reporting Purposes

Description of complaint

Reporter identification (eg, subject, investigator, site, etc.)

Reporter contact information (eg, address, phone number, e-mail address)

ID of material (product/compound name, coding)

Clinical protocol reference (number and/or trial name)

Dosage form/strength (if known)

Pictures (if available)

Availability for return
6.2.5.3
Return Process
Indicate during the report of the PQC if the complaint sample is available for return. If 
complaint sample is available for return, return it in the product retrieval package, which 
will be provided by the sponsor.
It must be documented in the site accountability record that a complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation.
6.2.5.4
Assessment/Evaluation
Assessment and evaluation of PQCs will be handled by the sponsor.
6.3
Measures to Minimize/Avoid Bias
Procedures for breaking the blind can be found in Section 8.8.7.
During the entire trial, treatment will be double-blind. In other words, neither the 
investigator nor the subject will have knowledge of the treatment assignment at any given 
visit.  
Treatment assignments will be based on a computer-generated randomization code 
provided by the Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) 
Biometrics Department. The randomization will be stratified by site and the status of 
background ADT use (with background ADT or without background ADT). Sponsor 
personnel, including those involved in monitoring, data management, and data analysis, 
will not have access to the treatment code during the trial. Access to the treatment codes 
will be restricted to personnel charged with generating and maintaining randomization 


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files, packaging IMP, operating the Interactive Response Technology, and reporting 
serious adverse events (SAEs) to regulatory agencies.
6.4
Subject Compliance
Responsible trial personnel will dispense the IMP (ie, brexpiprazole or placebo). 
Accountability and compliance verification should be documented in the subject’s trial 
records. Subjects must be counseled on the importance of taking the IMP as directed at 
all trial visits. If poor compliance continues (eg, multiple missed doses resulting in less 
than 80% overall compliance at any point in the trial), discontinuation of the subject from 
the trial should be considered. Subjects who habitually miss visits or habitually attend 
visits outside of the protocol-defined visit window are also noncompliant and should be 
considered for discontinuation. The medical monitor should be contacted if the 
investigator is uncertain whether a subject’s compliance issues merits discontinuation 
from the trial.
6.5
Concomitant Medications or Therapies
The investigator will record all available information for medications and therapies used 
for treatment of symptoms of BPD and other psychiatric conditions prior to the trial and 
through the end of the evaluation period (defined as the time period during which 
subjects are evaluated for primary and/or secondary objectives) on the eSource. Therapies 
used for the treatment of other conditions will be recorded from 30 days prior to signing 
the ICF through the end of the evaluation period on eSource. The investigator will also 
record all medications and therapies taken by the subject for treatment of an AE or which 
caused an AE until the end of the trial (defined as the last date of contact or date of final 
contact attempt) on eSource.
For concomitant medications, the following will be recorded in eSource: medication, 
indication, dose, frequency, route, start date and end date. For concomitant therapy, the 
following will be recorded in eSource: therapy, indication, start date and end date, and 
frequency.
6.5.1
Prohibited Medications
All subjects must agree to discontinue all prohibited medications during the screening 
period in order to meet the protocol-specified washout periods. Table 6.5-1 provides the 
required duration of washout for selected prohibited medications. All other prohibited 
medications must be discontinued at least 24 hours before the first dose of IMP.
Extensions to the screening period in order to achieve the appropriate wash-out periods 
may be permitted following discussion with the medical monitor. 


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Table 6.5-1
List of Medications Prohibited Before the Trial
1.
Neuroleptic agents (depot or long-acting injectable)
One full cycle plus 1/2 cycle
2.
Monoamine oxidase inhibitor
14 days
3.
Antipsychotic agents (oral)a
Oral aripiprazole
Oral cariprazine
Other oral antipsychotic agents (except for quetiapine
when used for insomnia)b
14 days
28 days
7 days
4.
Benzodiazepines (stable doses of short-acting [eg, lorazepam 
up to 2 mg/day or equivalent] and long-acting, [eg, 
clonazepam up to 1 mg/day] may be allowed)c
7 days
5.
Hypnotics, including ramelteond
7 days
6.
Mood stabilizers (ie, lithium)
7 days
7.
Anticonvulsants (except for gabapentin when used to treat 
anxiety or pain, after discussion with the medical monitor). 
7 days
8.
Antidepressant therapy

Multiple concurrent ADTs at a therapeutic dose range (for 
depressive symptoms) are not permittede
Tricyclic antidepressants and trazodone are excluded 
unless they are being used for sleep management (further 
discussion with the medical monitor is required before 
allowing these medications)
14 days
9.
Ketamine, esketamine, arketamine within 90 days prior to 
screening
90 days
10.
Investigational agents within 90 days prior to screening
90 days
aIf a subject was exposed to 2 or more atypical antipsychotic agents in the 12 months prior to screening 
or if the subject did not show improvement on their previous atypical antipsychotic therapy, 
additional discussion with the medical monitor is required.
bQuetiapine, if being used for treatment of insomnia at low doses (eg, 25 to 50 mg), may be washed out 
24 hours prior to enrollment.
cChronic, stable (ie, regularly scheduled maintenance dose that has not changed within 60 days of 
screening) use of specific oral benzodiazepines is permitted for the treatment of anxiety up to a 
maximum of 2 mg/day lorazepam (or equivalent) or 1 mg/day clonazepam.
dChronic, stable (ie, regularly scheduled maintenance dose that has not changed within 60 days of 
screening) use of non-benzodiazepine sleep aids is permitted for the management of sleep. 
eChronic, stable (ie, regularly scheduled maintenance dose that has not changed within 60 days of 
screening) treatment with 1 ADT is permitted; however, doses may not exceed > 60 mg/day for 
fluoxetine and > 50 mg/day for paroxetine.
Table 6.5-2 lists all medications prohibited during the trial, including exceptions, where 
appropriate.


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Table 6.5-2
List of Medications Prohibited During the Trial
1.
Psychotropic agents including, but not limited to, the following:
a) Antipsychotics, including depot or long-acting injectable formulations
b) Anticonvulsants (except gabapentin when used to treat anxiety or pain after further 
discussion with the medical monitor)
c) Monoamine oxidase inhibitors, tricyclic antidepressants,a trazodone,a nefazodone, fluoxetine 
(> 60 mg/day) and paroxetine (> 50 mg/day)
d) Mood stabilizers (ie, lithium)
e) Benzodiazepine use is restricted to chronic, stable treatment or when used to manage 
treatment-emergent AEs such as agitation and anxietyb
f)
Hypnotics, including ramelteonc
g) Stimulants and atomoxetine 
h) Opioid analgesics, unless approval is obtained from the medical monitor. Approval for 
opioid use may be considered for a documented and clinically appropriate indication 
(eg, episodic pain condition, tooth extraction) if prescribed at a medically appropriate dose 
and frequency. Buprenorphine is also excluded.
i)
Nutritional supplements and non-prescription herbal preparations with central nervous 
system effects (eg, St. John’s Wort, omega-3 fatty acids, kava extracts, gamma-aminobutyric 
acid supplements, etc)
j)
Disulfiram
k) Prazosin - allowed if currently being taken for an appropriate indication at a stable dose for 
at least 60 days prior to screening. Should be continued throughout trial participation
2.
Investigational agents
3.
Cytochrome P450 (CYP) 2D6 inhibitors or CYP3A4 inhibitors and inducers. Selected CYP2D6 
inhibitors are: celecoxib, hydroxyzine, chloroquine, methadone, chlorpheniramine, 
moclobemide, clemastine, clomipramine, pyrilamine, diphenhydramine, quinidine, terbinafine, 
halofantrine, tripelennamine. Selected CYP3A4 inhibitors are: amiodarone, amprenavir, 
indinavir, aprepitant, itraconazole, chloramphenicol, ketoconazole, cimetidine, nefazodone,
clarithromycin, nelfinavir, clotrimazole (if used orally), quinupristin/dalfopristin, delavirdine, 
ritonavir, diltiazem, saquinavir, erythromycin, troleandomycin, fluconazole, verapamil. Selected 
CYP3A4 inducers are: carbamazepine, oxcarbazepine, phenytoin, dexamethasone, primidone, 
efavirenz, rifampin, nevirapine, St. John’s Wort, phenobarbitol, troglitazone. The medical 
monitor should be consulted for any questions regarding the potential for pharmacokinetic 
interactions with concomitant medications used by subjects during the trial.
4.
Barbiturates
5.
Beta receptor antagonistsd
6.
Anticholinergic agents are prohibited within 8 hours of schedule EPS scale assessments.
aUnless they are being used for sleep management (further discussion with the medical monitor is 
required before allowing these medications)
bSee Section 6.5.2.
cChronic, stable (ie, regularly scheduled maintenance dose that has not changed within 60 days of 
screening) use of non-benzodiazepine sleep aids (ie, zolpidem, zaleplon, and eszopiclone only) is 
permitted for the management of sleep but not on the same day as administration of a benzodiazepine, 
regardless of indication. Intermittent use of specific non-benzodiazepine sleep aids is permitted for 
the short term management of treatment-emergent AEs related to sleep problems. For the 
non-benzodiazepine sleep aids, only 1 of the listed medications that are approved for this indication in 
the respective countries should be used and the country-specific prescribing information is to be used 
to determine the maximum allowable daily dose for the treatment of insomnia. Non-benzodiazepine 
sleep aids must not be administered within 8 hours prior to scheduled efficacy and safety assessments, 
including EPS scales.


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dPropranolol is permitted for akathisia or tremor up to a maximum of 20 mg 3 times daily (total of 
60 mg/day). Propranolol must not be administered within 8 hours prior to scheduled efficacy and 
safety assessments, including EPS scales.
6.5.2
Benzodiazepine Use During the Trial
Chronic, stable (ie, regularly scheduled maintenance dose that has not changed within 
60 days of screening) use of specific oral benzodiazepines is permitted for the treatment 
of anxiety up to a maximum of 2 mg/day lorazepam (or equivalent) or 1 mg/day 
clonazepam in divided doses. Intermittent use of specific oral benzodiazepines is 
permitted for the short term management of treatment-emergent AEs up to a maximum of 
2 mg/day lorazepam (or equivalent) or 1 mg/day clonazepam in divided doses. Short-
acting benzodiazepines are to be used whenever possible. In countries where no short-
acting benzodiazepines are commercially available, use of oral clonazepam may be 
acceptable if prior authorization is obtained from the medical monitor. The following 
guide should be used to determine approximate lorazepam equivalents: 1 mg lorazepam = 
15 mg oxazepam = 0.5 mg alprazolam = 5 mg diazepam = 0.5 mg clonazepam. If 
required for intermittent treatment of agitation, the prescribed benzodiazepine should be 
discontinued as soon as the AE for which it was initiated subsides, as per the 
investigator’s discretion to avoid any withdrawal effects. Benzodiazepines should not be 
administered within 8 hours prior to scheduled efficacy and safety assessments, including 
extrapyramidal symptom scales. Investigators are encouraged to delay scale 
administration until 8 hours have elapsed, if at all possible. However, if delaying 
administration of efficacy and safety scales is not feasible, the scales should still be 
administered and the use of benzodiazepine documented, including a notation of the drug 
name, dose, and time of administration on the eSource. For subjects entering the trial on 
regularly scheduled maintenance doses of benzodiazepines, routine doses may be taken at 
scheduled times per investigator instructions as long as drug name, dose, date, and time 
taken are clearly documented in eSource.
6.5.3
Permitted Medications
All medications that are not specifically prohibited (see Section 6.5.1) are permitted but 
need to be recorded on eSource as described in Section 6.5.
6.5.4
Rescue Medications
Not applicable.


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6.6
Intervention after the End of the Trial
Subjects who complete all trial visits through the Week 12 visit and meet the inclusion 
and exclusion criteria of the open-label extension trial may be offered entry into the
optional open-label extension trial.
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, IRBs/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.
7.3
Individual Subject Discontinuation
7.3.1
Treatment Interruption
All attempts should be made to avoid treatment interruptions during the trial. If a 
subject’s IMP treatment must be interrupted for medical or surgical reasons; liver test 
abnormalities; use of a prohibited concomitant medication; or other reasons (eg, hospital 
admission for an invasive procedure, a major medical condition, surgery; dental work, or 
a temporary situation that prevents subject compliance with the IMP dosing schedule), 
the subject’s IMP should be resumed as early as the situation allows (see Section 7.3.4). 
If > 4 consecutive doses of IMP are missed, a discussion should occur with the medical 
monitor to determine if the subject should be discontinued from the trial as a result of the 
treatment interruption.
7.3.2
Treatment Discontinuation
After treatment assignment, a subject may stop treatment permanently for a variety of 
reasons. Treatment discontinuations may be initiated by a subject who is not satisfied 
with treatment or may become medically necessary due to AEs, required treatment with a 
disallowed medication or therapy, or other issues, as determined by the investigator. 
However, each investigator must comprehensively review the circumstances and offer the 


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subject options for continued treatment to the degree possible as described in 
Section 7.3.5.
7.3.3
Documenting Reasons for Treatment Interruption or 
Discontinuation
A subject may temporarily interrupt or discontinue IMP for a number of reasons, 
including those listed below:

Adverse event

Subject decides to discontinue because of annoyance or discomfort due to a 
nonserious AE which is not otherwise determined to be an undue hazard

Continuing IMP places the subject at undue risk as determined by the investigator 
(eg, a safety concern that is possibly, probably, or likely related to IMP)

SAE

Other potentially IMP-related safety concerns or AEs

Death

Lack of efficacy

Lost to follow-up

Noncompliance with IMP

Physician decision

Pregnancy (see Section 10.3)

Protocol deviation

Site terminated by sponsor

Trial terminated by sponsor

Withdrawal by subject
If the subject temporarily interrupts or discontinues IMP due to an AE, the investigator, 
or other trial personnel, will make every effort to follow the event until it has resolved or 
stabilized. Follow-up procedures in Section 7.3.1 and Section 7.3.2 must be followed.
7.3.4
Withdrawal of Consent
All subjects have the right to withdraw their consent from further participation in the trial 
at any time without prejudice. Subjects cannot withdraw consent for use of data already 
collected as part of the trial, but only for future participation. The investigator can also 
discontinue a subject’s participation in the trial at any time if medically necessary. Unless 
the subject provides their written withdrawal of consent or there is other written 
documentation by the investigator confirming the subject’s verbal intent to completely 


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withdraw from the trial, subjects should be followed for all protocol-specified evaluations 
and assessments, if possible.
Complete withdrawal of consent requires a subject’s refusal of ALL of the following 
methods of follow-up:

Participation in all follow-up procedures specified in the protocol (whether in-clinic, 
by telephone, or by an in-home visit).

Participation in a subset of protocol specified follow-up procedures (by a frequency 
schedule and method, as agreed by subject and staff).

Contact of the subject by trial personnel, even if only by telephone, to assess current 
medical condition, and obtain necessary medical or laboratory reports relevant to the 
trial’s objectives.

Contact of alternative person(s) who have been designated in source records as being 
available to discuss the subject’s medical condition, even if only by telephone, mail, 
or e-mail (eg, family, spouse, partner, legal representative, friend, neighbor, or 
physician).

Access to medical information from alternative sources (eg, hospital/clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, social media sources).
Withdrawal of consent is a critical trial event and, therefore, should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent. 
The reasons for a subject’s intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial. 
A subject may initially express their desire to interrupt or modify or discontinue IMP 
administration, which is not equivalent to a complete withdrawal of consent for further 
participation (see Section 7.3.1 and Section 7.3.2, respectively). A subject may, however, 
indicate that further trial participation is creating a burden on their work, school, or social 
schedule. Therefore, the investigator should follow the procedures outlined in 
Section 7.3.3 to determine if the subject can continue participation in the trial if 
modifications to his/her treatment and/or schedule of assessments can be accommodated. 
Only subjects who withdraw their permission for all of the above methods of follow-up 
are considered to have completely withdrawn their consent to participate in the trial.
7.3.5
Procedures to Encourage Continued Trial Participation
In all cases of impending IMP discontinuation or consent withdrawal, investigators will 
be instructed to meet and discuss (without undue coercion) with the subject their options 
of continuing in the trial, preferably on therapy. The investigator should ensure 
understanding and documentation of the reasons for the subject’s desire to withdraw 
consent.


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7.4
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted on or before Week 12 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 subject, medical records, successful 
telephone contact with the subject, statement by a family member or primary care 
physician, or public records).
The site will make 3 documented attempts to contact the subject by telephone or other 
contact methods and in the event the site is unable to reach the subject by telephone, the 
site will attempt to contact the subject via certified mail or an alternative similar method, 
where appropriate, before assigning a “lost to follow-up” status.
If the subject was classified as “lost to follow-up”, “Were you able to contact the 
subject?”, “Date of contact/Date of final contact attempt” and “Contact method” will be 
recorded in the source documents.
8
Trial Procedures
The assessments to be conducted during the trial and timing of assessments are 
summarized in Section 1.3.
8.1
Efficacy Assessments
It is required that trained and experienced clinicians administer all rating scales. The 
number of raters within each trial center should be kept to a minimum. All efforts will be 
made to ensure that the same clinician administers the scales for a given subject. 
Notations in the subject’s trial records should substantiate the ratings. Training, 
certification, and materials for rating will be provided by OPDC or designee. Quality 
reviews of audio recording may be performed for some assessments, including eligibility 
review, in order to verify the quality of the assessment/interview and accuracy of scoring.
8.1.1
Clinician Administered
8.1.1.1
Zanarini Rating Scale for Borderline Personality Disorder
The ZAN-BPD is a clinician-administered scale for the assessment of change in 
Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) borderline 
psychopathology.26 Although the DSM-IV was updated to DSM-5, the diagnostic criteria 


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for BPD remain unchanged. The ZAN-BPD is designed to assess severity of disease 
symptoms in patients with BPD based on clinician rating.
The questions for the ZAN-BPD reflect a 1-week time frame. Each of the 9 criteria for 
BPD is rated on a 5-point anchored rating scale of 0 to 4. These scores are clustered into 
4 sector scores (akin to domains) and a total score. The 3 affective symptoms have a 
sector score range from 0 to 12. The 2 cognitive symptoms have a sector score range 
from 0 to 8. The 2 impulsive symptoms have a sector range from 0 to 8. The 
2 interpersonal symptoms have a sector score range of 0 to 8. These 4 sector scores add 
up to provide the overall total score for the ZAN-BPD, which ranges from 0 to 36.
8.1.1.2
Clinical Global Impression-Severity of Illness Scale
The severity of illness for each subject will be rated using the CGI-S.27 To perform this 
assessment, the investigator (or designee) will answer the following question: 
“Considering your total clinical experience with borderline personality disorder, how ill 
is the subject at this time?” Response choices are 0 = not assessed; 1 = normal, not at all 
ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 
and 7 = among the most extremely ill subjects. 
8.1.1.3
Clinical Global Impression-Improvement Scale
Change from baseline in the subject’s condition will be assessed using the CGI-I scale.27
The investigator (or designee) will answer the following question: “Rate total 
improvement whether or not in your judgment it is due entirely to drug treatment. 
Compared to his/her condition at Day 0, how much has the patient changed?”. All 
responses will be compared with the subject’s condition at baseline (Day 0). Response 
choices are 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.  
 
 
 
 
 
 


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8.1.2
Patient Completed
8.1.2.1
Patient’s Global Impression - Severity
The PGI-S is a 7-point single-item self-report scale for the patient to rate the severity of 
symptoms of BPD. Subjects answer the following question: “Taking into account all of 
your symptoms, how severe is your Borderline Personality Disorder at this time?” Scores 
range from 1 “no symptoms” to 7 “very severe”.
8.1.2.2
Patient’s Global Impression - Change
The Patient’s Global Impression of Change (PGI-C) is a 7-point single-item self-report 
scale depicting a patient’s rating of overall change in their condition since starting trial
medication. Subjects answer the following question: “Since starting study medication, 
how much have your symptoms of Borderline Personality Disorder changed?” Scores 
range from 1 “very much improved” to 7 “very much worse”.
 
 
 
 
 
 
 
 
 
 
 
8.1.3
Screening Assessments
8.1.3.1
Structured Clinical Interview for DSM-5 Personality Disorders
The SCID-5-PD33 is a validated diagnostic instrument and will be conducted at screening
to confirm the subject’s diagnosis of BPD. Detailed instructions for administration of this 
diagnostic interview will be provided.


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8.1.3.2
Mini International Neuropsychiatric Interview for Psychotic 
Disorders
The Mini International Neuropsychiatric Interview (MINI) version 7.0.2 for Psychotic 
Disorders34,35,36,37 will be conducted at screening to rule out exclusionary comorbid 
psychiatric diagnoses. This version of the MINI is suitable for settings where specific 
psychotic disorders are a focus of interest (ie, for exclusionary purposes). Detailed 
instructions for administration of this structured interview will be provided.
8.2
Pharmacokinetic Assessments
The PK samples will be collected as described in the schedule of assessments 
(Table 1.3-1). The time of last 3 doses of IMP will be recorded at the time of PK 
sampling.
8.2.1
Pharmacokinetic Blood Samples
Blood samples will be collected in vacutainers containing sodium heparin and processed 
into plasma to determine the concentrations of brexpiprazole.
 
 
The total volume of 
blood to be collected during the trial will be documented in the ICF.
Blood samples for PK analysis will be collected at the time points as shown in 
Table 1.3-1 (schedule of assessments). The actual date and time of the PK sample 
collection will be recorded in eSource.
When vital signs or ECGs are scheduled at the same nominal time as PK sample 
collections, vital signs should be measured and ECGs should be performed before PK 
samples are collected.
After processing into plasma, aliquots will be placed into appropriately labeled tubes and 
will be placed in a freezer set at −70° C or −20°C, unless otherwise instructed in the 
Operations/Laboratory Manual.
All plasma samples will be shipped to the bioanalytical laboratory for analysis. 
Additional information will be provided in the Operations Manual.
8.3
Pharmacodynamic Assessments
Not applicable.




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8.7
Safety Assessments
Details pertaining to the definitions, collection, reporting, and follow-up of AEs are 
described in Section 8.8.
8.7.1
Clinical Laboratory Assessments
Clinical laboratory samples will be collected at the time points described in the schedule 
of assessments (Table 1.3-1) to perform the clinical laboratory assessments described in 
Section 10.2. Vital sign and ECG assessments should be completed before any blood 
samples are collected. Refer to Section 10.5 for criteria for identifying laboratory values 
of potential clinical relevance.
A central laboratory designated by the sponsor will be used for all laboratory testing 
required during the trial. The central laboratory should be used for all laboratory testing 
whenever possible (including unscheduled and follow-up, if needed). In cases where an 
immediate result is required for a particular laboratory test, the sample should be divided 
and sent to both a local laboratory and the designated central laboratory. Subjects should 
be fasting for a minimum of 8 hours prior to the blood draws, if possible. If fasting blood 


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samples are not feasible at screening, nonfasting blood samples may be obtained initially 
for determining eligibility for the trial. A fasting blood sample is required at Day 0 prior 
to dosing. If a fasting blood sample was not obtained at the Screening Visit, clinical 
laboratory tests (hematology, serum chemistry [including blinded prolactin], HbA1c, TSH 
with reflex to T4 if the result for TSH is abnormal, and urinalysis) need to be repeated at 
the Day 0 Visit. The results of these tests at screening must be reviewed by the 
investigator prior to initiation of the administration of the IMP. Additional urine and 
blood samples may be collected for further evaluation of safety as warranted by the 
investigator’s judgment. Reports from the central laboratory should be filed with the 
source documents for each subject. The central laboratory will provide laboratory results 
to the sponsor electronically.
Any value outside the normal range will be flagged for the attention of the investigator 
who must indicate whether or not a flagged value is of clinical significance. If one or 
more values are questionable, the test(s) may be repeated. If the result of any test (or 
repeat test, if done) is indicated as clinically significant in the samples taken during the 
screening period, the subject will NOT be enrolled into the trial without the permission of 
the medical monitor. In addition, unscheduled laboratory tests should be performed if 
clinically significant abnormalities are observed. Unscheduled laboratory tests may be 
repeated at any time at the discretion of the investigator for appropriate medical care. 
Refer to Appendix 5 (Section 10.5) for criteria for identifying values of potential clinical 
relevance. Refer to Section 5.2.2 for laboratory test results that are exclusionary at 
screening.
The total volume of blood to be collected during the trial is documented in the ICF.
A pregnancy test will be conducted in FOCBP (refer to Section 10.3 for definition) prior 
to trial intervention; results must be available prior to the administration of the IMP. 
Pregnancy tests can be performed at any point during the trial if pregnancy is suspected.
8.7.2
Physical Examination
Physical examinations will be performed at the time points described in the schedule of 
assessments (Table 1.3-1).
A complete physical examination will consist of measurement of height and waist 
circumference and a review of the following body systems:  head, eyes, ears, nose, and 
throat; thorax; abdomen; urogenital; extremities; neurological; and skin and mucosa. At 
screening, height will be measured with a stadiometer, measuring stick or tape. Repeat 
measurement of height is not required at the physical examinations scheduled for the 


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Week 12 or ET visit. Waist circumference will be measured at each physical examination 
(screening and Week 12 or ET), using the provided measuring tape. The following 
procedures will aid in the standardization of these measurements:

The subject should be minimally clothed (ie, lightweight clothing; no heavy 
overgarments).

Waist circumference should be recorded before a subject’s meal and at approximately 
the same time at each visit.

Measurement will be accomplished by locating the upper hip bone and the top of the 
right iliac crest and placing a weighted measuring tape in a horizontal plane around 
the abdomen at the level of the crest. Before reading the tape measure, the assessor 
should assure that the tape is snug, but does not compress the skin, and is parallel to 
the floor. The measurement is to be made at the end of a normal exhalation.38
The investigator (or designee) is responsible for performing the physical examination. If 
the appointed designee is to perform the physical examination, he or she must be 
permitted by local regulations and his or her name must be included on the delegation of 
authority log. Whenever possible, the same individual should perform all physical 
examinations. Any condition present at the post-treatment physical examination that was 
not present at the baseline examination should be documented as an AE and followed to a 
satisfactory conclusion.
8.7.3
Vital Signs
Vital signs will be collected at the time points described in the schedule of assessments 
(Table 1.3-1). Vital sign measurements scheduled for the same visit as blood samples are 
to be completed before blood is drawn. Subjects should be monitored for potentially 
clinically significant vital signs values (Section 10.6).
Vital sign measurements will include body weight, body temperature, systolic blood 
pressure (SBP), diastolic blood pressure (DBP), and heart rate. The following guidelines 
will aid in the standardization of body weight measurements:

The same scale should be used to weigh a given subject each time, if possible.

Scales should be calibrated and reliable; scales should be at zero just prior to each 
subject’s weigh-in session.

A subject should void prior to being weighed and be minimally clothed (ie, no shoes 
or heavy overgarments).

Weight should be recorded before a subject’s meal and at approximately the same 
time at each visit.


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Blood pressure and heart rate measurements will be made in the supine and standing 
positions after the subject has been in position for at least 3 minutes. The supine 
measurements will be performed first, followed by standing. 
Subjects with uncontrolled hypertension (screening DBP > 95 mmHg in any position) or 
symptomatic hypotension at screening or baseline are excluded from the trial as are 
subjects with orthostatic hypotension, which is defined as a decrease of ≥ 30 mmHg in 
SBP or a decrease of ≥20 mmHg in DBP within 3 minutes of standing compared with
the previous supine blood pressure or development of symptoms. In addition, subjects 
should be excluded if they have any other vital sign measurement at screening or baseline 
that, in the investigator’s judgment, is medically significant in that it would impact the 
safety of the subject or the interpretation of the trial results. However, any abnormal 
screening or baseline vital sign result(s) considered to be clinically significant should be 
repeated to confirm the finding(s) before excluding the subject from the trial. 
8.7.4
Electrocardiogram
Electrocardiograms will be performed at the time points described in the schedule of 
assessments (Table 1.3-1). Vital sign and ECG assessments should be completed before 
any blood samples are collected. Subjects should be monitored for potentially clinically 
significant ECG results (Section 10.7).
Electrocardiogram recordings will be obtained after the subject has been supine and at 
rest for at least 5 minutes. Additional ECGs may be obtained at the investigator’s 
discretion and should always be obtained in the event of an ET. The ECG results will be 
evaluated at the investigational site to determine the subject’s eligibility and to monitor 
safety during the trial. The principal investigator (or qualified designee) will review, sign, 
and date each ECG reading, noting whether or not any abnormal results are of clinical 
significance. The ECG will be repeated if any results are considered to be clinically 
significant. A central ECG service will be used for reading all ECGs in order to 
standardize interpretations for the safety analysis.
If during screening, according to the investigator’s judgment, any abnormal ECG finding 
is deemed medically significant (impacting the safety of the subject or the interpretation 
of the trial results) or meets an exclusion criterion (see Section 5.2.2), the subject should 
be excluded from the trial. Abnormal results for ECGs should be repeated once at 
screening with 3 consecutive ECG recordings to ensure reproducibility of the 
abnormality before excluding a subject based on the criteria noted above. Each ECG 
recording should be taken approximately 5 minutes apart (the ECG result reported will be 
evaluated at each time point). The central ECG service will provide the corrections for 


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the 3 ECGs performed. Based on the QT interval as corrected for heart rate by 
Fridericia’s formula (QTcF) reported by the central service, a subject will be excluded if 
the corrections are ≥450 msec in men and ≥ 470 msec in women for 2 of the 3 time 
points of the ECGs done, unless due to ventricular pacing. If only 1 ECG time point has a 
QTcF of ≥450 msec in men and ≥ 470 msec in women, and this is not reproduced at 
either of the other 2 time points, the subject can be included in the trial.
Exclusion criteria for screening do not apply as mandatory discontinuation criteria for 
subjects who are already randomized. Please consult the medical monitor in case of 
questions.
8.7.5
Suicidality Monitoring - Columbia-Suicide Severity Rating Scale
Suicidality monitoring will occur at the time points described in the schedule of 
assessments (Table 1.3-1).
Suicidality will be monitored during the trial using the C-SSRS. This trial will use the 
“Baseline/Screening” and “Since Last Visit” versions of the scale. The 
“Baseline/Screening” version, which assesses the lifetime experience of the subject with 
suicide events and suicidal ideation and the occurrence of suicide events or ideation 
within a specified time period prior to entry into the trial, will be completed for all 
subjects at screening and Day 0 to determine eligibility. Any subject who presents a 
serious risk of suicide should be excluded from the trial (see Section 5.2.2). The “Since 
Last Visit” C-SSRS form will also be completed at all visits after screening. 
Discussion with the medical monitor during regarding any concerns or guidance 
regarding the C-SSRS during the trial is recommended.
8.7.6
Other Safety Variables
It is required that an adequately trained and experienced clinician administer the safety 
assessments, including the EPS scales (SAS, AIMS, and BARS). The number of raters 
within each trial center should be kept to a minimum. All efforts will be made to ensure 
that the same clinician administers the scales for a given subject. Notations in the 
subject’s trial records should substantiate the ratings. Training and materials for rating 
will be provided by a rater training group.
8.7.6.1
Simpson Angus Scale
The SAS39 consists of a list of 10 symptoms of Parkinsonism (gait, arm dropping, 
shoulder shaking, elbow rigidity, wrist rigidity, head rotation, glabella tap, tremor, 
salivation, and akathisia). Each item will be rated on a 5-point scale, with a score of zero 


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representing absence of symptoms and a score of 4 representing a severe condition. The 
SAS total score is the sum of the scores for all 10 items. 
Anticholinergics, benzodiazepines, non-benzodiazepine sleep aids, and propranolol are 
not permitted within 8 hours of scale administration (see Section 6.5.1). Investigators are 
encouraged to delay scale administration until 8 hours have elapsed, if at all possible. 
However, if delaying administration of the scale is not feasible, the SAS should still be 
administered and the use of the medication documented, including a notation of the drug 
name, dose, and time of administration on the eSource.
8.7.6.2
Abnormal Involuntary Movement Scale
The AIMS27 assessment consists of 10 items describing symptoms of dyskinesia.  Facial 
and oral movements (items 1 through 4), extremity movements (items 5 and 6), and trunk 
movements (item 7) will be observed unobtrusively while the subject is at rest (eg, in the 
waiting room), and the investigator will also make global judgments on the subject’s 
dyskinesias (items 8 through 10). Each item will be rated on a 5-point scale, with a score 
of zero representing absence of symptoms (for item 10, no awareness), and a score of 4, 
indicating a severe condition (for item 10, awareness, severe distress). For this scale, the 
subject is to be sitting on a hard, firm chair. In addition, the AIMS includes 2 yes or no 
questions that address the subject’s dental status. 
Anticholinergics, benzodiazepines, non-benzodiazepine sleep aids, and propranolol are 
not permitted within 8 hours of scale administration (see Section 6.5.1). Investigators are 
encouraged to delay scale administration until 8 hours have elapsed, if at all possible. 
However, if delaying administration of the scale is not feasible, the AIMS should still be 
administered and the use of the medication documented, including a notation of the drug 
name, dose, and time of administration on the eSource. 
The AIMS Movement Rating Score is defined as the sum of items 1 through 7 (ie, items 
1 through 4, facial and oral movements; items 5 and 6, extremity movements; and item 7, 
trunk movements).
8.7.6.3
Barnes Akathisia Rating Scale
The BARS40 consists of 4 items related to akathisia:  objective observation of akathisia 
by the investigator, subjective feelings of restlessness by the subject, subjective distress 
due to akathisia, and global clinical assessment of akathisia. The first 3 items will be 
rated on a 4-point scale, with a score of zero representing absence of symptoms and a 
score of 3 representing a severe condition. The global clinical evaluation will be made on 
a 6-point scale, with zero representing absence of symptoms and a score of 5 representing 
severe akathisia. To complete this scale, subjects will be observed while they are seated 


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and then standing for a minimum of 2 minutes in each position. Symptoms observed in 
other situations (eg, while engaged in neutral conversation or engaged in other activity) 
may also be rated. Subjective phenomena are to be elicited by direct questioning.  
Anticholinergics, benzodiazepines, non-benzodiazepine sleep aids, and propranolol are 
not permitted within 8 hours of scale administration (see Section 6.5.1). Investigators are 
encouraged to delay scale administration until 8 hours have elapsed, if at all possible. 
However, if delaying administration of the scale is not feasible, the BARS should still be 
administered and the use of the medication documented, including a notation of the drug 
name, dose, and time of administration on the eSource.
8.8
Adverse Events
8.8.1
Definitions
An AE is defined as any untoward medical occurrence in a clinical trial subject 
administered an IMP 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 
an IMP related to any dose administered.
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE. For the purpose of IND safety reporting, “reasonable possibility” 
means there is evidence to suggest a causal relationship between the IMP and the AE. 
Suspected adverse reaction implies a lesser degree of certainty about causality.
Treatment-emergent AEs are defined as AEs with an onset date on or after the start of 
double-blind treatment. In more detail, TEAEs are all adverse events which started after 
start of double-blind IMP treatment; or if the event was continuous from baseline and was 
worsening, serious, IMP related, or resulted in death, discontinuation, interruption or 
reduction of IMP.
An SAE includes any event that results in any of the following outcomes:

Death

Life-threatening; ie, the subject was, in the opinion of the investigator, 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.


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
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 subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above; eg, allergic 
bronchospasm requiring intensive treatment in an emergency room or home, 
blood dyscrasias or convulsions that do not result in hospitalization, or the 
development of drug dependency or drug abuse.
Nonserious AEs are all AEs that do not meet the criteria for a “serious” AE.
Adverse Events of Special Interest (AESIs): A noteworthy event for the particular 
product/IMP or class of products that a sponsor may wish to monitor carefully. All AESIs 
are to be reported as immediately reportable events (IREs).
Immediately Reportable Event:

Any SAE.

Any AE related to occupational exposure.

Any AESIs (pathological gambling and other compulsive behaviors)

Potential serious hepatotoxicity (see Section 8.8.6).

Pregnancies are also defined as IREs. Although normal pregnancy is not an AE, it 
will mandate IMP discontinuation and must be reported on an IRE form and the 
Pregnancy Surveillance Form(s) to the sponsor. Pregnancy will only be 
documented on the AE eSource if there is an abnormality or complication. This 
includes pregnancy of the subject or the partner of the subject.
Clinical Laboratory Test Value Changes: It is the investigator’s responsibility to review 
the results of laboratory tests for each individual subject as they become available. This 
review will be documented by the investigator’s dated signature on the laboratory report. 
The investigator may repeat the laboratory test or request additional tests to verify the 
results of the original laboratory tests. If this laboratory value is considered medically 
relevant (ie, clinically significant) by the investigator (subject is symptomatic, requiring 
corrective treatment or further evaluation), or if the laboratory value leads to 
discontinuation, and/or fulfills a seriousness criterion, this is considered an AE. 


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Severity: Adverse events will be graded on a 3-point scale and reported as indicated on 
eSource. The severity of an adverse experience is defined as follows:
1 = Mild:
Discomfort noticed, but no disruption to daily activity.
2 = Moderate:
Discomfort sufficient to reduce or affect normal daily activity.
3 = Severe:
Inability to work or perform normal daily activity.
IMP Causality: Assessment of causal relationship of an AE to the use of the IMP is 
defined as follows:
Related: 
There is a reasonable possibility of a temporal and causal 
relationship between the IMP and the AE.
Not Related: 
There is no temporal or causal relationship between the IMP and 
the AE.
8.8.2
Eliciting and Reporting Adverse Events
The investigator will regularly assess subjects for the occurrence of AEs. To avoid bias in 
eliciting AEs, subjects should be asked the nonleading question: “How have you felt 
since your last visit?” All AEs (serious and nonserious) reported by the subject must be 
recorded on the source documents and eSource provided by the sponsor. Adverse event 
collection will begin after a subject signs the ICF.
Medical terminology should be used for AE reporting. Adverse events should be reported 
as a single unifying diagnosis whenever possible or, in the absence of a unifying 
diagnosis, as individual signs or symptoms.
Exacerbation or disease progression should be reported as an AE only if there are 
unusual or severe clinical features that were not present, or experienced earlier, or not 
expected based on the course of the condition. 
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 8.8.3. Special attention 
should be paid to recording hospitalization and concomitant therapy.
Adverse event, start date, end date, seriousness, severity, relationship to trial treatment
(IMP Causality), action taken with trial treatment and outcome will be recorded on the 
source documents and in eSource.
8.8.3
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 


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exposure, AESI, potential serious hepatotoxicity, 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 eSource.).
8.8.4
Medical Device Incidents (Including Malfunctions)
Not applicable.
8.8.5
Adverse Events of Special Interest
The new onset or exacerbation of “Pathological Gambling and Other Compulsive 
Behaviors” will be analyzed as an AESI.
8.8.6
Potential Serious Hepatotoxicity
For a subject who experiences an elevation in AST or ALT that is 3 times the ULN, a 
total bilirubin level should also be evaluated. If the total bilirubin is 2 times the ULN, 
complete an IRE form with all values listed and also report as an AE on eSource.
8.8.7
Procedure for Breaking the Blind
The investigator is encouraged to contact the sponsor/Clinical Research Organization 
(CRO) medical monitor to discuss their rationale for unblinding. However, to prevent 
delays to the investigator or medical personnel responding to a potentially emergent 
situation, unblinding of IMP will not be dependent upon the investigator receiving 
approval from the sponsor/CRO medical advisor (ie, the investigator will be able to 
obtain the code break information independent of the sponsor/CRO medical advisor). The 
investigator must contact the sponsor/CRO medical advisor by telephone or e-mail with 
an explanation of the need for opening the treatment assignment code within 24 hours of 
opening the code. If the blind is broken, the Global Pharmacovigilance Department must 
be notified immediately (see the cover page of this protocol for contact information). 
Documentation of breaking the blind should be recorded in the subject’s medical record 
with the date and time the blind was broken and the names of the personnel involved.
Once the blind is broken for a subject, that subject may not reinitiate treatment with the 
IMP.
8.8.8
Follow-up of Adverse Events
8.8.8.1
Follow-up of Nonserious Adverse Events
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE eSource 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 on eSource. For any AE having been identified throughout the trial, during 


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analysis, additional relevant medical history information may be requested by the sponsor 
to further ascertain causality (including, but not limited to, information such as risk-
related behavior, family history and occupation).
8.8.8.2
Follow-up of Immediately Reportable Events
This trial requires that subjects be actively monitored for IREs up to 21 days after the last 
dose of IMP is administered.
Immediately reportable events that are identified or ongoing at the last scheduled 
contact must be recorded as such on the AE eSource page and the IRE form. If updated 
information (eg, resolved status) on IRE status becomes available after a subject’s last 
scheduled contact (up to last in-clinic visit for the entire trial), this must be reported to the 
sponsor and recorded on the AE eSource page and the IRE form, according to the 
appropriate reporting procedures described in Section 8.8.3.
It is expected that the investigator will provide or arrange appropriate supportive care for 
the subject and will provide prompt updates on the subject’s status to the sponsor. The 
investigator will follow IREs until the events are:

resolved,

stabilized,

the subject is lost to follow-up, or

has died.
Resolution means that the subject has returned to the baseline state of health and 
stabilized means that the investigator does not expect any further improvement or 
worsening of the subject’s condition. The investigator will continue to report any 
significant follow-up information to the sponsor up to the point the event has resolved or 
stabilized, or the subject is lost to follow-up, or has died.
Refer to Section 10.3 for additional information regarding the follow-up period for 
subjects that become pregnant or for pregnant partners of male subjects.
8.8.8.3
Follow-up and Reporting of Immediately Reportable Events 
Occurring After Last Scheduled Contact
Any new IREs reported to the investigator which occur after the last scheduled contact
and are determined by the investigator to be reasonably associated with the use of the 
IMP, should be reported to the sponsor according to the procedures outlined in 
Section 8.8.3. This may include IREs that are captured on follow-up telephone contact or 
at any other time point after the defined trial period and continue to report any significant 


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follow-up information to the sponsor until the events are resolved or stabilized, or the 
subject is lost to follow-up or has died.
8.9
Treatment of Overdose
For treatment of overdose, please refer to IB Section 6.3, Overdosage. 
8.10
Subject Assessment Recording
Subject assessment recordings are included under efficacy assessments in Section 8.1.
8.11
Other Assessments
Not applicable.
9
Statistical Considerations
Complete details of the planned statistical analysis will be presented in the statistical 
analysis plan (SAP).
9.1
Sample Size
Approximately 240 subjects will be enrolled in the trial.
 
9.2
Datasets for Analysis
The following analysis samples are defined for this trial:
Enrolled Sample: comprises all subjects who signed an ICF for the trial and enrolled into 
the trial on Day 0.
Safety Sample: comprises those randomized subjects in the double-blind treatment period 
who received at least 1 dose of double-blind IMP as indicated on the dosing record. 
Intent-to-treat: Sample: comprises all subjects in the Safety Sample who have 
measurements of ZAN-BPD total score before randomization and at least 1 post-
randomization time point.
9.3
Handling of Missing Data for Primary and Key Secondary Endpoint 
Analysis
.


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9.4
Statistical Analyses
9.4.1
Efficacy Analyses
9.4.1.1
Primary Efficacy Endpoint Analysis
The primary efficacy analysis will be performed by fitting a mixed-effect model repeated 
measure (MMRM) analysis with an unstructured variance covariance structure in which 
the change from the baseline in ZAN-BPD total score during the double-blind treatment 
period will be the dependent variable based on the observed cases data set. The model 
will include fixed class effect terms for treatment, trial site, visit week, and an interaction 
term of treatment by visit week. The model will also include the interaction term of 
baseline values of ZAN-BPD total score by visit week as covariates. All scheduled visits 
after baseline during the double-blind treatment period will be included in the model.
 
9.4.1.2
Key Secondary Efficacy Endpoint Analysis
The key secondary efficacy endpoint will be analyzed by fitting the same MMRM model 
described in the primary analysis. 
9.4.1.3
Secondary Efficacy Endpoint Analysis
9.4.1.4
Control of Experiment-wise Type 1 Error
9.4.2
Safety Analysis
Standard safety variables to be analyzed include AEs, clinical laboratory tests, vital signs, 
ECGs, and physical examinations. In addition, data from the following safety scales will 
be evaluated:  assessments of suicidality (C-SSRS) and EPS (eg, the SAS, AIMS, and 
BARS). Safety analysis will be conducted based on the Safety Sample defined in 
Section 9.2. In general, baseline of a safety variable is defined as the last observation of 
the variable before taking the first dose of IMP, unless specified otherwise. Prospectively 
defined criteria will be used to identify potentially clinically relevant abnormal values for 
clinical laboratory tests, vital signs, ECGs, and body weight. Details of safety analyses 
will be provided in the SAP.


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9.4.2.1
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 
treatment group:

TEAEs

TEAEs by severity

TEAEs potentially causally related to the IMP

TEAEs with an outcome of death

Serious TEAEs

TEAEs leading to discontinuation of the IMP 

AESI
9.4.2.2
Clinical Laboratory Data
Summary statistics for changes from baseline in the routine clinical laboratory 
measurements and prolactin concentrations will be provided. In addition, the incidence of 
potentially clinically relevant values identified using prospectively defined in the SAP 
criteria for laboratory tests will be summarized.
9.4.2.3
Physical Examination and Vital Signs Data
Physical examination findings will be listed by subject. Potentially clinically relevant 
results in vital signs and body weight will also be summarized.
Summary statistics for change from baseline in vital signs, body weight, and waist 
circumference will be provided.
9.4.2.4
Electrocardiogram Data
Mean change from baseline will be summarized by visit.
The incidence of clinically relevant changes will be calculated for ECG parameters and 
summarized by visit.
For the analysis of QT and corrected QT interval (QTc) data from 3 consecutive 
complexes (representing 3 consecutive heart beats) will be measured to determine 
average values. The following QT corrections will be used:
1) QTcB is the length of the QT interval corrected for heart rate by the Bazett’s formula:
QTcB=QT/(RR)0.5, and
2) QTcF is the length of the QT interval corrected for heart rate by the Fridericia formula:


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QTcF=QT/(RR)0.33
3) QTcN is the length of the QT interval corrected for heart rate by the Food and Drug 
Administration (FDA) Neuropharm Division formula: 
QTcN=QT/(RR)0.37
Results will be summarized by visit.
9.4.2.5
Other Safety Data
Change from baseline in scores for EPS (eg, SAS, AIMS, and BARS) will be evaluated 
using descriptive statistics. The analyses will be based on the observed case (OC) and last 
observation carried forward datasets of the Safety Sample.
Suicidality (eg, C-SSRS) will be summarized by treatment group by descriptive statistics. 
Details will be described in SAP.
9.4.3
Other Analyses
9.4.3.1
Analysis of Demographic and Baseline Characteristics
Baseline demographic characteristics including age, race, ethnicity, gender, weight, 
height, and BMI will be summarized by descriptive statistics (frequency, mean, median, 
standard deviation, maximum, minimum, and percentage when applicable).
9.4.3.2
Pharmacokinetic Analysis
Pharmacokinetic samples will be analyzed for brexpiprazole (OPC-34712) and its 
metabolite(s) and descriptive statistics will be calculated. No formal statistical 
comparisons are planned. 
9.4.3.3
Pharmacodynamic Analysis
Not applicable.
 
 


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9.5
Interim Analysis and Adaptive Design
No interim analysis or adaptive design are planned.
9.5.1
Data Monitoring Committee
Not applicable.


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10
Supporting Documentation and Operational Considerations
10.1
Appendix 1: Regulatory, Ethical, and Trial Oversight 
Considerations
10.1.1
Ethics and Responsibility
This trial must be conducted in compliance with the protocol, Food and Drug 
Administration (FDA) regulations, International Conference for Harmonisation (ICH)
GCP: Consolidated Guideline (E6[R2]), international ethical principles derived from the 
Declaration of Helsinki and Council for International Organizations of Medical Science 
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 eSource, the investigator, subinvestigator and their staff will take measures to 
ensure adequate care in protecting subject privacy. To this end, a subject ID will be used 
to identify each subject.
Financial aspects, subject insurance and 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 subjects (or their guardian or legally 
acceptable representative, as applicable for local laws). The electronic ICF will be 
approved by the same IRB/IEC that approves this protocol. 
Each ICF will comply with the ICH GCP: Consolidated Guideline E6(R2)41 and local 
regulatory requirements. The investigator will ensure that the sponsor reviews and 
authorizes any written site-specific ICF used in the trial before submission to the 
IRB/IEC. 
Investigators may discuss trial availability and the possibility for entry with a potential 
subject without first obtaining consent. However, informed consent must be obtained and 
documented before initiation of any procedures that are performed solely for the purpose 
of determining eligibility for this trial, including withdrawal from current medication(s). 
Potential subjects are free to refuse entry into the trial, or withdraw from the trial at any 
time, without justification, and there will be no consequences to their further care.
Prospective trial subjects will be provided with controlled access to the electronic ICF 
application by trial site staff. When the trial site staff and the subject agree that the 


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subject has enough information to make an informed decision to participate, the subject 
will electronically sign in the electronic ICF application and an electronic date and 
timestamp will be applied to the signature. The subject 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 electronically and these 
signatures will be stored with the electronic 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 subject by the investigator (or a qualified designee), and it has 
been documented that the subject has had the opportunity to ask questions, the
IRB/IEC-approved written ICF will be signed and dated by both the subject and the 
person obtaining consent (investigator or designee), as well as by any other parties 
required by the IRB/IEC. The subject will receive a copy of the signed ICF; the original 
shall be kept on file by the investigator.
Subjects may be asked to sign additional ICFs if the protocol is amended and the changes 
to the protocol results in additional information that needs to be provided to the subjects, 
so that they can make a knowledgeable and voluntary decision on continued trial 
participation. Female partners of male subjects who become pregnant during the course 
of the trial may be asked to sign additional ICFs in order to collect additional information 
regarding the nonsubject partner and fetus.
 
 
10.1.3
Confidentiality
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission. Subject confidentiality requirements of the region(s) where the trial is 
conducted will be met. However, authorized regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy the records, 
consistent with local requirements. All IMPs, subject bodily fluids, and/or other materials 
collected shall be used solely in accordance with this protocol, unless otherwise agreed to 
in writing by the sponsor.


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Subjects will be identified only by unique subject ID in eSource. If further subject 
identification is required, subjects’ full names may be made known to a regulatory 
agency or other authorized officials if necessary, subject to local regulations.
10.1.4
Quality Control and Quality Assurance
10.1.4.1
Monitoring
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, the ICH GCP: Consolidated Guideline (E6[R2]), and 
applicable regulatory requirements and local laws. As part of a concerted effort to fulfill 
these obligations (maintain current personal knowledge of the progress of the trial), the 
sponsor’s monitors will visit the site during the trial, as well as communicate frequently 
via telephone, e-mail, and written communications. In addition, all investigators 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, IMP supply, presence of required documents, 
the informed consent process, and a review of eSource with source documents, as 
applicable. The investigator agrees to participate with audits.
Regulatory authorities may inspect the investigator site during or after the trial. The 
investigator will cooperate with such inspections and will contact the sponsor 
immediately if such an inspection occurs.
10.1.5
Protocol Deviations
In the event of a significant deviation from the protocol due to an emergency, accident, or 
mistake (eg, violation of informed consent process, IMP dispensing or subject dosing 
error, treatment assignment error, subject enrolled in violation of eligibility criteria or 
concomitant medication criteria), the investigator or designee will contact the sponsor or 
designee at the earliest possible time by telephone or via e-mail. The investigator and 
sponsor (or designee) will come as quickly as possible to a joint decision regarding the 
subject’s continuation in the trial. This decision will be documented by the investigator 
and the sponsor (or designee) and reviewed by the site monitor.
Any major protocol deviation will be recorded in eSource along with the start date and 
details of the deviation.


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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, screening logs, and recorded data from automated instruments. 
All source documents pertaining to this trial will be maintained by the investigators and 
made available for direct inspection by authorized persons.
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, subject confidentiality must be 
maintained in accordance with local regulatory requirements.
10.1.6.2
Data Collection
During each subject’s visit to the site or remote visit, an investigator or their designee 
participating in the trial will record information to document all significant observations. 
At a minimum, these notes will contain:

Documentation of the informed consent process, including any revised consents;

Documentation of the investigator’s decision to enroll the subject into the trial, 
the review of all inclusion/exclusion criteria prior to IMP administration, and 
confirmation of the subject’s actual participation in the trial;

The date of the visit and the corresponding Visit or Day in the trial schedule;

General subject status remarks, including any significant medical findings. The 
severity, frequency, duration, action taken, and outcome of any AEs and the 
investigator’s assessment of relationship to IMP must also be recorded;

Any changes in concomitant medications or dosages;

A general reference to the procedures completed; 

The signature (or initials) and date of the investigator (or designee) who made an 
entry in the medical record.
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as 
described above.
Source documents and source data will be captured electronically (where permitted by 
local regulation) in this trial and will meet the same fundamental elements of data quality 
(eg, attributable, legible, contemporaneous, original, and accurate) as paper records. 


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These data will be collected into a system that is fully validated according to 21 CFR 
Part 11. Changes to the data will be captured by an automatic audit trail.
Designated trial site staff will not be given access to the electronic source system until 
they have been appropriately trained. Information to be originally captured and reviewed 
electronically shall include details of the subject visit and the protocol required 
assessments performed as a part of these visits, medical history, AEs, and concomitant 
medications. Because this trial is using an electronic source record as the original point of 
data capture, there is no additional data entry step for the trial site for data collected 
directly into the application, rather, the electronic source record directly populates the 
trial database.
Some data may be captured via paper and then entered into the eSource system. These 
and any other data treated in this manner will be source data verified per the monitoring 
plan and the location of the source data (ie, eSource, 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, wrong data right data). If the reason for the change is not apparent, a 
brief explanation for the change will be written in the source documentation by the 
investigator or their designee.
Another exception will be safety laboratory (or central ECG data), where the official 
source documentation will be considered the report issued by the analyzing laboratory.
Remote monitoring of the original electronic source records will take place; however,
on-site monitoring inspections will continue to take place in order to review data entry of 
source documentation directly captured on paper and transcribed into the system, to 
ensure protocol adherence, to assess trial 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 eSource 
application are complete and accurate. After database lock, the investigator will receive 
an electronic copy of the subject data.
10.1.6.3
File Management at the Trial Site
The investigator will ensure that the trial site file is maintained in accordance with 
Section 8 of the ICH GCP: Consolidated Guideline (E6[R2]) 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 IMP 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 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 subject 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 subjects who do not qualify for authorship may be 
acknowledged in publications resulting from the trial. By agreeing to participate in the 
trial, investigators or other trial subjects consent to such acknowledgement in any 
publications resulting from its conduct.


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10.2
Appendix 2: Clinical Laboratory Tests
The tests detailed in Table 10.2-1 will be performed.
Table 10.2-1
Clinical Laboratory Assessments
Hematology:
Hemoglobin
Hematocrit
MCH
MCHC
MCV
Platelet count 
RBC count
RBC morphology
RDW
WBC count with differential 
Urinalysis:
Specimen Appearance
Color 
Occult Blood
Glucose
Microscopic analysis, WBC/RBC counts per high 
powered field
pH
Protein
Specific Gravity
Ketones
Urine Drug Screens:
Amphetamines/MDMA
Barbiturates
Benzodiazepines
Cannabinoids
Cocaine
Methadone
Opiates
Phencyclidine
Propoxyphene
Drug and Alcohol Screening
Blood alcohol
Serum Chemistry:
ALP
ALT
AST
Bilirubin, total
BUN
Calcium
Cholesterol (total, LDL, and HDL)
CPK
Creatinine
GGT
Glucose
Lactic Dehydrogenase
Magnesium
Potassium
Prolactina
Protein, total
Sodium
Triglycerides
Uric acid
Additional Tests:
Urine and serum pregnancy for FOCBPb
TSH, with reflex to free T4 if TSH is abnormal
Prothrombin time, Activated partial 
thromboplastin time, and International 
normalized ratio (screening only)
HbA1c
Additional Tests (screening only):
HIV
HBsAg
Anti-HCV
ALP = alkaline phosphatase; anti-HCV = hepatitis C antibodies; BUN = blood urea nitrogen; 
GGT = gamma glutamyl transferase; HBsAg = hepatitis B surface antigen; HDL = high density 
lipoprotein; LDH = lactic dehydrogenase; LDL = low density lipoprotein; MCH = mean corpuscular 
hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular 
volume; MDMA = methylenedioxymethamphetamine; RBC = red blood cell; RDW = red cell 
distribution width; WBC = white blood cell.
a Prolactin results will be blinded to the investigators and trial staff.
b All positive urine pregnancy test results must be confirmed by a serum test. Subjects with a positive 
serum pregnancy test result at screening must not be enrolled and subjects with a positive serum 
pregnancy test result during the trial must discontinue treatment and be withdrawn from the trial.


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10.3
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information
Females of child-bearing 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).
For males and FOCBP, who are sexually active, there must be a documented agreement 
that the subject and their partner will take effective measures (ie, 2 different approved 
methods of birth control or remains abstinent) to prevent pregnancy during the course of 
the trial and for 30 days after the last dose of IMP. Unless the subject 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 
orchidectomy) or remains abstinent during the trial and for 30 days after the last dose of 
IMP, 2 of the following approved methods of birth control must be used: vasectomy, 
tubal ligation, intrauterine device, birth control pills, birth control implant, birth control 
depot injection, 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 eSource. 
Abstinence is defined as refraining from heterosexual intercourse during the entire period 
of risk associated with the trial treatments. The reliability of sexual abstinence should be
evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the subject. Consensual sexual activity that cannot biologically result in 
pregnancy may not be subject to required birth control methods, following discussion 
with the medical monitor. The contraceptive method will be documented in eSource. 
Male subjects must also agree not to donate sperm from trial screening through 30 days
after the last dose of IMP.
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

Informed consent form

Pregnancy prevention information

Drug interactions with hormonal contraceptives

Contraceptives in current use

Follow-up of a reported pregnancy


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Before trial enrollment, males and FOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy. Subjects must sign the ICF confirming that the above-mentioned risk factors 
and the consequences were discussed.
A urine or serum pregnancy test for human chorionic gonadotropin will be performed at 
screening on all FOCBP. If a urine test is performed and is positive, the investigator will 
follow-up with a confirmatory serum test.
During the trial, all FOCBP should be instructed to contact the investigator immediately 
if they suspect they might be pregnant (eg, missed or late menstrual cycle). Male subjects 
must be instructed to contact the investigator immediately, during the trial, if their partner 
suspects that they might be pregnant (eg, missed or late menstrual cycle).
If a subject is suspected to be pregnant before she receives IMP, the IMP administration 
must be withheld until the results of serum pregnancy tests are available. If the pregnancy 
is confirmed, the subject must not receive the IMP and must not be enrolled in the trial. If 
pregnancy is suspected while the subject is taking IMP, the IMP must be withheld 
immediately (if reasonable, taking into consideration any potential withdrawal risks) until 
the result of the pregnancy test is known. If pregnancy is confirmed, the IMP will be 
permanently discontinued in an appropriate manner (eg, dose tapering if necessary for 
subject safety) and the subject will be withdrawn from the trial. Exceptions to trial 
discontinuation may be considered for life-threatening conditions only after consultations 
with the IRE contact (see the title page of this protocol for contact information).
The investigator must immediately notify the sponsor (within 24 hours) of any pregnancy 
associated with IMP exposure during the trial and for at least 30 days after the last dose 
of IMP, and record the event on the IRE form and forward it to the sponsor. The sponsor 
will forward the Pregnancy Surveillance Form(s) to the investigator for monitoring the 
outcome of the pregnancy.
Protocol required procedures for trial discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated. In addition, the 
investigator must report to the sponsor, on the Pregnancy Surveillance Form(s), follow-
up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome. Infants will be followed for a minimum of 6 months from the date of birth. 


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10.4
Appendix 4: Abbreviations
Abbreviation
Definition
5-HT
Serotonin
AAD
Agitation in Alzheimer’s disease
ADHD
Attention-deficit/hyperactivity disorder
ADT
Antidepressant therapy
AE
Adverse event
AESI
Adverse event of special interest
AIMS
Abnormal Involuntary Movement Scale
ALT 
Alanine aminotransferase
ALP
Alkaline phosphatase
anti-HCV
Hepatitis C antibodies
aPTT
Activated partial thromboplastin time
AST 
Aspartate aminotransferase
BARS
Barnes Akathisia Rating Scale
BMI
Body mass index
BPD
Borderline personality disorder
BPM
Beats per minute
BUN
Blood urea nitrogen
CGI-I
Clinical Global Impression-Improvement of Illness
CGI-S
Clinical Global Impression-Severity of Illness
CPK
Creatine phosphokinase
CRO
Contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
Cytochrome P450
D
Dopamine
DBP
Diastolic blood pressure
DNA
Deoxyribonucleic acid
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders, 4th edition
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
ECG
Electrocardiogram
EPS
Extrapyramidal symptoms
ET
Early termination
FBR
Future Biospecimen Research
FDA
Food and Drug Administration
FOCBP
Females of childbearing potential
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
HbA1c
Glycosylated hemoglobin
HBsAg
Hepatitis B surface antigen
HDL
High-density lipoprotein
HIV
Human immunodeficiency virus
CCI


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Abbreviation
Definition
ICF
Informed consent form
ICH
International Council for Harmonisation
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee
IMP
Investigational medicinal product(s)
IND
Investigational New Drug
INR
International normalized time
IRB
Institutional Review Board
IRE
Immediately reportable event
Ki
Inhibitory constant
LDH
Lactate dehydrogenase
LDL
Low-density lipoprotein
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MDD
Major depressive disorder
MDMA
Methylenedioxymethamphetamine
MINI
Mini International Neuropsychiatric Interview
MMRM
Mixed-effect model repeated measure
OC
Observed case
OPDC
Otsuka Pharmaceutical Development & Commercialization, Inc 
PGI-C
Patient’s Global Impression of Change
PGI-S
Patient’s Global Impression of Severity
PGx
Pharmacogenomic(s)
PK
Pharmacokinetic(s)
PQC
Product Quality Complaint
PT
Prothrombin time
PTSD
Post-traumatic stress disorder
QTcB
QT interval as corrected by Bazett’s formula
QTcF
QT interval as corrected by Fridericia’s formula
QTcN
QT interval as corrected by the FDA Neuropharm Division formula
RBC
Red blood cell
RNA
Ribonucleic acid
RR
Response rate
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Simpson Angus Scale
SBP
Systolic blood pressure
SCID-5-PD
Structured Clinical Interview for DSM-5 Personality Disorders
SYE
Subject years of exposure
T4
Thyroxine
TEAE
Treatment-emergent adverse event
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
US
United States
WBC
White blood cell


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Abbreviation
Definition
ZAN-BPD
Zanarini Rating Scale for Borderline Personality Disorder


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10.5
Appendix 5: Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance
Laboratory Tests
Criteria
Chemistry
AST (SGOT)
3 x ULN
ALT (SGPT)
3 x ULN
Alkaline phosphatase
3 x ULN
Lactate dehydrogenase
3 x ULN
Blood urea nitrogen
30 mg/dL
Creatinine
2.0 mg/dL
Uric acid
Men
10.5 mg/dL
Women
8.5 mg/dL
Bilirubin (total)
2.0 mg/dL
Creatine phosphokinase
> 3 x ULN
Prolactin
> ULN
Hematology
Hematocrit
Men
37 % and decrease of 3 percentage points from baseline
Women
32 % and decrease of 3 percentage points from baseline
Hemoglobin
Men
11.5 g/dL
Women
9.5 g/dL
WBC count
2,800 mm3 or 16,000 mm3
Eosinophils
10%
Neutrophils
15%
Absolute neutrophil count
1,500/mm3
Platelet count
75,000/mm3 or 700,000/mm3
Urinalysis
Protein
Increase of 2 units
Glucose
Increase of 2 units
Casts
Increase of 2 units
Additional Criteria
Chloride
90 mEq/L or 118 mEq/L
Potassium
2.5 mEq/L or 6.5 mEq/L
Sodium
126 mEq/L or 156 mEq/L
Calcium
8.2 mg/dL or 12 mg/dL
Glucose
Fasting
100 mg/dL
Nonfasting
200 mg/dL
Total cholesterol, fasting
240 mg/dL
LDL cholesterol, fasting
160 mg/dL
HDL cholesterol, fasting
Men
< 40 mg/dL
Women
< 50 mg/dL
Triglycerides, fasting
150 mg/dL


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10.6
Appendix 6: Criteria for Identifying Vital Signs of Potential Clinical 
Relevance
Variable
Criterion Valuea
Change Relative to 
Baselinea
Heart rateb
> 120 bpm
< 50 bpm
15 bpm increase
15 bpm decrease
Systolic blood pressureb
> 180 mmHg
< 90 mmHg
20 mmHg increase
20 mmHg decrease
Diastolic blood pressureb
> 105 mmHg
< 50 mmHg
15 mmHg increase
15 mmHg decrease
Orthostatic hypotension
20 mmHg decrease in systolic blood 
pressure and a 25 bpm increase in heart 
rate from supine to standing
Not applicable
(baseline status not 
considered)
Weight
−
7% increase
7% decrease
bpm = beats per minute.
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 New Drug Application Submission and for Organizing Information in Periodic Safety 
Updates,” FDA Division of Neuropharmacological Drug Products draft (2/27/87).


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10.7
Appendix 7: Criteria for Identifying ECG Measurements of 
Potential Clinical Relevance
Variable
Criterion Valuea
Change Relative to 
Baselinea
Rate
Tachycardia
120 bpm
increase of 15 bpm
Bradycardia
50 bpm
decrease of 15 bpm
Rhythm
Sinus tachycardiab
120 bpm
increase of 15 bpm
Sinus bradycardiac
50 bpm
decrease of 15 bpm
Supraventricular premature beat
all
not present present
Ventricular premature beat
all
not present present
Supraventricular tachycardia
all
not present present
Ventricular tachycardia
all
not present present
Atrial fibrillation
all
not present present
Atrial flutter
all
not present present
Conduction
1 atrioventricular block
PR 200 msec
increase of 50 msec
2 atrioventricular block
all
not present present
3 atrioventricular block
all
not present present
Left bundle-branch block
all
not present present
Right bundle-branch block
all
not present present
Pre-excitation syndrome
all
not present present
Other intraventricular conduction blockd
QRS 120 msec
increase of 20 msec
Infarction
Acute or subacute
all
not present present
Old
all
not present present
12 weeks post trial entry
ST/T Morphological
Myocardial ischemia
all
not present present
Symmetrical T-wave inversion
all
not present present
Increase in QTc
QTcF > 450 msec
(males)
QTcF > 470 msec
(females)
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column.
bNo current diagnosis of supraventricular tachycardia, ventricular tachycardia, atrial fibrillation, atrial 
flutter, or other rhythm abnormality.
cNo current diagnosis of atrial fibrillation, atrial flutter, or other rhythm abnormality.
dNo current diagnosis of left bundle branch block or right bundle branch block.


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10.8
Appendix 8: 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 subjects, conduct or management of the trial, trial design, or the quality 
or safety of IMP(s) used in the trial. A protocol change intended to eliminate an apparent 
immediate hazard to subjects should be implemented immediately 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 
subject, the currently approved written ICF will require similar modification. In such 
cases, after approval/favorable opinion of the new ICF by the IRB/IEC, repeat written 
informed consent will be obtained from subjects enrolled in the trial before expecting 
continued participation and before the amendment-specified changes in the trial are 
implemented.






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11
References
1
Lieb K, Zanarini MC, Schmahl C, Linehan MM, Bohus M. Borderline personality 
disorder. Lancet. 2004;364(9432):453-61.
2
Gask L, Evans M, Kessler D. Clinical review: personality disorder. BMJ. 
2013;347(10):f5276.
3
National Institute of Mental Health [homepage on the Internet]. Bethesda: Borderline 
Personality Disorder; Updated December 2017, Accessed 28 Aug 2018. Available 
from: http://www.nimh.nih.gov/health/topics/borderline-personality-
disorder/index.shtml.
4
Grant BF, Chou SP, Goldstein RB, Huang B, Stinson FS, Saha TD, et al. Prevalence, 
correlates, disability, and comorbidity of DSM-IV borderline personality disorder: 
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Truven Marketscan Treatment Pathways; January 2016-December 2017, Otsuka Data 
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National Comorbidity Survey Replication. Biol Psychiatry. 2007.
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American Psychiatric Association. Practice Guideline for the Treatment of Patients 
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American Psychiatric Association: Diagnostic and Statistical Manual of Mental 
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Lenzenweger MF, Lane MC, Loranger AW, Kessler RC. DSM-IV personality 
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10 Otsuka Pharmaceutical Co, Ltd., Otsuka Pharmaceutical Development & 
Commercialization, Inc., H. Lundbeck A/S. REXULTI® (brexpiprazole) 
Investigator's Brochure, Edition 14. Otsuka Report, issued 01 Aug 2018.
11 Black DW, Zanarini MC, Romine A, Shaw M, Allen J, Schulz SC. Comparison of 
low and moderate dosages of extended-release quetiapine in borderline personality 
disorder: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 
2014;171(11):1174.
12 Zanarini MC, Schulz SC, Detke HC, Tanaka Y, Zhao F, Lin D, et al. A dose 
comparison of olanzapine for the treatment of borderline personality disorder: a 12-
week randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 
2011;72(10):1353-1362.
13 Schulz SC, Camlin KL, Berry SA, Jesberger JA. Olanzapine safety and efficacy in 
patients with borderline personality disorder and comorbid dysthymia. Biol 
Psychiatry. 1999;46(10):1429-1435.
14 Schulz SC, Zanarini MC, Bateman A, Bohus M, Detke HC, Trzaskoma Q, et al. 
Olanzapine for the treatment of borderline personality disorder: variable dose 12-
week randomised double-blind placebo-controlled study. Br J Psychiatry. 
2008;193(6):485-492.


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15 Chengappa KN, Ebeling T, Kang JS, Levine J, Parepally H. Clozapine reduces severe 
self-mutilation and aggression in psychotic patients with borderline personality 
disorder. J Clin Psychiatry. 1999;60(7):477-484.
16 Belli H, Ural C, Akbudak M.  Borderline personality disorder:  bipolarity, mood 
stabilizers and atypical antipsychotics in treatment. J Clin Med Res. 2012;4(5):301-
308.
17 Nickel MK, Muehlbacher M, Nickel C, Kettler C, Pedrosa Gil F, Bachler E, et al. 
Aripiprazole in the treatment of patients with borderline personality disorder: a
double-blind, placebo-controlled study. Am J Psychiatry. 2006;163(5):833-838.
18 Nickel MK, Loew TH, and Pedrosa Gil, F. Aripiprazole in treatment of borderline 
patients, part II: an 18-month follow-up. Psychopharmacology. 2007;191:1023-1026.
19 DeBellis MD, Lefter L, Trickett PK, Putnam FW. Urinary catecholamine excretion in 
sexually abused girls. J Am Acad Child Adol Pschiatry. 1997;33(3):320-327.
20 Friedel RO. Dopamine dysfunction in borderline personality disorder: a hypothesis. 
Neuropsychopharmacol. 2004;29:1029-1039.
21 Joyce PR, Stephenson J, Kennedy M, Mulder RT, McHugh PC. The presence of both 
serotonin 1A receptor (HTR1A) and dopamine transporter (DAT1) gene variants 
increase the risk of borderline personality disorder. Frontiers in Genetics. 
2014;4(313):1-7.
22 Martin-Blanco A, Ferrer M, Soler J, Arranz MJ, Vega D, Bauza J, et al. An 
exploratory association study of the influence of noradrenergic genes and childhood 
trauma in borderline personality disorder. Psychiatry Research. 2015;229:589-592.
23 Oquendo MA, Mann JJ. The biology of impulsivity and suicidality. Psychiatric 
Clinics of North America. 2000;23(1):11-25.
24 Haddjeri N, de Montigny C, Blier P. Modulation of the firing activity of 
noradrenergic neurons in the rat locus coeruleus by the 5-hydroxytryptamine system. 
Br J Pharmacol. 1997;120:865-875.
25 Skodol AE, Gunderson JG, McGlashan TH, Dyck IR, Stout RL, Bender DS, et al. 
Functional impairment in patients with schizotypal, borderline, avoidant, or 
obsessive-compulsive personality disorder. Am J Psychiatry. 2002;159(2):276-283.
26 Zanarini MC, Vujanovic AA, Parachini EA, Boulanger JL, Frankenburg FR, Hennen 
J. Zanarini rating scale for borderline personality disorder (ZAN-BPD): a continuous 
measure of DSM-IV borderline psychopathology. J Pers Disord. 2003;17(3):233-242.
27 Guy W. ECDEU Assessment Manual for Psychopharmacology. US Department of 
Health, Education, and Welfare publication (ADM) 76-338. Rockville, MD: National 
Institute of Mental Health; 1976.
28 Lindenmayer JP, Czobor P, Alphs L, Nathan AM, Anand R, Islam Z, et al. The 
InterSePT scale for suicidal thinking reliability and validity. Schizophr Res. 
2003;63:161-170.
29 Larry Alphs, personal communication.
30 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.


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31 Üstün TB, Chatterji S, Kostanjsek N, Rehm J, Kennedy C, Epping-Jordan J, Saxena 
S, von Korff M, Pull C, World Health Organization. National Institutes of Health 
Developing the World Health Organization Disability Assessment Schedule 2.0. Bull 
World Health Organ. 2010 Nov 1;88(11):815–823.
32 Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr 
Scand. 1983;67:361-370.
33 First MB, Williams JBW, Benjamin LS, Spitzer RL,. User’s Guide for the SCID-5-
PD (Structured Clinical Interview for DSM-5 Personality Disorder). Arlington, VA, 
American Psychiatric Association, 2015.
34 Sheehan DV, Lecrubier Y, Harnett-Sheehan K, Amorim P, Janavs J, Weiller E, et al. 
The Mini International Neuropsychiatric Interview (M.I.N.I): The development and 
validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J 
Clin Psychiatry. 1998;59(Suppl 20):22-33.
35 Sheehan DV, Lecrubier Y, Harnett-Sheehan K, Janavs J, Weiller E, Bonara LI, et al. 
The validity of the MINI International Neuropsychiatric Interview (M.I.N.I.): 
According to the SCID-P. Eur Psychiatry. 1997;12(5):232-241.
36 Lecrubier Y, Sheehan DV, Weiller E, Amorim P, Bonora I, Sheehan KH, et al. The 
MINI International Neuropsychiatric Interview (M.I.N.I.) A short diagnostic 
structured interview: Reliability and validity according to the CIDI. Eur Psychiatry. 
1997;12:224-231.
37 Amorim P, Lecrubier Y, Weiller E, Hergueta T, Sheehan D. DSM-IH-R Psychotic 
Disorders: Procedural validity of the Mini International Neuropsychiatric Interview 
(M.I.N.I). Concordance and causes for discordance with the CIDI. Eur Psychiatry. 
1998;13(1):26-34.
38 The Practical Guide: Identification, evaluation, and treatment of overweight and 
obesity in adults. Developed by National Institutes of Health National Heart, Lung 
and Blood Institute. North American Association for the Study of Obesity. NIH 
Publication Number 00-4084, October 2000.
39 Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta 
Psychiatr Scand Suppl. 1970;212(Suppl 44):S11-19.
40 Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672-
676.
41 E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1). Geneva, 
Switzerland: International Conference on Harmonisation; 2018.


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Agreement
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator's Brochure) and agree that it contains all the ethical, legal and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor's (or designee's) Clinical Trial Agreement.
I will provide copies of the protocol to all physicians, nurses, and other professional personnel to 
whom I delegate trial responsibilities. I will discuss the protocol with them to ensure that they are 
sufficiently informed regarding the investigational new drug, OPC-34712, the concurrent medications, 
the efficacy and safety parameters and the conduct of the trial in general. I am aware that this protocol 
must be approved by the Institutional Review Board (IRB) or receive a favorable opinion by the
Independent Ethics Committee (IEC) responsible for such matters in the clinical trial facility where 
OPC-34712 will be tested prior to commencement of this trial. I agree to adhere strictly to the attached 
protocol (unless amended in the manner set forth in the sponsor's Clinical Trial Agreement, at which 
time I agree to adhere strictly to the protocol as amended).
I understand that this IRB/IEC-approved protocol will be submitted to the appropriate regulatory 
authority/ies by the sponsor. I agree that clinical data entered on eSource by me and my staff will be 
utilized by the sponsor in various ways, such as for submission to governmental regulatory authorities 
and/or in combination with clinical data gathered from other research sites, whenever applicable. I 
agree to allow sponsor and designee monitors and auditors full access to all medical records at the 
research facility for subjects screened or enrolled in the trial.
I agree to await IRB/IEC approval before implementation of any substantial amendments to this 
protocol. If, however, there is an immediate hazard to subjects, I will implement the amendment 
immediately, and provide the information to the IRB/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 subjects with informed consent forms, as required by the applicable regulations 
and by ICH guidelines. I agree to report to the sponsor any adverse experiences in accordance with the 
terms of the sponsor's Clinical Trial Agreement and the relevant regional regulation(s) and 
guideline(s). I further agree to provide all required information regarding financial certification or 
disclosure to the sponsor for all investigators and subinvestigators in accordance with the terms of the 
relevant regional regulation(s). I understand that participation in the protocol involves a commitment 
to publish the data from this trial in a cooperative publication before publication of efficacy and safety 
results on an individual basis may occur, and I consent to be acknowledged in any such cooperative 
publications that result.
____________________________
_____________________________
___________
Principal Investigator Print Name
Signature
Date


T hi s p a g e i s a m a nif e st ati o n of a n el e ctr o ni c all y c a pt ur e d si g n at ur e
SI G N A T U R E P A G E
D o c u m e nt N a m e: 3 3 1- 2 0 1- 0 0 2 4 2 _ Pr ot o c ol A m e n d m e nt 1
D o c u m e nt N u m b er: 1 0 0 0 0 3 4 9 9 8
D o c u m e nt V er si o n: 4. 0
Si g n e d b y
M e a ni n g of Si g n at ur e
S er v er D at e
( d d- M M M-
y y y y h h: mi n) -
U T C ti m e z o n e
Cli ni c al A p pr o v al
0 7- J ul- 2 0 2 0
1 6: 5 3: 4 0
A p pr o v e d f or Cli ni c al
P h ar m a c ol o g y
a n d N o n cli ni c al
0 7- J ul- 2 0 2 0
1 6: 3 1: 4 7
Bi o st ati sti c s A p pr o v al
0 7- J ul- 2 0 2 0
1 9: 1 8: 5 3

SAP_001.pdf: 
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Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigational New Drug
Brexpiprazole (OPC-34712)
A Multicenter, Randomized, Flexible-dose, Double-blind Trial of Brexpiprazole versus 
Placebo for the Treatment of Adults With Borderline Personality Disorder
Protocol No. 331-201-00242
IND No. 141091
EudraCT No. 2019-002813-20
Statistical Analysis Plan
Version: 3.0
Date: June 21, 2021
CONFIDENTIAL – PROPRIETARY INFORMATION
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Otsuka Pharmaceutical Development & Commercialization, Inc.


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Table of Contents
Table of Contents ..........................................................................................2
List of In-text Tables.....................................................................................5
List of In-text Figures ...................................................................................6
1
Introduction..........................................................................................7
2
Study Objectives...................................................................................7
3
Trial Details ..........................................................................................7
3.1
Study Design .......................................................................................................7
3.2
Trial Treatments ................................................................................................10
4
Sample Size and Power Justification................................................10
5
Data Sets for Analysis and Missing Data .........................................11
5.1
Data Sets for Analysis.......................................................................................11
5.2
Handling of Missing Data .................................................................................12
6
Study Conduct ....................................................................................12
6.1
Subject Disposition, Completion Rate and Reasons for Discontinuation.........12
6.2
Treatment Compliance ......................................................................................12
6.3
Protocol Deviation.............................................................................................12
7
Baseline Characteristics.....................................................................13
7.1
Baseline Definition............................................................................................13
7.2
Demographic Characteristics ............................................................................13
7.3
Medical and Psychiatric History .......................................................................13
7.4
Neuropsychiatric Diagnosis ..............................................................................13
7.5
Baseline Psychiatric Evaluation........................................................................13
8
Efficacy Analysis ................................................................................14
8.1
Primary Efficacy Endpoint................................................................................14
8.1.1
Primary Estimand ...........................................................................................14
8.1.2
Primary Efficacy Analysis..............................................................................16
8.1.3
Technical Computation Details for Primary Efficacy Analysis .....................17
8.1.4
Sensitivity Analyses........................................................................................17
8.1.4.1
Sensitivity Analyses for Missing at Random (MAR) Assumption.............17


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8.1.4.2
Supplemental Analyses for Violation of Normality Assumption ...............19
8.1.4.3
COVID-19 Pandemic Related Sensitivity Analyses...................................19
8.1.5
Subgroup Analyses.........................................................................................20
8.2
Key Secondary Endpoint Analysis....................................................................21
8.3
Control of Experiment-wise Type 1 Error ........................................................21
8.4
Secondary Efficacy Endpoint Analysis.............................................................21
9
Safety Analysis....................................................................................23
9.1
Adverse Events..................................................................................................23
9.2
Clinical Laboratory Tests..................................................................................25
9.2.1
Drug Induced Liver Injury (DILI)..................................................................25
9.2.2
Metabolic Change...........................................................................................25
9.3
Vital Signs.........................................................................................................26
9.4
12-Lead ECG.....................................................................................................27
9.5
Physical Examinations ......................................................................................28
9.5.1
Body Weight, Waist Circumference and BMI ...............................................28
9.6
SAS, AIMS, and BARS ....................................................................................28
9.7
Suicidality Data.................................................................................................29
9.8
Concomitant Medications .................................................................................29
9.9
Extent of Exposure............................................................................................29
10
Conventions.........................................................................................30
10.1
Study Visit Windows ........................................................................................30
10.2
Pooling of small centers ....................................................................................31
10.3
Scales: Rules for Scoring and Handling of Missing Data.................................31
10.3.1
ZAN-BPD.......................................................................................................31
10.3.2
CGI-S..............................................................................................................32
10.3.3
CGI-I...............................................................................................................32
10.3.5
PGI-S ..............................................................................................................32
10.3.6
PGI-C..............................................................................................................33


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10.3.9
SAS.................................................................................................................33
10.3.10
AIMS ..............................................................................................................34
10.3.11
BARS..............................................................................................................34
10.3.12
C-SSRS...........................................................................................................34
11
References ...........................................................................................35
12
Potential Clinical Relevance Criteria from Protocol ......................36
13
Proposed List of Summary Tables....................................................41
14
History of SAP Amendments ............................................................53
 


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List of In-text Tables
Table 3.2-1
Dosing Schedule ............................................................................10


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List of In-text Figures
Figure 3.1-1
Trial Design Schematic....................................................................9


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1
Introduction
This statistical analysis plan (SAP) documents the statistical methodology and data analysis 
algorithms and conventions to be applied for statistical analysis and reporting of efficacy and 
safety data of study 331-201-00242.  All amendments and addendums (including the COVID-
19 specific protocol addendum) to the protocol are taken into consideration in developing this 
SAP.  In addition, if the analyses described in the protocols differ from those in this SAP, the 
methods of the SAP prevail.
2
Study Objectives
Primary:  To compare the efficacy of brexpiprazole versus placebo for the treatment of 
subjects with a diagnosis of borderline personality disorder (BPD).
Secondary:  To evaluate the safety and tolerability of brexpiprazole for the treatment of 
subjects with a diagnosis of BPD.
3
  Trial Details
3.1
Study Design
This will be a 12-week, multicenter, randomized, double-blind, placebo-controlled trial of 
brexpiprazole in subjects diagnosed with BPD according to the Diagnostic and Statistical 
Manual of Mental Disorders, 5th edition (DSM-5) and confirmed by a valid diagnostic 
instrument (Structured Clinical Interview for DSM-5 Personality Disorders [SCID-5-PD]). 
See Figure 3.1-1 for a schematic of the trial design. 
The trial will be organized as follows:
Screening Period:  The screening period will begin after written informed consent has been 
obtained and will take place between Day −21 and Day −1 prior to enrollment. Eligible 
subjects are required to meet all inclusion criteria at both screening and the start 
 
including a total score of ≥ 12 on the Zanarini Rating Scale for 
Borderline Personality Disorder (ZAN-BPD). In addition, a score of ≥ 2 in at least 2 of the 
following 4 ZAN-BPD scale items will be required at screening and Day 0: 1) “inappropriate, 
intense anger or difficulty controlling anger” (hereafter referred to as inappropriate anger), 
2) “transient stress-related paranoid ideation or severe dissociative symptoms” (paranoid 
ideation), 3) “affective instability due to a marked reactivity of mood” (affective instability), 
and 4) “impulsivity in at least other two areas that are potentially self-damaging” 
(impulsivity).     


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Double-blind Treatment Period 
 subjects will be randomly 
assigned to treatment with brexpiprazole 2 to 3 mg/day or placebo in a 1:1 fashion. Subjects 
will receive their assigned treatment during an 11-week, double-blind treatment period 
 
The timing of the primary and key secondary endpoints will be blinded to the investigator; 
these endpoints will be assessed after 9 weeks of assigned treatment (Week 10). Subjects will 
continue treatment through Week 12 of the trial. The primary endpoint and the key secondary 
endpoint will be the change from baseline to Week 10 in the clinician administered 
ZAN-BPD total score and Clinical Global Impression Scale - Severity of Illness (CGI-S) 
score, respectively. Visits will occur at the end of Weeks 1, 2, 4, 6, 8, 10, and 12/early 
termination (ET).
Post-treatment (Safety) Follow-up Period:  Subjects who do not continue treatment in the 
open-label extension trial will be followed up for safety reasons via telephone contact or in 
clinic visit 21 (± 2) days after the last dose of investigational medicinal product (IMP). This 
contact also applies to subjects who are withdrawn prematurely from the trial.


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total of 200 subjects (100 subjects each in the brexpiprazole treatment arm and the placebo 
treatment arm) will yield 80% power to detect the treatment effects at a 2-tailed significance 
level of 0.05. In order to have 200 subjects randomized and evaluable (assuming a 5% non-
evaluable/dropout rate) in the Full Analysis Set for Enriched Subjects (FAS for Enriched 
Subjects) sample (defined in Section 5.1), approximate 240 subjects (120 subjects each in the 
brexpiprazole treatment arm and the placebo treatment arm) will be randomized in this trial.
5
Data Sets for Analysis and Missing Data 
5.1
Data Sets for Analysis
The following analysis samples are defined for this trial:
Enrolled Sample: comprises all subjects who signed an informed consent form (ICF) for the 
trial and enrolled 
Enriched Randomized Sample: comprises all subjects who were randomized satisfying the 
ITT for Enriched Subjects Criteria, where the ITT for Enriched Subjects Criteria are defined 
as the ZAN-BPD total score ≥ 10 at baseline, and a score ≥ 2 in at least 2 of the following 
4 ZAN-BPD subscale items at baseline: inappropriate anger, paranoid ideation, affective 
instability, and impulsivity 
Randomized Sample: comprises all subjects who were randomized
 Subjects are 
considered randomized when they are assigned a treatment number by the interactive 
response technology (IRT) 
 A subject 
receiving investigational medicinal product (IMP) outside of the IRT will not be considered 
randomized, but safety will be reported.
Safety Sample: comprises those randomized subjects 
 Randomized Sample who 
received at least 1 dose of double-blind IMP.
FAS for Enriched Subjects: comprises those subjects in the Enriched Randomized Sample 
who received at least 1 dose of double-blind IMP, and have a baseline value and at least 1 
valid post-randomization efficacy evaluation for ZAN-BPD total score 
 
 
Full analysis Set (FAS): comprises all subjects in the Safety Sample who have a baseline 
value and at least 1 valid post-randomization efficacy evaluation for ZAN-BPD total score  


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In general, baseline of an efficacy endpoint is defined as the last available measurement 
before the first dose of double-blind IMP, scheduled at Week 1 visit.  
Randomization in this trial will be stratified by site, status of background ADT therapy (with 
or without background ADT), and whether or not they meet the ITT for Enriched Subjects 
Criteria.
5.2
Handling of Missing Data
In general, missing data will be handled by analysis of mixed-effect model repeated measures 
(MMRM) methodology based on observed-case (OC) data from protocol-specified visits 
under the assumption of missing at random (MAR). The OC dataset consists of actual 
observations recorded at each visit 
 and no missing data will be imputed.
The last observation carried forward (LOCF) analysis will include data recorded at a 
scheduled double-blind treatment phase visit or, if no observation is recorded at that visit, data 
carried forward from the previous scheduled double-blind treatment phase visit.  Baseline data 
will not be carried forward to impute missing values for the LOCF analysis.
6
Study Conduct
6.1
Subject Disposition, Completion Rate and Reasons for Discontinuation
Subject disposition will be summarized for the Randomized Sample by the treatment group, 
and by center. 
Subject completion rate and reasons for discontinuation will be summarized for the 
Randomized Sample by treatment group. 
6.2
Treatment Compliance
Based on the Investigational medicinal product (IMP) panel of the CRF, compliance in taking 
IMP is calculated by dividing the number of tablets/capsules taken by the total number of 
tablets/capsules the patients were scheduled to take during the study period. For lost-to-follow 
up patients, last IMP end date record will be used as the treatment end date.  
6.3
Protocol Deviation
Protocol deviations will be summarized by center and type of deviation for randomized subjects 
by treatment group. A listing of protocol deviations will be provided.  In addition, protocol 
deviations affected by the COVID-19 will be summarized. Listing of subjects with protocol 
deviations affected by the COVID-19 will also be provided.


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7
Baseline Characteristics
7.1
Baseline Definition 
For analyses of the double-blind treatment period 
 data, baseline measurement is 
defined as the last available measurement prior to the first dose of double-blind IMP, 
scheduled at the Week 1 visit.
7.2
Demographic Characteristics
Baseline demographic characteristics include age, sex, race, ethnicity, height, weight, waist 
circumference, and body mass index (BMI). For the Randomized Sample, demographic 
characteristics will be summarized by treatment group. 
Mean, range and standard deviation will be used to describe continuous variables such as age. 
Frequency distributions will be tabulated for categorical variables such as race.
7.3
Medical and Psychiatric History 
A summary of medical, psychiatric, and borderline personality disorder history will be 
presented for the Randomized Sample (by treatment group and overall).
7.4
Neuropsychiatric Diagnosis 
A summary of the MINI International Neuropsychiatric Interview (M.I.N.I.) will be presented 
for the Randomized Sample (by treatment group and overall). Summarized will be the number 
and percentage of patients who meet each diagnosis criteria, and number and percentage of 
patients with each primary diagnosis.
A summary of the Structured Clinical Interview for DSM-5 Personality Disorders (SCID-5-
PD) will be presented for the Randomized Sample (by treatment group and overall). 
Summarized will be the number and percentage of patients who meet criteria of each 
personality disorder. 
7.5
Baseline Psychiatric Evaluation 
For the Randomized Sample, baseline psychiatric scale evaluation will be summarized by 
treatment group and overall. The mean, median, range and standard deviation will be used to 
summarize the assessments of: ZAN-BPD Total Score, Clinical Global Impression – Severity 


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of Illness Scale (CGI-S), PGI-S, 
, ZAN-BPD 
sector scores, 
. 
8
Efficacy Analysis
For analysis 
, baseline is defined as the last available measurement prior to the 
first dose of double-blind IMP, scheduled at the Week 1 visit. 
All efficacy analyses will be performed on the FAS for Enriched Subjects and on the FAS 
unless specified otherwise, with FAS for Enriched Subjects being primary. Statistical 
comparisons are based on 2-sided, 0.05 significance levels.
8.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the change from baseline to Week 10 visit in the ZAN-BPD 
total score.
8.1.1
Primary Estimand
The primary estimand defining the treatment effect of interest in the trial uses the hypothetical 
strategy specified in the International Conference for Harmonisation (ICH) E9 (R1) 
Addendum. The objective of the primary analysis is to compare the efficacy of brexpiprazole 
versus placebo for the treatment of subjects with a diagnosis of BPD. The estimand, or target 
of estimation, following the hypothetical strategy is the pharmacological effect seen, had no 
withdrawals occurred.  This hypothetical estimand is justifiable in this case, since the focus is 
on the pharmacological effect of the drug additional to non-specific effects. Subjects who 
withdraw from a symptomatic IMP treatment either could have lost their treatment effect, had 
the subjects not taken any other symptomatic medication after withdrawal, or could have their 
treatment effect been masked, had the subjects taken other symptomatic medication after 
withdrawal. This means that any observations taken after subjects stop IMP will most likely 
not contribute relevant information about the pharmacological effect of the drug. Due to this 
strategy, the last collected efficacy assessment after premature trial discontinuation will be 
done only once at the ET Visit. Every effort will be made to complete all of the ET 
evaluations prior to administering any additional medications for the treatment of BPD or 
other prohibited medications. In the case of terminal or lost to follow-up events no ET 
evaluations would be expected, and only scheduled assessments performed before such an 
event has occurred. 
The primary estimand for this trial is defined by the following components:


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
Target Population: FAS for Enriched Subjects

Endpoint: Change from Baseline to Week 10 in the ZAN-BPD total score

Intercurrent Events: Premature treatment discontinuation

Measure of Intervention Effect: Difference in endpoint means between Brexpiprazole 
and Placebo arm.
The National Emergency Announcement concerning the coronavirus disease 2019 (COVID-
19) pandemic was declared on March 13, 2020. The pandemic had a significant impact on 
many aspects of clinical trials. There are occasionally virtual visits (i.e., virtual assessments) 
and possibly early discontinuation of treatment directly or indirectly related to the pandemic.  
However, subjects were required to attend the screening, Day 0, Week 1, Week 10, and the 
end of trial visits in person (i.e., face-to-face). The details of trial conduct during the COVID-
19 pandemic are described in the COVID-19 specific protocol addendum. Note that virtual 
visits in the pandemic environment will not be treated as an intercurrent event for the primary 
analysis. Subjects who drop out with a reason relating to the COVID-19 pandemic will be 
handled as they would have dropped out for another reason if the pandemic had not happened.  
The hypothetical strategy of handling intercurrent events will be used to clarify the efficacy of 
the brexipiprazole had there be no occurrence of intercurrent events, regardless of being 
COVID-19 related or not.  In other words, the estimand as described above will use the 
hypothetical strategy to address the treatment effect of interest that would be envisioned under 
the hypothetical setting of no occurrence of intercurrent events in the planned 12-week 
treatment period. 
The estimator will be the Mixed Model Repeated Measurements (MMRM) estimate for 
treatment difference at Week 10, based on all observed case (OC) data until discontinuation 
from the trial. This reflects the chosen strategies for the identified intercurrent events. Details 
of the model are provided in the next section. 
In this hypothetical strategy, the event of withdrawing IMP is considered MAR, and the 
primary endpoint of the trial could be considered as a combination of the responses of on-
treatment completers at Week 10 and the imputation of the endpoint to Week 10 following the 
trend in each treatment group using the MMRM method for subjects who withdraw IMP 
during the trial. All data collected during the trial treatment period will be used for statistical 
analysis. For the primary efficacy analysis, the treatment effect will be estimated using the 
MMRM method described in Section 8.1.2. Under the MAR assumption, MMRM provides an 
unbiased estimate of treatment effect for the treatment period. Analyses with missing values 


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imputed by multiple imputation (MI) under MNAR, and other methods will be performed as 
sensitivity analyses.
It's assumed that the placebo effect is reduced in the FAS for Enriched Subjects comparing to 
the FAS.
8.1.2
Primary Efficacy Analysis
The primary analysis will be performed on the FAS for Enriched Subjects. The primary 
efficacy analysis will be performed by fitting a mixed-effect model repeated measure 
(MMRM) analysis with an unstructured variance covariance structure in which the change 
from the baseline in ZAN-BPD Total Score during the double-blind treatment phase will be 
the dependent variable based on the observed cases (OC) data set. The OC data set will 
consist of actual observations recorded at each visit during the double-blind treatment phase 
and no missing data will be imputed. The model will include fixed class effect terms for 
treatment, trial site, visit, ADT Status (with/without background ADT), and an interaction 
terms of treatment by visit, and gender by visit.  The model will also include the interaction 
term of baseline values of ZAN-BPD Total score by visit and age by visit as covariates.  All 
scheduled visits after baseline 
 including Week 12, will be included in the 
model but the primary comparison will be performed at the Week 10 visit. The primary 
comparison between the brexpiprazole group and the placebo group at the Week 10 visit 
 will be estimated as the difference between Least Squares (LS) means 
utilizing the computing software SAS procedure PROC MIXED.  The comparison between 
brexpiprazole group and placebo group will be tested at a significance level of 0.05 (2-sided).
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.
In the case of gross violations of the linear model assumptions, nonparametric van Elteren test 
stratified by center will be performed to compare treatment effect at Week 10 of the double-
blind treatment period 
 on Multiple Imputation (MI) data.  


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8.1.3
Technical Computation Details for Primary Efficacy Analysis
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:
proc mixed;
     class treatment center visit ADT_Status sex subjid;
    model change=treatment center visit ADT_Status treatment*visit baseline*visit  age*visit 
sex*visit/ s cl  ddfm=kenwardroger;    
    repeated visit /type=un subject=subjid r rcorr;
    lsmeans treament*visit / pdiff cl alpha=0.05 slice=visit;
run;
where baseline is the ZAN-BPD Total Score at baseline (Week 1 visit of the double-blind 
treatment period). 
8.1.4
Sensitivity Analyses
8.1.4.1
Sensitivity Analyses for Missing at Random (MAR) Assumption
The mixed-model repeated measures (MMRM) assume data are missing at random (MAR), 
which is a reasonable assumption in longitudinal clinical trials1. However, the possibility of 
“missing not at random” (MNAR) data can never be ruled out. As sensitivity analyses,  
pattern-mixture model2,3,4,5 and shared parameter model6 will be used to explore data missing 
mechanisms of MNAR and investigate the response profile of dropout reason.  Pattern 
Mixture Models based on Multiple Imputation (MI) with mixed missing data mechanisms will 
be used to investigate the response profile of dropout subjects by last dropout reason under 
MNAR mechanism for the following 3 scenarios: 1) Dropout reasons due to either AE or lack 
of efficacy (LOE) as MNAR, 2) Dropout reasons due to either AE or LOE or subject 
withdrew consent as MNAR, 3) All dropouts as MNAR using both 1) Delta adjustment 
imputation method which is to departure from MAR assumption by progressively increasing 
the delta until conclusion from the primary analysis is overturned, and 2) Placebo-based 
imputation methods in which missing data for both placebo and drug group are imputed based 
on the imputation model derived from placebo data.  If drug improved outcomes prior to 
dropout, this benefit is carried into subsequent imputed values, but will diminish over time in 
accordance with the correlation structure.  
Traditionally the dropout mechanisms are divided into three types (Little, 1995): (1) Missing 
Completely at Random (MCAR), in which the probability of dropout doesn’t depend on the 
observed data and the missing data; (2) Missing at Random (MAR), in which the probability of 
dropout depends on the observed data, and (3) Missing Not at Random (MNAR), where the 
probability of dropout depends on the missing data and possibly the observed data.


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Most of MNAR methods (Diggle P, Kenward MG, 1994) have treated all observations with 
dropout as if they fall within the same dropout type. In practice, we would find that different 
dropout reasons may be related to the outcomes in different ways, for example, detailed 
dropout reasons for this study are:  adverse event (AE), death, lack of efficacy (LOE), lost to 
follow-up, non-compliance with IMP, pregnancy, protocol deviation, withdrawal by subject, 
trial terminated by sponsor, site terminated by sponsor, physician decision, and other. Dropout 
due to an AE, death and LOE may lead to MNAR dropout. Subject withdrew consent may 
also lead to MNAR dropout. However, it is debatable whether a dropout caused by subjects 
withdrew consent is MAR or MNAR. Except AE, LOE, and subject withdrew consent, all the 
other dropout reasons may be assumed as either MCAR or MAR dropout. Missing data due to 
COVID-19 will also be assumed as MAR.
As sensitivity analyses for missing at random (MAR) assumption, analyses for missing not at 
random (MNAR) will be carried out.  Pattern Mixture Models (PMM) based on Multiple 
Imputation (MI) with mixed missing data mechanisms will be used to investigate the response 
profile of dropout patients by dropout reason under MNAR mechanism for the following three 
scenarios:
1) Dropout reasons due to either AE or LOE as MNAR
2) Dropout reasons due to either AE or LOE or subject withdrew consent as MNAR
3) All dropouts as MNAR
Delta Adjustment Imputation Methods
This MNAR sensitivity analysis is to departure from MAR assumption by progressively 
increasing the delta until conclusion from the primary analysis is overturned.  The delta is 0%, 
10%, 20%, 30%,  ..,  of the expected treatment difference of 2.6 points and/or the observed 
treatment difference between Brex and Placebo from the primary analysis of MMRM model until 
conclusion of the primary analysis is overturned. That is, until the primary efficacy results will tip 
over with p-value ≥ 0.05. When delta=0 it is MAR. When delta > 0 it is MNAR. 
1) Using Monte Carlo Markov Chain (MCMC) methodology from PROC MI to impute the 
intermittent missing data to a monotone missing pattern;
2) Using a standard MAR-based multiple imputation approach from PROC MI to impute the 
monotone missingness data
3) For patients in the treated group and with a dropout reason of AE or LOE or subject 
withdrew consent, a delta will be added for all the values after the dropout time. 
4) Using ANCOVA model in the primary analysis to analyze the completed data using 
PROC MIXED on the multiple imputed data
5) Obtaining the overall results using PROC MIANALYZE. 


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The details of the imputation model under the MI procedure and related SAS codes are provided 
in Appendix 4.
Placebo Based Imputation Methods
Similar to “Standard” multiple imputations, except parameters for imputation model obtained 
from only the placebo (control) group. Missing data for both placebo and drug group are imputed 
based on the imputation model derived from placebo data. If drug improved outcomes prior to 
dropout, this benefit is carried into subsequent imputed values, but will diminish over time in 
accordance with the correlation structure.
8.1.4.2
Supplemental Analyses for Violation of Normality Assumption
The primary endpoint MMRM analysis is a maximum likelihood method that relies on 
normality assumption. Residual analyses will be carried out to examine model assumption. 
In the case of gross violations of the normality assumptions, nonparametric van Elteren test7 
(van Elteren, 1960) stratified by center will be performed to compare treatment effect at Week 
10 on Multiple Imputation (MI) data. The van Elteren test is a generalized Cochran-Mantel-
Haenszel (CMH) procedure useful for stratified continuous data in non-normal setting. It 
belongs to a general family of Mantel-Haenszel mean score tests. The test is performed via 
SAS procedure PROC FREQ, by including CMH2 and SCORES=MODRIDIT options in the 
TABLE statement. The stratification factor is trial center.  
In addition, other methods that are robust to distributional assumption will also be performed 
to provide different views on the primary efficacy result, these include generalized estimating 
equations (GEE), weighted GEE (WGEE), and MI-robust regression9. 
For MI-van Elteren test and MI-robust regression, imputation datasets will be generated with 
SAS MI procedure, each dataset will be analyzed, and then an overall estimate is derived with 
SAS MIANALYZE procedure. 
8.1.4.3
COVID-19 Pandemic Related Sensitivity Analyses
On March 13, 2020, the national emergence concerning the COVID-19 pandemic was 
announced in the US. The following analyses will be performed on the FAS for Enriched 
Subjects and the FAS, respectively, to evaluate the sensitivity of the primary and key 
secondary analysis results to the impact of the pandemic. The same model (e.g., with the same 
set of explanatory variables and the response variable) as that for the primary efficacy 
analysis will be used for these analyses specified below. Of note, the definition of intercurrent 


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events and the strategy for handling intercurrent events are identical to that for the primary 
efficacy analysis.
1. An MMRM analysis excluding the virtual assessments based on the FAS for Enriched 
Subjects and the FAS, respectively. 
2. An MMRM analysis using the non-COVID data set based on the FAS for Enriched 
Subjects and the FAS, respectively. The non-COVID data set consists of the OC data 
during the non-COVID treatment period. For each subject, the non-COVID treatment 
period starts from randomization and ends on the Week 12/ET date, the date before 
the first virtual assessment or the date before the first COVID-19 related protocol 
deviation, whichever occurs earlier. The non-COVID treatment period represents the 
time period when subjects did not have any COVID-19 related protocol deviations or 
virtual assessments during the double-blind treatment period. 
3. An MMRM analysis based on the non-COVID Sample. The non-COVID Sample 
comprises those subjects in the FAS for Enriched Subjects (or FAS) who did not have  
any virtual assessments nor COVID-19 related protocol deviations.
4. To explore the impact of assessments before versus after the COVID breakout, a 
subgroup analysis for subjects who completed or discontinued from the study before 
March 13, 2020 and subjects who completed or discontinued from the study on or 
after March 13, 2020 will be performed. An MMRM analysis based on the FAS for 
Enriched Subjects and the FAS will be performed to the extent where data allow or 
the summary statistics will be provided.
In addition, demographics and baseline characteristics by subgroup of subjects with or 
without any virtual visits will be provided.   
8.1.5
Subgroup Analyses
Subgroup analyses of change from baseline in ZAN-BPD Total Score to every study week in 
the double-blind treatment period will be performed by the following factors:

Sex (Based on the biological status)

Race (White and All Other Races)

Age group (Age<55 and Age≥55)

Region (North America and Europe)

Status of Background ADT (With ADT and Without ADT)


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All subgroup analyses will be conducted using the same MMRM analysis as for the primary 
efficacy analysis except that the fixed class effect term for trial center will not be included in 
the model
Interaction effects of treatment-by-subgroup will be assessed at Week 10 for the subgroups 
identified in the previous paragraph. The same MMRM model will be used as for the primary 
efficacy analysis with the addition of terms for subgroup-by-week and treatment-by-
subgroup-by-week. These treatment-by-subgroup interaction analyses will be presented in 
statistical documentation.
8.2
Key Secondary Endpoint Analysis
The key secondary efficacy endpoint is the change from baseline to Week 10 in the 
double-blind treatment period 
 in CGI-S score. This endpoint will be analyzed by 
fitting the similar MMRM model described in the primary analysis.
This endpoint will be analyzed by similar analysis described in Section 8.1.4.3 to evaluate the 
impact of COVID.
8.3
Control of Experiment-wise Type 1 Error
To control the family-wise type I error when testing for both the primary efficacy endpoint 
and the key secondary efficacy endpoint, a stepwise hierarchical testing procedure is applied. 
The statistical testing will be performed in the following order. The statistical test between 
brexpiprazole and placebo group for an endpoint after the first one will be performed only 
when the nominal p-value reaches significance level at 0.05 (2-sided) for all the preceding 
endpoints:
1) Primary efficacy endpoint based on the FAS for Enriched Subjects
2) Key secondary endpoint based on the FAS for Enriched Subjects
3) Primary efficacy endpoint based on the FAS
4) Key secondary endpoint based on the FAS
8.4
Secondary Efficacy Endpoint Analysis
Secondary efficacy endpoints are as follows:
1) Change from baseline in the Patient’s Global Impression of Severity (PGI-S) to each 
trial visit during the double-blind treatment period
2) Patient’s Global Impression of Change (PGI-C) score at each trial visit during the 
double-blind treatment period




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9
Safety Analysis
Standard safety variables to be analyzed include AEs, clinical laboratory tests, vital signs, 
ECGs, and physical examinations. In addition, data from the following safety scales will be 
evaluated:  assessments of suicidality (C-SSRS) and EPS (eg, the SAS, AIMS, and BARS). 
Safety analysis will be conducted based on the Safety Sample defined in Section 5.1. In 
general, baseline of a safety variable is defined as the last observation of the variable before 
taking the first dose of IMP, unless specified otherwise. Prospectively defined criteria will be 
used to identify potentially clinically relevant abnormal values for clinical laboratory tests, 
vital signs, ECGs, and body weight. 
9.1
Adverse Events 
All adverse events will be coded by System Organ Class (SOC) and Preferred Term (PT) 
according to the Medical Dictionary for Regulatory Activities (MedDRA). AEs that are sex-
specific, e.g., ovarian cancer, will have their incidence rates evaluated for the specific sex.
Treatment-emergent AEs (TEAEs) are defined as AEs with an onset date on or after the start 
of double-blind treatment period. In more detail, TEAEs are all adverse events which started 
after start of double blind IMP; or if the event was continuous from baseline and was 


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worsening, serious, study drug related, or resulted in death, discontinuation, interruption or 
reduction of study therapy. Adverse events occurring up to 30 days after the last day of IMP 
will be included in the summary tables. 
The incidence of the following events in the double-blind treatment period will be tabulated 
by treatment group and overall using the Safety Sample:
a) TEAEs 
b) TEAEs by severity
c) TEAEs potentially causally related to the IMP
d) TEAEs with an outcome of death
e) Serious TEAEs
f)
TEAEs leading to discontinuations of the IMP
g) AESI
The above summaries (b), (e) and (f) will also be prepared for TEAEs potentially causally 
related to the IMP.
In addition, incidence of TEAE during the double-blind treatment period of at least 5% in any 
treatment group other than placebo group, and also greater than placebo by SOC and PT will 
be provided.
Incidence of TEAEs by SOC and PT will be summarized for sex, race, age and region 
subgroups.
Extrapyramidal symptoms (EPS)-related AEs will be grouped into five categories.
1) Dystonic Events, which include cervical spasm, dystonia, emprosthotonos, muscle 
contractions involuntary, muscle rigidity, muscle spasms, muscle spasticity, myotonia, nuchal 
rigidity, oculogyration, opisthotonos, pleurothotonus, risus sardonicus, torticollis, and trismus;
2) Parkinsonian Events, which include akinesia, asterixis, athetosis, bradykinesia, cogwheel 
rigidity, essential tremor, extrapyramidal disorder, freezing phenomenon, gait festinating, 
hypertonia, hypokinesia, hypokinesia neonatal, intention tremor, masked facies, parkinson’s 
disease, parkinsonian crisis, parkinsonian gait, parkinsonian rest tremor, parkinsonism, 
tremor, and tremor neonatal;
3) Akathisia Events, which include akathisia, hyperkinesia, and psychomotor hyperactivity;


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4) Dyskinetic Events, which include ballismus, buccoglossal syndrome, choreoathetosis, 
clumsiness, dyskinesia, dyskinesia neonatal, dyskinesia oesophageal, fumbling, nodding of 
head, on and off phenomenon, and tardive dyskinesia;
5) Residual Events, which include chorea, Huntington’s chorea, muscle twitching, and 
myoclonus.
Unless otherwise specified, in general, analysis of safety data will be performed on observed 
case and for last visit.
Adverse Events of Special Interest
The new onset or exacerbation of “Pathological Gambling and Other Compulsive Behaviors” 
will be analyzed as an AESI.
9.2
Clinical Laboratory Tests
Summary statistics for mean and mean change from baseline in the routine clinical laboratory 
measurements, prolactin concentrations, coagulation parameters (PT, aPTT, and INR), 
HbA1c, and TSH will be provided by treatment and by visit.
Potentially clinically relevant laboratory measurement test results in the double-blind 
treatment period 
 will be identified for the Safety Sample and will be summarized 
by treatment group and listed. Criteria for identifying laboratory values of potential clinical 
relevance are provided in Appendix 2.
9.2.1
Drug Induced Liver Injury (DILI)
Total bilirubin level should be checked for any subject with increased ALT or AST levels  
three times the upper normal limits (ULN) or baseline. 

Reporting all DILI as SAE to the FDA based on Hy's Law: 
o
AST or ALT > 3 x ULN or baseline and 
o
T_Bili  > 2 x ULN or baseline
A separate incidence table will be provided for DILI cases, and the corresponding listing will 
be provided for Safety Sample during the double-blind treatment period.
9.2.2
Metabolic Change
In addition to mean change from baseline, incidence of treatment emergent significant 
changes in fasting lipids, fasting glucose, and metabolic syndrome will be summarized by 
treatment group using the following criteria.


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Criteria for Treatment-Emergent Significant Change in Lipids and Glucose
LAB PARAMETER
BASELINE¹
ANYTIME POST BASELINE     
LDL Direct (FAS)ting  
(MG/DL)
Borderline 100-<160   
Normal/Borderline <160
Normal <100           
Any Value             
High >=160            
High >=160            
Borderline/High >=100 
Increased >=30        
HDL Cholesterol (FAS)ting 
(MG/DL)
Normal >=40  
Any Value    
Low <40            
Decreased >=20     
Triglycerides (FAS)ting  
(MG/DL)   
Normal <150           
Borderline 150-<200   
Normal/Borderline <200
Normal <150           
Any Value    
High 200-<500             
High 200-<500             
High 200-<500             
Borderline/High/Very High >=150       
Increased >=50            
Glucose Fasting, Serum  
(MG/DL)   
Normal <100           
Impaired 100-<126     
Normal/Impaired <126  
Any Value             
High >=126       
High >=126       
High >=126       
Increased >=10   
    
Criteria for Treatment-Emergent Metabolic Syndrome 
DESCRIPTION
ANYTIME POST BASELINE¹     
Central Obesity        
                       
Dyslipidemia           
                       
Dyslipidemia           
                       
Supine Blood Pressure  
                       
Glucose Fasting, Serum
Waist Circumference >=102cm(MALE), >=88cm (FEMALE)    
                                                     
Triglycerides >= 150mg/dl                            
                                                     
HDL < 40mg/dl (MALE), <50mg/dl (FEMALE)              
                                                     
Systolic>=130mmHg and Diastolic>=85mmHg              
                                                     
>=100mg/dl                                           
Metabolic Syndrome             
Met 3 Or More of the Above Criteria at a Visit
    
9.3
Vital Signs 
Summary statistics for vital signs will be provided. For the double-blind treatment period 
 vital signs, change from baseline will be summarized for the Safety Sample by 
treatment group. 
Potentially clinically relevant vital signs measurements identified in the double-blind 
treatment period 
 for the Safety Sample will be summarized by treatment group. 


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Criteria for identifying vital signs of potential clinical relevance are provided in Appendix 1. 
All potentially clinically relevant events or changes will be listed and included in summary 
tables. 
9.4
12-Lead ECG
Summary statistics and incidence of potentially clinically relevant changes will be provided 
for ECG parameters.
For the analysis of QT and QTc, data from three consecutive complexes (representing three 
consecutive heart beats) will be measured to determine average values.  The following QT 
corrections will be used for reporting purposes in the clinical study report:
1) QTcB is the length of the QT interval corrected for heart rate by the Bazett formula: 
QTcB=QT/(RR)0.5 and
2) QTcF is the length of the QT interval corrected for heart rate by the Fridericia formula: 
QTcF=QT/(RR)0.33
3) QTcN is the length of the QT interval corrected for heart rate by the FDA Neuropharm 
Division formula:  QTcN=QT/(RR)0.37 
Potentially clinically relevant changes in the 12-lead ECG identified in the double-blind 
treatment period for the Safety Sample will be listed and summarized by treatment group. 
Criteria for identifying ECG measurements of potential clinical relevance are provided in 
Appendix 3.
Categorical changes in ECG parameters during the double-blind treatment period will be 
summarized based on the following criteria:
Categorical Change Criteria in QT/QTc Parameters
Classification
Category
Criteria 
QT
New Onset (> 450 Msec)
New onset (>450 msec) in QT means a subject who 
attains a value > 450 msec during treatment period 
but not at baseline.
QTc *
New Onset (≥ 450 Msec 
for men and ≥ 470 Msec 
for women)
New onset (≥ 450 Msec for men and (≥ 470 Msec 
for women) in QTc means a subject who attains a 
value ≥ 450 Msec for men or ≥ 470 Msec for 
women during treatment period but not at baseline.
New Onset (≥ 450 Msec 
for men and ≥ 470 Msec 
for women) 
And > 10% Increase
New onset (≥ 450 Msec for men and ≥ 470 Msec for 
women) and 
> 10% increase in QTc means a subject who attains 
a value ≥ 450 Msec for men or  ≥ 470 Msec for 
women, and > 10% increase during treatment period 
but not at baseline


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Categorical Change Criteria in QT/QTc Parameters
Classification
Category
Criteria 
New Onset (> 500 Msec)
New onset (> 500 msec) in QTc means a subject 
who attains a value > 500 msec during treatment 
period but not at baseline.
Increase 30 - 60 Msec
Increase from baseline value > 30 and  60 msec in 
QTc
Increase > 60 Msec
Increase from baseline value > 60 msec in QTc
* QTc categorical change criteria apply to QTcB, QTcF and QTcN.
9.5
Physical Examinations
By-patient listings will be provided for physical examination.
9.5.1
Body Weight, Waist Circumference and BMI 
Analyses of body weight, waist circumference and BMI will be performed for the Safety 
Sample. The mean change from baseline to Week 10 (OC) and last visit in the double-blind 
treatment period in body weight will be tabulated and analyzed using ANCOVA. The 
ANCOVA models for both the OC and last visit analyses will include the baseline as a 
covariate and the treatment group as fixed effect.  The mean change from screening to Week 
12 in waist circumference will be analyzed using ANCOVA. 
Percentages of patients showing significant weight gain (≥ 7 % increase in weight), as well as 
percentages of patients showing significant weight loss (≥ 7 % decrease in weight) from 
baseline to Week 10 (OC and LOCF) will be analyzed using CMH General Association Test. 
Body mass index is defined as weight in kilograms divided by the square of height in meters.
9.6
SAS, AIMS, and BARS
The mean change from baseline to every trial visit in the double-blind treatment period 
obtained from the SAS total score, AIMS total score (total of the first 7 item scores), and the 
BARS Global Clinical Assessment will be tabulated and analyzed using ANCOVA. Analyses 
will be performed on the OC data set. In addition, analyses will be performed using the 
maximum (i.e. the worst) value observed during the double-blind treatment period and the last 
visit data to determine the change from baseline score. The ANCOVA model for the OC data 
set will include the baseline measure and the treatment group. The ANCOVA model for 
change at the last visit and for change to the maximum value will include the baseline 
measure, study center and treatment group. The same analyses will be performed on the 
AIMS individual item scores 8, 9, and 10. In addition, incidence of BARS Global Clinical 


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Assessment of Akathisia during the double-blind treatment period by severity category will be 
provided. Analyses of these EPS rating scales will be performed for the Safety Sample.
9.7
Suicidality Data
Suicidality will also be monitored during the study using the C-SSRS 
and will be summarized as number and 
percentage of subjects reporting any suicidal behavior, ideation, behavior by type (4 types), 
ideation by type (5 types) and treatment emergent suicidal behavior and ideation. Summary 
will be provided for the double-blind treatment period.
Suicidality is defined as report of at least one occurrence of any type of suicidal ideation or at 
least one occurrence of any type of suicidal behavior during assessment period (count each 
person only once).
Treatment emergent suicidal behavior and ideation is summarized by four types: Emergence 
of suicidal ideation, Emergence of serious suicidal ideation, Worsening of suicidal ideation, 
Emergence of suicidal behavior. 
Emergence of suicidal behavior/ideation is defined as report of any type of suicidal 
behavior/ideation during treatment when there was no baseline suicidal behavior/ideation.
Emergence of serious suicidal ideation is defined as observation of suicidal ideation severity 
rating of 4 or 5 during treatment when there was no baseline suicidal ideation.                                                   
Worsening of suicidal ideation is defined as a suicidal ideation severity rating that is more 
severe than it was at baseline.
9.8
Concomitant Medications
Number and proportion of patients taking concomitant medications prior to study therapy, 
during the double-blind treatment period 
 and after study therapy are tabulated by 
drug classification using the WHO drug dictionary. 
9.9
Extent of Exposure
The start date of double-blind treatment period study therapy after randomization - 
brexpiprazole or placebo - will be the first day of double-blind treatment period dosing after 
randomization. The number and percentage of patients who receive double-blind treatment 
period study medication, will be presented by week and by treatment group. Each dosing 
week will be based on the actual week; i.e., Day 1-7 in Week 1, Day 8-14 in Week 2, etc. This 
summary will be performed on the Safety Sample. 


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The mean daily dosage will be summarized by week and treatment group using descriptive 
statistics. The mean daily dosage per patient per week will be determined for each week of the 
study. This will be calculated by dividing the sum of individual total doses by the number of 
days in the week interval. The summary will contain for each treatment group the number of 
patients receiving double-blind study medication`, and the mean and range of the mean daily 
dose for each week.
10 Conventions
10.1 Study Visit Windows
Study visit windows will be used to map visits using study day intervals. Observations at each 
scheduled visit and Early Termination will be assigned to Week 1, Week 2, Week 4, Week 6, 
Week 8 , Week 10 and Week 12 visits based on their visit windows as shown in Table 10.1A. 
This visit window convention applies to tables and listings for all efficacy and safety scales 
(ZAN-BPD, CGI-S, CGI-I, 
 PGI-S, PGI-C, 
, SAS, 
AIMS and BARS). This derived study window variable will be named as DAY and will be 
footnoted. In listings, it will be listed along with the CRF study visit.
Table 10.1A shows classifications for study day intervals in the double-blind period. The 
variable “target day” is defined using the number of days since the start of double-blind 
dosing. The first day of double-blind dosing is defined as “Day 1”.
If more than one observation falls within a particular study day interval, then the last 
observation within that interval is used. Evaluations occurring more than 7 days after the last 
double-blind dosing date will not be mapped into study visit windows, and will be excluded 
from the analysis.
Table 10.1A: Study Day and Visit Windows
Week
Target Day a
Study Day Interval a
2
7
2-13
4
21
14-27
6
35
28-41
8
49
42-55
10
63
56-69


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12
77
70-84 b
a Relative to the first day of IMP in the double-blind treatment period.
b Evaluations occurring more than seven days after the last dosing date of IMP in the double-blind treatment 
period will be excluded from the efficacy analyses.
10.2 Pooling of small centers
Primary efficacy analysis will be performed on the FAS for Enriched Subjects  which 
comprises those subjects in the Randomized Sample who have a baseline value and at least 
one post-baseline value for ZAN-BPD Total Score in the double-blind treatment period. Small 
centers will be defined as centers that do not have at least one evaluable subject (evaluable 
with regard to the primary efficacy variable) in each treatment arm and each ADT Status 
(with/without background ADT) in FAS for Enriched Subjects in the double-blind treatment 
period. All small centers will be pooled to form “pseudo centers” for the purpose of analysis 
according to the following algorithm. Small centers will be ordered from the largest to the 
smallest based on the number of evaluable subjects (i.e., subjects who have a Baseline value 
and at least one post-randomization value for ZAN-BPD Total Score in the double-blind 
treatment period).  The process will start by pooling the largest of the small centers with the 
smallest of the small centers until a non-small center is formed.  This process will be repeated 
using the centers left out of the previous pass.  In case of ties in center size, the center with the 
smallest center code will be selected.  If any centers are left out at the end of this process, they 
will be pooled with the smallest pseudo centers, or if no pseudo centers exist, they will be 
pooled with the smallest non-small center.
10.3 Scales: Rules for Scoring and Handling of Missing Data
10.3.1
ZAN-BPD
The ZAN-BPD is utilized as the primary efficacy assessment of a subject’s severity of disease 
symptoms in patients with BPD.  The questions for the ZAN-BPD reflect a 1-week time 
frame. Each of the 9 criteria for BPD is rated on a 5-point anchored rating scale of 0 to 4. 
These scores are clustered into 4 sector scores (akin to domains) and a total score. The 3 
affective symptoms (anger, moodiness, and emptiness scores) have a sector score range from 
0 to 12. The 2 cognitive symptoms (identity disturbance and 
distrust/suspiciousness/dissociation scores) have a sector score range from 0 to 8. The 2 
impulsive symptoms (self-mutilation/suicidality and other forms of impulsivity scores) have a 
sector range from 0 to 8. The 2 interpersonal symptoms (efforts to avoid abandonment and 
unstable relationships scores) have a sector score range of 0 to 8. These 4 sector scores add up 


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to provide the overall total score for the ZAN-BPD, which ranges from 0 to 36.  The total 
score is missing if any element comprising toward the total score is missing.
10.3.2
CGI-S 
The severity of illness for each subject will be rated using the CGI-S. To perform this 
assessment, the investigator (or designee) will answer the following question: “Considering 
your total clinical experience with borderline personality disorder, how ill is the subject at this 
time?” Response choices are 0 = not assessed; 1 = normal, not at all ill; 2 = borderline ill; 3 = 
mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most 
extremely ill subjects
10.3.3
CGI-I
Change from baseline in the subject’s condition will be assessed using the CGI-I scale. The 
investigator (or designee) will answer the following question: “Rate total improvement 
whether or not in your judgment it is due entirely to drug treatment. Compared to his/her 
condition at Day 0, how much has the patient changed?”. All responses will be compared with 
the subject’s condition at baseline (Day 0). Response choices are 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.  
 
 
 
 
 
  
10.3.5
PGI-S
The PGI-S is a 7-point single-item self-report scale for the patient to rate the severity of 
symptoms of BPD. Subjects answer the following question: “Taking into account all of your 
symptoms, how severe is your Borderline Personality Disorder at this time?” Scores range 
from 1 “no symptoms” to 7 “very severe”.


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10.3.6
PGI-C
The Patient’s Global Impression of Change (PGI-C) is a 7-point single-item self-report scale 
depicting a patient’s rating of overall change in their condition since starting trial medication. 
Subjects answer the following question: “Since starting study medication, how much have 
your symptoms of Borderline Personality Disorder changed?” Scores range from 1 “very 
much improved” to 7 “very much worse”.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
10.3.9
SAS
The SAS will be used to evaluate extrapyramidal symptoms (EPS). It consists of a list of 10 
symptoms of Parkinsonism (gait, arm dropping, shoulder shaking, elbow rigidity, wrist 
rigidity, head rotation, glabella tap, tremor, salivation, and akathisia). Each item will be rated 


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on a 5-point scale, with a score of zero representing absence of symptoms, and a score of 4 
representing a severe condition. The SAS Total score is the sum of ratings for all 10 items, 
with possible Total scores from 0 to 40. The SAS Total score will be un-evaluable if less than 
8 of the 10 items are recorded. If 8 or 9 of the 10 items are recorded, the Total score will be 
the mean of the recorded items multiplied by 10 and then rounded to the first decimal place.
10.3.10
AIMS
The AIMS is a 12-item scale. The first 10 items are rated from 0 to 4 (0=best, 4=worst). An 
item score of 0, depending on the item, either means: no abnormal involuntary movement 
(AIM), or no incapacitation due to AIM, or no awareness of AIM. An item score of 4 either 
means: severe AIM, or severe incapacitation due to AIM, or being aware of, and severe 
distress caused by AIM. Items 11 and 12, related to dental status, have dichotomous 
responses, 0=no and 1=yes. The AIMS Total Score is the sum of the ratings for the first seven 
items. The possible total scores are from 0 to 28. The AIMS Total Score will be un-evaluable 
if less than 6 of the first 7 items are recorded. If 6 of the items are recorded, then the total 
score will be the mean of the recorded items multiplied by 7 and then rounded to the first 
decimal place.
10.3.11
BARS
The BARS consists of 4 items related to akathisia: objective observation of akathisia by the 
investigator, subjective feelings of restlessness by the subject, subjective distress due to 
akathisia, and global clinical assessment of akathisia. The first 3 items will be rated on a 4-
point scale, with a score of zero representing absence of symptoms and a score of 3 
representing a severe condition. The global clinical evaluation will be made on a 6-point 
scale, with zero representing absence of symptoms and a score of 5 representing severe 
akathisia.
10.3.12
C-SSRS
Suicidality will be monitored during the trial using the C-SSRS. This trial will use the 
“baseline/screening” and “Since Last Visit” versions of the scale. The “baseline/screening” 
version, which assesses the lifetime experience of the subject with suicide events and suicidal 
ideation and the occurrence of suicide events and/or ideation within a specified time period 
prior to entry into the trial, will be completed for all subjects at screening to determine 
eligibility. The “Since Last Visit” C-SSRS form will also be completed at all visits after 
screening.




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12 Potential Clinical Relevance Criteria from Protocol
Appendix 1
Criteria for Identifying Vital Signs of Potential Clinical Relevance
Variable
Criterion Valuea
Change Relative to Baselinea
Heart Rateb
> 120 bpm
< 50 bpm
 15 bpm increase
 15 bpm decrease
Systolic Blood Pressureb
> 180 mmHg
< 90 mmHg
 20 mmHg increase
 20 mmHg decrease
Diastolic Blood Pressureb
> 105 mmHg
< 50 mmHg
 15 mmHg increase
 15 mmHg decrease
Orthostatic Hypotension
 20 mmHg decrease in systolic blood 
pressure and a  25 bpm increase in 
heart rate from supine to 
sitting/standing
Not Applicable
(baseline status not considered)
Weight
-
 7% increase
 7% decrease
a In 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.
b As 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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Appendix 2
Criteria for Identifying Laboratory Values of Potential Clinical 
Relevance
Laboratory Tests
Criteria
Chemistry
AST (SGOT)
 3 x upper limit of normal (ULN)
ALT (SGPT)
 3 x ULN
Alkaline phosphatase
 3 x ULN
Lactate dehydrogenase (LDH)
 3 x ULN
Blood urea nitrogen (BUN)
 30 mg/dL
Creatinine
 2.0 mg/dL
Uric Acid
Men
 10.5 mg/dL
Women
 8.5 mg/dL
Bilirubin (total)
 2.0 mg/dL
Creatine phosphokinase (CPK)
 3 x ULN
Prolactin
> ULN
Hematology
Hematocrit
Men
 37 % and decrease of  3 percentage points from Baseline
Women
 32 % and decrease of  3 percentage points from Baseline
Hemoglobin
Men
 11.5 g/dL
Women
 9.5 g/dL
White blood count
 2,800/ mm3 or  16,000/ mm3
Eosinophils
 10%
Neutrophils
 15%
Absolute neutrophil count
 1,500/ mm3
Platelet count
 75,000/ mm3 or  700,000/ mm3
Urinalysis
Protein
Increase of  2 units
Glucose
Increase of  2 units
Casts
Increase of  2 units
Additional Criteria
Chloride
 90 mEq/L or  118 mEq/L
Potassium
 2.5 mEq/L or  6.5 mEq/L
Sodium
 126 mEq/L or  156 mEq/L
Calcium
 8.2 mg/dL or  12 mg/dL
Glucose
Fasting
 100 mg/dL 
Non-Fasting
 200 mg/dL
Total Cholesterol (FAS)ting
 240 mg/dL 
LDL Cholesterol (FAS)ting
 160 mg/dL 
HDL Cholesterol (FAS)ting
Men
< 40 mg/dL
Women
< 50 mg/dL
Triglycerides (FAS)ting
 150 mg/dL


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Appendix 3
Criteria for Identifying ECG Measurements of Potential Clinical 
Relevance
Variable
Criterion Valuea
Change Relative to Baselinea
Rate
Tachycardia
 120 bpm
increase of   15 bpm
Bradycardia
 50 bpm
decrease of  15 bpm
Rhythm
Sinus tachycardiab
 120 bpm
increase of  15 bpm
Sinus bradycardiac
 50 bpm
decrease of  15 bpm
Supraventricular premature beat
all
not present  present
Ventricular premature beat
all
not present  present
Supraventricular tachycardia
all
not present  present
Ventricular tachycardia
all
not present  present
Atrial fibrillation
all
not present  present
Atrial flutter
all
not present  present
Conduction
1 atrioventricular block
PR  200 msec
increase of   50 msec
2 atrioventricular block
all
not present  present
3 atrioventricular block
all
not present  present
Left bundle-branch block
all
not present  present
Right bundle-branch block
all
not present  present
Pre-excitation syndrome
all
not present  present
Other intraventricular conduction blockd
QRS  120 msec
increase of  20 msec
Infarction
Acute or subacute
all
not present  present
Old
all
not present  present
 12 weeks post study entry
ST/T Morphological
Myocardial Ischemia
all
not present  present
Symmetrical T-wave inversion
all
not present  present
Increase in QTc
QTcF  450 msec 
(men)
QTcF  470 msec 
(women)
a In 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.
b No current diagnosis of supraventricular tachycardia, ventricular tachycardia, atrial fibrillation, atrial flutter, 
or other rhythm abnormality.
c No current diagnosis of atrial fibrillation, atrial flutter, or other rhythm abnormality.
d No current diagnosis of left bundle branch block or right bundle branch block.


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Appendix 4
Details and SAS codes for MI Procedure in Delta Adjustment 
Imputation Methods and Placebo Based Imputation Methods
Delta Adjustment Imputation Methods
Step 1: Use MCMC to obtain monotone missing data pattern. Dataset mi_indata contains 
the original OC data.
proc mi data=mi_indata out=mi_mono nimpute=100 seed=12345;
  var y0 y2 y4 y6 y8 y10 ;
  by treatment;
  mcmc chain=multiple impute=monotone;
run;
Step 2: Use a standard MAR-based regression method to impute monotone missingness 
data:
proc mi data=mi_mono out=mi_reg seed=54321 nimpute=1;
  by _Imputation_;
  var treatment y0 y2 y4 y6 y8 y10 ;
  class treatment;
  monotone regression;
run;
Placebo Based Imputation Methods (Use MI for Copy Placebo MNAR)
Method 1: Use MCMC methodology to impute Placebo arm as MAR  
proc mi data=mi_indata (where=(treatment in (“pbo”))) out=mi_mcmc_pbo nimpute=100 
seed=12345;
  var y0 y2 y4 y6 y8 y10;
  mcmc chain=multiple outest=mcmc_pbo;
run;
proc mi data=mi_indata (where=(treatment in (“drug”))) out=mi_mcmc_drug;
  var y0 y2 y4 y6 y8 y10;
 mcmc inest=mcmc_pbo;
run;
data mi_mcmc ;
   set mi_mcmc_drug mi_mcmc_pbo;
run;
Method 2: Use MI for Copy Placebo MNAR 
Step 1: Perform the same steps 1 and 2 in the delta adjusted imputation method as 
described above.
proc mi data=mi_indata out=mi_mono nimpute=100 seed=12345;
  var y0 y2 y4 y6 y8 y10;
  by treatment;
  mcmc chain=multiple impute=monotone ;
run;


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Step 2: Use MNAR Copy Placebo Imputation 
data mi_imp0; 
  set mi_mono;
  by _imputation_;
run;
The following are repeated for i=1 to 4 (corresponding to Weeks 4,6,8,10, denoted by k=4, 
6, 8, 10 and j=i-1).
data mono_imp&i mono_rest&i;
  set mi_imp&j;
  if treatment in (“drug”) and lastvisit >=&k then output mono_rest&i;
  else output mono_imp&i;
run;
proc mi data=mono_imp&i out=reg_imp&i nimpute=1 seed=xxxxx;
   by _Imputation_;
   %if &k =4 %then %do;
   var Y0 Y2 Y4;
   %end;
   %if &k =6 %then %do;
   var Y0 Y2 Y4 Y6;
   %end;
   %if &k =8 %then %do;
   var Y0 Y2 Y4 Y6 Y8;
   %end;
    %if &k =10 %then %do;
   var Y0 Y2 Y4 Y6 Y8 Y10;
   %end;
   monotone reg(Y&k);
run;
data mi_imp&i;
  set mono_rest&i reg_imp&i;
run;






























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Document Name: P331-201-00242_Statistical_Analysis_Plan_Amendment 2
Document Number: 1000144391
Document Version: 2.0
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yyyy hh:min) -
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Clinical Approval
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17:08:22
Biostatistics Approval
21-Jun-2021
16:57:17