A Phase 3, Multicenter, Randomized, Double-blind Trial of Fixed-Dose Brexpiprazole as Combination Therapy With Sertraline in the Treatment of Adults With Post-traumatic Stress Disorder
Phase: PHASE3
Conditions: Post Traumatic Stress Disorder
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

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Table of Contents.............................................................................................................
1
Study 331-201-00072 Protocol Amendment 04; 04 Jan 2023.........................................
2
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Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigational Medicinal Product
Brexpiprazole (OPC-34712)
REVISED CLINICAL PROTOCOL
A Phase 3, Multicenter, Randomized, Double-blind Trial of Fixed-Dose Brexpiprazole as 
Combination Therapy with Sertraline in the Treatment of Adults with Post-traumatic 
Stress Disorder 
A Trial of Fixed-Dose Brexpiprazole with Sertraline in the Treatment of Post-traumatic 
Stress Disorder
Protocol No. 331-201-00072
IND No. 117,549
CONFIDENTIAL ⎯ PROPRIETARY INFORMATION
Drug Development Phase:
3
Sponsor:
Otsuka Pharmaceutical Development & 
Commercialization, Inc.
2440 Research Boulevard
Rockville, Maryland 20850, United States
Immediately Reportable Event 
Syneos Health Safety and 
Pharmacovigilance
Amendment 4 Approval:
04 Jan 2023
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Protocol 331-201-00072
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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 relates to coronavirus disease 2019 (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 virtual visits (phone or video) as deemed necessary by the investigator to ensure 
subject safety and maintain protocol requirements. 
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Table of Contents
Trial Conduct for COVID-19.......................................................................2
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 ..............................................................................................................15
1.3
Schedule of Assessments ..................................................................................16
2
Introduction........................................................................................19
2.1
Trial Rationale...................................................................................................20
2.2
Background .......................................................................................................20
2.2.1
Nonclinical Pharmacology..............................................................................20
2.2.2
Nonclinical Pharmacokinetics ........................................................................21
2.2.3
Clinical............................................................................................................21
2.3
Known and Potential Risks and Benefits ..........................................................21
3
Objectives and Endpoints..................................................................23
4
Trial Design.........................................................................................24
4.1
Type/Design of Trial .........................................................................................24
4.2
Scientific Rationale for Trial Design.................................................................25
4.3
Dosing Rationale...............................................................................................26
4.4
End of Trial Definition......................................................................................27
4.5
Definition of Completed Subjects.....................................................................28
5
Trial Population..................................................................................28
5.1
Subject Selection and Numbering.....................................................................28
5.2
Eligibility Criteria .............................................................................................28
5.2.1
Inclusion Criteria ............................................................................................28
5.2.2
Exclusion Criteria...........................................................................................29
5.3
Lifestyle Considerations....................................................................................32
5.3.1
Meals and Dietary Restrictions.......................................................................32
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5.3.2
Caffeine, Alcohol, and Tobacco.....................................................................33
5.3.3
Activity ...........................................................................................................33
5.4
Screen Failures ..................................................................................................33
6
Trial Treatments ................................................................................34
6.1
Trial Treatments Administered .........................................................................34
6.1.1
Medical Devices .............................................................................................34
6.2
Management of Investigational Medicinal Product ..........................................34
6.2.1
Packaging and Labeling..................................................................................34
6.2.2
Storage............................................................................................................35
6.2.3
Accountability.................................................................................................35
6.2.4
Returns and Destruction .................................................................................35
6.2.5
Reporting of Product Quality Complaints......................................................35
6.2.5.1
Eliciting and Reporting Product Quality Complaints .................................36
6.2.5.2
Information Required for Reporting Purposes............................................36
6.2.5.3
Return Process.............................................................................................36
6.2.5.4
Assessment/Evaluation ...............................................................................37
6.3
Measures to Minimize/Avoid Bias....................................................................37
6.4
Subject Compliance...........................................................................................37
6.5
Concomitant Medications or Therapies ............................................................37
6.5.1
Prohibited Medications and Therapies ...........................................................38
6.5.2
Permitted Medications....................................................................................40
6.5.3
Rescue Medications........................................................................................42
6.6
Intervention after the End of the Trial...............................................................42
7
Stopping Rules, Withdrawal Criteria, and Procedures..................42
7.1
Entire Trial or Treatment...................................................................................42
7.2
Individual Site ...................................................................................................42
7.3
Individual Subject Discontinuation...................................................................42
7.3.1
Treatment Interruption....................................................................................42
7.3.2
Treatment Discontinuation .............................................................................43
7.3.3
Documenting Reasons for Treatment Interruption or Discontinuation ..........43
7.3.4
Withdrawal of Consent or Assent...................................................................44
7.3.5
Procedures to Encourage Continued Trial Participation ................................45
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7.4
Definition of Subjects Lost to Follow-up..........................................................45
8
Trial Procedures.................................................................................45
8.1
Efficacy Assessments........................................................................................46
8.1.1
Clinician-Administered PTSD Scale for DSM-5 ...........................................46
8.1.2
Clinical Global Impression - Severity ............................................................47
8.1.3
PTSD Checklist for DSM-5............................................................................47
8.1.4
Hospital Anxiety and Depression Scale .........................................................47
8.1.6
Brief Inventory of Psychosocial Function......................................................48
8.1.7
Screening Assessments...................................................................................48
8.1.7.1
Emory Treatment Resistance Interview for PTSD......................................48
8.1.7.2
Life Events Checklist for DSM-5 ...............................................................48
8.1.7.3
Mini International Neuropsychiatric Interview...........................................48
8.1.7.4
Ohio State University Traumatic Brain Injury Identification Method........48
8.2
Pharmacokinetic Assessments...........................................................................49
8.2.1
Pharmacokinetic Blood Samples....................................................................49
8.3
Pharmacodynamic Assessments........................................................................49
8.4
Pharmacogenomic Assessments........................................................................49
8.4.1
Pharmacogenomic Samples............................................................................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....................................................................................55
8.7.6
Other Safety Variables....................................................................................55
8.7.6.1
Abnormal Involuntary Movement Scale.....................................................55
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8.7.6.2
Barnes Akathisia Rating Scale....................................................................56
8.7.6.3
Simpson-Angus Scale .................................................................................56
8.8
Adverse Events..................................................................................................56
8.8.1
Definitions ......................................................................................................56
8.8.2
Eliciting and Reporting Adverse Events.........................................................58
8.8.3
Immediately Reportable Events......................................................................59
8.8.4
Medical Device Incidents (Including Malfunctions)......................................59
8.8.5
Adverse Events of Special Interest.................................................................59
8.8.6
Potential Serious Hepatotoxicity ....................................................................59
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............................................60
8.8.8.3
Follow-up and Reporting of Immediately Reportable Events 
Occurring After Last Scheduled Contact....................................................61
8.9
Treatment of Overdose......................................................................................61
8.10
Subject Assessment Recording .........................................................................61
8.10.1
Subject Diary ..................................................................................................61
8.10.2
Quality of Life ................................................................................................61
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 ...........................................................................................62
9.4.1
Efficacy Analyses...........................................................................................62
9.4.1.1
Primary Efficacy Endpoint Analysis...........................................................62
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
9.4.1.5
Other Efficacy Endpoint Analysis ..............................................................63
9.4.2
Safety Analysis...............................................................................................63
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9.4.2.1
Adverse Events ...........................................................................................63
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
9.4.2.5
Other Safety Data........................................................................................64
9.4.3
Other Analyses................................................................................................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
9.4.3.5
Pharmacogenomic Analysis........................................................................65
9.5
Interim Analysis and Adaptive Design .............................................................65
9.5.1
Data Monitoring Committee...........................................................................65
10
Supporting Documentation and Operational Considerations .......66
10.1
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations.............66
10.1.1
Ethics and Responsibility ...............................................................................66
10.1.2
Informed Consent ...........................................................................................66
10.1.3
Confidentiality................................................................................................67
10.1.4
Quality Control and Quality Assurance..........................................................68
10.1.4.1
Monitoring ..................................................................................................68
10.1.4.2
Auditing ......................................................................................................68
10.1.5
Protocol Deviations ........................................................................................68
10.1.6
Records Management .....................................................................................69
10.1.6.1
Source Documents ......................................................................................69
10.1.6.2
Data Collection ...........................................................................................69
10.1.6.3
File Management at the Trial Site...............................................................70
10.1.6.4
Records Retention at the Trial Site .............................................................71
10.1.6.5
Publication Authorship Requirements ........................................................71
10.2
Appendix 2: Clinical Laboratory Tests .............................................................73
10.3
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information........................................................................................................74
10.4
Appendix 4: Abbreviations ...............................................................................76
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10.8
Appendix 8: Protocol Amendments ..................................................................81
10.8.1
Protocol Amendment(s)/Administrative Change(s) .......................................82
10.8.1.4
Protocol Amendment 4 ...............................................................................85
11
References ...........................................................................................86
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List of In-text Tables
Table 1.3-1
Schedule of Assessments...............................................................16
Table 3-1
Trial Objectives and Endpoints .....................................................23
Table 6.5.1-1
List of Medications Prohibited Prior to the Trial and 
Required Washout Period..............................................................38
Table 6.5.1-2
List of Medications Prohibited/Restricted During the Trial..........39
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List of In-text Figures
Figure 1.2-1
Trial Design Schematic..................................................................15
Clinical Study Report 331-201-00072
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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.: 331-201-00072
IND No.: 117,549
Protocol Title: A Phase 3, Multicenter, Randomized, Double-blind Trial of Fixed-Dose 
Brexpiprazole as Combination Therapy with Sertraline in the Treatment of Adults with 
Post-traumatic Stress Disorder
Protocol Lay Person Short Title: A Trial of Fixed-Dose Brexpiprazole with Sertraline 
in the Treatment of Post-traumatic Stress Disorder
Clinical Phase/Trial Type: 3
Treatment/Indication: Post-traumatic stress disorder (PTSD)
Objectives and Endpoints:
Trial Objectives and Endpoints
Objectives
Endpoints
Primary: To evaluate the 
efficacy of brexpiprazole + 
sertraline in adult subjects 
with PTSD.
Primary Efficacy: Change from baseline to the end of the efficacy 
period in the CAPS-5 total score
Key Secondary Efficacy: 
•
Change from baseline to the end of the efficacy period in the 
CGI-S score
•
Change from baseline to the end of the efficacy period in 
B-IPF score
Other Efficacy:
•
Change from baseline to the end of the efficacy period in the 
PCL-5 score
•
Change from baseline to the end of the efficacy period in the 
HADS-A and HADS-D score
•
Response defined by decrease ≥ 30% from baseline to the end 
of the efficacy period in the CAPS-5 total score
•
Change from baseline to the end of the efficacy period in the 
CAPS-5 subscales/domain scores
Clinical Study Report 331-201-00072
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screening and to have a Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total 
score ≥ 33 at screening and baseline (Day 0) visits in order to be considered for 
enrollment.
Trial Sites:
This trial will be conducted in the United States.
Investigational Medicinal Products, Dose, Dosage Regimen, Treatment Duration, 
Formulation, Mode of Administration:
During the double-blind treatment period, subjects will receive IMP, consisting of 
brexpiprazole + sertraline, or sertraline, or placebo, depending on the subject’s treatment 
assignment.  IMP assignments can change during the double-blind treatment period.
All doses of IMP should be taken together 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:  CAPS-5, Clinical Global Impression - Severity (CGI-S), 
PTSD Checklist for DSM-5 (PCL-5), Hospital Anxiety and Depression Scale (HADS), 
 and Brief Inventory of 
Psychosocial Function (B-IPF).
Assessments for Safety:  Adverse event (AE), clinical laboratory tests (hematology, 
serum chemistry [including glycosylated hemoglobin (HbA1c) and blinded prolactin], 
and urinalysis), thyroid-stimulating hormone (TSH), 12-lead 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).
Assessments for Pharmacokinetics: Blood sampling for IMP plasma concentrations.
Screening/Other:  Life Events Checklist for DSM-5 (LEC-5), MINI, and Ohio State 
University Traumatic Brain Injury Identification Method (OSU TBI-ID), medical history, 
psychiatric history (including PTSD history), and PTSD treatments (pharmacological, 
nonpharmacological, and Emory Treatment Resistance Interview for PTSD [E-TRIP]), 
urine drug screen/blood alcohol test, and urine pregnancy test. 
Data Monitoring Committee:  No
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Statistical Methods:
It is anticipated that approximately 585 subjects will be enrolled into the trial. 
The change from baseline to the end of the efficacy period in the CAPS-5 total score will 
be analyzed using a mixed-effect model repeated measures analysis with an unstructured 
variance covariance structure.  The model will include fixed class-effect terms for 
treatment, trial site, visit week, and an interaction term of treatment by visit week, and 
will include the interaction term of baseline values of the CAPS-5 total score by visit 
week as a covariate.  All scheduled visits after baseline during the double-blind treatment 
period will be included in the model.
Trial Duration:
The anticipated duration for participants to complete the trial is approximately 17 weeks.  
This is inclusive of a screening period (up to 14 days), a 12-week double-blind treatment 
period, and a safety follow-up period (21 [+2] days after the last dose of IMP).
Overall, the trial duration from first informed consent form signed to the final subject 
assessment is expected to be approximately 47 months. 
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1.3
Schedule of Assessments
Table 1.3-1
Schedule of Assessments
Assessment
Screen-
ing
(Day 
−14 to 
Day 
−1)a 
Base-
line
(Day 
0)
Week 1 
Visit
( 2 days)
Week 2 
Visit
( 2 days)
Week 3 
Visit
( 2 days)
Week 4 
Visit
( 2 days)
Week 6 
Visit
( 3 days)
Week 8 
Visit
( 3 days)
Week 10 
Visit
( 3 days)
Week 12/ 
ET Visit
( 3 days)
Post-
treatment 
Follow-up
(21 
[+ 2] days)
Notes:
ENTRANCE CRITERIA
Informed Consent
X
Section 10.1.2
(Appendix 1)
Inclusion/exclusion criteria
X
X
Section 5.2
Demography
X
Section 5.1
Medical history
X
Section 5.1
Psychiatric history 
(including PTSD history)
X
Section 5.1
PTSD treatments 
(pharmacological, non-
pharmacological, and 
E-TRIP)
X
Section 6.5
Prior medication washout
X
Section 6.5.1
LEC-5b
X
Section 8.1.7.2
MINI 
X
Section 8.1.7.3
OSU TBI-ID
X
Section 8.1.7.4
HIV, HBsAg, and 
anti-HCV
X
Section 10.2
(Appendix 2)
Review of birth control 
methods
X
X
X
X
X
X
X
X
X
X
X
Section 10.3
(Appendix 3)
EFFICACY
CAPS-5
X
X
X
X
X
X
X
X
Section 8.1.1
CGI-S
X
X
X
X
X
X
X
X
X
Section 8.1.2
PCL-5c
X
X
X
X
X
X
Section 8.1.3
HADSc
X
X
X
X
X
X
Section 8.1.4
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Table 1.3-1
Schedule of Assessments
Assessment
Screen-
ing
(Day 
−14 to 
Day 
−1)a 
Base-
line
(Day 
0)
Week 1 
Visit
(± 2 days)
Week 2 
Visit
(± 2 days)
Week 3 
Visit
(± 2 days)
Week 4 
Visit
(± 2 days)
Week 6 
Visit
(± 3 days)
Week 8 
Visit
(± 3 days)
Week 10 
Visit
(± 3 days)
Week 12/ 
ET Visit
(± 3 days)
Post-
treatment 
Follow-up
(21 
[+ 2] days)
Notes:
B-IPFc
X
X
X
Section 8.1.6
SAFETY
Clinical laboratory tests 
(hematology, serum 
chemistry [including 
blinded prolactin], 
urinalysis), TSH
X
X 
X
X
Section 8.7.1
HbA1c
X
X
Section 8.7.1
Physical examination
X
X
Section 8.7.2
Vital signs
X
X
X
X
X
X
X
X
X
X
Section 8.7.3
12-lead ECG
X
X
X
Section 8.7.4
Urine drug screen/blood 
alcohol
X
X
X
Section 10.2
(Appendix 2)
Urine pregnancy test
X
X
X
X
Section 10.2
(Appendix 2)
C-SSRS
X
X
X
X
X
X
X
X
X
X
Section 8.7.5
AIMS
X
X
X
X
Section 8.7.6.1
BARS
X
X
X
X
Section 8.7.6.2
SAS
X
X
X
X
Section 8.7.6.3
Adverse events
X
X
X
X
X
X
X
X
X
X
X
Section 8.8
Concomitant medications
X
X
X
X
X
X
X
X
X
X
Section 6.5
OTHER
Drug dispensing
X
X
X
X
X
X
X
X
Section 6.2.3
Drug accountability
X
X
X
X
X
X
X
X
Section 6.2.3
Pharmacokinetic and Pharmacogenomic Sampling
PK sample
X
X
Section 8.2
Pharmacogenomic sample
X
Section 8.4
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2
Introduction
Post-traumatic stress disorder (PTSD) is a prevalent, debilitating, and often chronic 
neuropsychiatric illness that may develop in a person who has experienced, witnessed, or 
been confronted with an event or events that involve actual or threatened death or serious 
injury, or a threat to the physical integrity of oneself or others.  The person’s response 
involves intense fear, helplessness, or horror.  According to Diagnostic and Statistical 
Manual of Mental Disorders, 5th edition (DSM-5), the diagnostic criteria for PTSD 
include a history of exposure to a traumatic event that meets specific stipulations and 
symptoms from each of 4 symptom clusters:  intrusion, avoidance, negative alterations in 
cognition and mood, and alterations in arousal and reactivity.  The sixth criterion 
concerns duration of symptoms, the seventh assesses functioning, and the eighth criterion 
clarifies symptoms as not attributable to a substance or co-occurring medical condition.  
The United States (US) National Comorbidity Survey Replication found a PTSD lifetime 
prevalence of 6.8%, and a 12-month prevalence of 3.6%, with rates of 5.2% for women 
and 1.8% for men.1,2
The risk of developing PTSD depends on the type of trauma, with interpersonal violence 
carrying the highest risk.3,4  In the World Health Organization World Mental Health 
Surveys, the most common traumas at the respondent level were as follows: traumas of 
loved ones or were witnessed (35.7%), accidents (34.3%), and unexpected death of a 
loved one (31.4%). These were followed by physical violence (22.9%), intimate partner 
or sexual violence (14.0%), war-related trauma (13.1%), and ‘other’ traumas (8.4%). The 
trauma type associated with the highest PTSD risk is intimate partner or sexual violence 
(11.4%). The risk of developing PTSD based on the other types of trauma is as follows: 
‘other’ traumas (9.2%), unexpected death of loved one (5.4%), war-related trauma 
(3.5%), physical violence (2.8%), traumas of loved ones or were witnessed (2.4%), and 
accidents (2.0%).4
Like many other psychiatric disorders, PTSD has been purported to result from a 
dysregulation in monoaminergic neurotransmission. While dysfunction of the 
dopaminergic system has emerged as one of the most important hypotheses, recent 
reports have found higher levels of norepinephrine and epinephrine in PTSD patients as 
well.3,4 
Brexpiprazole (REXULTI®, OPC-34712, OPC-331, and Lu AF41156) is a new chemical 
entity discovered by Otsuka Pharmaceutical Development and Commercialization 
(OPDC) that is being co-developed by OPDC and Lundbeck Inc.  Brexpiprazole is a 
novel atypical antipsychotic that is a serotonin-dopamine activity modulator and is 
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indicated in the 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) in adult patients.
2.1
Trial Rationale
The selective serotonin reuptake inhibitors (SSRIs) paroxetine and sertraline are currently 
approved for the treatment of PTSD by the Food and Drug Administration (FDA) in the 
US.  Response rates with SSRIs in PTSD are modest and vary from a low of 24.3% to a 
high of 60%.5  There is relatively low satisfaction with paroxetine and sertraline, as 
evidenced by the low use of these products (2.1% and 19.1%, respectively) as first-line 
therapy for PTSD treatment.6  In addition, sertraline’s efficacy for the treatment of PTSD 
has been inconsistent with in the short-term randomized, controlled trials: 2 of the 4 US 
registrational trials were negative on the primary efficacy endpoint.  Physicians are 
seeking alternative options and there are several products that are registered for other 
indications that are used off-label for symptom relief in patients with PTSD.  There is an 
important unmet medical need for new efficacious and safe treatments for individuals 
suffering from PTSD.   
A more detailed scientific rationale for the trial is provided in Section 4.2.
2.2
Background
2.2.1
Nonclinical Pharmacology 
The pharmacology of brexpiprazole has been extensively investigated both in vitro and in 
vivo.  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 serotoninergic (5-HT) and 
dopaminergic (DA) systems that combines partial agonist activity at 5-HT1A and at D2 
receptors with antagonist activity at 5-HT2A receptors, with similar high affinities at all of 
these receptors (inhibition constant [Ki]:  0.1 - 0.5 nM).  Brexpiprazole also shows 
antagonist activity at noradrenergic α1B/2C with affinity in the same subnanomolar Ki 
range (Ki:  0.2 - 0.6 nM).  The 5-HT1A/D2 receptor partial agonist activity in combination 
with 5-HT2A and α1B/2C receptors antagonism of brexpiprazole may correlate with 
antipsychotic and antidepressant efficacy, reduced impulsive behavior, and cognitive 
improvement.7 
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Adjunctive treatment with brexpiprazole and escitalopram reduced behavioral stress 
responses and increased hypothalamic neuropeptide Y (NPY) immunoreactivity in a rat 
model of PTSD-like symptoms.8
2.2.2
Nonclinical Pharmacokinetics
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 Investigator’s Brochure (IB).7
2.2.3
Clinical 
Currently, brexpiprazole is approved in the US for use in adult patients as an adjunctive 
therapy to antidepressants for the treatment of MDD and monotherapy treatment of 
schizophrenia.  Additionally, the current clinical development program is designed to 
show safety and efficacy of brexpiprazole for the treatment of the following indications: 
treatment of agitation associated with dementia of the Alzheimer’s type (AAD), and 
treatment of adult PTSD.7
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 Applications (INDs) (59 completed and 8 ongoing) for 
schizophrenia, adjunctive treatment of MDD, adjunctive treatment of attention-deficit 
hyperactivity disorder (ADHD), AAD, PTSD, or bipolar disorder; and 7 non-US IND 
trials completed in either Korea or Japan conducted in healthy subjects and subjects with 
schizophrenia.7
2.3
Known and Potential Risks and Benefits 
Phase 1 data indicated that brexpiprazole had good safety and tolerability when 
administered to healthy volunteers at single doses of 0.2 to 6 mg and at a repeated dose of 
2 mg/day.  Data from completed repeated dosing trials in the US indicate that 
brexpiprazole had good tolerability when administered to patients with schizophrenia or 
schizoaffective disorder at doses of up to 12 mg/day; when administered to patients with 
MDD at doses of up to 4 mg/day in combination with a marketed antidepressant; and 
when administered to patients with ADHD at doses of up to 4 mg/day in combination 
with a marketed stimulant.7
In subjects who participated in the 59 completed brexpiprazole trials conducted under US 
INDs, the most frequently reported treatment-emergent adverse events (TEAEs) 
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(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%).  Please 
refer to the brexpiprazole IB for a summary of available nonclinical and clinical safety 
data.7 
In Trial 331-201-00061, brexpiprazole + sertraline combination therapy was shown to be 
efficacious in the improvement of PTSD-related symptoms as demonstrated by 
superiority versus placebo as well as superiority over sertraline monotherapy and 
brexpiprazole monotherapy on the primary efficacy endpoint, the Clinician-Administered 
PTSD Scale for DSM-5 (CAPS-5) total score.  Concordant support for the efficacy of 
brexpiprazole + sertraline therapy was also seen in multiple other clinician- and 
subject-assessed secondary endpoints including the Clinical Global Impression - Severity 
(CGI-S), PTSD Checklist for DSM-5 (PCL-5), Hospital Anxiety and Depression 
Scale - Depression subscale (HADS-D), CAPS-5 response rate, and CAPS-5 subscale 
domains.  Brexpiprazole + sertraline combination therapy was safe and well tolerated 
when administered for up to 12 weeks in adults with PTSD; no new safety signals were 
observed in this population.  The TEAEs that occurred at an incidence of > 5% and twice 
more than placebo in the active treatment groups were as follows:  brexpiprazole + 
sertraline: decreased appetite (7.5%) and akathisia (6.3%); brexpiprazole monotherapy: 
fatigue (8.0%), decreased appetite (6.7%), akathisia (13.3%), and sedation (6.7%); and 
sertraline monotherapy: nausea (20.3%).9
Zoloft (sertraline) is indicated for the treatment of PTSD at dose of 50-200 mg/day.  Per 
the US package insert, the most common TEAEs (≥ 5% for Zoloft and twice placebo) in 
pooled placebo-controlled MDD, obsessive-compulsive disorder, panic disorder, PTSD, 
social anxiety disorder, and premenstrual dysphoric disorder clinical trials were nausea, 
diarrhea/loose stool, tremor, dyspepsia, decreased appetite, hyperhidrosis, ejaculation 
failure, and decreased libido.10
Trial sites will receive updated versions of the IB, when available, and trial sites should 
refer to the most current version as needed.
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3
Objectives and Endpoints
Table 3-1
Trial Objectives and Endpoints
Objectives
Endpoints
Primary: To evaluate 
the efficacy of 
brexpiprazole + 
sertraline in adult 
subjects with PTSD.
Primary Efficacy: Change from baseline to the end of the 
efficacy period in the CAPS-5 total score
Key Secondary Efficacy: 
•
Change from baseline to the end of the efficacy period 
in the CGI-S score
•
Change from baseline to the end of the efficacy period 
in B-IPF score
Other Efficacy:
•
Change from baseline to the end of the efficacy period 
in the PCL-5 score
•
Change from baseline to the end of the efficacy period 
in the HADS-A and HADS-D score
•
Response defined by decrease ≥ 30% from baseline to 
the end of the efficacy period in the CAPS-5 total score
•
Change from baseline to the end of the efficacy period 
in the CAPS-5 subscales/domain scores
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all prohibited medications during the screening period in order to meet the 
protocol-specified washout periods.
Double-blind Treatment Period:
During the double-blind treatment period, subjects will receive IMP, consisting of 
brexpiprazole + sertraline, or sertraline, or placebo, depending on the subject’s treatment 
assignment.  IMP assignments can change during the double-blind treatment period.
Subjects will attend visits at Weeks 1, 2, 3, 4, 6, 8, 10, and 12/early termination (ET) 
during the treatment period.
Follow-up: 
For any subject who discontinues the trial early, the site should make every effort to 
complete the ET evaluations as soon as possible and prior to the subject starting any new 
medication or treatment.  All subjects (completers and early withdrawals) will be 
monitored for safety events via telephone or clinic visit (at the investigator’s discretion) 
21 (+ 2) days after the last dose of IMP.  For any subject who withdraws due to a serious 
adverse event (SAE), every effort should be made to ensure that the safety follow-up is 
performed face-to-face.  Given that this may not be feasible in all circumstances, safety 
follow-up via phone is permitted in cases where face-to-face follow up cannot be 
performed.
Upon completion of the 12-week trial period, participants may be eligible to receive up to 
a six months’ supply of sertraline or paroxetine through TrialCard®.  Participants in this 
program will have prescribed medication shipped directly to their home by a designated 
retail mail-in pharmacy free of charge.  
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 PTSD.  More specifically, as a partial dopamine D2/D3 receptor agonist, 
brexpiprazole may quell the hyper-responsiveness in the dopaminergic circuitry 
purported to exist in PTSD patients.11,12  By dampening dopaminergic tone, 
brexpiprazole may improve upon symptoms such as memory/cognitive dysfunction, 
mood, and impulsivity.  Similarly, brexpiprazole may help normalize aberrations that are 
believed to exist in a heightened adrenergic system as well.  It is postulated that 
noradrenaline release is accentuated in PTSD, which is linked with the establishment of 
long-term aversive memories that induce strong emotions and arousal such as fear, 
hyper-responsiveness, and anxiety.  The effect of brexpiprazole as an α1B and α2C 
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receptor antagonist may be advantageous in this regard.  Furthermore, 5-HT2A and α1 
receptors are co-localized in GABAergic interneurons in the prefrontal cortex, which is 
involved in behavioral control and cognitive processing.13  Brexpiprazole may exert an 
added beneficial effect on cortical functioning, impulsivity, and contextual fear by 
simultaneous blocking α1 and 5-HT2A receptors.  Data also suggest that 5-HT2A plays a 
significant role in learning and may contribute to the autonomic dysregulation and 
maladaptive re-experiencing of traumatic memories in PTSD.14  Attenuation of 
contextual fear appears to involve 5-HT1A in the extended amygdala.  SSRIs 
administered concomitantly with extinction training in mice facilitate a rapid and 
enduring loss of conditioned fear memory.  A similar process appears to occur in humans 
with PTSD who ingest SSRIs while engaged in trauma-focused psychotherapy.14,15  
Taken together and given its effects as a 5-HT1A partial receptor agonist, brexpiprazole 
may lessen the anxiety noted in these patients as well.
Two clinical trials have been conducted with brexpiprazole in subjects with PTSD.  Trial 
14865A was a phase 3 trial for adjunctive treatment with brexpiprazole in subjects with 
PTSD who had an inadequate response to treatment with paroxetine or sertraline.  Trial 
14865A was terminated prematurely when the Sponsor realized that it would likely be 
unable to enroll enough participants to fully power the trial.  No safety concerns factored 
into the decision to terminate the trial and the recruited population at the time of 
termination was too small to analyze from an efficacy perspective.  Trial 331-201-00061 
was a phase 2 trial of brexpiprazole as monotherapy or combination therapy with 
sertraline in the treatment of adults with PTSD.  Results demonstrated that brexpiprazole 
+ sertraline was more effective in relieving PTSD symptoms (as determined by 
improvements in the Clinician-Administered PTSD Scale for DSM-5 [CAPS-5] total 
score) than sertraline alone, brexpiprazole alone, or placebo.  Brexpiprazole + sertraline 
combination therapy resulted in significant improvement on both clinician- and 
subject-assessed endpoints and was safe and well tolerated when administered for up to 
12 weeks in adults with PTSD.9
This phase 3 trial is intended to provide persuasive evidence that treatment of PTSD with 
combination treatment with brexpiprazole + sertraline is efficacious, safe, and 
well-tolerated.  
4.3
Dosing Rationale
The dosing paradigm to be used in this trial has been determined based on completed 
phase 1 clinical pharmacology trials as well as phase 2/3 trials in PTSD.  
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The maximum tolerated dose (MTD) for healthy subjects has been determined to be 6 mg 
for single-dose administration and 2 mg for once-daily (QD), multiple-dose 
administration.  The MTD of brexpiprazole administered as monotherapy in subjects with 
schizophrenia or schizoaffective disorder or coadministration with marketed 
antidepressant in subjects with MDD has not been established.  The following doses of 
brexpiprazole have been tolerated in completed QD, multiple-dose, phase 1 clinical 
pharmacology trials: up to 12 mg/day in adult subjects with schizophrenia or 
schizoaffective disorder, and up to 4 mg/day in adult subjects with MDD when 
coadministered with a marketed antidepressant.7
The efficacy, safety and tolerability of brexpiprazole coadministered with sertraline has 
been investigated in 2 completed phase 2/3 trials.  Trial 14865A was a phase 3 trial for 
adjunctive treatment with brexpiprazole in subjects with PTSD who had an inadequate 
response to treatment with paroxetine or sertraline.  Trial 14865A was terminated early 
due to challenges with patient eligibility.  There were not enough subjects randomized for 
any efficacy analyses; the decision to terminate was not based on any safety concerns.16  
A second trial, 331-201-00061, a phase 2 trial which evaluated brexpiprazole as 
combination treatment with sertraline in adult subjects with PTSD, was then conducted.  
In that trial, brexpiprazole + sertraline combination therapy was shown to be efficacious 
in the improvement of PTSD-related outcomes.  At the trial endpoint, combination 
treatment with brexpiprazole + sertraline demonstrated statistically significant results 
over placebo as well as superiority over sertraline monotherapy and brexpiprazole 
monotherapy.  The incidence of TEAEs were similar across treatment groups.  No new 
safety signals were observed in the PTSD population.9
Based on the collective safety, tolerability, and efficacy data, doses of up to a maximum 
of 3 mg/day brexpiprazole and 150 mg/day sertraline will be evaluated in this phase 3 
trial.  The doses given in the phase 2 PTSD trial (331-201-00061) were within this range 
and were well tolerated.  In addition, Zoloft (sertraline) is indicated for the treatment of 
PTSD at doses of 50-200 mg/day.10  
4.4
End of Trial Definition
The end of trial date is defined as the last date of contact or the date of final contact 
attempt from the post-treatment follow-up eSource page for the last subject completing or 
withdrawing from the trial.
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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 (Week 12) will be defined as trial completers.  
5
Trial Population
5.1
Subject Selection and Numbering
All subjects will be given a unique subject identifier (site number [3 digits] + subject 
number [‘S’ + 5 digits] upon providing consent).  Site number will be designated by the 
sponsor.  The subject number will be given sequentially from S00001.
Demographic information (collection date, date of birth, sex, childbearing potential, race, 
ethnicity), medical history, and psychiatric history will be recorded in eSource at the 
screening visit.
Eligible subjects will be randomized.
5.2
Eligibility Criteria
Up to 20% of subjects with an index trauma related to combat can be enrolled.
Exceptions for eligibility criteria will not be permitted during the trial.
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) Subjects who are able to complete the consent process and/or consent obtained 
from a legally acceptable representative (as required by the institutional review 
board [IRB]/independent ethics committee [IEC]) prior to the initiation of any 
protocol-required procedures.
2) 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/capsule ingestion, and discontinuation of prohibited concomitant 
medication; to read and understand the written word in order to complete 
subject-reported outcomes measures; and to be reliably rated on assessment 
scales.
3) Male and female outpatients 18 to 65 years of age, inclusive, at the time of 
informed consent.
4) Subjects who have PTSD, diagnosed according to DSM-5, and confirmed by the 
MINI.
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5) Subjects have a CAPS-5 total score ≥ 33 at screening and baseline (Day 0) Visits.
6) Onset of symptoms meeting the DSM-5 criteria for PTSD symptoms for a 
minimum of 6 months prior to screening.
7) Subjects willing to discontinue all prohibited medications to meet 
protocol-required washouts prior to and during the trial period.  
NOTE: Prohibited medications and therapies are discussed in Section 6.5.1.  
Permitted medications and rescue medications are discussed in Section 6.5.2 and 
Section 6.5.3.
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).
1) Sexually active males or women of childbearing potential (WOCBP) 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. 
Males who do not agree to abstain from sperm donation during the trial and for 
30 days after the last dose of IMP.
2) Females who are breast-feeding and/or who have a positive pregnancy test result 
prior to receiving IMP.
3) Subjects who are receiving disability payments because of PTSD or any other 
psychiatric disorder; unless the disability payments will not be impacted by 
potential improvements demonstrated in the trial, OR the subject is engaged in 
compensation litigation or other processes whereby personal gain would be 
achieved from prolonged symptoms of PTSD or any other psychiatric disorder.
4) The index traumatic event that led to development of PTSD took place > 9 years 
before screening.
5) The index traumatic event occurred before age 16.
6) Subjects who are currently experiencing trauma, have ongoing contact with their 
assailant/abuser, or have ongoing legal matters related to their assault/abuse.
7) Subjects with PTSD who, in the investigator’s opinion, are considered 
resistant/refractory to psychotropic treatment by history.
8) Subjects who are currently receiving sertraline with adequate dose and duration 
(> 50 mg/day for a minimum of 8 weeks).
9) Subjects who have had initiation of, or a change in, psychotherapy or any other 
intervention for the treatment of PTSD within 28 days prior to the screening visit 
or it is anticipated that the subject will have a change in psychotherapy or in any 
other intervention for PTSD (eg, equine therapy, yoga, mindfulness, etc) during 
the trial.
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10) Subjects who meet the DSM-5 criteria for a current major depressive episode (ie, 
currently symptomatic).
11) Subjects who have current or recent history (within 6 months prior to the 
screening visit) of an anxiety disorder that has been the primary focus of 
psychiatric treatment including generalized anxiety disorder, social anxiety 
disorder, panic disorder, obsessive-compulsive, and other related disorders.
12) Subjects who have a DSM-5 diagnosis of delirium, major neurocognitive, or other 
cognitive disorder; schizophrenia, schizoaffective disorder, or other psychotic 
disorder; bipolar I or II disorder, or bipolar disorder not otherwise specified; 
eating disorder (including anorexia nervosa or bulimia); or borderline or antisocial 
personality disorders, or intellectual disability.
13) Subjects who have a current diagnosis or history of substance or alcohol use 
disorder (excluding nicotine) (DSM-5 criteria) 120 days prior to the screening 
visit.
14) Subjects who have a positive urine drug screen that, in the judgment of the 
investigator with concurrence of the medical monitor, indicates substance abuse 
that could compromise the subject’s safety or ability to comply with the trial 
procedures that could interfere with the interpretation of trial results.
15) Subjects who have a history of moderate or severe head trauma as assessed by the 
OSU TBI-ID or other neurological disorders or systemic medical diseases where 
the traumatic brain injury or neurological/systemic disorder is likely to affect 
assessment of efficacy or safety or directly impact subject safety, in the 
investigator’s opinion.
16) Subjects who have experienced a traumatic event within 3 months of screening.
17) Subjects with a significant risk of committing suicide based on history, mental 
status examination, investigator’s judgment, or C-SSRS answer of “yes” to 
question 4 or 5 (current or within the last 90 days) or subjects with any suicidal 
behavior during the last year prior to the screening visit.
18) Subjects with hypothyroidism or hyperthyroidism (unless condition has been 
stabilized with medications for at least the past 90 days prior to the baseline [Day 
0] Visit).
19) Subjects who currently have clinically significant neurological, hepatic, renal, 
metabolic, hematological, immunological, gastrointestinal, pulmonary, or 
cardiovascular disorders such as ischemic heart disease, myocardial infarction, 
congestive heart failure (whether controlled or uncontrolled), angioplasty, 
stenting, or coronary artery bypass surgery, human immunodeficiency virus 
(HIV) seropositive status/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]), 
or bariatric surgeries that may cause malabsorption. 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 
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of the condition(s) on trial participation. Subjects who are severely obese, as 
confirmed by a corresponding high body mass index (≥ 40 kg/m2), need to be 
reviewed and discussed with the medical monitor.
20) 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 (NIDDM) (ie, any subjects 
not using insulin) must also satisfy the below criterion:
a) Subject has been maintained on a stable regimen of oral 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.
21) Subjects with uncontrolled hypertension (diastolic blood pressure [DBP] 
> 95 mmHg in any position) or symptomatic hypotension, or orthostatic 
hypotension which is defined as a decrease of ≥ 30 mmHg in systolic blood 
pressure (SBP) and/or a decrease of ≥ 20 mmHg in DBP after at least 3 minutes 
standing compared to the previous supine blood pressure, OR development of 
symptoms.
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.
22) Subjects with epilepsy or a history of seizures, except for a single seizure episode; 
for instance childhood febrile seizure, a post traumatic seizure episode, or an 
alcohol withdrawal seizure.
23) Subjects with abnormal laboratory tests results, vital signs results, or 
electrocardiogram (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 any of the following laboratory test and ECG results at 
screening must be excluded from the trial:
a) Platelets ≤ 75000/mm3
b) Hemoglobin ≤ 9 g/dL
c) Neutrophils, absolute ≤ 1000/mm3
d) AST > 2 × ULN
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e) ALT > 2 × ULN
f)
Creatine phosphokinase (CPK) > 3 × ULN, unless discussed with and 
approved by the medical monitor
g) Creatinine ≥ 2 mg/dL
h) QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥ 
450 msec in men and ≥ 470 msec in women, unless due to ventricular pacing
Tests with exclusionary results should be repeated once 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
24) Subjects who would be likely to require prohibited concomitant therapy during 
the trial.
25) Subjects who received brexpiprazole in any prior clinical trial or subjects who 
have taken or are currently taking commercially available brexpiprazole 
(Rexulti®).
26) Subjects with a history of neuroleptic malignant syndrome or serotonin syndrome.
27) Subjects with a history of true allergic response (ie, not intolerance) to more than 
1 class of medications.
28) 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.
29) Subjects who participated in a clinical trial within the last 60 days or who 
participated in more than 2 clinical trials within the past year.
30) 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 (Appendix 3).
Subjects must agree to restrictions to medications and lifestyle described in Section 6.5.1 
and Section 5.3, respectively.
5.3
Lifestyle Considerations 
5.3.1
Meals and Dietary Restrictions
Consumption of grapefruit, grapefruit products, Seville oranges, or Seville orange 
products within 72 hours prior to dosing and during the trial is prohibited.  
For subjects with NIDDM, their diabetes must be well-controlled by diet for at least 
28 days prior to screening if they have not been maintained on a stable regimen of oral 
antidiabetic medication(s) during that time.
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5.3.2
Caffeine, Alcohol, and Tobacco
Excessive alcohol consumption will be prohibited.
Subjects with a prescription for medical marijuana may continue at their prescribed dose 
(see Section 6.5.2).  Recreational marijuana use is not exclusionary if, in the 
investigator’s documented opinion, the subject does not meet DSM-5 criteria for 
substance abuse or dependence, and its use would remain stable during the trial.  
The investigator may request a blood or urine drug screen at any time during the trial if 
there is a suspicion of illicit drug use.
Consumption of caffeine and use of tobacco products are permitted.
5.3.3
Activity
Subjects may only receive psychotherapy (including, but not limited to, individual, 
group, marriage, family, pet therapy, etc.) or other intervention if they have been 
participating in the therapy regularly for at least 28 days prior to screening and commit to 
maintain their participation during the course of the trial at the current frequency or 
unless permission is obtained from the medical monitor.
Current participation in substance abuse treatment will require consultation with the 
medical monitor prior to potential enrollment.
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 in 
the trial.
Subjects who sign an ICF but who are not started on treatment are permitted to be 
re-screened one time.  Screen failures due to exclusionary criteria may be re-screened one 
time if the exclusion characteristic has changed.  In the event that a subject cannot be 
enrolled prior to expiration of the 14-day screening period, an additional 14-day 
extension of screening may be requested from the medical monitor.  Any extension 
should be requested prior to the expiration of the previous extension screening period.  In 
the event that the subject is re-screened for trial participation, and the re-screening is not 
completed within the original screening window, a new ICF must be signed.
If the subject meets the definition of a screen failure in this trial, the following 
information will be recorded in eSource:
•
Date of informed consent
•
Visit date (screening visit)
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•
Demographics (collection date, birth date, sex, race, ethnicity, country)
•
Result of eligibility assessment
•
Screen failure date
•
Reason for screen failure
6
Trial Treatments
6.1
Trial Treatments Administered
All doses of IMP should be taken together at the same time each day, if possible.  The 
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.
Should a subject forget to ingest a dose of IMP, he/she can take the scheduled dose later 
that same day.  However, if a subject forgets to ingest a dose on the scheduled day, he/she 
should be encouraged to leave the missed dose in the blister card and return all unused 
IMP to the site.
The dose of IMP cannot be adjusted.  Dose decreases are not permitted.  If a subject is 
unable to maintain the dose due to tolerability issues, the subject must be withdrawn from 
the trial.
6.1.1
Medical Devices
Not applicable.
6.2
Management of Investigational Medicinal Product
For full details on IMP management, please refer to the brexpiprazole IB.7
6.2.1
Packaging and Labeling
Investigational medicinal product will be provided to the investigators and the persons 
designated by the investigator(s) or institution(s) by the sponsor or designated agent.  The 
IMP will be supplied as blister cards.  Each blister card used in the dosing period will be 
labeled to clearly disclose the protocol number, blister card number, subject ID (written 
on the label by the site), compound ID, trial number, sponsor’s name and address, 
instructions for use, route of administration, and appropriate precautionary and regulatory 
statements.
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6.2.2
Storage
The IMP will be stored in a securely locked cabinet or enclosure.  Access will be limited 
to investigators and their designees. Neither investigators nor any designees may provide 
IMP to any subject not participating in this protocol.
The IMP will be stored according to the conditions indicated on the respective IMP 
labels.
The clinical site staff will maintain a temperature log in the IMP storage area to record 
the temperature.  The monitor will inspect the storage area and verify the temperature 
logs to ensure that the site is maintaining the security of all IMP.
6.2.3
Accountability
The investigator or designee must maintain an inventory record of IMP (including 
investigational, control, or placebo) received, dispensed, administered, and returned. 
Neither the investigator nor any designees may provide IMP to any subject not 
participating in this protocol.
6.2.4
Returns and Destruction
The IMP will be destroyed by the clinical trial site in accordance with local regulations 
after obtaining Sponsor approval.  In cases where local regulations do not allow the 
clinical trial site to destroy IMP, sites will contact the Sponsor to work out a plan to 
destroy the IMP which complies with 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 oral communication 
provided by a healthcare professional, consumer, subject, medical representative, 
regulatory agency, Partner, or other third party that alleges deficiencies related to the 
identity, quality, durability, reliability, safety, effectiveness, or performance of a Medical 
Device or Medicinal Product or a falsified, tampered or diverted product after it is 
released for distribution to a clinical trial.  Examples include, but are not limited to, 
communications involving:
•
Failure/malfunction of a product to meet any of its specifications
•
Incorrect or missing labeling
•
Packaging issues (eg, damaged, dirty, crushed, missing product)
•
Blister defects (eg, missing, empty blisters)
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•
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 PQC reporting information to the OPDC IMP complaints mailbox email: 
IMP-PQC@otsuka-us.com.  Also indicate whether or not the complaint sample is 
available for return.
Identification of a PQC by the subject should be reported to the site investigator, who 
should then follow the reporting mechanism 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 of complaint sample (if available)
•
Availability of complaint sample for return
6.2.5.3
Return Process
Indicate during the report of the PQC if the complaint sample is available for return.  If 
the complaint sample is available for return, the return instructions 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.
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6.2.5.4
Assessment/Evaluation
Assessment and evaluation of PQCs will be handled by the sponsor.
6.3
Measures to Minimize/Avoid Bias
During the entire trial, treatment will be double-blind.  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.  Randomization will be stratified.  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 files, packaging IMP, 
operating the IRT, and reporting SAEs to regulatory agencies.
Procedures for breaking the blind can be found in Section 8.8.7.
6.4
Subject Compliance
Responsible trial personnel will dispense the IMP.  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.  Dosing 
compliance will be assessed by a pill count of doses remaining in the returned blister 
cards.  Subjects will also record daily doses in a subject diary, which will be reviewed by 
site staff.  If poor compliance with dosing is observed and 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 will be permitted to complete site visits within ± 2 days of the scheduled visit 
day during Weeks 1 to 4 and within ± 3 days of the scheduled visit day during Weeks 6 
to 12 in order to allow flexibility with the goal of decreasing the number of missed visits.  
However, 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 lack of compliance merits discontinuation from the trial.
6.5
Concomitant Medications or Therapies
The investigator will record all medications and therapies taken by the subject beginning 
when they sign the informed consent through the end of the evaluation period (defined as 
the time period during which subjects are evaluated for primary and/or secondary 
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objectives) 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) in eSource.
6.5.1
Prohibited Medications and Therapies
All subjects must agree to discontinue all prohibited medications during the screening 
period in order to meet the protocol-specified washout periods, as shown in 
Table 6.5.1-1.  Washout of prohibited medications begins after completion of the consent 
process.  
Table 6.5.1-1
List of Medications Prohibited Prior to the Trial and 
Required Washout Period
Prohibited Medication
Required Washout Period
Psychotropic agents: antipsychotic agents (oral), 
anticonvulsants, antidepressants, mood stabilizers, 
benzodiazepines (except as permitted in Section 6.5.2), 
hypnotics, opioid analgesics, and disulfiram
at least 7 days
Varenicline
at least 5 days
Controlled stimulants (eg, amphetamine and 
dextroamphetamine)
at least 7 days
Nutritional supplements and non-prescription herbal 
preparations with central nervous system effects (eg, 
St. John’s Wort, kava extracts, gamma-aminobutyric acid 
supplements, etc)
at least 7 days
CYP2D6 inhibitors: celecoxib, hydroxyzine, chloroquine, 
chlorpheniramine, moclobemide, clemastine, pyrilamine, 
diphenhydramine, quinidine, terbinafine, halofantrine, and 
tripelennamine
at least 7 days
CYP3A4 inhibitors: amiodarone, amprenavir, indinavir, 
aprepitant, itraconazole, chloramphenicol, ketoconazole, 
cimetidine, clarithromycin, nelfinavir, clotrimazole (if used 
orally), quinupristin/dalfopristin, delavirdine, ritonavir, 
diltiazem, saquinavir, erythromycin, troleandomycin, 
fluconazole, and verapamil
at least 7 days
CYP3A4 inducers: dexamethasone, primidone, efavirenz, 
rifampin, nevirapine, and troglitazone
at least 7 days
Barbiturates
at least 7 days
Diazepam and MAOIs
at least 14 days
Cariprazine, fluoxetine, and aripiprazole
at least 28 days
Neuroleptic agents (depot or long acting injectable)
1 full cycle plus half 
cycle
CYP = cytochrome P450; MAOI = monoamine oxidase inhibitor.
A complete list of medications prohibited during the trial is provided in Table 6.5.1-2.
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Table 6.5.1-2
List of Medications Prohibited/Restricted During the Trial
All psychotropic agents including, but not limited to, the following:
•
Antipsychotics, including depot or long-acting injectable formulations
•
Anticonvulsants used for the purposes of mood stabilization, or the treatment of 
seizures are prohibited. Low dose anticonvulsants, such as gabapentin, used for 
the purposes of promoting sleep, treating neuropathic pain, treating 
headaches/migraines, or relieving acute anxiety, are permitted with medical 
monitor approval.
•
Antidepressants 
•
MAOIs, anti-platelet drugs, and any drugs mentioned in the sertraline label as 
having clinically significant drug interactions with sertraline
•
Mood stabilizers (ie, lithium)
•
Benzodiazepines, except when used to manage TEAEs such as agitation and 
anxiety
•
Hypnotics, including ramelteon and other non-benzodiazepine sleep aids, except 
for specific medications when used to manage TEAEs related to insomnia
•
Non-controlled stimulants and atomoxetine are allowed if currently being taken for 
an appropriate indication at a stable dose for at least 14 days prior to Baseline (Day 
0) Visit and should be continued throughout trial participation.
•
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.
•
Nutritional supplements and non-prescription herbal preparations with central 
nervous system effects (eg, St. John’s Wort, kava extracts, gamma-aminobutyric 
acid supplements, etc)
•
Disulfiram
•
Prazosin is allowed if currently being taken for an appropriate indication at a stable 
dose for at least 14 days prior to Baseline (Day 0) Visit and should be continued 
throughout trial participation.
Varenicline.
Investigational agents within 60 days prior to Baseline (Day 0) Visit.
CYP2D6 inhibitors or CYP3A4 inhibitors and inducers.  
•
Selected CYP2D6 inhibitors:  celecoxib, hydroxyzine, chloroquine, methadone, 
chlorpheniramine, moclobemide, clemastine, clomipramine, pyrilamine, 
diphenhydramine, quinidine, terbinafine, halofantrine, tripelennamine
•
Selected CYP3A4 inhibitors:  amiodarone, fluvoxamine, amprenavir, indinavir, 
aprepitant, itraconazole, chloramphenicol, ketoconazole, cimetidine, nefazodone, 
clarithromycin, nelfinavir, clotrimazole (if used orally), quinupristin/dalfopristin, 
delavirdine, ritonavir, diltiazem, saquinavir, erythromycin, troleandomycin, 
fluconazole, verapamil
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Table 6.5.1-2
List of Medications Prohibited/Restricted During the Trial
•
Selected CYP3A4 inducers:  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.
Barbiturates, except for the treatment of migraine headaches, provided that in the opinion 
of the investigator the dosing is medically appropriate
In particular, the investigator should caution the subject about concomitant use of the 
following during the trial:
•
Non-steroidal anti-inflammatory drugs, aspirin, or other drugs that interfere with 
coagulation, since the combined use of psychotropic drugs that interfere with 
serotonin reuptake and these agents has been associated with an increased risk of 
upper gastrointestinal bleeding.17 
•
Triptans (eg, sumatriptan, naratriptan, almotriptan, frovatriptan, rizatriptan, 
eletriptan, and zolmitriptan), linezolid, and methylene blue, since there have been 
rare post-marketing reports of serotonin syndrome or serotonin syndrome-like 
reactions (eg, mental status changes, hyperreflexia, autonomic effects, lack of 
coordination, and diarrhea) following the concomitant use of SSRIs or 
serotonin-norepinephrine reuptake inhibitors and these drugs.18,19,20
Use of intramuscular benzodiazepines is prohibited throughout the trial.  
Use of controlled stimulants (e.g. methylphenidate, amphetamine, methamphetamine, 
dextroamphetamine, lisdextroamphetamine) is prohibited throughout the trial.
Electroconvulsive therapy and transcranial magnetic stimulation are prohibited within 
60 days of screening.  In addition, subjects may not undergo implantation of a device for 
vagus nerve stimulation or deep brain stimulation during the trial.
For subjects who discontinue early, attempts should be made to complete ALL 
evaluations for the Week 12/ET visit prior to the administration of any new medications 
for the treatment of PTSD.
6.5.2
Permitted Medications
The investigator should examine the acceptability of all concomitant medications not 
explicitly prohibited.  In order to ensure that appropriate concomitant therapy is 
administered, it is essential that subjects be instructed not to take any medications (either 
self-administered non-prescription drugs or prescription therapy prescribed by another 
physician) without prior consultation with the investigator.  
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Administration of specific oral benzodiazepines is permitted for the short-term 
management of TEAEs such as anxiety and agitation up to a maximum of 6 mg/day 
lorazepam (or equivalent) in divided doses.  The dose of 6 mg/day may be taken for up to 
2 days.  
Short-acting benzodiazepines are to be used whenever possible.  In countries where no 
short-acting benzodiazepines are commercially available, use of oral diazepam or 
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.  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 must not be administered within 12 hours prior 
to scheduled efficacy and safety assessments, including extrapyramidal symptoms (EPS) 
scales.  Investigators should delay scale administration until 12 hours have elapsed.  
Non-benzodiazepine sleep aids (ie, zolpidem, zaleplon, zopiclone, suvorexant, and 
eszopiclone only) are permitted for the treatment of TEAEs related to insomnia for up to 
4 days per week, but not on the same day as administration of a benzodiazepine, 
regardless of indication.  For the non-benzodiazepine sleep aids, sites should only utilize 
1 of the listed medications that are approved for this indication in their respective 
countries 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 12 hours prior to scheduled efficacy and safety 
assessments, including EPS scales.  Investigators should delay scale administration until 
12 hours have elapsed.  
Anticholinergics are permitted for the treatment of EPS up to a maximum of 4 mg/day 
benztropine or its equivalent and propranolol is permitted for akathisia or tremor up to a 
maximum of 20 mg 3 times daily (total of 60 mg/day).  Sites should only utilize 
medications that are approved for these indications.  Daily administration of propranolol 
for the treatment of chronic hypertension or chronic anxiety is not permitted.
If a benzodiazepine, non-benzodiazepine sleep aid, anticholinergic, or propranolol is 
given within 12 hours of scale administration, the drug name, dose, and time of 
administration should be documented in eSource. The use of the benzodiazepine, non-
benzodiazepine sleep aid, anticholinergic, or propranolol, including a notation of the drug 
name, dose, and time of administration, should be documented in eSource.
Subjects who are prescribed atomoxetine and other non-controlled stimulants can 
continue those medications if they are being taken for an appropriate indication at a stable 
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dose for at least 14 days prior to the baseline (Day 0) visit and will be continued 
throughout trial participation.
When given for an appropriate indication, marijuana as a medical treatment and prazosin 
may be continued during the trial if maintained at a stable dose for at least 14 days prior 
to the baseline visit and should be continued throughout trial participation.
6.5.3
Rescue Medications
Short-term use of benzodiazepines and non-benzodiazepine sleep aids are permitted as 
specified in Section 6.5.2.
Use of antidepressants, barbiturates, and antipsychotics for rescue purposes are not 
permitted.
6.6
Intervention after the End of the Trial
Not applicable.
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 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 
by the IRB 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 at the site.
7.3
Individual Subject Discontinuation
7.3.1
Treatment Interruption
In this approximately 3-month trial, it is expected that subjects may have one or more 
treatment interruptions during the treatment phase.  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 
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resumed as early as the situation allows.  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 (see Section 7.3.4).
7.3.2
Treatment Discontinuation
After enrollment, 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 
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 permanently discontinue IMP for a number of 
reasons, including those listed below:
•
Reasons related to 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
•
Withdrawal of informed consent
•
Lost to follow-up
•
Pregnancy (see Section 10.3 [Appendix 3])
•
Failure to meet enrollment criteria
•
Physician decision
•
Noncompliance with IMP
•
Termination of all or part of the trial by the sponsor
If the subject temporarily interrupts or permanently 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.
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7.3.4
Withdrawal of Consent or Assent
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 
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 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. 
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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.
7.4
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted on or before Visit 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 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 duration of this trial for an individual subject who completes the trial without ET is 
approximately 17 weeks.  This is inclusive of a screening period (up to 14 days), a 
12-week double-blind treatment period, and a safety follow-up period (21 [+2] days after 
the last dose of IMP).
The assessments to be conducted during the trial are summarized in Section 1.3.
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8.1
Efficacy Assessments
It is required that trained and experienced clinicians administer all clinician-rated 
psychometric scales.  In addition, the raters must be certified for this trial to administer 
the CAPS-5.  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.
8.1.1
Clinician-Administered PTSD Scale for DSM-5
The CAPS-521,22 is a clinician-rated, structured interview designed to assess PTSD 
diagnostic status and symptoms severity as defined by the DSM-5.  This trial will use the 
CAPS-5 Past Month version (at screening only) and CAPS-5 Past Week version (at all 
other assessment timepoints) of the scale.  The CAPS-5 Past Month version will be 
completed for all subjects at screening to determine eligibility.  The CAPS-5 Past Week 
version will be completed at the Baseline (Day 0) Visit to assure that the subject 
continues to qualify for the trial and at all visits after the Baseline (Day 0) Visit when the 
assessment is scheduled for collection.
The CAPS-5 comprises questions that target the onset and duration of symptoms, 
subjective distress, impact of symptoms on social and occupational functioning, 
improvement in symptoms since a previous CAPS-5 administration, overall response 
validity, overall PTSD severity, and specifications for the dissociative subtype 
(depersonalization and derealization).  
The CAPS-5 is scored by summing severity scores for the 20 DSM-5 PTSD symptoms.  
Similarly, CAPS-5 symptom cluster severity scores are calculated by summing the 
individual item severity scores for symptoms corresponding to a given DSM-5 cluster:  
Criterion B (items 1-5); Criterion C (items 6-7); Criterion D (items 8-14); and, 
Criterion E (items 15-20).  A symptom cluster score may also be calculated for 
dissociation by summing items 29 and 30. 
The CAPS-5 will be administered by a qualified and certified rater on the visits as 
specified in Section 1.3.  It takes on average between 45 and 60 minutes to administer the 
CAPS-5.
The CAPS-5 interviews may be audio recorded and randomly selected interviews 
subjected to quality reviews to verify accuracy of CAPS-5 scoring and reduce potential 
therapeutic benefit to participants derived from overly long and detailed CAPS-5 
interviews by investigators.  
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8.1.2
Clinical Global Impression - Severity
The severity of illness for each subject will be rated using the CGI-S.23  To perform this 
assessment, the rater or investigator will answer the following question:  “Considering 
your total clinical experience with this particular population, how mentally ill is the 
subject at this time?”  Response choices include:  0 = not assessed; 1 = normal, not at all 
ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 
6 = severely ill; and 7 = among the most extremely ill subjects.  The CGI-S will be 
administered on the visits as specified in Section 1.3.
8.1.3
PTSD Checklist for DSM-5
The PCL-524 is a subject-rated instrument intended to assess the degree to which 
individual DSM-5 PTSD symptoms have impaired a patient’s functioning.  Subjects need 
to indicate a number to the right of each problem to indicate how much they have been 
bothered by that problem in the past week.  The scale rates items from 0 (not at all), 1 (a 
little bit), 2 (moderately), 3 (quite a bit), and 4 (extremely).  The PCL-5 will be 
administered on the visits as specified in Section 1.3.
8.1.4
Hospital Anxiety and Depression Scale
The HADS25 is a subject-rated scale designed to screen for anxiety and depressive states 
in medical subjects.  The HADS consists of 2 subscales:  The D-scale measures 
depression and the A-scale measures anxiety.  Each subscale contains 7 items, and each 
item is rated from 0 (absent) to 3 (maximum severity).  The score of each subscale ranges 
from 0 to 21, and the subscales are analyzed separately.  It takes approximately 5 to 
10 minutes to complete the HADS.  The HADS will be administered on the visits as 
specified in Section 1.3.
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8.1.6
Brief Inventory of Psychosocial Function
The Brief Inventory of Psychosocial Function (B-IPF)27 is a short patient-reported 
questionnaire consisting of 7 questions which measure PTSD-specific psychosocial 
function on a 7 point Likert scale (0 = not at all to 6 = very much, and a not applicable 
option) with a recall period of 30 days.  The B-IPF measures the concepts of romantic 
relationships, parenting, family, friendships and socializing, work, education, and 
self-care.  The B-IPF will be administered on the visits as specified in Section 1.3.
8.1.7
Screening Assessments
8.1.7.1
Emory Treatment Resistance Interview for PTSD
The E-TRIP28 consists of clinician-administered questions to assess the adequacy and 
benefit derived from past treatment trials.  For each adequately delivered treatment to 
which the subject failed to respond, a score is assigned depending on the strength of 
evidence supporting the treatment’s efficacy.
8.1.7.2
Life Events Checklist for DSM-5
The LEC-529 is a self-report measure designed to screen for potentially traumatic events 
in a respondent’s lifetime.  The LEC-5 assesses exposure to 16 events known to 
potentially result in PTSD or distress and includes one additional item assessing any 
other extraordinarily stressful event not captured in the first 16 items.  The LEC-5 will be 
administered as specified in Section 1.3.
8.1.7.3
Mini International Neuropsychiatric Interview
The MINI30,31,32,33 will be conducted as specified in Section 1.3 to confirm the subject’s 
diagnosis of PTSD and to rule out exclusionary comorbid psychiatric diagnoses.  
Detailed instructions for administration of this structured interview will be provided.
8.1.7.4
Ohio State University Traumatic Brain Injury Identification 
Method
The OSU TBI-ID34 is a standardized procedure for eliciting a person’s lifetime history of 
TBI via a 3-to-5-minute structured interview.  The OSU EBI-ID will be conducted as 
specified in Section 1.3.
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8.2
Pharmacokinetic Assessments
A PK sample will be collected at the same time of collection of clinical laboratory 
samples as specified in Section 1.3.  Time and date of the last 3 doses of brexpiprazole 
and sertraline will be recorded at the time of PK sampling.
8.2.1
Pharmacokinetic Blood Samples
Blood samples (4 mL) will be collected in vacutainers containing sodium heparin and 
processed into plasma to determine the concentrations of brexpiprazole and sertraline.  
Metabolites that are not identified in the protocol may also be analyzed, if needed.  In 
addition, PK samples may be used for the investigation of a bioanalytical method, if 
needed.
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 shipped immediately or 
otherwise instructed in the Operations/Laboratory Manual.
All plasma samples will be shipped to the central laboratory, who will then subsequently 
ship the samples to the bioanalytical laboratory for analysis.  Additional information will 
be provided in the Operations/Laboratory Manual.
8.3
Pharmacodynamic Assessments
Not applicable.
8.4
Pharmacogenomic Assessments
A PGx sample to assess the CYP2D6 metabolism status will also be collected at the same 
time of collection of clinical laboratory samples as specified in Section 1.3 
8.4.1
Pharmacogenomic Samples
Whole blood samples (4 mL) will be collected in 4-mL potassium 
ethylenediaminetetraacetic acid vacutainer tubes for PGx testing.  Genomic 
deoxyribonucleic acid (DNA) will be extracted from a whole blood sample and used to 
determine genotypes and related phenotypes for CYP2D6.  The method used to 
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determine these genotypes may also generate genotype data for additional genes related 
to absorption, distribution, metabolism, and excretion.  Phenotyping of these additional 
genes is not currently planned but may be considered in the future.  If so, the genotyping 
data may be included as part of covariate analysis in a population PK analysis to be 
reported separately.
The date and time of the sample collection for pharmacogenomics (PGx) analysis will be 
recorded in eSource.
All PGx samples will be shipped to the central laboratory, who will then subsequently 
ship the PGx samples to the PGx laboratory for analysis.  Additional information will be 
provided in the Operations/Laboratory Manual.
8.5
Biomarker 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 (Appendix 2).  Refer to Section 10.5 (Appendix 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 
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 baseline 
prior to dosing.  If a fasting blood sample was not obtained at the screening visit and if 
more than 10 days have elapsed since 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 baseline 
(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 will be retained electronically within the 
lab vendor’s online portal and assessed by the investigator or qualified designee for 
clinical significance within eSource.
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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, follow-up 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.  
The following laboratory test results at screening are exclusionary:
•
Platelets  75000/mm3
•
Hemoglobin ≤ 9 g/dL
•
Neutrophils, absolute  1000/mm3
•
AST > 2 × ULN
•
ALT > 2 × ULN
•
CPK > 3 × ULN, unless discussed with and approved by the medical monitor
•
Creatinine ≥ 2 mg/dL
•
HbA1c ≥ 8%
•
Blood glucose > 125 mg/dL (fasting)
Tests with exclusionary results should be repeated to ensure reproducibility of the 
abnormality before excluding a subject based on the criteria noted above.
The total volume of blood to be collected during the trial is expected to be approximately 
100 to 115 mL.
A pregnancy test will be conducted in WOCBP 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; extremities; neurological; and skin and mucosae.  Height will be 
measured at screening only with a stadiometer, measuring stick, or tape.  Waist 
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circumference will be measured at each physical examination.  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.
•
The waist circumference 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.35 
The principal investigator or his/her appointed designee is primarily responsible to 
perform the physical examination.  If the appointed designee is to perform the physical 
examination, he/she must be permitted by local regulations and his/her name must be 
included on the FDA Form 1572.  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).  Subjects should be monitored for potentially clinically significant vital 
signs values (Section 10.6 [Appendix 6]).
Measurement of vital signs will include body weight, body temperature, SBP, 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.
Blood pressure and heart rate measurements will be made in the supine and standing 
positions after the subject has been in each position for at least 3 minutes.  The supine 
measurements will be performed first followed by standing.  
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Subjects with uncontrolled hypertension (screening DBP > 95 mmHg in any position) or 
symptomatic hypotension are excluded from the trial as are subjects with orthostatic 
hypotension defined as a decrease of  30 mmHg in SBP and/or a decrease of 
 20 mmHg in DBP after at least 3 minutes standing compared to 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 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 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).  Subjects should be monitored for potentially clinically 
significant ECG results (Section 10.7 [Appendix 7]).
All ECG recordings will be obtained after the subject has been supine and at rest for at 
least 5 minutes.  Additional 12-lead ECGs may be obtained at the investigator’s 
discretion and should always be obtained in the event of an ET.  Electrocardiogram 
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 the ECG tracing and cardiology report within the central ECG vendor’s 
online portal, assess the findings, noting whether or not any abnormal results are 
clinically significant within eSource.
The ECG will be repeated if any results are considered to be clinically significant.  A 
central ECG service will be utilized for reading all ECGs in order to standardize 
interpretations for the safety analysis.
If, according to the investigator’s judgment, any abnormal ECG finding is deemed 
medically significant (impacting the safety of the subject and/or the interpretation of the 
trial results) or meets an exclusion criterion, the subject should be excluded from the trial.  
Exclusion criteria for screening do not apply as mandatory discontinuation criteria for 
subjects who are already enrolled.  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 
the 3 ECGs performed.  Based on the QTcF reported by the central service, a subject will 
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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.  
8.7.5
Suicidality Monitoring
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 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.  Any subject who in the clinical judgment of the investigator 
presents a serious risk of suicide should be excluded from the trial.  The “since last visit” 
C-SSRS form will also be completed at all visits after screening.  
8.7.6
Other Safety Variables
8.7.6.1
Abnormal Involuntary Movement Scale
The AIMS assessment will be conducted at the time points described in the schedule of 
assessments (Table 1.3-1).
The AIMS36 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/no 
questions that address the subject’s dental status.  Investigators should delay scale 
administration until 12 hours have elapsed after a benzodiazepene, non-benzodiazepene 
sleep aid, anticholinergic, or propranolol is given.
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).
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8.7.6.2
Barnes Akathisia Rating Scale
The BARS assessment will be conducted at the time points described in the schedule of 
assessments (Table 1.3-1).
The BARS37 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 
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.  
Investigators should delay scale administration until 12 hours have elapsed after a 
benzodiazepene, non-benzodiazepene sleep aid, anticholinergic, or propranolol is given.
The BARS Global Score is defined as the global clinical assessment of akathisia.
8.7.6.3
Simpson-Angus Scale
The Simpson-Angus Scale (SAS) assessment will be conducted at the time points 
described in the schedule of assessments (Table 1.3-1).
The SAS38 evaluates 10 symptoms associated with antipsychotic-induced Parkinsonism, 
including gait changes, 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 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.  Investigators should delay scale administration until 12 hours have elapsed 
after a benzodiazepene, non-benzodiazepene sleep aid, anticholinergic, or propranolol is 
given.
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 
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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.

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.
Immediately Reportable Event: 
•
Any SAE.
•
Any AE related to occupational exposure.
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•
Potential serious hepatotoxicity (see Section 8.8.6).
•
Pregnancies are also defined as immediately reportable events (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. 
Severity: Adverse events will be graded on a 3-point scale and reported as indicated in 
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.
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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 medications.
Adverse event, start date (and time, if possible), end date (and time, if possible), 
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 
exposure, 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 page in eSource.)  Details 
regarding the follow-up of IREs is included in Section 8.8.8.2.
8.8.4
Medical Device Incidents (Including Malfunctions)
Not applicable.
8.8.5
Adverse Events of Special Interest 
Not applicable.
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 in eSource.
If the total bilirubin is < 2 times the ULN, weekly AST or ALT should be obtained until 
the value has either normalized or the value has decreased on two consecutive laboratory 
draws, whichever occurs first.  If AST, ALT, or total bilirubin increase on 2 consecutive 
laboratory draws or increase to > 5 ULN, stop all IMP immediately, report the event as an 
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SAE in eSource, and provide whatever supportive medical care is needed to stabilize the 
participant.  After stabilization, the subject should be discontinued from the trial.
8.8.7
Procedure for Breaking the Blind
The investigator is encouraged to contact the sponsor/Clinical Research Organization 
(CRO) medical advisor 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 page in 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 in eSource.  For any AE having been identified throughout the 
trial, during analysis, additional relevant medical history information may be requested 
by the sponsor to further ascertain causality (including, but not limited to, information 
such as risk-related behavior, family history and occupation).
8.8.8.2
Follow-up of Immediately Reportable Events
This trial requires that subjects be actively monitored for IREs for 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 page in eSource 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 
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reported to the sponsor and recorded on the AE page in eSource 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 (Appendix 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 
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 overdoses, please refer to IB Section 6.3.7
8.10
Subject Assessment Recording
8.10.1
Subject Diary
Each subject will complete a subject diary in order to record daily IMP administration.
8.10.2
Quality of Life
Quality of life assessments are detailed in Section 8.1.5 and Section 8.1.6.
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8.11
Other Assessments
Not applicable.
9
Statistical Considerations
Complete details of the planned statistical analysis will be presented in the unblinded 
addendum to this protocol and in the statistical analysis plan (SAP).
9.1
Sample Size
It is anticipated that approximately 585 subjects will be enrolled in this trial.  
9.2
Datasets for Analysis
The following samples are defined for this trial:
•
Enrolled sample: all subjects who are enrolled at baseline
•
Intent-to-treat sample: all randomized subjects administered at least one dose of 
double-blind IMP, who have measurements on the CAPS-5 total score at or prior 
to randomization and at least one post-randomization time point
•
Safety sample: all randomized subjects administered at least one dose of 
double-blind IMP
9.3
Handling of Missing Data for Primary and Key Secondary Endpoint 
Analysis
The handling of missing data for primary and key secondary endpoint analysis is 
described in the unblinded addendum and in the SAP.
9.4
Statistical Analyses
9.4.1
Efficacy Analyses
9.4.1.1
Primary Efficacy Endpoint Analysis
The primary efficacy endpoint is the change from baseline to the end of the efficacy 
period in the CAPS-5 total score.  The change from baseline to the end of the efficacy 
period in the CAPS-5 total score will be analyzed using a mixed-effect model repeated 
measures (MMRM) analysis with an unstructured variance covariance structure.  The 
model will include fixed class-effect terms for treatment, trial site, visit week, and an 
interaction term of treatment by visit week, and will include the interaction term of 
baseline values of the CAPS-5 total score by visit week as a covariate.  All scheduled 
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visits after baseline during the double-blind treatment period will be included in the 
model.
Complete details of the planned statistical analysis will be presented in the unblinded 
addendum and in the SAP.
9.4.1.2
Key Secondary Efficacy Endpoint Analysis
The key secondary efficacy endpoints are the change from baseline to the end of the 
efficacy period in the CGI-S score and the change from baseline to the end of the efficacy 
period in B-IPF score.  Both endpoints will be analyzed using an MMRM model similar 
to that prespecified for the primary efficacy endpoint, correcting for the relevant values at 
randomization.
9.4.1.3
Secondary Efficacy Endpoint Analysis
Not applicable.
9.4.1.4
Control of Experiment-wise Type 1 Error
Control of experiment-wise Type 1 error is described in the unblinded addendum and in 
the SAP.
9.4.1.5
Other Efficacy Endpoint Analysis
Analysis of the other efficacy endpoint analysis is described in the unblinded addendum 
and in the SAP.
9.4.2
Safety Analysis
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 
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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.
Summary statistics for change from baseline in vital signs, body weight, and waist 
circumference will be provided.
Potentially clinically relevant results in vital signs and body weight will also be 
summarized.
9.4.2.4
Electrocardiogram Data
Mean change from baseline will be summarized by treatment group and by visit.
Incidence of potentially clinically relevant changes will be calculated for ECG 
parameters and summarized by treatment group and by visit.
For the analysis of QT and corrected QT interval (QTc) data from three consecutive 
complexes (representing 3 consecutive heart beats) will be measured to determine 
average values. The following QT corrections will be used:
1) QT interval corrected for heart rate using Bazett’s formula (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 Food and 
Drug Administration 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 the EPS (eg, the SAS, the AIMS, and the BARS) and 
suicidality (eg, C-SSRS) will be summarized by treatment group based on the OC dataset 
of the safety sample.  Details will be described in SAP.
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9.4.3
Other Analyses
9.4.3.1
Analysis of Demographic and Baseline Characteristics
Demographic characteristics and disease severity at baseline will be summarized by 
descriptive statistics, eg, proportion, mean, median, SD, and minimum and maximum 
values.
9.4.3.2
Pharmacokinetic Analysis
No pharmacokinetic analysis is planned as only sparse samples will be obtained.  Plasma 
concentrations of brexpiprazole and sertraline will be summarized using descriptive 
statistics by dose and timepoint.
9.4.3.3
Pharmacodynamic Analysis
No PD analysis is planned.
9.4.3.4
Pharmacokinetic/Pharmacodynamic Analysis
A population or pharmacokinetic/pharmacodynamic modeling may be performed using 
the data from this trial and other trials and would be reported separately.
9.4.3.5
Pharmacogenomic Analysis
CYP2D6 genotype and predicted phenotype will be listed for brexpiprazole-treated 
subjects.
9.5
Interim Analysis and Adaptive Design
No interim analysis is planned for this study. 
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, FDA regulations, 
International Conference on Harmonisation (ICH) GCP: Consolidated Guideline (E6), 
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 according to 
regional requirements, and the investigator will provide that documentation to the 
sponsor.  The IRB will evaluate the ethical, scientific and medical appropriateness of the 
trial.  Further, in preparing and handling 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 ICF will be approved by the 
same IRB that approves this protocol.
Each ICF will comply with the ICH GCP: Consolidated Guideline E639 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.  In 
support of the site’s standard process for administering informed consent, this trial will 
also allow for electronic informed consent (eICF) as a tool within applicable regions and 
trial sites.  The eICF utilizes the IRB-approved site-specific ICF to offer subjects an 
enhanced platform to review and understand their rights as a research subject as well as 
required trial procedures.  When possible, trial sites will have subjects review and sign 
the eICF prior to starting any trial procedures; however if local regulations does not allow 
for use of the electronic format, subjects may continue in the trial utilizing the standard 
paper and wet ink signature process.  Irrespective of the format used, subjects must sign 
informed consent prior to any trial procedures being conducted.
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 
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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 
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 (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-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.  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, 
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consistent with local requirements.  All IMPs, subject bodily fluids, and/or other 
materials collected shall be used solely in accordance with this protocol, unless otherwise 
agreed to in writing by the sponsor.
Subjects will be identified only by unique subject 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), 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/major 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.
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Any major protocol deviation will be recorded in eSource along with the start date and 
details of the deviation.
10.1.6
Records Management
10.1.6.1
Source Documents
Source documents are defined as the results of original observations and activities of a 
clinical investigation.  Source documents will include but are not limited to medical 
records, electronic data, screening logs, progress notes, paper-based assessments and 
scales, 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 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, 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 
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(eg, attributable, legible, contemporaneous, original, accurate, and complete) as paper 
records. These data will be collected into a system that is fully validated according to 21 
Code of Federal Regulations 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) and as required by applicable 
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local regulations. The investigator/institution will take measures to prevent accidental or 
premature destruction of these documents.
10.1.6.4
Records Retention at the Trial Site
Food and Drug Administration regulations require all investigators participating in 
clinical drug trials to maintain detailed clinical data for one of the following periods:
•
A period of at least 2 years after the date on which a New Drug Application is 
approved by the FDA;
•
A period of 2 years after the sponsor has notified the FDA that investigation with this 
drug is discontinued.
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
8) Drafting the work or revising it critically for important intellectual content; AND
9) Final approval of the version to be published; AND
10) 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
MCHC
MCV
RBC count
WBC count with differential 
Platelet count
Urinalysis:
Appearance
Color 
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
LDH
Potassium
Prolactina
Protein, total 
Sodium
Triglycerides
Chloride
Magnesium
Bicarbonate
Inorganic phosphorus
Uric acid
Albumin
Additional Tests:
Urine pregnancy for WOCBP
TSH
HbA1c
Additional Tests (screening only):
HIV
HBsAg
Anti-HCV
ALP = alkaline phosphatase; BUN = blood urea nitrogen; GGT = gamma glutamyl transferase; 
HDL = high density lipoprotein; LDH = lactate dehydrogenase; LDL = low density lipoprotein; 
MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; RBC = red 
blood cell; MDMA = methylenedioxymethamphetamine; WBC = white blood cell.
aProlactin results will be blinded to the investigators and trial staff.
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10.3
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information
Women 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 WOCBP, 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.  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
Before trial enrollment, males and WOCBP 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.
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A urine or serum pregnancy test for human chorionic gonadotropin will be performed at 
screening, baseline, Week 6, and Week 12/ET on all WOCBP.  If a urine test is 
performed and is positive, the investigator will follow-up with a confirmatory serum test.
During the trial, all WOCBP 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
AAD
Agitation associated with dementia of the Alzheimer’s type
AE
Adverse event
AIMS
Abnormal Involuntary Movement Scale
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
Anti-HCV
Hepatitis C antibodies
AST 
Aspartate aminotransferase
BARS
Barnes Akathisia Rating Scale
B-IPF
Brief Inventory of Psychosocial Function
bpm
Beats per minute
BUN
Blood urea nitrogen
CAPS-5
Clinician-Administered PTSD Scale for DSM-5
CGI-S
Clinical Global Impression - Severity
COVID-19
Coronavirus disease 2019
CPK
Creatine phosphokinase
CRO
Contract research organization
C-SSRS
Columbia Suicide Severity Rating Scale
CYP
Cytochrome P450
DA
Dopaminergic
DBP
Diastolic blood pressure
DNA
Deoxyribonucleic acid
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
ECG
Electrocardiogram
eICF
Electronic informed consent form
EPS
Extrapyramidal symptoms
ET
Early termination
E-TRIP
Emory Treatment Resistance Interview for PTSD
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
Gamma glutamyl transferase
HADS-A
Hospital Anxiety and Depression Scale - Anxiety subscale
HADS-D
Hospital Anxiety and Depression Scale - Depression subscale
HbA1c
Glycosylated hemoglobin
HBsAg
Hepatitis B surface antigen
HDL
High-density lipoprotein
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
IND
Investigational New Drug
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Abbreviation
Definition
IRB
Institutional review board
IRE
Immediately reportable event
Ki
Inhibition constant
LDH
Lactate dehydrogenase
LDL
Low-density lipoprotein
MAOI
Monoamine oxidase inhibitor
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MDD
Major depressive disorder
MTD
Maximum tolerated dose
NIDDM
Non-insulin-dependent diabetes mellitus
NPY
Neuropeptide Y
OPDC
Otsuka Pharmaceutical Development and Commercialization
OSU TBI-ID
Ohio State University Traumatic Brain Injury Identification Method
PCL-5
PTSD Checklist for DSM-5
PGx
Pharmacogenomic(s)
PK
Pharmacokinetic
PQC
Product quality complaint
PTSD
Post-traumatic stress disorder
QD
Once-daily
QTc
Corrected QT interval
QTcB
QT interval corrected for heart rate using Bazett’s formula
QTcF
QT interval corrected for heart rate using Fridericia’s formula
QTcN
QT interval corrected for heart rate by the Food and Drug 
Administration Neuropharm Division formula
RBC
Red blood cell count
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Simpson-Angus Scale
SSRI
Selective serotonin reuptake inhibitor
SBP
Systolic blood pressure
TEAE
Treatment-emergent adverse event
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
US or USA
United States or United States of America
WBC
White blood cell count
WOCBP
Women of childbearing potential
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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.  Any permanent 
change to the protocol, whether an overall change or a change for specific trial site(s), 
must be handled as a protocol amendment.  Any amendment will be written by the 
sponsor.  Each amendment will be submitted to the IRB, as required by local regulations.  
Except for “administrative” or “nonsubstantial” amendments, investigators will wait for 
IRB approval/favorable opinion of the amended protocol before implementing the 
change(s).  Administrative amendments are defined as having no effect on the safety of 
subjects, conduct or management of the trial, trial design, or the quality or safety of 
IMP(s) used in the trial.  A protocol change intended to eliminate an apparent immediate 
hazard to subjects should be implemented immediately after agreement by the sponsor 
and investigator, followed by IRB notification within local applicable timelines.  The 
sponsor will submit protocol amendments to the applicable regulatory agencies within 
local applicable timelines.
When the IRB, 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, 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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Protocol 331-201-00072
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Confidential - Proprietary Information
Amendment 4 Approval: 04 Jan 2023
10.8.1
Protocol Amendment(s)/Administrative Change(s)
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Amendment 4 Approval: 04 Jan 2023
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Protocol 331-201-00072
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Confidential - Proprietary Information
Amendment 4 Approval: 04 Jan 2023
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Protocol 331-201-00072
89
Confidential - Proprietary Information
Amendment 4 Approval: 04 Jan 2023
Agreement
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator's Brochure) and agree that it contains all the ethical, legal and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor's (or designee's) Clinical Trial Agreement.
I will provide copies of the protocol to all physicians, nurses, and other professional personnel to 
whom I delegate trial responsibilities.  I will discuss the protocol with them to ensure that they are 
sufficiently informed regarding the investigational new drug, brexpiprazole (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 Brexpiprazole (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-approved protocol will be submitted to the appropriate regulatory 
authority/ies by the sponsor.  I agree that clinical data entered in 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 approval before implementation of any substantial amendments to this protocol.  
If, however, there is an immediate hazard to subjects, I will implement the amendment immediately, 
and provide the information to the IRB within the required local applicable timelines.  Administrative 
changes to the protocol will be transmitted to the IRB for informational purposes only, if required by 
local regulations.
I agree to provide all subjects with informed consent forms, as required by the applicable regulations 
and by ICH guidelines.  I agree to report to the sponsor any adverse 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
__________________________
__________________________
__________
Sponsor Representative Print Name
Signature
Date
Clinical Study Report 331-201-00072
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
90

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 0 7 2 Pr ot o c ol A m e n d m e nt 4 _ dr aft
D o c u m e nt N u m b er: 
D o c u m e nt V er si o n: 6. 0
Si g n e d b y
M e a ni n g of Si g n at ur e
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a n d N o n cli ni c al
0 9- J a n- 2 0 2 3
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Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 0 7 2
1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
U ntil t he i nf or m ati o n herei n is rele ase d b y Ots u k a t o t he p u blic d o m ai n, t he c o nte nts of t his d oc u me nt are Ots u k a
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D o c u m e nt N a m e: 3 3 1- 2 0 1- 0 0 0 7 2 A d d e n d u m U p d at e 3
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D o c u m e nt V er si o n: 5. 0
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D o c u m e nt N u m b er: 
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