A Phase 2, Multicenter, Randomized, Double-blind, Placebo- and Active-controlled Trial of Brexpiprazole (1 - 3 mg/Day) as Monotherapy or as Combination Therapy in the Treatment of Adults With Post-traumatic Stress Disorder
Phase: PHASE2
Conditions: Stress Disorders, Post-Traumatic
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

Official Title: 
A Phase 2, Multicenter, Randomized, Double-blind, Placebo- and Active-controlled 
Trial of Brexpiprazole (1 - 3 mg/day) as Monotherapy or as Combination Therapy in 
the Treatment of Adults with Post-traumatic Stress Disorder
NCT Number: 
NCT03033069 
Document Dates: 
Protocol Amendment 1 : 07 June 2017
Protocol Addendum Amendment 1; 8 June 2017

1
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Protocol and/or Protocol Amendments
Table of Contents
Table of Contents..................................................................................................
Study 331-201-00061 Protocol Amendment 1; 7 June 2017................................
Study 331-201-00061 Protocol Addendum Amendment 1; 8 June 2017.............
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Otsuka Pharmaceutical
Development & Commercialization, Inc.
Investigational Medicinal Product
Brexpiprazole (OPC-34712)
REVISED CLINICAL PROTOCOL
A Phase 2, Multicenter, Randomized, Double-blind, Placebo- and Active-controlled Trial 
of Brexpiprazole (1 - 3 mg/day) as Monotherapy or as Combination Therapy in the 
Treatment of Adults with Post-traumatic Stress Disorder
Protocol No. 331-201-00061
IND No. 117,549
CONFIDENTIAL – PROPRIETARY INFORMATION
Drug Development Phase: 
2
Sponsor:
Otsuka Pharmaceutical Development & 
Commercialization, Inc.
2440 Research Boulevard
Rockville, Maryland  20850, United States
Immediately Reportable Event 
INC Research Pharmacovigilance & Drug 
Safety
Fax:  
Issue Date:
29 Sep 2016
Date of Amendment 1:
7 Jun 2017
Version No.:
2.0
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Protocol Synopsis
Name of Sponsor:  Otsuka Pharmaceutical
Development & Commercialization, Inc.
Name of Investigational Medicinal Product:  
REXULTI, Brexpiprazole (OPC-34712)
Protocol No.:  331-201-00061
IND No.:  117,549
Protocol Title:
A Phase 2, Multicenter, Randomized, Double-blind, Placebo-
and Active-controlled Trial of Brexpiprazole (1 - 3 mg/day) as 
Monotherapy or as Combination Therapy in the Treatment of 
Adults with Post-traumatic Stress Disorder
Clinical Phase:
2
Treatment Indication: Post-traumatic stress disorder (PTSD)
Objective(s): 
Primary: To evaluate the efficacy of brexpiprazole as 
monotherapy or as combination treatment with Zoloft 
(sertraline) in adult subjects with PTSD.
Secondary:  To evaluate the safety and tolerability of 
brexpiprazole 1 to 3 mg/day as monotherapy or as combination 
treatment with Zoloft (sertraline) in adult subjects with PTSD.
Trial Design:
This is a phase 2, randomized, double-blind, placebo- and 
active-controlled 4-arm trial to evaluate the efficacy, safety,
and tolerability of brexpiprazole (1 - 3 mg/day) as 
monotherapy or as combination therapy with Zoloft 
(sertraline) in adult subjects with PTSD.
The trial will be organized as follows: 
Screening Phase:  The screening period will be up to 14 days 
and will begin when consent has been obtained.  Additional 
extension(s) of up to 14 additional days can be requested from 
the medical monitor, if needed to meet eligibility requirements.  
The purpose of the screening period is to assess eligibility 
criteria at 1 or more visits (as necessary to complete screening 
assessments) and to washout prohibited concomitant 
pharmacotherapy, if applicable.  An eSource method will be 
used to obtain an identification (ID) number for each subject 
with documented consent.  Subjects will be between 18 and 65 
years of age, inclusive, at the time of screening and will have a 
diagnosis of PTSD as defined by Diagnostic and Statistical 
Manual of Mental Disorders, 5th edition (DSM-5) criteria.
All subjects must agree to discontinue all prohibited 
medications during the screening period in order to meet the 
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protocol-specified washout periods.
Treatment Phase:  Subjects will be enrolled into a 12-week 
double-blind treatment period and randomized in a 1:1:1:1
ratio to one of the following double-blind treatment regimens:

brexpiprazole monotherapy

brexpiprazole and Zoloft (sertraline) combination therapy

Zoloft (sertraline) monotherapy

placebo
Subjects will attend visits at Baseline (Day 0) and Weeks 1, 2, 
3, 4, 6, 8, 10, and 12 during the treatment phase.
Follow-up:  If any subject discontinues the trial early, every 
effort should be made to complete the Week 12/early 
termination (ET) evaluations as soon as possible and whenever 
possible prior to starting any new medication or treatment.  All 
subjects (completers and early withdrawals) will be contacted 
to monitor for safety events via telephone or clinic visit, 
14 (+ 2) days after the last dose of investigational medicinal 
product (IMP).  Any subject who withdraws because of a 
serious adverse event (SAE) should be seen in the clinic, if 
possible.
Subject Population:
The trial population will include male and female outpatients 
between 18 and 65 years of age at the time of consent, 
inclusive, with a DSM-5 diagnosis of PTSD.
Inclusion/Exclusion 
Criteria: 
Key Inclusion Criteria:
1) Subjects who are able to complete the consent process
and/or consent obtained from a legally acceptable 
representative (as required by institutional review 
board [IRB]/independent ethics committee [IEC]) prior 
to the initiation of any protocol-required procedures.
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.
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4) Subjects who have PTSD, diagnosed according to 
DSM-5, and confirmed by the Mini International 
Neuropsychiatric Interview (MINI).
5) The subject has a Clinician-Administered PTSD Scale 
for DSM-5 (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.
Key Exclusion Criteria:
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 >15 years before screening.
5) The index traumatic event occurred before age 16.
6) Subjects with PTSD who, in the investigator's opinion, 
are considered resistant/refractory to psychotropic 
treatment by history.
7) Subjects who are currently receiving Zoloft (sertraline) 
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with adequate dose and duration (> 50 mg/day for a 
minimum of 8 weeks).
8) Subjects who have had initiation of, or a change in, 
psychotherapy, eye-movement desensitization and 
reprocessing (EMDR) therapy or any other intervention 
for the treatment of PTSD symptoms within 28 days 
prior to the Screening Visit or it is anticipated that the 
subject will have a change in psychotherapy, EMDR 
therapy, or in any other intervention during the trial.
9) Subjects who meet the DSM-5 criteria for a current 
Major Depressive Episode (ie, currently symptomatic).
10) 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.
11) 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.
12) 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.  
13) Subjects who have a positive urine drug screen that, in 
the judgment of the investigator with concurrence of 
the medical monitor, could compromise the subject’s 
safety or ability to comply with the trial procedures that 
could interfere with the interpretation of trial results.
14) Subjects who have a history of moderate or severe head 
trauma as assessed by the Ohio State University 
Traumatic Brain Injury Identification Method (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 
patient safety, in the investigator’s opinion.
15) Subjects who have experienced a traumatic event 
within 3 months of screening.
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16) 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).
17) 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).
18) Subjects who currently have clinically significant 
neurological, hepatic, renal, metabolic, hematological, 
immunological, cardiovascular, pulmonary, or 
gastrointestinal disorders, 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 × the 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 adverse event (AE) or interfere with 
assessments of safety or efficacy during the course of 
the trial.  The medical monitor should be contacted in 
any instance where the investigator is uncertain 
regarding the stability of a subject’s medical 
condition(s) and the potential impact of the 
condition(s) on trial participation.
19) Subjects with insulin-dependent diabetes mellitus
(IDDM) (ie, any subjects using insulin) are excluded.  
Subjects with non-IDDM may be eligible for the trial if 
their condition is stable as determined by satisfying 
ALL of the following criteria:

Glycosylated hemoglobin (HbA1c) < 7.0%, AND

Screening glucose must be ≤ 125 mg/dL (fasting) 
or < 200 mg/dL (nonfasting).  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

Subject has been maintained on a stable regimen of 
oral anti-diabetic 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 
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screening, AND

Subject has not had any hospitalizations within the 
12 months prior to screening due to diabetes or 
complications related to diabetes, AND

Subject’s diabetes is not newly diagnosed during 
screening for the trial.
20) 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.
21) Subjects with epilepsy or a history of seizures, except 
for a single seizure episode; for instance childhood 
febrile seizure, post traumatic, or alcohol withdrawal.
22) 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 the following laboratory test and 
ECG results at screening must be excluded from the 
trial:

Platelets ≤ 75000/mm3

Hemoglobin ≤ 9 g/dL

Neutrophils, absolute ≤ 1000/mm3

AST > 2 × ULN

ALT > 2 × ULN

Creatine phosphokinase (CPK) > 3 × ULN, unless 
discussed with and approved by the medical 
monitor

Creatinine ≥ 2 mg/dL

QT interval as corrected by Fridericia’s formula 
(QTcF) ≥ 450 msec in men and ≥ 470 msec in 
women, unless due to ventricular pacing
23) Subjects who would be likely to require prohibited 
concomitant therapy during the trial.
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24) Subjects who received brexpiprazole in any prior 
clinical trial or currently taking commercially available 
brexpiprazole (Rexulti®).
25) Subjects with a history of neuroleptic malignant 
syndrome or serotonin syndrome.
26) Subjects with a history of true allergic response (ie, not 
intolerance) to more than 1 class of medications.
27) 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.
28) 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.
29) Any subject who, in the opinion of the sponsor, 
investigator, or medical monitor, should not participate 
in the trial.
Trial Site(s):
It is planned that approximately 610 subjects will be screened 
to enroll 332 subjects at approximately 45 trial sites in the 
United States (US).
Investigational 
Medicinal Product(s), 
Dose, Dosage 
regimen, Treatment 
period, Formulation, 
Mode of 
Administration:
During the double-blind treatment phase, subjects will receive 
IMP, consisting of brexpiprazole, brexpiprazole + Zoloft 
(sertraline), Zoloft (sertraline), or placebo depending on the 
subject’s treatment assignment.
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.
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Trial Assessments:
Efficacy:  CAPS-5, Symptoms of Trauma Scale (SOTS),
Clinical Global Impression - Severity (CGI-S), PTSD 
Checklist for DSM-5 (PCL-5), Hospital Anxiety and 
Depression Scale (HADS) and a wearable device.
Pharmacokinetic (PK):  A PK sample will be collected at 
Week 6 and Week 12 at the same time of collection of clinical 
labs. Time of last 3 doses will be recorded at the time of PK 
sampling.
Safety:  AE reporting, clinical laboratory tests, ECGs, vital 
signs, physical examination, body weight, height, waist 
circumference, Simpson-Angus Scale (SAS) total score, 
Abnormal Involuntary Movement Scale (AIMS) Movement 
Rating Score, and Barnes Akathisia Rating Scale (BARS)
Global Score, and C-SSRS.
Screening/Other:  MINI, Life Events Checklist for DSM-5 
(LEC-5), OSU TBI-ID, and Emory Treatment Resistance 
Interview for PTSD (E-TRIP) will be collected at screening. A 
pharmacogenomics sample to assess the cytochrome P450 
(CYP) 2D6 metabolism status will also be collected at Week 6. 
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Criteria for 
Evaluation:
Primary Endpoint:  Change from baseline in the CAPS-5 
total score.
Other Endpoints:  Other efficacy endpoints are as follows:

Change from baseline in SOTS score

Change from baseline in CGI-S score

Change from baseline in PCL-5 score

Change from baseline in HADS score

Sleep related endpoints
Safety Endpoints:  Standard safety variables will include 
AEs, clinical laboratory tests (hematology, serum chemistry 
[including blinded prolactin], HbA1c, and urinalysis), physical 
examinations, vital sign measurements, and ECGs.  Body 
weight, height, and waist circumference will also be measured.
Extrapyramidal symptoms (EPS) will be evaluated by 
calculating mean change from baseline in SAS total score, 
AIMS Movement Rating Score, and BARS Global Score.  The 
C-SSRS will be used to assess and classify reported suicidal 
behavior.  By-subject listings of physical examination findings 
will be reviewed as a further assessment of safety.
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Statistical Methods:
Complete details of the planned statistical analysis will be 
presented in the unblinded addendum to this protocol and in 
the statistical analysis plan (SAP).
Descriptive statistics will be provided for all efficacy and 
safety variables in general.  Continuous variables will be 
summarized by tabulations of mean, median, range, and 
standard deviation (SD).  Tabulations of frequency 
distributions will be provided for categorical variables. 
The change from baseline in CAPS-5 total score will be 
analyzed using a mixed-effect model repeated measures 
(MMRM) methodology with the unstructured variance 
covariance matrix.  The model will include fixed class-effect 
terms for treatment, trial center, type of trauma, visit week, and 
an interaction term of treatment by visit week and include the 
interaction term of baseline values of CAPS-5 total score by 
visit week as a covariate.  
Other continuous efficacy endpoints will also be analyzed 
using MMRM methodology. Complete model details will be 
specified in the SAP.
Trial Duration:
The duration of this trial for an individual subject who 
completes the trial without ET is approximately 16 weeks.  
This is inclusive of a 14-day screening period, a 12-week 
double-blind treatment period, and a safety follow-up period 
14 (+2) days after the dose of IMP.
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Table of Contents 
Protocol Synopsis...........................................................................................2
Table of Contents.........................................................................................12
List of In-text Tables ...................................................................................17
List of In-text Figures..................................................................................18
List of Appendices........................................................................................19
List of Abbreviations and Definitions of Terms .......................................20
1
Introduction ........................................................................................22
1.1
Nonclinical Data................................................................................................23
1.2
Clinical Data......................................................................................................23
1.3
Known and Potential Risks and Benefits ..........................................................23
2
Trial Rationale and Objectives..........................................................24
2.1
Trial Rationale...................................................................................................24
2.2
Dosing Rationale...............................................................................................24
2.3
Trial Objectives.................................................................................................25
3
Trial Design.........................................................................................26
3.1
Type/Design of Trial .........................................................................................26
3.2
Trial Treatments ................................................................................................29
3.3
Trial Population.................................................................................................29
3.3.1
Number of Subjects and Description of Population .......................................29
3.3.2
Subject Selection and Numbering ..................................................................30
3.4
Eligibility Criteria..............................................................................................30
3.4.1
Electronic Informed Consent..........................................................................30
3.4.2
Inclusion Criteria ............................................................................................31
3.4.3
Exclusion Criteria...........................................................................................32
3.5
Endpoints...........................................................................................................35
3.5.1
Primary Efficacy Endpoint .............................................................................35
3.5.2
Other Efficacy Endpoints ...............................................................................36
3.5.3
Safety Endpoints.............................................................................................36
3.5.4
Pharmacokinetic/Pharmacogenomic Variables ..............................................36
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3.6
Measures to Minimize/Avoid Bias....................................................................37
3.7
Trial Procedures ................................................................................................37
3.7.1
Schedule of Assessments................................................................................42
3.7.1.1
Screening.....................................................................................................42
3.7.1.2
Baseline (Day 0) Visit.................................................................................43
3.7.1.3
Treatment Phase - Week 1 ..........................................................................44
3.7.1.4
Treatment Phase - Week 2 ..........................................................................45
3.7.1.5
Treatment Phase - Week 3 ..........................................................................45
3.7.1.6
Treatment Phase - Week 4 ..........................................................................46
3.7.1.7
Treatment Phase - Week 6 ..........................................................................46
3.7.1.8
Treatment Phase - Week 8 ..........................................................................47
3.7.1.9
Treatment Phase - Week 10 ........................................................................48
3.7.1.10
End of Week 12/Early Termination............................................................48
3.7.1.11
Post-treatment Follow-up Period ................................................................50
3.7.2
Efficacy Assessments .....................................................................................50
3.7.2.1
Clinician-Administered PTSD Scale for DSM-5 (CAPS-5).......................50
3.7.2.2
Symptoms of Trauma Scale (SOTS)...........................................................51
3.7.2.3
Clinical Global Impression - Severity (CGI-S)...........................................51
3.7.2.4
PTSD Checklist for DSM-5 (PCL-5)..........................................................51
3.7.2.5
Hospital Anxiety and Depression Scale (HADS) .......................................51
3.7.2.6
Wearable Device.........................................................................................52
3.7.2.7
Other Assessments ......................................................................................52
3.7.2.7.1
Emory Treatment Resistance Interview for PTSD (E-TRIP)..................52
3.7.2.7.2
Life Events Checklist for DSM-5 (LEC-5) .............................................52
3.7.2.7.3
Mini International Neuropsychiatric Interview (MINI) ..........................52
3.7.2.7.4
Ohio State University Traumatic Brain Injury Identification 
Method.....................................................................................................53
3.7.3.1
Adverse Events............................................................................................53
3.7.3.2
Clinical Laboratory Assessments................................................................53
3.7.3.3
Physical Examination and Vital Signs........................................................55
3.7.3.3.1
Physical Examination..............................................................................55
3.7.3.3.2
Measurement of Vital Signs ....................................................................56
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3.7.3.4
Electrocardiogram Assessments..................................................................57
3.7.3.5
Other Safety Assessments...........................................................................58
3.7.3.5.1
Abnormal Involuntary Movement Scale .................................................58
3.7.3.5.2
Barnes Rating Scale For Drug-induced Akathisia...................................58
3.7.3.5.3
Simpson-Angus Scale..............................................................................59
3.7.3.5.4
Columbia-Suicide Severity Rating Scale ................................................59
3.7.3.5.5
Deoxyribonucleic Acid (DNA) Blood Samples for 
Pharmacogenomic Testing ......................................................................59
3.7.4
Pharmacokinetic Assessments........................................................................60
3.7.4.1
Pharmacokinetic Blood Samples.................................................................60
3.7.5
Future Biospecimen Research ........................................................................60
3.7.6
End of Trial.....................................................................................................60
3.8
Stopping Rules, Withdrawal Criteria, and Procedures......................................60
3.8.1
Entire Trial......................................................................................................60
3.8.2
Individual Site.................................................................................................61
3.8.3
Individual Subject Discontinuation ................................................................61
3.8.3.1
Treatment Interruption ................................................................................61
3.8.3.2
Treatment Discontinuation..........................................................................61
3.8.3.3
Documenting Reasons for Treatment Interruption/Discontinuation...........61
3.8.3.4
Withdrawal of Consent ...............................................................................62
3.8.3.5
Procedures to Encourage Continued Trial Participation.............................63
3.9
Screen Failures ..................................................................................................63
3.10
Definition of Completed Subjects.....................................................................64
3.11
Definition of Subjects Lost to Follow-up..........................................................64
3.12
Subject Compliance...........................................................................................64
3.13
Protocol Deviations...........................................................................................65
4
Restrictions..........................................................................................65
4.1
Prohibited Medications......................................................................................65
4.2
Other Restrictions..............................................................................................67
4.2.1
Restricted Therapies and Precautions.............................................................67
4.2.2
Non-therapy Precautions and Restrictions......................................................69
4.2.2.1
Precautions..................................................................................................69
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4.2.2.2
Restrictions..................................................................................................69
5
Reporting of Adverse Events.............................................................69
5.1
Definitions.........................................................................................................69
5.2
Eliciting and Reporting Adverse Events ...........................................................71
5.3
Immediately Reportable Events ........................................................................72
5.4
Potential Drug-Induced Liver Injury.................................................................72
5.5
Pregnancy..........................................................................................................72
5.6
Procedure for Breaking the Blind......................................................................74
5.7
Follow-up of Adverse Events............................................................................74
5.7.1
Follow-up of Nonserious Adverse Events......................................................74
5.7.2
Follow-up of Serious Adverse Events and Immediately Reportable 
Events .............................................................................................................75
5.7.3
Follow-up and Reporting of Serious Adverse Events Occurring after 
Last Scheduled Contact ..................................................................................75
6
Pharmacokinetic/Pharmacogenomic Analysis ................................75
7
Statistical Analysis..............................................................................75
7.1
Sample Size.......................................................................................................76
7.1.1
Efficacy Analysis............................................................................................76
7.2
Safety Analysis..................................................................................................76
7.2.1
Adverse Events ...............................................................................................76
7.2.2
Clinical Laboratory Data ................................................................................77
7.2.3
Physical Examination and Vital Signs Data ...................................................77
7.2.4
Electrocardiogram Data..................................................................................77
7.2.5
Other Safety Data ...........................................................................................78
8
Management of Investigational Medicinal Product........................78
8.1
Packaging and Labeling ....................................................................................78
8.2
Storage...............................................................................................................78
8.3
Accountability ...................................................................................................79
8.4
Returns and Destruction....................................................................................79
8.5
Reporting of Product Quality Complaints.........................................................79
8.5.1
Eliciting and Reporting Product Quality Complaints.....................................80
8.5.2
Information Required for Reporting Purposes ...............................................80
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8.5.3
Return Process ................................................................................................80
8.5.4
Assessment/Evaluation...................................................................................80
9
Records Management.........................................................................81
9.1
Source Documents.............................................................................................81
9.2
Data Collection..................................................................................................81
9.3
File Management at the Trial Site.....................................................................82
9.4
Records Retention at the Trial Site....................................................................82
10
Quality Control and Quality Assurance...........................................83
10.1
Monitoring.........................................................................................................83
10.2
Auditing.............................................................................................................83
11
Ethics and Responsibility...................................................................83
12
Confidentiality ....................................................................................84
13
Amendment Policy..............................................................................84
14
Publication Authorship Requirements.............................................85
15
References............................................................................................85
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List of In-text Tables
Table 3.4.2-1
Inclusion Criteria .......................................................................... 31
Table 3.4.3-1
Exclusion Criteria ......................................................................... 32
Table 3.7-1
Schedule of Assessments.............................................................. 38
Table 3.7.3.2-1
Clinical Laboratory Assessments.................................................. 54
Table 4.1-1
List of Medications Prohibited Before the Trial (Prior to 
Day 0)............................................................................................ 65
Table 4.1-2
List of Medications Prohibited/Restricted During the Trial ......... 66
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List of In-text Figures
Figure 3.1-1
Trial Design Schematic................................................................. 28
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List of Appendices
Appendix 1
Handling and Shipment of Bioanalytical Samples ....................... 88
Appendix 2
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance ........................................................................ 90
Appendix 3
Criteria for Identifying Vital Signs of Potential Clinical 
Relevance...................................................................................... 91
Appendix 4
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance ........................................................................ 92
Appendix 5
Past Month Version of the Clinician-Administered PTSD 
Scale For DSM-5 (CAPS-5) ......................................................... 93
Appendix 6
Past Week Version of the Clinician-Administered PTSD 
Scale For DSM-5 (CAPS-5) ....................................................... 115
Appendix 7
Symptoms of Trauma Scale (SOTS)........................................... 134
Appendix 8
Clinical Global Impression - Severity (CGI-S) .......................... 160
Appendix 9
PTSD Checklist for DSM-5 (PCL-5).......................................... 161
Appendix 10
Hospital Anxiety and Depression Scale (HADS)....................... 164
Appendix 11
Emory Treatment Resistance Interview for PTSD (E-TRIP) ..... 165
Appendix 12
Life Events Checklist for DSM-5 (LEC-5)................................. 175
Appendix 13
Mini International Neuropsychiatric Interview (MINI).............. 177
Appendix 14
Ohio State University Traumatic Brain Injury Identification 
Method (OSU TBI-ID) ............................................................... 218
Appendix 15
Abnormal Involuntary Movement Scale (AIMS)....................... 221
Appendix 16
Barnes Akathisia Rating Scale (BARS)...................................... 222
Appendix 17
Simpson-Angus Scale (SAS)...................................................... 224
Appendix 18
Baseline Columbia-Suicide Severity Rating Scale..................... 227
Appendix 19
Since Last Visit Columbia-Suicide Severity Rating Scale ......... 233
Appendix 20
Protocol Amendment(s)/Administrative Change(s) ................... 239
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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
5-HT
Serotonin
ADHD
Attention-deficit hyperactivity disorder
ADT
Antidepressive therapy
AE
Adverse event
AIMS
Abnormal Involuntary Movement Scale
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
anti-HCV
Antibodies to hepatitis C virus
AST
Aspartate aminotransferase
BARS
Barnes Akathisia Rating Scale
BMI
Body mass index
BUN
Blood urea nitrogen
CAPS-5
Clinician-Administered PTSD Scale for DSM-5
CGI-S
Clinical Global Impression - Severity
CPK
Creatine phosphokinase
CRO
Clinical research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
Cytochrome P450
DA
Dopamine
DBP
Diastolic blood pressure
DILI
Drug-induced liver injury
DNA
Deoxyribonucleic acid
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
ECG
Electrocardiogram
EMDR
Eye-movement desensitization and reprocessing
EPS
Extrapyramidal symptoms
ET
Early termination
EU
European Union
FBR
Future biospecimen research
FDA
(United States) Food and Drug Administration
GCP
Good Clinical Practice
GGT
Gamma glutamyl transferase
HADS
Hospital Anxiety and Depression Scale
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 Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
ID
Identification
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IDDM
Insulin-dependent diabetes mellitus
IEC
Independent ethics committee
IMP
Investigational medicinal product
IND
Investigational new drug
IRB
Institutional review board
IRE
Immediately reportable event
IRT
Interactive response technology
LDH
Lactic dehydrogenase
LDL
Low density lipoprotein
LEC-5
Life Events Checklist for DSM-5
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MDD
Major depressive disorder
MINI
Mini International Neuropsychiatric Interview
MMRM
Mixed-effect model repeated measure
MTD
Maximum tolerated dose
OC
Observed case
OPDC
Otsuka Pharmaceutical Development and Commercialization, Inc.
OSU TBI-ID
Ohio State University Traumatic Brain Injury Identification Method
PCL-5
PTSD Checklist for DSM-5
PET
Positron-emission tomography
PK
Pharmacokinetic
PQC
Product quality complaint
PTSD
Post-traumatic stress disorder
QD
Once-daily
QTcF
QT interval as corrected by Fridericia’s formula
RBC
Red blood cell
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Simpson-Angus Scale
SBP
Systolic blood pressure
SD
Standard deviation
SOTS
Symptoms of Trauma Scale
SSRI
Selective serotonin reuptake inhibitor
T4
Free thyroxine
TEAE
Treatment-emergent adverse event
TSH
Thyroid-stimulating hormone
US or USA
United States or United States of America
ULN
Upper limit of normal
WBC
White blood cell
WOCBP
Women of childbearing potential
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1
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 
cognitions 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 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 moderate, reaching approximately 60%.3  
Several clinical trials have been conducted with atypical antipsychotics in PTSD.4  
Brexpiprazole (OPC-34712, OPC-331, and Lu AF41156) is a new chemical entity 
discovered by Otsuka that is being codeveloped by Otsuka and Lundbeck.  Brexpiprazole 
is currently approved in the US for use as an adjunctive therapy to antidepressants for the 
treatment of major depressive disorder (MDD) and monotherapy treatment of 
schizophrenia.  While the precise mechanism of action of brexpiprazole in treating 
psychiatric conditions is unknown, the pharmacology of brexpiprazole is believed to be 
mediated by a combination of high binding affinity and functional activities at multiple 
monoaminergic receptors.  It has modulatory activity at the serotonin (5-HT) and 
dopamine (DA) systems that combines partial agonist activity at serotonergic 5-HT1A and 
at dopaminergic D2 receptors with antagonist activity at serotonergic 5-HT2A receptors, 
with similar high affinities at all of these receptors (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 
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may correlate with antipsychotic and antidepressant efficacy, reduced impulsive 
behavior, and cognitive improvement.5
1.1
Nonclinical Data
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) for more detailed 
information.5
1.2
Clinical Data
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:
adjunctive treatment of adult attention-deficit hyperactivity disorder (ADHD; 
coadministered with marketed stimulant therapy); treatment of agitation associated with 
dementia of the Alzheimer’s type; and treatment of adult PTSD.5
As of 17 Apr 2016, the brexpiprazole clinical development program consisted of a total 
of 65 clinical trials conducted in North America, Latin America, Europe, and Asia 
(53 completed and 12 ongoing).  This includes 59 trials conducted under US 
Investigational New Drug Applications (INDs) (47 completed and 12 ongoing) for 
schizophrenia, adjunctive treatment of MDD, adjunctive treatment of ADHD, agitation 
associated with dementia of the Alzheimer’s type, or PTSD; and 6 non-US IND trials 
completed in either Korea or Japan conducted in healthy subjects and subjects with 
schizophrenia.5
Please refer to the IB for more detailed information.5
1.3
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 
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when administered to patients with ADHD at doses of up to 4 mg/day in combination 
with a marketed stimulant.5
Please refer to the current IB for a summary of available nonclinical and clinical safety 
data.5
Zoloft (sertraline) is indicated for the treatment of PTSD at dose of 50-200 mg/day.  The
most frequently reported treatment-emergent adverse events (TEAEs) (incidence of at 
least 5% for Zoloft and at least twice that for placebo) in patients with PTSD were 
ejaculation failure, fatigue, anorexia, libido decreased, and tremor.6
2
Trial Rationale and Objectives
2.1
Trial Rationale
Two pharmacologic therapies (paroxetine and sertraline) are currently approved for 
treatment for PTSD by the US FDA, but only moderate clinical success has been 
demonstrated.  Most clinical guidelines recommend paroxetine and sertraline as the first-
line pharmacological intervention for PTSD.  However, the response rates to paroxetine 
and sertraline in PTSD are moderate and few patients achieve remission.  Consequently, 
there is a need for additional treatment options.
Only 1 trial has 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 early due to challenges with patient eligibility; the decision to terminate 
was not based on any safety concerns.
Trial 331-201-00061 aims to evaluate whether brexpiprazole as monotherapy or 
combination treatment is more effective than Zoloft (sertraline) alone or placebo in 
relieving PTSD symptoms in non-newly diagnosed subjects and to confirm that it is safe 
and well tolerated.
2.2
Dosing Rationale
The doses of brexpiprazole to be used in Trial 331-201-00061 have been determined 
based on results of previously completed clinical phase 1 pharmacology trials, a 
positron-emission tomography (PET) trial in healthy subjects, and a phase 3 trial in 
PTSD.
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The clinical pharmacology program consists of multiple ascending dose monotherapy 
trials in healthy subjects and subjects with schizophrenia as well as adjunctive trials in 
subjects with MDD, and ADHD.  The maximum tolerated dose (MTD) for healthy 
subjects has been determined to be 6 mg after single-dose administration and 2 mg after 
once-daily (QD), multiple-dose (14 days) administration.  The MTD of brexpiprazole in 
subjects with schizophrenia, MDD, or ADHD has not been established.  The following 
doses of brexpiprazole have been tolerated in completed phase 1 clinical pharmacology 
trials:

12 mg/day after QD, multiple-dose administration to adult subjects with 
schizophrenia or schizoaffective disorder,

4 mg/day after QD, multiple-dose administration to adult subjects with MDD 
when coadministered with marketed antidepressive therapy (ADT),

3 mg/day after QD, multiple-dose administration to elderly subjects (70 -
85 years of age) with MDD when coadministered with marketed ADT, and

4 mg/day after QD, multiple-dose administration to adult subjects with ADHD 
when coadministered with marketed stimulant therapy.
Results from the PET trial in healthy subjects (Trial 331-07-202) predicted steady state 
dopamine D2 and D3 receptor occupancies of at least 80% to 90% at brexpiprazole doses 
of 1 to 2 mg/day and higher (79.3% predicted occupancy at brexpiprazole 1 mg/day, 
88.8% at brexpiprazole 2 mg/day, and 95.1% at brexpiprazole 4 mg/day).
Results from subjects with PTSD (Trial 14865A) showed that brexpipazole doses of 1 to 
3 mg/day were well tolerated.
Therefore, based in the collective safety, tolerability, and receptor occupancy data, a dose 
range of 1 to 3 mg/day brexpiprazole was chosen for evaluation in Trial 331-201-00061.
Zoloft (sertraline) is indicated for the treatment of PTSD at doses of 50-200 mg/day.  
2.3
Trial Objectives
The primary objective is to evaluate the efficacy of brexpiprazole as monotherapy or as 
combination treatment with Zoloft (sertraline) in adult subjects with PTSD.
The secondary objective is to evaluate the safety and tolerability of brexpiprazole 1 to 
3 mg/day as monotherapy or as combination treatment with Zoloft (sertraline) in adult 
subjects with PTSD.
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3
Trial Design
3.1
Type/Design of Trial
This is a phase 2, randomized, double-blind, placebo- and active-controlled, 4-arm trial to 
evaluate the efficacy, safety, and tolerability of brexpiprazole (1 - 3 mg/day) as 
monotherapy or as combination therapy with Zoloft (sertraline) in adult subjects with 
PTSD.  See Figure 3.1-1 for a schematic of the trial design.
The trial will be organized as follows: 
Screening Phase:  The screening period will be up to 14 days and will begin when 
consent has been obtained.  Additional extension(s) of up to 14 additional days can be 
requested from the medical monitor, if needed to meet eligibility requirements. The 
purpose of the screening period is to assess eligibility criteria at 1 or more visits (as 
necessary to complete screening assessments) and to washout prohibited concomitant 
pharmacotherapy, if applicable.  An eSource method will be used to obtain an 
identification (ID) number for each subject with documented consent.  Subjects will be 
between 18 and 65 years of age, inclusive, at the time of screening and will have a 
diagnosis of PTSD as defined by DSM-5 criteria.
All subjects must agree to discontinue all prohibited medications during the screening 
period in order to meet the protocol-specified washout periods.
Treatment Phase:  Subjects will be enrolled into a 12-week double-blind treatment period 
and randomized in a 1:1:1:1 ratio to one of the following double-blind treatment 
regimens:  

brexpiprazole monotherapy

brexpiprazole and Zoloft (sertraline) combination therapy

Zoloft (sertraline) monotherapy

placebo
Subjects will attend visits at Baseline (Day 0) and Weeks 1, 2, 3, 4, 6, 8, 10, and 12 
during the treatment phase.
Follow-up:  If any subject discontinues the trial early, every effort should be made to 
complete the Week 12/early termination (ET) evaluations as soon as possible and 
whenever possible prior to starting any new medication or treatment.  All subjects 
(completers and early withdrawals) will be contacted to monitor for safety events via 
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telephone or clinic visit, 14 (+ 2) days after the last dose of investigational medicinal 
product (IMP).  Any subject who withdraws because of a serious adverse event (SAE)
should be seen in the clinic, if possible.
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Figure 3.1-1
Trial Design Schematic
12/
End of
Treatment
Double-blind Treatment Phase
Follow-up
Screening
3 to 14 days
prior to Day 0
Adults aged 18 to 
65 years with 
PTSD 
Telephone 
contact or 
clinic visit 
after 14 (+2) 
days
Baseline 
Day 0
Post-treatment 
Subjects will be assigned to one of the following treatment regimens:
Brexpiprazole + placebo 
Zoloft (sertraline) + placebo
Placebo + placebo
Brexpiprazole + Zoloft (sertraline)
Week
1 
Week
2 
Week
3 
Week
4 
Week
6 
Week
8 
Week
10
N = 332
N ~ 610
Week
Follow-up
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3.2
Trial Treatments
During the first 3 weeks of the trial, subjects will be titrated according to the blinded 
titration schedule, based on the treatment group to which they will be randomized.  Per 
this schedule, at Week 3, subjects will receive:
1. Brexpiprazole monotherapy 2 mg/day; or
2. Brexpiprazole 2 mg/day + Zoloft (sertraline) 150 mg/day; or
3. Zoloft (sertraline) monotherapy 150 mg/day; or
4. Placebo.
No dose adjustments are allowed during the 3 week titration period, thus any subject 
unable to tolerate the assigned dose of IMP during the titration period must be withdrawn 
from the trial.
Once the subject takes the first dose following the forced titration period, the dose of IMP 
can be adjusted to optimize efficacy and safety/tolerability according to the following 
rules:

Dose increases can occur only at the Week 4 visit. 

Dose decreases can occur at scheduled or unscheduled visits starting after the first 
dose following Week 3 and are not allowed after the Week 6 visit.  

Dose may be maintained, decreased (if not decreased already) or increased at the 
Week 4 visit.  No further dose increases are permitted after Week 4.

Dose decreases will be allowed between Week 3 (following the first post-visit 
dose as above) and Week 6, if there are tolerability issues. 

Dose must be maintained for the remainder of the treatment period after Week 6.

If subjects are unable to maintain the Week 6 dose due to tolerability issues, the 
subject must be withdrawn from the trial.
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.
3.3
Trial Population
3.3.1
Number of Subjects and Description of Population
It is planned that approximately 610 subjects will be screened to enroll 332 subjects at
approximately 45 trial sites in the US.
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The trial population will include male and female outpatients between 18 and 65 years of 
age at the time of consent, inclusive, with a DSM-5 diagnosis of PTSD.
3.3.2
Subject Selection and Numbering
At screening, subjects will be assigned a unique subject ID number upon completion of
the consent process based on sequential enrollment in the trial.  
3.4
Eligibility Criteria
3.4.1
Electronic Informed Consent
Informed consent will be freely obtained from all subjects (or their guardian or legally 
acceptable representative, as applicable for local laws).  The informed consent form (ICF) 
will be approved by the same institutional review board (IRB)/independent ethics 
committee (IEC) that approves this protocol.
Each ICF will comply with the International Conference on Harmonisation (ICH) Good 
Clinical Practice (GCP) Guideline7 and local regulatory requirements.  The investigator 
will ensure that the sponsor reviews and authorizes any site‑specific ICF used in the trial 
before submission to the IRB/IEC.
Investigators may discuss trial availability and the possibility for entry with a potential 
subject without first obtaining consent.  However, informed consent must be obtained and 
documented prior to initiation of any procedures that are performed solely for the purpose 
of determining eligibility for the 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 participants will be provided with controlled access to the electronic 
informed consent application by site personnel.  When the site staff and the participant 
agree that the participant has enough information to make an informed decision to 
participate, the participant will electronically sign the electronic ICF application and an 
electronic date and time stamp will be applied to the signature.  The participant will be 
given a printed copy of the consent form.  Any other parties required by the IRB/IEC 
(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.
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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 trial participation.
3.4.2
Inclusion Criteria
Subjects are required to meet the inclusion criteria presented in Table 3.4.2-1.
Table 3.4.2-1
Inclusion Criteria
1.
Subjects who are able to complete the consent process and/or consent obtained from a legally 
acceptable representative (as required by IRB/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.
5.
The subject has 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.
CAPS-5 = Clinician-Administered PTSD Scale for DSM-5; MINI = Mini International Neuropsychiatric 
Interview.
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3.4.3
Exclusion Criteria
Subjects will be excluded if they meet any of the exclusion criteria in Table 3.4.3-1.
Table 3.4.3-1
Exclusion Criteria
Sex and Reproductive Status
1.
Sexually active males or 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.
Target Disease
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 > 15 years before screening.
5.
The index traumatic event occurred before age 16.
6.
Subjects with PTSD who, in the investigator's opinion, are considered resistant/refractory to 
psychotropic treatment by history.
7.
Subjects who are currently receiving Zoloft (sertraline) with adequate dose and duration (> 50 
mg/day for a minimum of 8 weeks). 
8.
Subjects who have had initiation of, or a change in, psychotherapy, EMDR therapy or any other 
intervention for the treatment of PTSD symptoms within 28 days prior to the Screening Visit or it 
is anticipated that the subject will have a change in psychotherapy, EMDR therapy, or in any other 
intervention during the trial.
9.
Subjects who meet the DSM-5 criteria for a current Major Depressive Episode (ie, currently 
symptomatic).
10.
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.
11.
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.
12.
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.  
13.
Subjects who have a positive urine drug screen that, in the judgment of the investigator with 
concurrence of the medical monitor, could compromise the subject’s safety or ability to comply 
with the trial procedures that could interfere with the interpretation of trial results.  
14.
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 
patient safety, in the investigator’s opinion.
15.
Subjects who have experienced a traumatic event within 3 months of screening.
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Table 3.4.3-1
Exclusion Criteria
Medical History and Concurrent Diseases
16.
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).
17.
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).
18.
Subjects who currently have clinically significant neurological, hepatic, renal, metabolic, 
hematological, immunological, cardiovascular, pulmonary, or gastrointestinal disorders such as 
ischemic heart disease, myocardial infarction, congestive heart failure (whether controlled or 
uncontrolled), angioplasty, stenting, or coronary artery bypass surgery, HIV seropositive 
status/acquired immunodeficiency syndrome, chronic hepatitis B or C (defined as positive serology 
and AST or ALT elevated to > 2 × 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 of the condition(s) on trial participation.  Subjects who are 
severely obese, as confirmed by a corresponding high BMI (BMI ≥ 40 kg/m2), need to be reviewed 
and discussed with the medical monitor.
19.
Subjects with IDDM (ie, any subjects using insulin) are excluded.  Subjects with non-IDDM may 
be eligible for the trial if their condition is stable as determined by satisfying ALL of the following 
criteria:

HbA1c < 7.0%, AND

Screening glucose must be ≤125 mg/dL (fasting) or < 200 mg/dL (nonfasting).  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

Subject has been maintained on a stable regimen of oral anti-diabetic 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, AND

Subject has not had any hospitalizations within the 12 months prior to screening due to 
diabetes or complications related to diabetes, AND

Subject’s diabetes is not newly diagnosed during screening for the trial.
20.
Subjects with uncontrolled hypertension (DBP > 95 mmHg in any position) or symptomatic 
hypotension, or orthostatic hypotension which is 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.
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.
21
Subjects with epilepsy or a history of seizures, except for a single seizure episode; for instance 
childhood febrile seizure, post traumatic, or alcohol withdrawal.
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Table 3.4.3-1
Exclusion Criteria
Physical and Laboratory Results
22.
Subjects with abnormal laboratory tests results, vital signs results, or ECG findings, unless, based 
on the investigator’s judgment, the findings are not medically significant and would not impact the 
safety of the subject or the interpretation of the trial results.  The medical monitor should be 
contacted to discuss individual cases, as needed.  Criteria are provided in Appendix 2, Appendix 3, 
and Appendix 4 to assist investigators in their assessments of results that may be potentially 
medically significant, depending on the subject’s medical history and clinical presentation.
In addition, subjects with the following laboratory test and ECG results at screening must be 
excluded from the trial:

Platelets ≤75000/mm3

Hemoglobin ≤9 g/dL

Neutrophils, absolute ≤1000/mm3

AST > 2 × ULN

ALT > 2 × ULN

CPK > 3 × ULN, unless discussed with and approved by the medical monitor

Creatinine ≥2 mg/dL

QTcF 450 msec in men and 470 msec in women (see Section 3.7.3.4 for further details), 
unless due to ventricular pacing
Tests with exclusionary results should be repeated to ensure reproducibility of the abnormality 
before excluding a subject based on the criteria noted above.  For ECG, perform 3 consecutive 
recordings.  If 2 of the 3 remain exclusionary then the subject must be excluded.
Disallowed Recent and Concomitant Medication
23.
Subjects who would be likely to require prohibited concomitant therapy during the trial (see
Table 4.1-2).
24.
Subjects who received brexpiprazole in any prior clinical trial or currently taking commercially 
available brexpiprazole (Rexulti®).
Allergies and Adverse Drug Reactions
25.
Subjects with a history of neuroleptic malignant syndrome or serotonin syndrome.
26.
Subjects with a history of true allergic response (ie, not intolerance) to more than 1 class of 
medications.
Other
27.
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.
28.
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.
29.
Any subject who, in the opinion of the sponsor, investigator, or medical monitor, should not 
participate in the trial.
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body 
mass index; CPK = creatine phosphokinase; C-SSRS = Columbia-Suicide Severity Rating Scale;
DBP = diastolic blood pressure; ECG = electrocardiogram; EMDR = eye-movement desensitization 
and reprocessing; HbA1c = glycosylated hemoglobin; HIV = human immunodeficiency virus; 
IDDM = insulin-dependent diabetes mellitus; OSU TBI-ID = Ohio State University Traumatic Brain 
Injury Identification Method; QTcF = QT interval as corrected by Fridericia’s formula;
SBP = systolic blood pressure; ULN = upper limit of normal.
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Nonchildbearing potential is defined as male and female subjects who are surgically 
sterile (ie, male subjects who have undergone bilateral orchidectomy and female subjects 
who have undergone bilateral oophorectomy and/or hysterectomy) and female subjects 
who have been postmenopausal for at least 12 consecutive months with no menses 
without an alternative medical cause.
Subjects must agree to restrictions to medications and lifestyle as described in Section 4.
Subjects with a positive blood alcohol screen should be reassessed for alcohol abuse and 
dependence before consultation with medical monitor about approval for inclusion.  
Subjects with a positive drug screen that, in the judgment of the investigator with 
concurrence of the medical monitor, could compromise the subject’s safety or ability to 
comply with the trial procedures that could interfere with the interpretation of trial 
results.  Detectable levels of marijuana, barbiturates, stimulants, or opiates in the drug 
screen are not exclusionary if:

In the investigator’s documented opinion, the subject does not meet DSM-5 
criteria for substance abuse or dependence, and

In the investigator’s documented opinion, the positive test does not signal a 
clinical condition that would impact the safety of the subject or interpretation 
of the trial results, and

The medical monitor’s approval is obtained prior to the Baseline (Day 0) 
Visit.
Screen failures due to exclusionary criteria may be rescreened at any time if the exclusion 
characteristic has changed.  In the event that a subject cannot be randomized prior to 
expiration of the 14-day screening period, additional 14-day extension(s) of screening 
may be requested from the medical monitor.  Any extension should be requested prior to 
the expiration of the previous extension or screening period, as applicable.  If no 
extension is granted, a new ICF must be signed, a new screening number assigned, and 
all screening procedures repeated. Subjects may be rescreened twice for this trial.
3.5
Endpoints
3.5.1
Primary Efficacy Endpoint
Change from baseline in the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) 
total score.
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3.5.2
Other Efficacy Endpoints
Other efficacy endpoints are as follows:

Change from baseline in Symptoms of Trauma Scale (SOTS) score

Change from baseline in Clinical Global Impression - Severity (CGI-S) score

Change from baseline in PTSD Checklist for DSM-5 (PCL-5) score

Change from baseline in Hospital Anxiety and Depression Scale (HADS) 
score

Sleep related endpoints
3.5.3
Safety Endpoints
Standard safety variables will include adverse events (AEs), clinical laboratory tests 
(hematology, serum chemistry [including blinded prolactin], glycosylated hemoglobin
[HbA1c], and urinalysis), physical examinations, vital sign measurements, and 
electrocardiograms (ECGs).  Body weight, height, and waist circumference will also be 
measured.
Extrapyramidal symptoms (EPS) will be evaluated by calculating mean change from 
baseline in Simpson-Angus Scale (SAS) total score, Abnormal Involuntary Movement 
Scale (AIMS) Movement Rating Score, and Barnes Akathisia Rating Scale (BARS)
Global Score.  The Columbia-Suicide Severity Rating Scale (C-SSRS) will be used to 
assess and classify reported suicidal behavior.  By-subject listings of physical 
examination findings will be reviewed as a further assessment of safety.
3.5.4
Pharmacokinetic/Pharmacogenomic Variables
A PK sample will be collected at Week 6 and Week 12 at the same time of collection of 
clinical labs.  Samples will be analyzed for brexpiprazole and its major metabolite, 
DM-3411, concentrations using a high-performance liquid chromatography with tandem 
mass spectrometry method.
A pharmacogenomics sample to assess the cytochrome P450 (CYP)2D6 metabolism 
status will also be collected at Week 6.  Time of last 3 doses will be recorded at the time 
of PK sampling.
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3.6
Measures to Minimize/Avoid Bias
During the entire trial, treatment will be double-blind.  In other words, neither the 
investigator nor the subject will have knowledge of the treatment assignment at any given 
visit.  
Treatment assignments will be based on a computer-generated randomization code 
provided by the Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) 
Biometrics Department.  The randomization will be stratified by trial site and type of 
trauma (combat related Yes/No).  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.
3.7
Trial Procedures
This is a phase 2, randomized, double-blind, placebo- and active-controlled, 4-arm trial to 
evaluate the efficacy, safety, and tolerability of brexpiprazole (1 - 3 mg/day) as 
monotherapy or as combination therapy with Zoloft (sertraline) in adult subjects with 
PTSD.  The trial is a continuous, 12-week, double-blind treatment period with a 14-day 
follow-up (Figure 3.1-1).
Trial assessment time points are summarized in Table 3.7-1.
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Table 3.7-1
Schedule of Assessments
Assessment
Screeninga
(Day −14 to 
Day −3) 
Baseline
(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
(2 days)
Week 8
Visit
(2 days)
Week 10
Visit
(2 days)
Week 12/
ETb Visit
(2 days)
Post-
treatment 
Follow-upc
(+ 2 days)
ENTRANCE CRITERIA
Informed Consent
X
Inclusion/exclusion criteria
X
X
Demography
X
Medical history
X
Psychiatric history including 
PTSD history
X
MINI 
X
PTSD treatments: 
pharmacological and non-
pharmacological and E-TRIP
X
Prior medication washoutd
X
LEC-5
X
OSU TBI-ID
X
HIV, HBsAg, and anti-HCV
X
Review of birth control 
methods
X
X
X
X
X
X
X
X
X
X
X
EFFICACY
CAPS-5e
X
X
X
X
X
X
X
SOTS
X
X
X
CGI-S
X
X
X
X
X
X
X
X
X
PCL-5
X
X
X
X
X
X
HADS
X
X
X
X
X
X
Wearable devicef
X
X
X
X
X
X
X
X
X
SAFETY
Assess need for double-blind 
IMP dose modification
X
X
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Table 3.7-1
Schedule of Assessments
Assessment
Screeninga
(Day −14 to 
Day −3) 
Baseline
(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
(2 days)
Week 8
Visit
(2 days)
Week 10
Visit
(2 days)
Week 12/
ETb Visit
(2 days)
Post-
treatment 
Follow-upc
(+ 2 days)
Physical examinationg
X
X
Vital signsh
X
X
X
X
X
X
X
X
X
X
12-lead ECGi
X
X
X
Clinical laboratory tests 
(hematology, serum chemistry
[including blinded prolactin], 
urinalysis), TSHj
X
Xk
X
X
HbA1c
X
X
Insulin
X
Xk
X
Urine drug screen/blood 
alcoholl
X
X
Urine pregnancy testm
X
X
X
X
X
C-SSRSn
X
X
X
X
X
X
X
X
X
X
SAS
X
X
X
X
AIMS
X
X
X
X
BARS
X
X
X
X
Adverse eventso
X
X
X
X
X
X
X
X
X
X
X
Concomitant medicationsp
X
X
X
X
X
X
X
X
X
X
OTHER
Drug dispensingq
X
X
X
X
X
X
X
X
Drug accountability
X
X
X
X
X
X
X
X
Pharmacokinetic and Pharmacogenomic Sampling
PK sampler
X
X
Pharmacogenomic samples
X
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Table 3.7-1
Schedule of Assessments
Assessment
Screeninga
(Day −14 to 
Day −3) 
Baseline
(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
(2 days)
Week 8
Visit
(2 days)
Week 10
Visit
(2 days)
Week 12/
ETb Visit
(2 days)
Post-
treatment 
Follow-upc
(+ 2 days)
FBR samplet
X
anti-HCV = antibodies to hepatitis C virus; E-TRIP = Emory Treatment Resistance Interview for PTSD; FBR = future biospecimen research; 
HBsAg = hepatitis B surface antigen; LEC-5 = Life Events Checklist for DSM-5; TSH = thyroid-stimulating hormone.
aScreening begins upon completion of the consent process.  Although the screening period takes place between Day −14 and Day −3 prior to enrollment, 
subjects will participate in screening activities for a minimum of 3 days.  It is requested to complete screening as quickly as possible.  In the event that a 
subject cannot be randomized prior to expiration of the 14-day screening period, additional 14-day extension(s) of screening may be requested from the 
medical monitor.  Any extension should be requested prior to the expiration of the previous extension or screening period, as applicable.  
bIf a subject discontinues early, every effort should be made to complete the “End of Week 12/ET” evaluations as soon as possible and whenever possible 
prior to starting any new medication or treatment.
cTelephone contact or clinic visit (investigator’s discretion) for evaluation of safety.
dWashout of prohibited medications begins after completion of the consent process and must comply with the required washout periods in Section 4.1.
eThe CAPS-5 Past Month version will be completed for all subjects at screening to determine eligibility and 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.  The CAPS-5 Past Week version will also be completed at all visits 
after the Baseline (Day 0) Visit when the assessment is scheduled for collection.
fThe wearable device will be put on the subject’s nondominant wrist, whenever possible, at the Baseline (Day 0) Visit and worn daily until Week12/ET.  The 
trial site will download Actigraphy data during each subject visit.
gTo include measurement of height (at screening only) and waist circumference.
hVital sign measurements include body weight, body temperature, SBP, DBP, and heart rate.  Blood pressure and heart rate will be measured in the following 
order:  supine and standing after the subject has been in each position for at least 3 minutes.
iStandard 12-lead ECGs will be performed after the subject has been supine and at rest for 5 minutes prior to the ECG.  Electrocardiogram results will be 
evaluated at the investigational site to determine the subject’s eligibility and to monitor safety.  Any screening ECG with abnormal result(s) considered to 
be clinically significant should be repeated in triplicate to confirm the finding(s) before excluding the subject from the trial (see Section 3.7.3.4).  A central 
ECG service will be utilized to review all ECGs in order to standardize interpretations for the safety analysis.
jBlood samples for clinical laboratory tests should be drawn after a minimum 8-hour fast at the Baseline (Day 0) Visit and should be drawn after a minimum 
8-hour fast at screening, if possible.  If blood draws are not part of the site’s SOP, the subject should not be asked to fast for the study prior to signing the 
ICF.  
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kIf 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], TSH with reflex to T4 if the result for TSH is abnormal, and urinalysis) need to be repeated at 
the Baseline (Day 0) Visit.
lA urine drug screen and a blood alcohol test are required at the designated times, but either or both can be conducted at any time during the trial at the 
discretion of the investigator (Section 4.2.2.2).  See Section 3.4.3 for exclusions based on urine drug screen and blood alcohol tests at screening and 
baseline requirements based on urine drug screen and blood alcohol results.
mFor women of childbearing potential only (WOCBP).  All positive urine pregnancy test results must be confirmed by a serum test. Pregnancy tests can be 
performed at any point during the trial if pregnancy is suspected.
nThe “Baseline/Screening” C-SSRS form will be completed for all subjects at screening to determine eligibility and the “Since Last Visit” C-SSRS form will 
be completed at the Baseline (Day 0) Visit to assure that the subject continues to qualify for the trial.  The “Since Last Visit” C-SSRS form will also be 
completed at all visits after the Baseline (Day 0) Visit.
oAdverse events will be recorded starting after the subject completes the consent process.
pAll prescription and non-prescription medications taken during the trial will be recorded.  Details of prohibited medications are provided in Section 4.
qThe subject will be instructed to take their first dose the day after the Baseline (Day 0) Visit (see Section 3.7.1.2).
rA PK sample will be collected at the same time of collection of clinical labs. Time of last 3 doses will be recorded at the time of PK sampling.
sA pharmacogenomics sample to assess the CYP2D6 metabolism status will also be collected.
tFBR sample will be collected if subject consent is received and if allowed by IRB/IEC (see Section 3.7.5).
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3.7.1
Schedule of Assessments
3.7.1.1
Screening
The screening period begins after consent has been obtained.  Although the screening 
period takes place between Day −14 and Day −3, subjects will participate in screening 
activities for a minimum of 3 days.  It is requested to complete screening as quickly as 
possible.  In the event that a subject cannot be randomized prior to expiration of the 
14-day screening period, additional 14-day extension(s) of screening may be requested 
from the medical monitor.  Any extension should be requested prior to the expiration of 
the previous extension or screening period, as applicable.  After a subject has provided 
consent, sites will obtain a subject ID number for the subject by accessing eSource.  
Completion of screening activities may require more than one visit; however, only the 
initial visit will be registered in the eSource.  Screening evaluations will include the 
following:

An assessment of all inclusion and exclusion criteria will be made to determine the 
subject’s eligibility for the trial.

Demographic data will be recorded.

A general clinical evaluation will be performed, including concurrent medical 
conditions, medical history over the past 2 years, and medical history beyond 2 years 
which is considered to be clinically relevant per the investigator’s judgment.

Psychiatric history will be recorded, including the DSM-5 diagnosis of PTSD that 
will be made by an adequately trained and experienced clinician and will be 
confirmed by the administration of the Mini International Neuropsychiatric Interview
(MINI).

Medications (including those that were taken within 30 days preceding the first dose 
of IMP) will be recorded.  In addition, all prescription and non-prescription 
medications taken during the trial will be recorded as concomitant medications.  
Details of prohibited/restricted medications are provided in Table 4.1-2.

All pharmacological and non-pharmacological treatments for PTSD using the Emory 
Treatment Resistance Interview for PTSD (E-TRIP) assessment.

Washout from prohibited concomitant medications will begin, if applicable, (see
Table 4.1-1).

Subject will complete the Life Events Checklist for DSM-5 (LEC-5) assessment.  The 
LEC-5 assessment will be reviewed for completeness by the same qualified and 
certified rater administering the CAPS-5.

A qualified and certified rater will administer the CAPS-5.  Subjects with CAPS-5 
total score < 33 at screening or baseline are excluded from the trial.

The investigator (or qualified designee) will administer the Ohio State University 
Traumatic Brain Injury Identification Method (OSU TBI-ID).
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
A complete physical examination (including height and waist circumference) will be 
performed.

Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded.  Blood pressure and heart rate are to be measured in the 
following order:  supine and standing after the subject has been in each position at 
least 3 minutes.  See Table 3.4.3-1 for exclusions based on outcome of screening vital 
sign measurements.  

A standard 12-lead ECG will be performed after the subject has been supine and at 
rest for at least 5 minutes.  See Table 3.4.3-1 for exclusions based on ECG results.  

Blood samples for clinical laboratory tests (hematology, serum chemistry [including 
blinded prolactin], HbA1c, thyroid-stimulating hormone [TSH] with reflex to free 
thyroxine [T4] if the result for TSH is abnormal, insulin, and urinalysis) should be 
drawn after a minimum 8-hour fast at screening.  See Table 3.4.3-1 for exclusions 
based on outcome of screening clinical laboratory tests.  

Blood samples will be drawn for human immunodeficiency virus (HIV) serology and 
the presence of hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C
virus (anti-HCV).  

Samples will be obtained for blood alcohol testing.  See Section 3.4.3 for detail of 
subjects with a positive blood alcohol test.

Urine will be collected from all potential subjects for urinalysis and urine screen(s) 
for drugs of abuse.  See Section 3.4.3 for exclusions based on outcome of screening 
urinalysis and urine screen(s) for drugs of abuse.

A urine pregnancy test will be performed for all women of childbearing potential
(WOCBP).  All positive results must be confirmed by a serum pregnancy test.  
Subjects with a positive serum pregnancy test result will be excluded from the trial.

The investigator (or qualified designee) will complete the “Baseline/Screening” 
C-SSRS form to exclude subjects with a significant risk of suicidal behavior (see
Table 3.4.3-1).

Adverse events will be recorded beginning with the completion of the consent 
process.
3.7.1.2
Baseline (Day 0) Visit
If the subject is found to be eligible for the trial during the screening period, the subject 
will attend a baseline visit during which the following procedures will be performed:

An assessment of all inclusion and exclusion criteria will be made to determine the 
subject’s eligibility for the trial.

A qualified and certified rater will administer the CAPS-5. Whenever possible, it is 
recommended that the CAPS-5 is conducted as the first assessment of the visit.

The investigator (or qualified designee) will administer the CGI-S and SOTS.
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
The subject will complete the HADS and PCL-5.  Assessments will be reviewed for 
completeness by the investigator (or qualified designee).

An adequately trained and experienced clinician will administer the SAS, AIMS, and 
BARS to assess EPS.

Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded.  Blood pressure and heart rate are to be measured in the 
following order:  supine and standing after the subject has been in each position at 
least 3 minutes.  See Table 3.4.3-1 for exclusions based on outcome of vital sign 
measurements.  

A standard 12-lead ECG will be performed after the subject has been supine and at 
rest for at least 5 minutes.  See Table 3.4.3-1 for exclusions based on ECG results.

If a fasting blood sample was not obtained at the Screening Visit and if more than 
10 days have elapsed since the Screening Visit, blood samples for clinical laboratory 
tests (hematology, serum chemistry [including blinded prolactin], TSH with reflex to 
T4 if the result for TSH is abnormal, insulin, and urinalysis) should be drawn after a 
minimum 8-hour fast at Baseline (Day 0) Visit. 

A urine pregnancy test will be performed for all WOCBP.  All positive results must 
be confirmed by a serum pregnancy test.  Subjects with a positive serum pregnancy 
test result will be excluded from the trial.

The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form to assure that the subject continues to qualify for the trial.

Adverse events and concomitant medications will be recorded.

The assigned IMP will be dispensed to the subject.  The subjects should be instructed 
to take their first dose the day after the Baseline (Day 0) Visit.

The wearable device will be put on subject’s nondominant wrist.  The wearable 
device will be worn continuously throughout the double-blind treatment period.
3.7.1.3
Treatment Phase - Week 1
Visit is to occur within 2 days of the target visit date.  The following procedures will be 
performed during the Treatment Phase visit:

A qualified and certified rater will administer the CAPS-5.  Whenever possible, it is 
recommended that the CAPS-5 is conducted as the first assessment of the visit.

The investigator (or qualified designee) will administer the CGI-S.

The subject will complete the HADS and PCL-5.  Assessments will be reviewed for 
completeness by the investigator (or qualified designee).

Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded.  Blood pressure and heart rate are to be measured in the 
following order:  supine and standing after the subject has been in each position at 
least 3 minutes.
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
The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form to assure that the subject continues to qualify for the trial.

Adverse events and concomitant medications will be recorded.

The assigned IMP will be dispensed to the subject.

Drug accountability will be performed.

The wearable device will be taken off and the data will be downloaded to the 
computer, prior to putting the device back on to continue recording.
3.7.1.4
Treatment Phase - Week 2
Visit is to occur within 2 days of the target visit date.  The following procedures will be 
performed during the Treatment Phase visit:

The investigator (or qualified designee) will administer the CGI-S.

An adequately trained and experienced clinician will administer the SAS, AIMS, and 
BARS to assess EPS.

Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded.  Blood pressure and heart rate are to be measured in the 
following order:  supine and standing after the subject has been in each position at 
least 3 minutes.

The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form to assure that the subject continues to qualify for the trial.

Adverse events and concomitant medications will be recorded.

The assigned IMP will be dispensed to the subject.

Drug accountability will be performed.

The wearable device will be taken off and the data will be downloaded to the 
computer, prior to putting the device back on to continue recording.
3.7.1.5
Treatment Phase - Week 3
Visit is to occur within 2 days of the target visit date.  The following procedures will be 
performed during the Treatment Phase visit:

A qualified and certified rater will administer the CAPS-5.  Whenever possible, it is 
recommended that the CAPS-5 is conducted as the first assessment of the visit.  

The investigator (or qualified designee) will administer the CGI-S.

The subject will complete the HADS and PCL-5.  Assessments will be reviewed for 
completeness by the investigator (or qualified designee).

Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded.  Blood pressure and heart rate are to be measured in the 
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following order:  supine and standing after the subject has been in each position at 
least 3 minutes.

The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form to assure that the subject continues to qualify for the trial.

Adverse events and concomitant medications will be recorded.

The assigned IMP will be dispensed to the subject.

Drug accountability will be performed.

The wearable device will be taken off and the data will be downloaded to the 
computer, prior to putting the device back on to continue recording.
3.7.1.6
Treatment Phase - Week 4
Visit is to occur within 2 days of the target visit date.  The following procedures will be 
performed during the Treatment Phase visit:

The investigator (or qualified designee) will administer the CGI-S and SOTS.

Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded.  Blood pressure and heart rate are to be measured in the 
following order:  supine and standing after the subject has been in each position at 
least 3 minutes.  

All WOCBP will be given a urine pregnancy test.  The result must be negative prior 
to dosing.  All positive results must be confirmed by a serum pregnancy test.

The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form to assure that the subject continues to qualify for the trial.

Adverse events and concomitant medications will be recorded.

Trial personnel will assess need for double-blind IMP dose modification.

The assigned IMP will be dispensed to the subject.

Drug accountability will be performed.

The wearable device will be taken off and the data will be downloaded to the 
computer, prior to putting the device back on to continue recording.
3.7.1.7
Treatment Phase - Week 6
Visit is to occur within 2 days of the target visit date.  The following procedures will be 
performed during the Treatment Phase visit:

A qualified and certified rater will administer the CAPS-5.  Whenever possible, it is 
recommended that the CAPS-5 is conducted as the first assessment of the visit.

The investigator (or qualified designee) will administer the CGI-S.
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
The subject will complete the HADS and PCL-5.  Assessments will be reviewed for 
completeness by the investigator (or qualified designee).

An adequately trained and experienced clinician will administer the SAS, AIMS, and 
BARS to assess EPS.

Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded.  Blood pressure and heart rate are to be measured in the 
following order:  supine and standing after the subject has been in each position at 
least 3 minutes.  

Blood samples for clinical laboratory tests (hematology, serum chemistry [including 
blinded prolactin], TSH with reflex to T4 if the result for TSH is abnormal, and 
urinalysis) should be drawn after a minimum of 8-hour fasting.

A PK sample will be collected at the same time of collection of clinical labs. Time of 
last 3 doses will be recorded at the time of PK sampling.

A pharmacogenomics sample to assess the CYP2D6 metabolism status will also be 
collected. 

A future biospecimen research (FBR) sample will be collected to explore and identify 
biomarkers if subject consent is received and if allowed by IRB/IEC.

The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form to assure that the subject continues to qualify for the trial.

Adverse events and concomitant medications will be recorded.

Trial personnel will assess need for double-blind IMP dose modification.

The assigned IMP will be dispensed to the subject.

Drug accountability will be performed.

The wearable device will be taken off and the data will be downloaded to the 
computer, prior to putting the device back on to continue recording.
3.7.1.8
Treatment Phase - Week 8
Visit is to occur within 2 days of the target visit date.  The following procedures will be 
performed during the Treatment Phase visit:

The investigator (or qualified designee) will administer the CGI-S.

Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded.  Blood pressure and heart rate are to be measured in the 
following order:  supine and standing after the subject has been in each position at 
least 3 minutes.

All WOCBP will be given a urine pregnancy test.  The result must be negative prior 
to dosing.  All positive results must be confirmed by a serum pregnancy test.  

The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form to assure that the subject continues to qualify for the trial.
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
Adverse events and concomitant medications will be recorded.

The assigned IMP will be dispensed to the subject.

Drug accountability will be performed.

The wearable device will be taken off and the data will be downloaded to the 
computer, prior to putting the device back on to continue recording.
3.7.1.9
Treatment Phase - Week 10
Visit is to occur within 2 days of the target visit date.  The following procedures will be 
performed during the Treatment Phase visit:

A qualified and certified rater will administer the CAPS-5.  Whenever possible, it is 
recommended that the CAPS-5 is conducted as the first assessment of the visit.

The investigator (or qualified designee) will administer the CGI-S.

The subject will complete the HADS and PCL-5.  Assessments will be reviewed for 
completeness by the investigator (or qualified designee).

Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded.  Blood pressure and heart rate are to be measured in the 
following order:  supine and standing after the subject has been in each position at 
least 3 minutes.

The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form to assure that the subject continues to qualify for the trial.

Adverse events and concomitant medications will be recorded.

The assigned IMP will be dispensed to the subject.

Drug accountability will be performed.

The wearable device will be taken off and the data will be downloaded to the 
computer, prior to putting the device back on to continue recording.
3.7.1.10
End of Week 12/Early Termination
The Week 12 Visit signifies the end of treatment for all subjects.  Therefore, all subjects 
will undergo a complete evaluation at Week 12 (± 2 days).  
In addition, Week 12 evaluations are to be completed for any subject withdrawn from the 
trial at any time (for any reason other than full withdrawal of consent).  Every effort 
should be made to complete the Week 12/ET evaluations as soon as possible after 
discontinuation and whenever possible prior to starting any new medication or treatment.  
Trial personnel should make every attempt to complete all evaluations, particularly 
efficacy assessments (ie, CAPS-5, SOTS, CGI-S, PCL-5, and HADS), scheduled for the 
Week 12/ET visit as soon as possible and before administration of any new treatments.  
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Any prohibited medications started before the end of the trial assessments should be 
documented as a protocol deviation in the source notes.  Emphasis should be placed on 
obtaining information on treatment received and healthcare resources used subsequent to 
withdrawal from trial treatment.
The following activities and assessments will occur at Week 12 (or at the ET visit, if 
applicable):

A qualified and certified rater will administer the CAPS-5.  Whenever possible, it is 
recommended that the CAPS-5 is conducted as the first assessment of the visit.

The investigator (or qualified designee) will administer the CGI-S and SOTS.

The subject will complete the HADS and PCL-5.  Assessments will be reviewed for 
completeness by the investigator (or qualified designee).

An adequately trained and experienced clinician will administer the SAS, AIMS, and 
BARS to assess EPS.

A complete physical examination (including waist circumference) will be performed.  
Repeat measurement of height is not required.

Measurements of vital signs (body weight, body temperature, blood pressure, and 
heart rate) will be recorded.  Blood pressure and heart rate are to be measured in the 
following order:  supine and standing after the subject has been in each position at 
least 3 minutes.

A standard 12-lead ECG will be performed after the subject has been supine and at 
rest for at least 5 minutes.

Blood samples for clinical laboratory tests (hematology, HbA1c, serum chemistry 
[including blinded prolactin], TSH with reflex to T4 if the result for TSH is abnormal,
insulin, and urinalysis) and blood alcohol testing should be drawn after a minimum 
8-hour fast at Week 12/ET.

A PK sample will be collected at the same time of collection of clinical labs. Time of 
last 3 doses will be recorded at the time of PK sampling.

Urine will be collected for urinalysis and urine screen(s) for drugs of abuse.

All WOCBP will be given a urine pregnancy test.  All positive results must be 
confirmed by a serum pregnancy test.

The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form.

Adverse events and concomitant medications will be recorded.

Drug accountability will be performed.

The wearable device will be taken off and the data will be downloaded to the 
computer, and the wearable device monitoring will be stopped.
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3.7.1.11
Post-treatment Follow-up Period
Subjects will be contacted to monitor for safety events via telephone contact or clinic 
visit (investigator’s discretion), 14 (+ 2) days after the last dose of IMP.  Adverse events 
and concomitant medications will be recorded.  This contact also applies to subjects 
withdrawn prematurely from the trial.
3.7.2
Efficacy Assessments
It is required that trained and experienced clinicians administer all rating 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.
3.7.2.1
Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)
The CAPS-58,9 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 and CAPS-5 Past Week versions of the scale.  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.  It takes on average 
between 45 and 60 minutes to administer the CAPS-5.  Samples of the CAPS-5 Past 
Month and CAPS-5 Past Week versions are provided in Appendix 5 and Appendix 6, 
respectively.
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3.7.2.2
Symptoms of Trauma Scale (SOTS)
The SOTS10 is a 12-item 7-point symptom severity rating scale designed to measure 
change. Ratings for each of the 12 symptoms can range from 1 = Absent to 7 = Extreme.  
Because the SOTS provides a means of rating of symptoms at 7 levels of severity (absent, 
minimal, mild, moderate, moderate severe, severe, and extreme), it can assess changes in 
trauma symptoms, which will become increasingly important as new interventions, both 
psychosocial and pharmacological, emerge.  Ratings are based upon information obtained 
from a structured clinical interview, using both behavior observed during the 20 to 30 
minute interview as well as the subject’s report regarding functioning for the past week.  
A sample of the SOTS is provided in Appendix 7.
3.7.2.3
Clinical Global Impression - Severity (CGI-S)
The severity of illness for each subject will be rated using the CGI-S.11  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.  A sample of the CGI-S is 
provided in Appendix 8.
3.7.2.4
PTSD Checklist for DSM-5 (PCL-5)
The PCL-512 is a checklist of problems that people sometimes have in response to a very 
stressful experience.  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 month.  The scale 
rates items from 0 (not at all), 1 (a little bit), 2 (moderately), 3 (quite a bit), and 
4 (extremely).  A sample of the PCL-5 is provided in Appendix 9.
3.7.2.5
Hospital Anxiety and Depression Scale (HADS)
The HADS13 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.  A sample of the HADS is provided in Appendix 10.
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3.7.2.6
Wearable Device
Use of the wearable device is optional and does not require a separate consent form. If 
the subject agrees to its use, the wearable device should be put on the subject’s 
nondominant wrist at the Baseline (Day 0) Visit. The wearable device is to be worn 
continuously throughout the double-blind treatment period. At each trial visit, the 
wearable device is taken off, the data will be downloaded to the computer and the device 
will be placed back on the subject’s nondominant wrist. At the Week 12/ET Visit, the 
wearable device monitoring will be stopped and the device returned to the trial site.  All 
data from device should be transferred to Phillips by the conclusion of the Week 12/ET 
Visit.
3.7.2.7
Other Assessments
3.7.2.7.1
Emory Treatment Resistance Interview for PTSD (E-TRIP)
The E-TRIP14 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.  A copy of the score sheet is provided in
Appendix 11.
3.7.2.7.2
Life Events Checklist for DSM-5 (LEC-5)
The LEC-515 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.  A copy of the 
score sheet is provided in Appendix 12.
3.7.2.7.3
Mini International Neuropsychiatric Interview (MINI)
The MINI16,17,18,19 will be conducted at the Screening Visit 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.  A 
copy of the score sheet is provided in Appendix 13.
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3.7.2.7.4
Ohio State University Traumatic Brain Injury Identification 
Method
The OSU TBI-ID20 is a standardized procedure for eliciting a person’s lifetime history of 
TBI via a 3-5 minute structured interview. A copy of the score sheet is provided in
Safety Assessments Appendix 14.
3.7.3
Safety Assessments
3.7.3.1
Adverse Events
Refer to Section 5, Reporting of Adverse Events. 
3.7.3.2
Clinical Laboratory Assessments
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, insulin, 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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Table 3.7.3.2-1
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
Insulin
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 = lactic 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.
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 
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tests may be repeated at any time at the discretion of the investigator for appropriate 
medical care.  Refer to Appendix 2 for criteria for identifying values of potential clinical 
relevance.
The following laboratory test results at screening are exclusionary:

Platelets 75000/mm3

Hemoglobin ≤ 9 g/dL

Neutrophils, absolute 1000/mm3

Aspartate aminotransferase (AST) > 2 × upper limit of normal (ULN)

Alanine aminotransferase (ALT) > 2 × ULN

Creatine phosphokinase (CPK) > 3 × ULN, unless discussed with and approved by 
the medical monitor

Creatinine ≥ 2 mg/dL
The total volume of blood to be collected during the trial is expected to be approximately 
100 - 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.
3.7.3.3
Physical Examination and Vital Signs
3.7.3.3.1
Physical Examination
A complete physical examination will consist of measurement of height and waist 
circumference and a review of the following body systems:  head, eyes, ears, nose, and 
throat; thorax; abdomen; urogenital; extremities; neurological; and skin and mucosae.  
Height will be measured with a stadiometer, measuring stick, or tape.  Waist 
circumference will be measured with 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 
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skin, and is parallel to the floor.  The measurement is to be made at the end of a 
normal exhalation.21
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.
3.7.3.3.2
Measurement of Vital Signs
Measurement of vital signs will include body weight, body temperature, systolic blood 
pressure (SBP), diastolic blood pressure (DBP), and heart rate.  The following guidelines 
will aid in the standardization of body weight measurements:

The same scale should be used to weigh a given subject each time, if possible.

Scales should be calibrated and reliable; scales should be at zero just prior to each 
subject’s weigh-in session.

A subject should void prior to being weighed and be minimally clothed (ie, no shoes 
or heavy overgarments).

Weight should be recorded before a subject’s meal and at approximately the same 
time at each visit.
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.  
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 (see Table 3.4.3-1).  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.  Appendix 3 is included to assist 
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investigators in their assessments of results that may be potentially medically significant, 
depending on the subject’s medical history and clinical presentation.
3.7.3.4
Electrocardiogram Assessments
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 (see Table 3.4.3-1), the subject should be 
excluded from the trial. Abnormal results for ECGs should be repeated once at screening 
with 3 consecutive ECG recordings to ensure reproducibility of the abnormality before 
excluding a subject based on the criteria noted above. Each ECG recording should be 
taken approximately 5 minutes apart (the ECG result reported will be evaluated at each 
time point). The central ECG service will provide the corrections for the 3 ECGs 
performed.  Based on the QT interval as corrected by Fridericia’s formula (QTcF) 
reported by the central service, a subject will be excluded if the corrections are 
≥450 msec in men and ≥ 470 msec in women for 2 of the 3 time points of the ECGs 
done, unless due to ventricular pacing.  If only 1 ECG time point has a QTcF of 
≥450 msec in men and ≥ 470 msec in women, and this is not reproduced at either of the 
other 2 time points, the subject can be included in the trial.  
Refer to Appendix 4 for a list of potentially clinically relevant ECG abnormalities to 
guide investigators for the assessment of potential ECG abnormalities for clinical 
significance postrandomization.  Exclusion criteria for screening do not apply as 
mandatory discontinuation criteria for subjects who are already randomized.  Please 
consult the medical monitor in case of questions.
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3.7.3.5
Other Safety Assessments
3.7.3.5.1
Abnormal Involuntary Movement Scale
The AIMS22 assessment (Appendix 15) 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.  
Anticholinergics, propranolol, benzodiazepines, and non-benzodiazepine sleep aids are 
not permitted within 12 hours of scale administration (see Section 4.1).  Investigators are 
encouraged to delay scale administration until 12 hours have elapsed, if at all possible.  
However, if delaying administration of the scale is not feasible, the AIMS should still be 
administered and the use of the medication documented, including a notation of the drug 
name, dose, and time of administration on the eSource.
The AIMS Movement Rating Score is defined as the sum of items 1 through 7 (ie, items 
1 through 4, facial and oral movements; items 5 and 6, extremity movements; and item 7, 
trunk movements).
3.7.3.5.2
Barnes Rating Scale For Drug-induced Akathisia
The BARS23 (Appendix 16) 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.  Anticholinergics, propranolol, benzodiazepines, and 
non-benzodiazepine sleep aids are not permitted within 12 hours of scale administration 
(see Section 4.1).  Investigators are encouraged to delay scale administration until 
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12 hours have elapsed, if at all possible.  However, if delaying administration of the scale 
is not feasible, the BARS should still be administered and the use of the medication 
documented, including a notation of the drug name, dose, and time of administration on 
the eSource.
The BARS Global Score is defined as the global clinical assessment of akathisia.
3.7.3.5.3
Simpson-Angus Scale
The SAS24 (Appendix 17) consists of a list of 10 symptoms of Parkinsonism (gait, arm 
dropping, shoulder shaking, elbow rigidity, wrist rigidity, head rotation, glabella tap, 
tremor, salivation, and akathisia).  Each item will be rated on a 5 point scale, with a score 
of zero representing absence of symptoms, and a score of 4 representing a severe 
condition.  The SAS total score is the sum of the scores for all 10 items.  
Anticholinergics, propranolol, benzodiazepines, and non-benzodiazepine sleep aids are 
not permitted within 12 hours of scale administration (see Section 4.1).  Investigators are 
encouraged to delay scale administration until 12 hours have elapsed, if at all possible.  
However, if delaying administration of the scale is not feasible, the SAS should still be 
administered and the use of the medication documented, including a notation of the drug 
name, dose, and time of administration on the eSource.
3.7.3.5.4
Columbia-Suicide Severity Rating Scale
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
(Table 3.4.3-1).  The “Since Last Visit” C-SSRS form will also be completed at all visits
after screening.  Copies of the C-SSRS forms are provided in Appendix 18 and 
Appendix 19.
3.7.3.5.5
Deoxyribonucleic Acid (DNA) Blood Samples for
Pharmacogenomic Testing
A blood sample will be collected at the time point presented in the Schedule of 
Assessments (Table 3.7-1) in order to extract deoxyribonucleic acid (DNA) and 
determine genotypes and related phenotypes for CYP2D6.  The method used to 
determine these genotypes also generates genotype data for additional genes related to 
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absorption, distribution, metabolism, and excretion (ADME) of the compound.  
Phenotyping of these additional genes is not currently planned but may be considered in 
the future.  All samples will be shipped to the central lab provided in Appendix 1.
3.7.4
Pharmacokinetic Assessments
A PK sample will be collected at Week 6 and Week 12 at the same time of collection of 
clinical labs. Time of last 3 doses will be recorded at the time of PK sampling.
3.7.4.1
Pharmacokinetic Blood Samples
All blood samples will be shipped to the testing facility for analysis.  Detailed handling 
and shipping instructions are provided in Appendix 1.
3.7.5
Future Biospecimen Research
A blood sample will be collected at the time point presented in the Schedule of
Assessments (Table 3.7-1) from consenting subjects, and if allowed by the IRB/IEC.  
Research performed on this sample may include genetic analyses (DNA), gene 
expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics and/or the 
measurement of other analytes.  Such research is for biomarker testing to address 
emergent questions not described elsewhere in the protocol (as part of the main trial) and 
will only be conducted on specimens from appropriately consented subjects.  The 
objective of collecting specimens for FBR is to explore and identify biomarkers that 
inform the scientific understanding of diseases and/or their therapeutic treatments.
Processing, storage, and shipping instructions for FBR samples are provided in 
Appendix 1. 
3.7.6
End of Trial
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 for the last subject completing or 
withdrawing from the trial.
3.8
Stopping Rules, Withdrawal Criteria, and Procedures
3.8.1
Entire Trial 
If the sponsor terminates or suspends the trial for any reason, prompt notification will be 
given to investigators, IRBs/IECs, and regulatory authorities in accordance with 
regulatory requirements.
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3.8.2
Individual Site
Individual trial site participation may be discontinued by the sponsor, the investigator, or 
the IRB/IEC if judged to be necessary for medical, safety, regulatory, ethical or other 
reasons consistent with applicable laws, regulations, and GCP.  The investigator will 
notify the sponsor promptly if the trial is terminated by the investigator or the IRB/IEC at 
the site.
3.8.3
Individual Subject Discontinuation
3.8.3.1
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 
resumed as early as the situation allows (see Section 3.8.3.4).  If > 4 consecutive doses of 
IMP are missed, a discussion should occur with the medical monitor to determine if the 
subject should be discontinued from the trial as a result of the treatment interruption.
3.8.3.2
Treatment Discontinuation
After randomization, 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 3.8.3.5.
3.8.3.3
Documenting Reasons for Treatment 
Interruption/Discontinuation
A subject may temporarily interrupt or permanently discontinue IMP for a number of 
reasons including those listed below:

Reasons related to AE:

Subject decides to discontinue because of annoyance or discomfort due to a 
non-serious AE which is not otherwise determined to be an undue hazard
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
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 5.5)

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 3.8.3.1 or Section 3.8.3.2
must be followed.
3.8.3.4
Withdrawal of Consent
All subjects have the right to withdraw their consent from further participation in the trial 
at any time without prejudice.  Subjects cannot withdraw consent for use of data already 
collected as part of the trial, but only for future participation.  The investigator can also 
discontinue a subject’s participation in the trial at any time if medically necessary.  
Unless the subject provides their written withdrawal of consent or there is other written 
documentation by the investigator confirming the subject’s verbal intent to completely 
withdraw from the trial, subjects should be followed for all protocol-specified evaluations 
and assessments, as possible.
Complete withdrawal of consent requires a subject’s refusal of ALL of the following 
methods of follow-up (these methods of follow-up will also be noted in the trial ICF):

Participation in all follow-up procedures specified in the protocol (whether in-clinic, 
by telephone, or by an in-home visit).

Participation in a subset of protocol-specified follow-up procedures (by a frequency 
schedule and method, as agreed by subject and staff).

Contact of the subject by trial personnel, even if only by telephone, to assess current 
medical condition, and obtain necessary medical or laboratory reports relevant to the 
trial’s objectives.

Contact of alternative person(s) who have been designated in source records as being 
available to discuss the subject’s medical condition, even if only by telephone, mail, 
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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 3.8.3.1 and Section 3.8.3.2).  A subject may, however, indicate 
that further trial participation is creating a burden on their work or social schedule.  
Therefore, the investigator should follow the procedures outlined in Section 3.8.3.3 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.
3.8.3.5
Procedures to Encourage Continued Trial Participation
In all cases of impending IMP discontinuation or consent withdrawal, investigators will 
be given instructions to meet and discuss 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.  
3.9
Screen Failures
A screen failure subject is one from whom informed consent is obtained and is 
documented (ie, subject who completes the consent process), but who is not randomized 
or assigned IMP.
Screen failures due to exclusionary criteria may be rescreened at any time if the exclusion 
characteristic has changed.  In the event that a subject cannot be randomized prior to 
expiration of the 14-day screening period, additional 14-day extension(s) of screening 
may be requested from the medical monitor.  Any extension should be requested prior to 
the expiration of the previous extension screening period, as applicable.  If no extension 
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is granted, a new ICF must be signed, a new screening number assigned, and all 
screening procedures repeated.  Subjects may be rescreened twice for this trial.
3.10
Definition of Completed Subjects
The treatment period is defined as the time period during which subjects are evaluated for 
primary and/or secondary objectives of the trial irrespective of whether or not the subject 
actually consumed all doses of the IMP.  Subjects who are evaluated at the last scheduled 
visit during the treatment period will be defined as trial completers.  For purposes of this 
trial, subjects who complete the Week 12 Visit will be defined as trial completers.
3.11
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted on or before the Week 12 Visit during the treatment 
period, who do not have a known reason for discontinuation (eg, withdrew consent or 
AE), and for whom a survival status at the end of the trial cannot be determined will be 
classified as “lost to follow-up” as the reason for discontinuation.  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.
3.12
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.  If poor 
compliance continues (eg, multiple missed doses resulting in less than 80% overall 
compliance at any point in the trial), discontinuation of the subject from the trial should 
be considered.  Subjects who habitually miss visits or habitually attend visits outside of 
the protocol-defined visit window are also noncompliant and should be considered for 
discontinuation.  The medical monitor should be contacted if the investigator is uncertain 
whether a subject's lack of compliance merits discontinuation from the trial.
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3.13
Protocol Deviations
In the event of a significant deviation from the protocol due to an emergency, accident, or 
mistake (eg, violation of informed consent process, IMP dispensing or subject dosing 
error, treatment assignment error, subject enrolled in violation of eligibility criteria or 
concomitant medication criteria), the investigator or designee will contact the sponsor at 
the earliest possible time by telephone.  The investigator and sponsor will come as 
quickly as possible to a joint decision regarding the subject’s continuation in the trial.  
This decision will be documented by the investigator and the sponsor, and reviewed by 
the site monitor.
4
Restrictions
4.1
Prohibited Medications
All subjects must agree to discontinue all prohibited medications during the screening 
period in order to meet the protocol-specified washout periods.  Table 4.1-1 provides the 
required duration of washout for selected prohibited medications.  All other prohibited 
medications must be discontinued at least 24 hours before the first dose of IMP.
Table 4.1-1
List of Medications Prohibited Before the Trial (Prior to 
Day 0)
1.
Neuroleptic agents (depot or long-acting injectable)
One full cycle plus 1/2 cycle
2.
Cariprazine, fluoxetine
28 days
3.
Monoamine oxidase inhibitor
14 days
4.
Antipsychotic agents (oral), antidepressants (expect 
fluoxetine, monoamine oxidase inhibitors and sertraline [if 
not at an adequate dose/duration)
7 days
5.
Benzodiazepines
7 days
6.
Hypnotics, including non-benzodiazepine sleep aids
7 days
7.
Mood stabilizers (ie, lithium and anticonvulsants)
7 days
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Table 4.1-2 lists all medications prohibited during the trial, including exceptions, where 
appropriate.
Table 4.1-2
List of Medications Prohibited/Restricted During the Trial
1.
All psychotropic agents including, but not limited to, the following:
a) Antipsychotics, including depot or long-acting injectable formulations
b) Anticonvulsants
c) Antidepressants 
d) Mood stabilizers (ie, lithium)
e) Benzodiazepines, except when used to manage TEAEs such as agitation and anxietya
f)
Hypnotics, including ramelteon and other non-benzodiazepine sleep aids, except for specific 
medications when used to manage TEAEs related to insomniab
g) Stimulants and atomoxetine – allowed if currently being taken for an appropriate indication at a 
stable dose for at least 14 days prior to Baseline (Day 0) Visit.  Should be continued throughout 
trial participation.
h) Opioid analgesics, unless approval is obtained from the medical monitor.  Approval for opioid 
use may be considered for a documented and clinically appropriate indication (eg, episodic pain 
condition, tooth extraction) if prescribed at a medically appropriate dose and frequency.
i)
Nutritional supplements and non-prescription herbal preparations with central nervous system
effects (eg, St. John’s Wort, omega-3 fatty acids, kava extracts, gamma-aminobutyric acid 
supplements, etc)
j)
Disulfiram
k) Prazosin - allowed if currently being taken for an appropriate indication at a stable dose for at 
least 14 days prior to Baseline (Day 0) Visit.  Should be continued throughout trial participation
2.
Investigational agents within 60 days prior to Baseline (Day 0) Visit.
3.
CYP2D6 inhibitors or CYP3A4 inhibitors and inducers.  Selected CYP2D6 inhibitors are:  
celecoxib, hydroxyzine, chloroquine, methadone, chlorpheniramine, moclobemide, clemastine, 
clomipramine, pyrilamine, diphenhydramine, quinidine, terbinafine, halofantrine, tripelennamine.  
Selected CYP3A4 inhibitors are:  amiodarone, 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.  Selected CYP3A4 inducers are:  
carbamazepine, oxcarbazepine, phenytoin, dexamethasone, primidone, efavirenz, rifampin, 
nevirapine, St. John’s Wort, phenobarbitol, troglitazone.  The medical monitor should be consulted 
for any questions regarding the potential for pharmacokinetic interactions with concomitant 
medications used by subjects during the trial.
4.
Barbiturates, except for the treatment of migraine headaches, provided that in the opinion of the 
investigator the dosing is medically appropriate.
aAdministration 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.  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 EPS scales.  Investigators are encouraged to 
delay scale administration until 12 hours have elapsed, if at all possible.  However, if delaying 
administration of efficacy and safety scales is not feasible, the scales should still be administered and
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the use of benzodiazepine documented, including a notation of the drug name, dose, and time of 
administration on the eSource.
bNon-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 are encouraged to delay scale administration 
until 12 hours have elapsed, if at all possible.  However, if delaying administration of efficacy and 
safety scales is not feasible, the scales should still be administered and the use of the sleep aid 
documented, including a notation of the drug name, dose, and time of administration on the eSource.
4.2
Other Restrictions 
4.2.1
Restricted Therapies and Precautions
The subject’s best medical interests should guide the investigator in the management of 
conditions that are pre-existing or that develop during the trial (intercurrent illness or 
AEs).  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.  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.25

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.26,27,28
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.
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Use of intramuscular benzodiazepines is prohibited throughout the trial.  Continual use of 
oral benzodiazepines is also not permitted during the trial and subjects must discontinue 
benzodiazepines for at least 7 days prior to the Baseline (Day 0) Visit.  However, 
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.  Short-acting benzodiazepines are to be used 
whenever possible.  If 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.
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 total during the treatment period, 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 and the prescribing information is to be used to determine the maximum 
allowable daily dose for the treatment of insomnia.
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.
Benzodiazepines, non-benzodiazepine sleep aids, anticholinergics, and propranolol must 
not be administered within 12 hours prior to scheduled efficacy and safety assessments, 
including EPS scales.  Investigators are encouraged to delay scale administration until 
12 hours have elapsed, if at all possible.  However, if delaying administration of efficacy 
and safety scales is not feasible, the scales should still be administered and the use of the 
medication documented, including a notation of the drug name, dose, and time of 
administration on the eSource.
All trial personnel should be familiar with the content of the IB for brexpiprazole in order 
to manage the subject’s condition adequately and select appropriate concomitant 
medications, if needed.
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4.2.2
Non-therapy Precautions and Restrictions
4.2.2.1
Precautions
Subjects should not undergo any elective medical procedure without prior consultation 
with the investigator.  An elective procedure (minor surgery, dental surgery, orthopedic 
surgery, etc) that might require hospitalization or general anesthesia should be deferred 
until after the trial whenever clinically appropriate.
4.2.2.2
Restrictions
Subjects may only receive psychotherapy (including but not limited to: individual, 
group, marriage, family, EMDR therapy, pet therapy, etc.) 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.
Consumption of grapefruit, grapefruit products, Seville oranges, or Seville orange 
products within 72 hours prior to dosing and during the trial is prohibited.  Subjects will 
be instructed to refrain from drinking alcoholic beverages or using illicit drugs during 
participation in 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.
5
Reporting of Adverse Events
5.1
Definitions
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  AEs would not include information recorded as medical 
history at screening for preplanned procedures for which the underlying condition was 
known and no worsening occurred.  An adverse reaction is any untoward and unintended 
response to an IMP related to any dose administered.
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE.  For the purpose of IND safety reporting, “reasonable possibility” 
means there is evidence to suggest a causal relationship between the IMP and the AE.  
Suspected adverse reaction implies a lesser degree of certainty about causality.
An SAE includes any event that results in any of the following outcomes:

Death
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
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 in-patient 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 non-medical need) are 
not considered SAEs.

Congenital anomaly/birth defect.

Other medically significant events that, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above; eg, allergic 
bronchospasm requiring intensive treatment in an emergency room or home, 
blood dyscrasias or convulsions that do not result in hospitalization, or the 
development of drug dependency or drug abuse.
Nonserious adverse events are all AEs that do not meet the criteria for a "serious" AE.
Immediately Reportable Event (IRE):  

Any SAE.

Any AE related to occupational exposure.

Potential drug-induced liver injury (DILI) case (see Section 5.4). 

Pregnancies are also defined as IREs.  Although normal pregnancy is not an 
AE, it will mandate IMP discontinuation and must be reported on an IRE form 
to the sponsor.  Pregnancy will only be documented on the AE eSource if 
there is an abnormality or complication.
Clinical Laboratory Test Value Changes:  It is the investigator’s responsibility to review 
the results of all laboratory tests as they become available.  This review will be 
documented by the investigator’s dated signature on the laboratory report.  For each 
abnormal laboratory test result, the investigator needs to ascertain if this is an abnormal 
(ie, clinically significant) change from baseline for that individual subject.  This 
determination, however, does not necessarily need to be made the first time an abnormal 
value is observed.  The investigator may repeat the laboratory test or request additional 
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tests to verify the results of the original laboratory tests.  If this laboratory value is 
considered medically relevant 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 on 
the eSource.  The intensity 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.
5.2
Eliciting and Reporting Adverse Events
The investigator will periodically assess subjects for the occurrence of AEs.  To avoid 
bias in eliciting AEs, subjects should be asked the non-leading 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.  All AE 
collection is to begin after a subject completes the consent process.  
Use medical terminology in AE reporting.  Adverse events should be reported as a single 
unifying diagnosis whenever possible or, in the absence of a unifying diagnosis, as 
individual signs or symptoms.  Exacerbation or disease progression should be reported as 
an AE only if there are unusual or severe clinical features that were not present, or 
experienced earlier, or not expected based on the course of the condition.
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 5.3.  Special attention should 
be paid to recording hospitalization and concomitant medications.
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5.3
Immediately Reportable Events 
The investigator must immediately report after either the investigator or site personnel 
become aware of any SAE, AE related to occupational exposure, DILI, or confirmed 
pregnancy, by telephone, fax, or e-mail to the sponsor using the contact information on 
the cover page of this protocol.  An IRE form must be completed and sent by e-mail, fax,
or overnight courier to the sponsor.  (Please note that the IRE form is NOT the AE 
eSource.) 
Subjects experiencing SAEs should be followed clinically until their health has returned 
to baseline status, or until all parameters have returned to normal or have otherwise been 
explained.  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.
5.4
Potential Drug-Induced Liver Injury
For a subject who experiences an elevation in AST or ALT that is 3 times the ULN, a 
total bilirubin level should also be evaluated.  If the total bilirubin is 2 times the ULN, 
complete an IRE form with all values listed and also report as an AE on the eSource.
5.5
Pregnancy
Women of childbearing potential (WOCBP) are defined as female subjects for whom 
menstruation has started and who are not documented as sterile (ie, have had a bilateral 
oophorectomy and/or hysterectomy or who have been postmenopausal for at least 
12 months with no menses without an alternative medical cause).
For WOCBP and for men who are sexually active, there must be a documented 
agreement that the subject and/or their partner will take effective measures 
(ie, double-barrier method) to prevent pregnancy during the course of the trial and for 
30 days after the last dose of IMP.  Unless the subject is sterile (ie, women who have had 
a bilateral oophorectomy and/or hysterectomy or who have been postmenopausal for at 
least 12 consecutive months with no menses without an alternative medical cause; or men 
who have had a bilateral orchidectomy) or remains abstinent, 2 of the following 
precautions must be used:  vasectomy, tubal ligation, vaginal diaphragm, intrauterine 
device, birth control pills, birth control depot injection, birth control implant, condom 
with spermicide, or sponge with spermicide.  Any single method of birth control, 
including vasectomy and tubal ligation, may fail, leading to pregnancy.  The 
contraceptive method will be documented at each trial visit.
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Before enrolling WOCBP in this clinical trial, investigators must review the below 
guidelines about trial participation with all WOCBP.  The topics should generally 
include:

General information

Informed consent form

Pregnancy prevention information

Drug interactions with hormonal contraceptives

Contraceptives in current use

Guidelines for the follow-up of a reported pregnancy
Before trial enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy.  The subject must sign an informed consent form stating that the above-
mentioned risk factors and the consequences were discussed with her.
A urine and/or serum pregnancy test for human chorionic gonadotropin will be performed 
at screening 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).
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 Clinical Safety and Pharmacovigilance department (see the cover 
page of this protocol for contact information).
The investigator must immediately notify the sponsor of any pregnancy associated with 
IMP exposure during the trial and for 30 days after the last dose of IMP, and record the 
event on the IRE form and forward it to the sponsor.  The sponsor will forward 
Pregnancy Surveillance Form(s) for monitoring the outcome of the pregnancy. 
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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 appropriate Pregnancy Surveillance Form(s), 
follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome.  Infants will be followed for a minimum of 6 months from the date of 
birth.  
5.6
Procedure for Breaking the Blind 
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 Clinical Safety and 
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.
5.7
Follow-up of Adverse Events 
5.7.1
Follow-up of Nonserious Adverse Events
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE eSource with the current status (ongoing or resolved/recovered) noted.  All 
nonserious events (that are not IREs) that are ongoing at the last scheduled contact will 
be recorded as ongoing on the 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).
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5.7.2
Follow-up of Serious Adverse Events and Immediately 
Reportable Events
This trial requires that subjects be actively monitored for SAEs and IREs up to 14 (+ 2)
days after the last dose of IMP is administered.
Serious AEs and nonserious IREs that are identified or ongoing at the last scheduled 
contact must be recorded as such on the AE eSource page.  If updated information (eg, 
resolved status) on SAE or IRE status becomes available after a subject’s last scheduled 
contact (up to last in-clinic visit for the entire trial), this must be reported to the sponsor 
and recorded on the AE eSource page according to the appropriate reporting procedures.  
The investigator will follow SAEs until the events are resolved, stabilized, or 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 been resolved, stabilized, or the subject is lost to follow-up or has died.
5.7.3
Follow-up and Reporting of Serious Adverse Events Occurring 
after Last Scheduled Contact
Any new SAEs or 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.  This may include SAEs or IREs that are 
captured on follow-up telephone contact or at any other time point after the defined trial 
period.  The investigator should follow SAEs or IREs identified after the defined trial 
period and continue to report any significant follow-up information to the sponsor until 
the events are resolved or stabilized, or the subject is lost to follow-up or has died.
6
Pharmacokinetic/Pharmacogenomic Analysis
Pharmacokinetic samples will be analyzed for brexpiprazole (OPC-34712) and its 
metabolite(s) and descriptive statistics will be calculated.  No formal statistical 
comparisons are planned.  A separate population or pharmacokinetic/pharmacodynamic 
modeling may be performed using the data from this trial and other trials.
7
Statistical Analysis
Complete details of the planned statistical analysis will be presented in the unblinded 
addendum to this protocol and in the statistical analysis plan (SAP).
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7.1
Sample Size
It is anticipated that approximately 332 subjects will be enrolled from an estimated 
45 sites in the US.
7.1.1
Efficacy Analysis
The efficacy sample will be the full analysis set based on the intent-to-treat principle, 
which includes all randomly assigned subjects who take at least one dose of IMP (ie, the 
safety sample) and who have both a randomization and at least one post randomization 
non-missing value for CAPS-5 total score.
The change from baseline in CAPS-5 total score will be analyzed using a mixed-effect 
model repeated measures (MMRM) methodology with the unstructured variance 
covariance matrix.  The model will include fixed class-effect terms for treatment, trial 
center, type of trauma, visit week, and an interaction term of treatment by visit week and 
include the interaction term of baseline values of CAPS-5 total score by visit week as a 
covariate.  The primary efficacy outcome measure is the mean change from baseline in 
the CAPS-5 total score. 
Other continuous efficacy endpoints will also be analyzed using MMRM methodology.  
Complete model details will be specified in the SAP.
7.2
Safety Analysis
Standard safety variables to be analyzed include AEs, clinical laboratory tests, vital signs, 
ECGs, and physical examinations. In addition, data from the following safety scales will 
be evaluated: assessments of suicidality (C-SSRS) and EPS (eg, the SAS, AIMS, and 
BARS). Safety analysis will be conducted based on the Safety Sample defined in
Section 7.1.1. In general, baseline of a safety variable is defined as the last observation 
of the variable before taking the first dose of IMP, unless specified otherwise. 
Prospectively defined criteria will be used to identify potentially clinically relevant 
abnormal values for clinical laboratory tests, vital signs, ECGs, and body weight. Details 
of safety analyses will be provided in the SAP.
7.2.1
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
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
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
The above summaries will also be prepared for TEAEs potentially causally related to the 
IMP.
7.2.2
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.
7.2.3
Physical Examination and Vital Signs Data
Physical examination findings will be listed by subject.  Potentially clinically relevant 
results in vital signs and body weight will also be summarized.
Summary statistics for change from baseline in vital signs, body weight, and waist 
circumference will be provided.
7.2.4
Electrocardiogram Data 
Mean change from baseline will be summarized by treatment group and by visit.
Incidence of clinically relevant changes will be calculated for ECG parameters and 
summarized by treatment group and by visit.
For the analysis of QT and QTc data from 3 consecutive complexes (representing 
3 consecutive heart beats) will be measured to determine average values.  The following 
QT corrections will be used:
1) QTcB is the length of the QT interval corrected for heart rate by the Bazett 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
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3) QTcN is the length of the QT interval corrected for heart rate by the FDA Neuropharm 
Division formula:  QTcN=QT/(RR)0.37
Results will be summarized by visit.
7.2.5
Other Safety Data
Change from baseline in scores for EPS (eg, SAS, AIMS, and BARS) will be evaluated 
using analysis of covariance with baseline value as covariate and treatment as main 
factors. The analyses will be based on the observed case (OC) and last observation 
carried forward datasets of the Safety Sample.  
Suicidality (eg, C-SSRS) will be summarized by treatment group based on the OC dataset 
of the Safety Sample. Details will be described in SAP.
8
Management of Investigational Medicinal Product
For full details on IMP management, please refer to the OPC- 34712 IB5 and Zoloft 
prescribing information.6
8.1
Packaging and Labeling
Trial medication 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 subject ID, compound ID, trial number, sponsor’s name and address, 
instructions for use, route of administration, and appropriate precautionary statements.
8.2
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 storage conditions indicated on the clinical 
label(s). The clinical site staff will maintain a temperature log in the IMP storage area 
recording the temperature at least once each working day.
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8.3
Accountability
The investigator or designee must maintain an inventory record of IMP (including 
investigational, active control, or placebo) received, dispensed, administered, and 
returned.
8.4
Returns and Destruction
Upon completion or termination of the trial, all used IMP containers, unused IMP, and 
partially‑used IMP must be returned to the sponsor or a designated agent, or destroyed at 
the trial site(s).  The IMP may be destroyed by the trial site(s), only if approved by the 
sponsor and if the IMP destruction meets all local regulations.
All IMP returned to the sponsor must be accompanied by appropriate documentation and 
be clearly identified by protocol number and trial site number on the outermost shipping 
container.  Returned supplies should be in the original containers (eg, subject kits).  The 
assigned trial monitor will facilitate the return or destruction (if applicable) of used IMP 
containers, unused IMP, and partially-used IMP.
8.5
Reporting of Product Quality Complaints
A Product Quality Complaint (PQC) is any written, electronic, or verbal communication 
by a healthcare professional, consumer, subject, medical representative, Competent 
Authority, regulatory agency, partner, affiliate or other third party that alleges 
deficiencies or dissatisfaction related to identity, quality, labeling, packaging, reliability, 
safety, durability, tampering, counterfeiting, theft, effectiveness or performance of a drug 
product or medical device after it is released for distribution.  Examples include, but are 
not limited to, communications involving:

Failure/malfunction of a product to meet any of its specifications

Incorrect or missing labeling

Packaging issues (eg, damaged, dirty, crushed, missing product)

Blister defects (eg, missing, empty blisters)

Bottle defects (eg, under/over-fill, no safety seal)

Vial defects

Product defect (eg, odor, chipped, broken, embossing illegible)

Loss or theft of product
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8.5.1
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 or telephone within 
24 hours of becoming aware of the PQC according to the procedure outlined below.

Online – Send information required for reporting purposes (listed below) to 

Phone - Rocky Mountain Call Center at 
.
Identification of a PQC by the subject should be reported to the site investigator, who 
should then follow one of the reporting mechanisms above.
8.5.2
Information Required for Reporting Purposes

Description of complaint

Reporter identification (ID) (eg, subject, investigator, site, etc.)

Reporter contact information (eg, address, phone number, e-mail address)

ID of material (product/compound name, coding)

Clinical protocol reference (number and/or trial name)

Dosage form/strength (if known)

Pictures (if available)

Availability for return
8.5.3
Return Process
Indicate during the report of the PQC if the complaint sample is available for return.  If 
complaint sample is available for return, return it in the product retrieval package, which 
will be provided by the sponsor.
It must be documented in the site accountability record that a complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation.
8.5.4
Assessment/Evaluation
Assessment and evaluation of PQCs will be handled by the sponsor.
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9
Records Management
9.1
Source Documents
Source documents are defined as the results of original observations and activities of a 
clinical investigation.  Source documents will include but are not limited to progress 
notes, electronic data, screening logs, and recorded data from automated instruments.  All 
source documents pertaining to this trial will be maintained by the investigators and made 
available for direct inspection by authorized persons.
Investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, 
and regulatory inspection(s) by providing direct access to source data/documents by 
authorized persons as defined in the ICF.  In all cases, subject confidentiality must be 
maintained in accordance with local regulatory requirements.
9.2
Data Collection
Source document and source data will be captured electronically in this trial, and will 
meet the same fundamental elements of data quality (eg, attributable, legible, 
contemporaneous, original, and accurate) as paper records.  These data will be collected 
into a system that is fully validated.  Changes to the data will be captured by an automatic 
audit trail.
The trial site will be given a tablet to directly record subject data and clinical 
observations on electronic forms.  Designated trial site staff will not be given access to 
the system until they have been appropriately trained.  Information to be originally 
captured and reviewed electronically shall include details of the 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 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 by the trial clinical 
research associate, 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 
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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 clinician.
Another exception will be safety laboratory data, where the official source documentation 
will be considered the report issued by the analyzing laboratory.
Remote monitoring of the original electronic source record will take place, however 
on-site monitoring inspections will continue to take place in order to review data entry 
source documentation directly captured on paper and transcribed into the system, to 
ensure protocol adherence, to assess site operational capabilities and to perform other 
monitoring activities that cannot be performed remotely.  
At the end of the trial, the investigator must certify that the data entered into the eSource 
application are complete and accurate.  After database lock, the investigator will receive 
an electronic copy of the subject data.
9.3
File Management at the Trial Site
The investigator will ensure that the trial site file is maintained in accordance with 
Section 8 of the ICH GCP Guideline E6 and as required by applicable local regulations.  
The investigator/institution will take measures to prevent accidental or premature 
destruction of these documents.
9.4
Records Retention at the Trial Site
The FDA 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 
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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
Quality Control and Quality Assurance 
10.1
Monitoring
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, the ICH E6 GCP: Consolidated Guidance, and 
applicable regulatory requirements and local laws.  As part of a concerted effort to fulfill 
these obligations (maintain current personal knowledge of the progress of the trial), the 
sponsor's monitors will visit the site during the trial, as well as communicate frequently 
via telephone, e-mail, and written communications.  In addition, all investigators and 
clinical site personnel will undergo initial and ongoing training for this particular trial, 
and this training will be clearly documented.
10.2
Auditing
The sponsor's Quality Assurance Unit (or representative) may conduct trial site audits.  
Audits will include, but are not limited to, IMP supply, presence of required documents, 
the informed consent process, and comparison of data in the eSource application with 
source documents.  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.
11
Ethics and Responsibility
This trial must be conducted in compliance with the protocol, FDA regulations, ICH GCP 
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 
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subject privacy.  To this end, a subject number and subject ID code 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.
12
Confidentiality
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission.  Subject confidentiality requirements of the region(s) where the trial 
is conducted will be met.  However, authorized regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy the records, 
consistent with local requirements.  All IMPs, subject bodily fluids, and/or other 
materials collected shall be used solely in accordance with this protocol, unless otherwise 
agreed to in writing by the sponsor.
Subjects will be identified only by unique subject numbers in the eSource application.  If
further subject ID is required, subjects’ full names may be made known to a regulatory 
agency or other authorized officials if necessary, subject to local regulations.
13
Amendment Policy
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval/favorable opinion by the IRB.  Any permanent 
change to the protocol, whether an overall change or a change for specific trial site(s), 
must be handled as a protocol amendment.  Any amendment will be written by the 
sponsor.  Each amendment will be submitted to the IRB, as required by local regulations.  
Except for “administrative” or “non-substantial” 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.
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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 informed consent will be 
obtained from subjects enrolled in the trial before expecting continued participation and 
before the amendment-specified changes in the trial are implemented.
14
Publication Authorship Requirements
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 
criteria (http://www.icmje.org/recommendations).  According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met:
1) Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors.
Investigators or other trial participants who do not qualify for authorship may be 
acknowledged in publications resulting from the trial.  By agreeing to participate in the 
trial, investigators or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct.
15
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Drug Safety Communication; 2011 26 Jul [updated 2011 21 Oct; cited 24 Oct 2011]. 
Available at 
www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalPr
oducts/ucm265476.htm
28 US Food and Drug Administration [homepage on the Internet]. Rockville, MD:  FDA 
Public Health Advisory; 2006 19 Jul [cited 24 Oct 2011]. Available at 
www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandPro
viders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm
124349.htm
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Appendix 1
Handling and Shipment of Bioanalytical Samples
Pharmacokinetic Sample Collection
Four mL of blood for PK testing will be collected into 4-mL Vacutainer tubes containing 
sodium heparin.  Each tube should be gently inverted three to four times and then 
centrifuged at 2500 rpm for at least 10 minutes at 4°C.  The separated plasma from the 
tube should then be divided equally between the 2 bar-code labeled polypropylene tubes.
All tubes must be labeled using the central lab’s bar-code labels provided with the sample 
collection kits.  The central lab’s requisition form must be completely filled out in 
regards to the PK sample information.  It is important to note the exact date and time of 
the blood collection, the date and time of the last dose of brexpiprazole/placebo prior to 
each blood draw, and the time of the meal closest to the last dose.
The sample must be stored at −70°C, if available, or −20°C or below.  If only a −20°C 
freezer is available, samples must be shipped within 30 days of collection.  Primary and 
backup samples may be shipped together.  If samples are stored in a −70°C freezer, then 
one tube (primary sample) will be shipped on dry ice to the central lab as soon as possible 
after collection.  Following confirmation that the first tube arrived safely, the second tube 
(backup sample) can also be shipped to the central lab.
If neither a −70°C nor −20°C freezer is available, the primary and backup PK samples 
must be shipped on dry ice in the same box to the central laboratory on the day of 
collection.  
Pharmacogenomic Sample Collection
A 10-mL whole blood sample for the pharmacogenomic determination of drug 
metabolizing enzymes and transporters and/or banking for future analysis will be 
collected by venipuncture into one 10-mL potassium ethylenediaminetetraacetic acid 
(K2EDTA) Vacutainer tube.  Each tube should be gently inverted 10 times to ensure 
proper mixing with the anticoagulant.  Refrigerate the whole blood samples at 4C for at 
least 1 day (but no longer than 4 days).  Then, the samples should be stored upright at 
−20C or below.  If refrigerating is not possible, samples can be frozen directly from 
ambient.  The tube will be shipped on dry ice to the central laboratory; the central 
laboratory will forward the sample to the pharmacogenomics laboratory.
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Pharmacokinetic and Pharmacogenomic Sample Shipment
Plasma or whole blood samples must be neatly packed in the kits provided by the central 
lab and restrained in a Styrofoam container (place Styrofoam container supplied within a 
cardboard box).  Boxes should be completely filled with dry ice to avoid air spaces that 
allow evaporation of the dry ice.  The Styrofoam container should be sealed with tape and 
placed in a cardboard box.  The central laboratory must be alerted of sample shipment.  
Packages must not be shipped on Thursdays, Fridays, Saturdays, or any day prior to a 
holiday without the expressed consent of OPDC.  Shipments from clinical sites will be 
via an overnight carrier to the central laboratory.
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Appendix 2
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance
Laboratory Tests
Criteria
Chemistry
AST (SGOT)
3 x ULN
ALT (SGPT)
3 x ULN
Alkaline phosphatase
3 x ULN
Lactate dehydrogenase
3 x ULN
Blood urea nitrogen
30 mg/dL
Creatinine
2.0 mg/dL
Uric acid
Men
10.5 mg/dL
Women
8.5 mg/dL
Bilirubin (total)
2.0 mg/dL
Creatine phosphokinase
> 3 x ULN
Prolactin
> ULN
Hematology
Hematocrit
Men
37 % and decrease of 3 percentage points from baseline
Women
32 % and decrease of 3 percentage points from baseline
Hemoglobin
Men
11.5 g/dL
Women
9.5 g/dL
WBC count
2,800 mm3 or 16,000 mm3
Eosinophils
10%
Neutrophils
15%
Absolute neutrophil count
1,500/mm3
Platelet count
75,000/mm3 or 700,000/mm3
Urinalysis
Protein
Increase of 2 units
Glucose
Increase of 2 units
Casts
Increase of 2 units
Additional Criteria
Chloride
90 mEq/L or 118 mEq/L
Potassium
2.5 mEq/L or 6.5 mEq/L
Sodium
126 mEq/L or 156 mEq/L
Calcium
8.2 mg/dL or 12 mg/dL
Glucose
Fasting
100 mg/dL
Nonfasting
200 mg/dL
Total cholesterol, fasting
240 mg/dL
LDL cholesterol, fasting
160 mg/dL
HDL cholesterol, fasting
Men
< 40 mg/dL
Women
< 50 mg/dL
Triglycerides, fasting
150 mg/dL
ULN = upper limit of normal
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Appendix 3
Criteria for Identifying Vital Signs of Potential Clinical 
Relevance
Variable
Criterion Valuea
Change Relative to Baselinea
Heart rateb
> 120 bpm
< 50 bpm
15 bpm increase
15 bpm decrease
Systolic blood pressureb
> 180 mmHg
< 90 mmHg
20 mmHg increase
20 mmHg decrease
Diastolic blood pressureb
> 105 mmHg
< 50 mmHg
15 mmHg increase
15 mmHg decrease
Orthostatic hypotension
20 mmHg decrease in systolic blood 
pressure and a 25 bpm increase in heart 
rate from supine to sitting/standing
Not applicable
(baseline status not 
considered)
Weight
−
7% increase
7% decrease
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column.
bAs defined in “Supplementary Suggestions for Preparing an Integrated Summary of Safety Information 
in an Original New Drug Application Submission and for Organizing Information in Periodic Safety 
Updates,” FDA Division of Neuropharmacological Drug Products draft (2/27/87).
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Appendix 4
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance
Variable
Criterion Valuea
Change Relative to Baselinea
Rate
Tachycardia
120 bpm
increase of 15 bpm
Bradycardia
50 bpm
decrease of 15 bpm
Rhythm
Sinus tachycardiab
120 bpm
increase of 15 bpm
Sinus bradycardiac
50 bpm
decrease of 15 bpm
Supraventricular premature beat
all
not present present
Ventricular premature beat
all
not present present
Supraventricular tachycardia
all
not present present
Ventricular tachycardia
all
not present present
Atrial fibrillation
all
not present present
Atrial flutter
all
not present present
Conduction
1atrioventricular block
PR 200 msec
increase of 50 msec
2atrioventricular block
all
not present present
3atrioventricular block
all
not present present
Left bundle-branch block
all
not present present
Right bundle-branch block
all
not present present
Pre-excitation syndrome
all
not present present
Other intraventricular conduction blockd
QRS 120 msec
increase of 20 msec
Infarction
Acute or subacute
all
not present present
Old
all
not present present
12 weeks post trial entry
ST/T Morphological
Myocardial ischemia
all
not present present
Symmetrical T-wave inversion
all
not present present
Increase in QTc
QTcF 450 msec
(men)
QTcF 470 msec
(women)
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column.
bNo current diagnosis of supraventricular tachycardia, ventricular tachycardia, atrial fibrillation, atrial 
flutter, or other rhythm abnormality.
cNo current diagnosis of atrial fibrillation, atrial flutter, or other rhythm abnormality.
dNo current diagnosis of left bundle-branch block or right bundle-branch block.
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Appendix 5
Past Month Version of the Clinician-Administered PTSD Scale 
For DSM-5 (CAPS-5)
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CAPS-5 Page 1 
National Center for PTSD 
CLINICIAN-ADMINISTERED PTSD SCALE FOR DSM-5 
PAST MONTH VERSION 
Name: 
Interviewer: 
Study: 
ID#: 
Date: 
Frank W. Weathers, Dudley D. Blake, Paula P. Schnurr, 
Danny G. Kaloupek, Brian P. Marx, & Terence M. Keane 
National Center for Posttraumatic Stress Disorder 
May 1, 2015 

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CAPS-5 Page 2 
Instructions 
Standard administration and soaring of the CAPS-5 are essential for producing reliable and valid scores and diagnostic 
decisions. The CAPS-5 should be administered only by qualified interviewers who have formal training in structured 
clinical interviewing and differential diagnosis, a thorough understanding of the conceptual basis of PTSD and its various 
symptoms, and detailed knowledge of the features and conventions of the CAPS-5 itself 
Administration 
1. 
Identify an index traumatic event to serve as the basis for symptom inquiry Administer the Life Events Checklist and 
Criterion A inquiry provided on p. 5, or use some other structured, evidence-based method. The index event may 
involve either a single incident (e.g., "the accident") or multiple, closely related incidents (e.g., "the worst parts of your 
combat experiences"). 
2. 
Read prompts verbatim, one at a time, and in the order presented, EXCEPT: 
a. Use the respondent's own words for labeling the index event or describing specific symptoms. 
b. 
Rephrase standard prompts to acknowledge previously reported information, but return to verbatim phrasing as 
soon as possible. For example, inquiry for item 20 might begin: "You already mentioned having problems 
sleeping What kinds of problems?" 
c. 
If you don't have sufficient information after exhausting all standard prompts, follow up ad lib. In this situation, 
repeating the initial prompt often helps refocus the respondent. 
d. As needed, ask for specific examples or direct the respondent to elaborate even when such prompts are not 
provided explicitly 
3. 
In general, DO NOT suggest responses If a respondent has pronounced difficulty understanding a prompt it may be 
necessary to offer a brief example to clarify and illustrate. However, this should be done rarely and only after the 
respondent has been given ample opportunity to answer spontaneously. 
4. DO NOT read rating scale anchors to the respondent. They are intended only for you, the interviewer, because 
appropriate use requires clinical judgment and a thorough understanding of CAPS-5 scoring conventions. 
5. 
Move through the interview as efficiently as possible to minimize respondent burden. Some useful strategies 
a. Be thoroughly familiar with the CAPS-5 so that prompts ftow smoothly. 
b. Ask the fewest number of prompts needed to obtain sufficient information to support a valid rating. 
c. 
Minimize note-taking and write while the respondent is talking to avoid long pauses 
d. 
Take charge of the interview. Be respectful but firm in keeping the respondent on task, transitioning between 
questions, pressing for examples, or pointing out contradictions. 
1. As with previous versions of the CAPS, CAPS-5 symptom severity ratings are based on symptom frequency and 
intensity, except for items 8 (amnesia) and 12 (diminished interest), which are based on amount and intensity. 
However, CAPS-5 items are rated with a single severity score, in contrast to previous versions of the CAPS which 
required separate frequency and intensity soores for each item that were either summed to create a symptom severity 
score or combined in various scoring rules to create a dichotomous (present/absent) symptom score. Thus, on the 

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CAPS-5 Page 3 
CAPS-5 the clinician combines information about frequency and intensity before making a single severity rating. 
Depending on the item, frequency is rated as either the number of occurrences (how often in the past month) or 
percent of time (how much of the time in the past month). Intensity is rated on a four-point ordinal scale with ratings of 
Minimal, Clearly Present, Pronounced, and Extreme. Intensity and severity are related but distinct. Intensity refers to 
the strength of a typical occurrence of a symptom. Severity refers to the total symptom load over a given time period, 
and is a combination of intensity and frequency. This is similar to the quantity/frequency assessment approach to 
alcohol consumption. In general, intensity rating anchors correspond to severity scale anchors described below and 
should be interpreted and used in the same way, except that severity ratings require joint consideration of intensity 
and frequency. Thus, before taking frequency into account, an intensity rating of Minimal corresponds to a severity 
rating of Mild I subthreshold, Clearly Present corresponds with Moderate !threshold, Pronounced corresponds with 
Severe I markedly elevated, and Extreme corresponds with Extreme I incapacitating. 
2. 
The five-point CAPS-5 symptom severity rating scale is used for all symptoms Rating scale anchors should be 
interpreted and used as follows: 
0 
Absent The respondent denied the problem or the respondent's report doesn't fit the DSM-5 symptom criterion. 
Mild I subthreshold The respondent described a problem that is consistent with the symptom criterion but isn't 
severe enough to be considered clinically significant. The problem doesn't satisfy the DSM-5 symptom criterion 
and thus doesn't count toward a PTSD diagnosis. 
2 
Moderate I threshold The respondent described a clinically significant problem. The problem satisfies the DSM-
5 symptom criterion and thus counts toward a PTSD diagnosis. The problem would be a target for intervention. 
This rating requires a minimum frequency of 2 X month or some of the time (20-30%) PLUS a minimum intensity 
of Clearly Present. 
3 
Severe I markedly elevated The respondent described a problem that is well above threshold. The problem is 
difficult to manage and at times overwhelming, and would be a prominent target for intervention. This rating 
requires a minimum frequency of 2 X week or much of the time (50-60%) PLUS a minimum intensity of 
Pronounced. 
4 
Extreme I incapacitating The respondent described a dramatic symptom, far above threshold. The problem is 
pervasive, unmanageable, and overwhelming, and would be a high-priority target for intervention. 
3. 
In general, make a given severity rating only if the minimum frequency and intensity for that rating are both met. 
However, you may exercise clinical judgment in making a given severity rating if the reported frequency is somewhat 
lower than required, but the intensity is higher. For example, you may make a severity rating of Moderate !threshold if 
a symptom occurs 1 X month (instead of the required 2 X month) as long as intensity is rated Pronounced or Extreme 
(instead of the required Clearly Present). Similarly, you may make a severity rating of Severe I markedly elevated if a 
symptom occurs 1 X week (instead of the required 2 X week) as long as the intensity is rated Extreme (instead of the 
required Pronounced). If you are unable to decide between two severity ratings, make the lower rating. 
4. You need to establish that a symptom not only meets the DSM-5 criterion phenomenologically, but is also functionally 
related to the index traumatic event, i.e , started or got worse as a result of the event CAPS-5 items 1-8 and 10 
(reexperiencing, effortful avoidance, amnesia, and blame) are inherently linked to the event Evaluate the remaining 
items for trauma-relatedness (TR) using the TR inquiry and rating scale. The three TR ratings are: 
a. Definite = the symptom can clearly be attributed to the index trauma, because (1) there is an obvious change 
from the pre-trauma level of functioning andlor (2) the respondent makes the attribution to the index trauma with 
confidence. 
b. Probable = the symptom is likely related to the index trauma, but an unequivocal connection can't be made. 
Situations in which this rating would be given include the following: (1) there seems to be a change from the pre-

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CAPS-5 Page 4 
trauma level of functioning, but it isn 't as clear and explicit as it would be for a "definite;" (2) the respondent 
attributes a causal link between the symptom and the index trauma, but with less confidence than for a rating of 
Definite; (3) there appears to be a functional relationship between the symptom and inherently trauma-linked 
symptoms such as reexperiencing symptoms (e.g., numbing or withdrawal increases when reexperiencing 
increases). 
c. Unlikely= the symptom can be attributed to a cause other than the index trauma because (1) there is an obvious 
functional link with this other cause and/or (2) the respondent makes a confident attribution to this other cause 
and denies a link to the index trauma. Because it can be difficult to rule out a functional link between a symptom 
and the index trauma, a rating of Unlikely should be used only when the available evidence strongly points to a 
cause other than the index trauma. NOTE: Symptoms with a TR rating of Unlikely should not be counted toward a 
PTSD diagnosis or included in the total CAPS-5 symptom severity score. 
5. CAPS-5 total symptom severity score is calculated by summing severity scores for items 1-20. NOTE: Severity 
scores for the two dissociation items (29 and 30) should NOT be included in the calculation of the total CAPS-5 
severity score. 
6. CAPS-5 symptom cluster severity scores are calculated by summing the individual item severity scores for 
symptoms contained in a given DSM-5 cluster. Thus, the Criterion B (reexperiencing) severity score is the sum of the 
individual severity scores for items 1-5; the Criterion C (avoidance) severity score is the sum of items 6 and 7; the 
Criterion D (negative alterations in cognitions and mood) severity score is the sum of items 8-14; and the Criterion E 
(hyperarousal) severity score is the sum of items 15-20. A symptom cluster score may also be calculated for 
dissociation by summing items 29 and 30. 
7. 
PTSD diagnostic status is determined by first dichotomizing individual symptoms as "present" or "absent," then 
following the DSM-5 diagnostic rule. A symptom is considered present only if the corresponding item severity score is 
rated 2=ModerateAhreshold or higher. Items 9 and 11-20 have the additional requirement of a trauma-relatedness 
rating of Definite or Probable. Otherwise a symptom is considered absent The DSM-5 diagnostic rule requires the 
presence of least one Criterion B symptom, one Criterion C symptom. two Criterion D symptoms. and two Criterion E 
symptoms. In addition, Criteria F and G must be met Criterion F requires that the disturbance has lasted at least one 
month. Criterion G requires that the disturbance cause either clinically significant distress or functional impairment, as 
indicated by a rating of 2=moderate or higher on items 23-25. 

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Criterion A: Exposure to actual or threatened death, serious injury, or sexual violence in one (or more) of the 
following ways: 
1. Directly experiencing the traumatic event(s). 
2. Witnessing, in person, the event(s) as it occurred to others. 
3. Learning that the traumatic event(s) occurred to a close family member or close friend. In cases of actual or 
threatened death of a family member or friend, the event(s) must have been violent or accidental. 
4. Experiencing repeated or extreme exposure to aversive details of the traumatic event(s) (e.g., first 
responders collecting human remains; police officers repeatedly exposed to details of child abuse). Note: 
Criterion A4 does not apply to exposure through electronic media, television, movies, or pictures, unless 
this exposure is work related. 
[Administer Life Events Checklist or other structured trauma screen] 
I'm going to ask you about the stressful experiences questionnaire you filled out. First I'll ask you to tell me a 
little bit about the event you said was the worst for you. Then I'll ask how that event may have affected you over 
the past month. In general I don't need a lot of information- just enough so I can understand any problems you 
may have had. Please let me know if you find yourself becoming upset as we go through the questions so we can 
slow down and talk about it. Also, let me know if you have any questions or don't understand something. Do you 
have any questions before we start? 
The event you said was the worst was (EVENT). What I'd like for you to do is briefly describe what happened. 
Index event (specify). 
What happened? (How old were you? How were you involved? 
Who else was involved? Was anyone seriously injured or killed? 
Was anyone's life in danger? How many times did this happen?) 
Exposure type: 
Experienced _ 
Witnessed 
Learned about 
Exposed to aversive details_ 
Life threat? 
NO YES [self_ 
other_] 
Serious injury? 
NO YES [self_ 
other__) 
Sexual violence? 
NO YES [self_ 
other _] 
Criterion A met? 
NO 
PROBABLE 
YES 
For the rest of the interview, I want you to keep (EVENT) in mind as I ask you about different problems it may 
have caused you. You may have had some of these problems before, but for this interview we're going to focus 
just on the past month. For each problem I'll ask if you've had it in the past month, and if so, how often and how 
much it bothered you. 

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Criterion B: Presence of one (or more) of the following intrusion symptoms associated with the traumatic 
event(s), beginning after the traumatic event(s) occurred: 
1. (81) Recurrent, involuntary, and intrusive distressing memories of the traumatic event(s) Note: In children older than 6 
years, repetitive play may occur in which themes or aspects of the traumatic event(s) are expressed 
In the past month, have you had any unwanted memories of (EVENT) while you were 
awake, so not counting dreams? [Rate O=Absent if only during dreams] 
How does it happen that you start remembering (EVENT)? 
[If not clear:] (Are these unwanted memories, or are you thinking about [EVENT] 
on purpose?) [Rate O=Absent unless perceived as involuntary and intrusive] 
How much do these memories bother you? 
Are you able to put them out of your mind and think about something else? 
[If not clear:] (Overall, how much of a problem is this for you? How so?) 
Circle: Distress = Minimal 
Clearly Present 
Pronounced 
Extreme 
How often have you had these memories in the past month? 
#of times ___ 
_ 
Key rating dimensions = frequency I Intensity of dis tress 
Moderate= at least 2 X month I distress clearly present, some difficulty dismissing memories 
Severe = at least 2 X week I pronounced distress, considerable difficulty dismissing memories 
0 Absent 
1 Mild I subthreshold 
2 Moderate I threshold 
3 Severe I markedly elevated 
4 Extreme I incapacitating 
2. (82) Recurrent distressing dreams in which the content and/or affect of the dream are related to the event(s). Note: In 
children, there may be frightening dreams without recognizable content 
In the past month, have you had any unpleasant dreams about (EVENT)? 
Describe a typical dream. (What happens?) 
[If not clear:] (Do they wake you up?) 
[If yes:] (What do you experience when you wake up? How long does it 
take you to get back to sleep?) 
[If reports not returning to sleep:] (How much sleep do you lose?) 
How much do these dreams bother you? 
Circle: Distress = Minimal 
Clearly Present 
Pronounced 
Extreme 
How often have you had these dreams in the past month? 
#of times ___ 
_ 
Key rating dimensions = frequency I intensity of dis tress 
Moderate = at least 2 X month I distress clearly present, less than 1 hour sleep loss 
Severe = at least 2 X week I pronounced distress, more than 1 hour sleep loss 
0 Ahsent 
1 Mild I subthreshold 
2 Moderate I threshold 
3 Severe I markedly elevated 
4 Extreme I Incapacitating 

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3. (83) Dissociative reactions (e.g., flashbacks) in which the individual feels or acts as if the traumatic event(s) were 
recurring. (Such reactions may occur on a continuum, with the most extreme expression being a complete loss of 
awareness of present surroundings.) Note: In children, trauma-specific reenactment may occur in play. 
In the past month, have there been times when you suddenly acted or felt as if 
(EVENT) were actually happening again? 
[If not clear:] (This is different than thinking about it or dreaming about it- now 
I'm asking about flashbacks, when you feel/ike you're actually back at the time 
of [EVENT], actually reliving it.) 
How much does it seem as if (EVENT) were happening again? (Are you confused about 
where you actually are?) 
What do you do while this is happening? (Do other people notice your behavior? What 
do they say?) 
How long does it last? 
Circle: Dissociation = Minimal 
Clearly Present 
Pronounced 
Extreme 
How often has this happened in the past month? 
#of times ___ 
_ 
Key rating dimensions= frequency I intensity of dissociation 
Moderate = at least 2 X month I dissociative quality clearly present, may retain some awareness of surroundings but 
relives event in a manner clearly distinct from thoughts and memories 
Severe = at least 2 X week I pronounced dissociative quality, reports vivid reliving, e.g. with images sounds smells 
0 Absent 
1 Mild I subthreshold 
2 Moderate I threshold 
3 Severe I markedly elevated 
4 Extreme I Incapacitating 
4. (84) Intense or prolonged psychological distress at exposure to internal or external cues that symbolize or resemble an 
aspect of the traumatic event(s). 
In the past month, have you gotten emotionally upset when something reminded YQ!! 
0 A bsent 
of(EVENT)? 
1 Mild I subthreshold 
What kinds of reminders make you upset? 
2 Moderate I threshold 
How much do these reminders bother you? 
3 Severe I markedly elevated 
Are you able to calm yourself down when this happens? (How long does it take?) 
4 Extreme I Incapacitating 
[If not clear:] (Overall, how much of a problem is this for you? How so?) 
Circle: Distress = Minimal 
Clearly Present 
Pronounced 
Extreme 
How often has this happened in the past month? 
#of times ----
Key rating dimensions = frequency I Intensity of dis tress 
Moderate = at least 2 X month I distress clearly present, some difficulty recovering 
Severe= at least 2 X week I pronounced distress, considerable difficulty recovering 

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5. (85) Marked physiological reactions to internal or external cues that symbolize or resemble an aspect of the traumatic 
event(s). 
In the past month, have you had any physical reactions when something reminded YQ!!. 
0 A bsent 
of(EVENT)? 
1 Mild I subthreshold 
Can you give me some examples? (Does your heart race or your breathing change? What 
2 Moderate I thresh old 
about sweating or feeling really tense or shaky?) 
3 Severe I markedly elevated 
What kinds of reminders trigger these reactions? 
4 Extreme I incapacitating 
How long does it take you to recover? 
Circle: Physiological reactivity = Minimal 
Clearly Present 
Pronounced 
Extreme 
How often has this happened in the past month? 
# of times ----
Key rating dimensions = frequen cy I intensity of physiological arousal 
Moderate = at least 2 X month I reactivity clearly present, some difficulty recovering 
Severe= at least 2 X week I pronounced reactivity, sustained arousal, considerable difficulty recovering 
Criterion C: Persistent avoidance of stimuli associated with the traumatic event(s), beginning after the traumatic 
event(s) occurred, as evidenced by one or both of the follow ing: 
6. (C1) Avoidance of or efforts to avoid distressing memories, thoughts, or feelings about or closely associated with the 
traumatic event(s). 
In the past month, have you tried to avoid thoughts or feelings about (EVENT)? 
0 Absent 
What kinds of thoughts or feelings do you avoid? 
1 Mild I subthreshold 
2 Moderate I threshold 
How hard do you try to avoid these thoughts or feelings? (What kinds of things do you 
do?) 
3 Severe I markedly elevated 
[If not clear:] (Overall, how much of a problem is this for you? How would things 
4 Extreme I incapacitating 
be different if you didn't have to avoid these thoughts or feelings?) 
Circle: Avoidance = Minimal 
Clearly Present 
Pronounced 
Extreme 
How often in the past month? 
#of times ----
Key rating d imensions = frequency I intensity of avoidance 
Moderate = at least 2 X month I avoidance clearly present 
Severe = at least 2 X week I pronounced avoidance 

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7. (C2) Avoidance of or efforts to avoid external reminders (people, places, conversations, activities, objects, situations) 
that arouse distressing memories, thoughts, or feelings about or closely associated with the traumatic event(s) 
In the past month, have you tried to avoid things that remind YQ!! of (EVENT), like 
0 Absent 
certain people, places, or situations? 
1 Mild I subthreshold 
What kinds of things do you avoid? 
2 Moderate I threshold 
How much effort do you make to avoid these reminders? (Do you have to make a plan or 
3 Severe I markedly elevated 
change your activities to avoid them?) 
4 Extreme I incapacitating 
[If not clear:] (Overall, how much of a problem is this for you? How would things 
be different if you didn't have to avoid these reminders?) 
Circle: Avoidance = Minimal 
Clearly Present 
Pronounced 
Extreme 
How often in the past month? 
#of times ----
Key rating dimensions = frequency I intensity of avoidance 
Moderate ;;; at least 2 X month I avoidance clearly present 
Severe= at least 2 X week I pronounced avoidance 
8. (01) Inability to remember an important aspect of the traumatic event(s) (typically due to dissociative amnesia and not 
to other factors such as head injury, alcohol, or drugs). 
In the past month, have you had difficulty remembering some important parts of 
(EVENT)? (De you feel there are gaps in your memory of [EVENT]?) 
What parts have you had difficulty remembering? 
Do you feel you should be able to remember these things? 
[If not clear:] (Why do you think you can't? Did you have a head injury during 
[EVENT]? Were you knocked unconscious? Were you intoxicated from alcohol 
or drugs?) [Rate O=Absent if due to head injury or loss of consciousness or intoxication during event) 
[If still not clear:] (Is this just normal forgetting? Or do you think you may 
have blocked it out because it would be too painful to remember?) [Rate 
O=Absent if due only to normal forgetting] 
Circle: Difficulty remembering = Minimal 
Clearly Present 
Pronounced 
Extreme 
In the past month, how many of the important parts of (EVENT) have you had difficulty 
remembering? (What parts do you still remember?) 
#of important aspects ___ 
_ 
Would you be able to recall these things if you tried? 
Key rating dimensions = aroount of event not recalled I intensity of inabJ/Jty to recall 
Moderate = at least one important aspect I difficulty remembering clearly present, some recall possible with effort 
Severe = several important aspects I pronounced difficulty remembering, little recall even with effort 
0 Absent 
1 Mild I subthreshold 
2 Moderate I thresh old 
3 Severe I markedly elevated 
4 Extreme I incapacitating 

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9. (02) Persistent and exaggerated negative beliefs or expectations about oneself, others, or the world (e.g., "I am bad," 
"No one can be trusted," "The world is completely dangerous," "My whole nervous system is permanently ruined"). 
In the past month, have you had strong negative beliefs about yourself, other people, 
or the world? 
Can you give me some examples? (What about believing things like "I am bad," "there is 
something seriously wrong with me," "no one can be trusted, " "the world is completely 
dangerous"?) 
How strong are these beliefs? (How convinced are you that these beliefs are actually true? 
Can you see other ways of thinking about it?) 
Circle: Conviction = Minimal 
Clearly Present 
Pronounced 
Extreme 
How much of the time in the past month have you felt that way, as a percentage? 
%oftime ___ 
_ 
Did these beliefs start or get worse after (EVENT)? (Do you think they're related to 
[EVENT]? How so?) Circle: Trauma-relatedness = Definite 
Probable 
Unlikely 
Key rating dimensions= frequency I intensity of beliefs 
Moderate = some of the time (20-30%) I exaggerated ne gative expectations clearly present, some difficulty 
considering more realistic beliefs 
Severe = much of the time (5Q-60%) I pronounced exaggerated negative expectations, considerable difficulty 
considering more realistic beliefs 
0 Absent 
1 Mild I subthreshold 
2 Moderate I threshold 
3 Severe I markedly elevated 
4 Extreme I incapacitating 
10. (03) Persistent, distorted cognitions about the cause or consequences of the traumatic event(s) that lead the 
individual to blame himself/herself or others. 
In the past month, have you blamed yourself for (EVENT) or what happened as a result o Absent 
of it? Tell me more about that. (In what sense do you see yourself as having caused 
[EVENT]? Is it because of something you did? Or something you think you should have done 
1 Mild I subthreshold 
but didn't? Is it because of something about you in general?) 
2 Moderate I threshold 
What about blaming someone else for (EVENT) or what happened as a result of it? Tell 
me more about that. (In what sense do you see [OTHERS] as having caused [EVENT]? Is 
3 severe !markedly elevated 
it because of something they did? Or something you think they should have done but didn't?) 
How much do you blame (YOURSELF OR OTHERS)? 
How convinced are you that [YOU OR OTHERS] are truly to blame for what happened? 
(Do other people agree with you? Can you see other ways of thinking about it?) 
[Rate O=Absent if only blames perpetrator, i.e., someone who deliberately caused the event and intended harm] 
Circle: Conviction = Minimal 
Clearly Present 
Pronounced 
Extreme 
How much of the time in the past month have you felt that way, as a percentage? 
%of time ___ 
_ 
Key rating dimensions = frequency I Intensity of blame 
Moderate = some of the time (20-30%) I distorted blame clearly present, some difficulty considering more realistic 
beliefs 
Severe= much of the time (50-60%) I pronounced distorted blame, considerable difficulty considering more realistic 
beliefs 
4 Extreme I incapacitating 

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11 (04) Persistent negative emotional state (e.g., fear, horror, anger, guilt, or shame). 
In the past month, have you had any strong negative feelings such as fear, horror, 
anger, guilt, or shame? 
Can you give me some examples? (What negative feelings do you experience?) 
How strong are these negative feelings? 
How well are you able to manage them? 
]If not clear:] (Overall, how much of a problem is this for you? How so?) 
Circle: Negative emotions ;;; Minimal 
Clearly Present 
Pronounced 
Extreme 
How much of the time in the past month have you felt that way, as a percentage? 
%of time ___ 
_ 
Did these negative feelings start or get worse after (EVENT)? (Do you think they're 
related to [EVENT]? How so?) Circle: Trauma-relatedness= Definite 
Probable 
Unlikely 
Key rating dimensions= frequency I intensity of negative emotions 
Moderate = some of the time (20-30%) I negative emotions clearly present, some difficulty managing 
Severe = much of the time (50-60%) I pronounced negative emotions, considerable difficulty managing 
12. (0 5) Markedly diminished interest or participation in significant activities. 
In the past month, have you been less interested in activities that you used to enjoy? 
What kinds of things have you lost interest in or don't do as much as you used to? 
(Anything else?) 
Why is that? [Rate O=Absent if diminished participation is due to lack of opportunity, physical inability, or 
developmentally appropriate change in preferred activities] 
How strong is your loss of interest? (Would you still enjoy [ACTIVITIES] once you got 
started?) 
Circle: Loss of interest;;; Minimal 
Clearly Present 
Pronounced 
Extreme 
Overall, in the past month, how many of your usual activities have you been less 
interested in, as a percentage? 
%of activities ___ 
_ 
What kinds of things do you still enjoy doing? 
Did this loss of interest start or get worse after (EVENT)? (Do you think it's related to 
[EVENT]? How so?) Circle: 
Definite 
Probable 
Unlikely 
Key rating dimensions = percent of activities affected I intensity of loss of interest 
Moderate ;;; some activities (20-30%) / loss of interest clearly present but still has some enjoyment of activities 
Severe;;; many activities (50-60%) I pronounced loss of interest, little interest or participation in activities 
CAPS-5 Page 11 
0 Absent 
1 Mild I subthreshold 
2 Moderate I threshold 
3 Severe I markedly elevated 
4 Extreme I incapacitating 
0 Absent 
1 Mild I subthreshold 
2 Moderate I threshold 
3 Severe I markedly elevated 
4 Extreme I incapacitating 

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13. (06) Feelings of detachment or estrangement from others. 
In the past month, have you felt distant or cut off from other people? 
Tell me more about that. 
How strong are your feelings of being distant or cut off from others? (Who do you feel 
closest to? How many people do you feel comfortable talking with about personal things?) 
Circle: Detachment or estrangement = Minimal 
Clearly Present 
Pronounced 
Extreme 
How much of the time in the past month have you felt that way, as a percentage? 
%oftime ___ 
_ 
Did this feeling of being distant or cut off start or get worse after (EVENT)? (Do you 
think it's related to [EVENT]? How so?) Circle: Trauma-relatedness = Definite 
Probable 
Unlikely 
Key rating dimensions = frequency I intensity of detachment or estrangement 
Moderate= some of the time (20-30%) /feelings of detachment clear1y present but still feels some interpersonal 
connection 
Severe= much of the time (50-60%) I pronounced feelings of detachment or estrangement from most people, may 
feel close to only one or two people 
CAPS-5 Page 12 
0 Absent 
1 Mild I subthreshold 
2 Moderate I threshold 
3 Severe I markedly elevated 
4 Extreme I incapacitating 
14. (07) Persistent inability to experience positive emotions (e.g., inability to experience happiness, satisfaction, or loving 
feelings) 
In the past month, have there been times when you had difficulty experiencing positive 
feelings like love or happiness? 
Tell me more about that. (What feelings are difficult to experience?) 
How much difficulty do you have experiencing positive feelings? (Are you still able to 
experience any positive feelings?) 
Circle: Reduction of positive emotions = Minimal 
Clearly Ftesent 
Pronounced 
Extreme 
How much of the time in the past month have you felt that way, as a percentage? 
% oftime ___ 
_ 
Did this trouble experiencing positive feelings start or get worse after (EVENT)? (Do 
you think it's related to [EVENT]? How so?) Circle: Trauma-relatedness = Definite 
Probable 
Unlikely 
Key rating dimensions = frequency I intensity of reduction in positive emotions 
Moderate= some of the time (20·30%) I reduction of positive emotional experience clearly present but still able to 
experience some positive emotions 
Severe = much of the time (50--60%) I pronounced redu ction of experience across range of positive emotions 
0 Absent 
1 Mild I subthreshold 
2 Moderate I threshold 
3 Severn I markedly elevated 
4 Extreme I incapacitating 

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15. (E1) Irritable behavior and angry outbursts (with little or no provocation) typically expressed as verbal or physical 
aggression toward people or objects. 
In the past month, have there been times when you felt especially irritable or angry 
0 Absent 
and showed it in your behavior? 
1 Mild I subthreshold 
Can you give me some examples? (How do you show if? Do you raise your voice or yelf? 
2 Moderate I threshold 
Throw or hit things? Push or hit other people?) 
3 Severe I markedly elevated 
Circle: Aggression = Minimal 
Clearly Present 
Pronounced 
Extreme 
4 Extreme I incapacitating 
How often in the past month? 
#of times ----
Did this behavior start or get worse after (EVENT)? (Do you think it's related to [EVENT]? 
How so?) Circle: Trauma-relatedness = Definite 
Probable 
Unlikely 
Key rating dimensions = frequency I Intensity of aggressive behavior 
Moderate ;;; at least 2 X month I aggression clearly present, primarily verbal 
Severe= at least 2 X week I oronounced aaaression, at least some ohvsical aaaression 
16. (E2) Reckless or self-destructive behavior. 
In the past month, have there been times when you were taking more risks or doing 
0 Absent 
things that might have caused you harm? 
1 Mild I subthreshold 
Can you give me some examples? 
2 Moderate I threshold 
How much of a risk do you take? (How dangerous are these behaviors? Were you injured 
3 Severe I m arkedly elevated 
or harmed in some way?) 
4 Extreme I incapacitating 
Circle: Risk = Minimal 
Clearly Present 
Pronounced 
Extreme 
How often have you taken these kinds of risks in the past month? 
# of times ----
Did this behavior start or get worse after (EVENT)? (Do you think it's related to [E VENT]? 
How so?) Circle: Trauma-relatedness= Definite 
Probable 
Unlikely 
Key rating dimensions = frequency I degree of risk 
Moderate = at least 2 X month I risk clearly present, may have been harmed 
Severe = at least 2 X week I pronounced risk, actual harm or high probability of harm 

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17. (E3) Hypervigilance. 
In the past month, have you been especially alert or watchful, even when there was no 
specific threat or danger? (Have you felt as if you had to be on guard?) 
Can you give me some examples? (What kinds of things do you do when you're alert or 
watchful?) 
[If not clear:[ (What causes you to react this way? Do you fee/like you're in 
danger or threatened in some way? Do you feel that way more than most 
people would in the same situation?) 
Circle: Hypervigilance = Minimal 
Clearly Present 
Pronounced 
Extreme 
How much of the time in the past month have you felt that way, as a percentage? 
% oftime ___ 
_ 
Did being especially alert or watchful start or get worse after (EVENT)? (Do you think 
it's related to [EVENT]? How so?) Circle: Trauma-relatedness = Definite 
Probable 
Unlikely 
Key rating dimensions= frequency I Intensity of hypervlgilance 
Moderate= some of the time (20-30%) I hypervigilance clearly present, e.g., watchful in public, heightened 
awareness of threat 
Severe= much of the time (50-60%) I pronounced hypervigilance, e.g., scans environment for danger, may have 
safety rituals, exaggerated concern for safety of selflfamily!l10me 
18. (E4) Exaggerated startle response. 
In the past month, have you had any strong startle reactions? 
What kinds of things made you startle? 
How strong are these startle reactions? (How strong are they compared to how most 
people would respond? Do you do anything other people would notice?) 
How long does it take you to recover? 
Circle: Startle = Minimal 
Clearly Present 
Pronounced 
Extreme 
How often has this happened in the past month? 
#of times ___ 
_ 
Did these startle reactions start or get worse after (EVENT)? (Do you think they're 
related to [EVENT]? How so?) Circle: Trauma-relatedness = Definite 
Probable 
Unlikely 
Key rating d imensions = frequency I intens ity of startle 
Moderate = at least 2 X month I startle clearly present, some difficulty recovering 
Severe = at least 2 X week I pronounced startle, sustained arousal, considerable difficulty recovering 
CAPS-5 Page 14 
0 Absent 
1 Mild I subthreshold 
2 Moderate I threshold 
3 Severe I markedly elevated 
4 Extreme I incapacitating 
0 Absent 
1 Mild I subthreshold 
2 Moderate I threshold 
3 Severe I markedly elevated 
4 Extreme I incapacitating 

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19. (E5) Problems with concentration. 
In the past month, have you had any problems with concentration? 
Can you give me some examples? 
Are you able to concentrate if you really try? 
]If not clear:] (Overall, how much of a problem is this for you? How would things 
be different if you didn't have problems with concentration?) 
Circle: Problem concentrating = Minimal 
Clearly Present 
Pronounced 
Extreme 
How much of the time in the past month have you had problems with concentration, as 
a percentage? 
%oftime ___ 
_ 
Did these problems with concentration start or get worse after (EVENT)? (Do you think 
they're related to {EVENT]? How so?) Circle: Trauma-relatedness= Deflnite 
Probable 
Unlikely 
Key rating dimensions= frequency I intensity of concentration problems 
Moderate = some of the time (20-30%) I problem concentrating clearly present, some difficulty but can concentrate 
with effort 
Severe= much of the time (50-60%) I pronounced problem concentrating, considerable difficulty even with effort 
20. (E6) Sleep disturbance (e.g., difficulty falling or staying asleep or restless sleep). 
In the past month, have you had any problems falling or staying asleep? 
What kinds of problems? (How long does it take you to fall asleep? How often do you 
wake up in the night? Do you wake up earlier than you want to?) 
How many total hours do you sleep each night? 
How many hours do you think you should be sleeping? 
Circle: Problem sleeping = Minimal 
Clearly Present 
Pronounced 
Extreme 
How often in the past month have you had these sleep problems? 
# of times ___ 
_ 
Did these sleep problems start or get worse after (EVENT)? (Do you think they're related 
to {EVENT]? How so?) Circle: Trauma-relatedness = Definite 
Probable 
Unlikely 
Key rating dimensions = frequency I intensity of sleep problems 
Moderate= at least 2 X month I sleep disturbance clearly present, clearly longer latency or clear difficulty staying 
asleep, 30-90 minutes loss of sleep 
Severe = at least 2 X week I pronounced sleep disturbance, considerably longer latency or marked difficulty staying 
asleep, 90 min to 3 hrs loss of sleep 
CAPS-5 Page 15 
0 Absent 
1 Mild I subthreshold 
2 Moderate I threshold 
3 Severe I markedly elevated 
4 Extreme I incapacitating 
0 A bsent 
1 Mild I subthreshold 
2 Moderate I threshold 
3 Severe I markedly elevated 
4 Extreme I incapacitating 

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Criterion F: Duration of the disturbance (Criteria B, C, D, and E) is more than 1 month. 
21 
Onset of symptoms 
[If not clear:] When did you first start having (PTSD SYMPTOMS) you've told 
me about? (How long after the trauma did they start? More than six months?) 
Total# months delay in onset ___ _ 
With delayed onset(?_ 6 months)? NO YES 
22. Duration of symptoms 
[If not clear:] How long have these (PTSD SYMPTOMS) lasted altogether? 
Total# months duration 
Duration more than 1 month? NO YES 
Criterion G: The disturbance causes clinically significant distress or impairment in social, occupational, or other 
important areas of functioning. 
23. Subjective distress 
Overall, in the past month, how much have you been 
bothered by these (PTSD SYMPTOMS) you've told me about? 
(Consider distress reported on earlier items] 
24. Impairment in social functioning 
In the past month, have these (PTSD SYMPTOMS) affected 
your relationships with other people? How so? [Consider 
impairment in social functioning reported on earlier items] 
None 
Mild, minimal distress 
Moderate, distress clearly present but still manageable 
Severe, considerable distress 
Extreme, incapacitating distress 
No adverse Impact 
Mild impact, minimal impairment in social functioning 
Moderate impact, definite impairment but many 
aspects of social functioning still intact 
Severe impact, marked impainnent, few aspects of 
social functioning still intact 
Extreme impact, little or no social functioning 

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25. Impairment in occupational or other important area of functioning 
]If not clear:] Are you working now? 
[If yes] In the past month, have these (PTSD SYMPTOMS) 
affected your work or your ability to work? How so? 
[If no 1 Why is that? (Do you feel that your [PTSD 
SYMPTOMS] are related to you not working now? How so?) 
[If unable to work because of PTSD symptoms, rate at least 3=Severe. If 
unemployment is not due to PTSD symptoms, or if the link is not clear, base 
rating only on impairment in other important areas of functioning] 
Have these (PTSD SYMPTOMS) affected any other 
important part of your life? [As appropriate. suggest examples such 
as parenting, housework, schoolwork, volunteer work, etc.] How so? 
Global Ratings 
26. Global validity 
Estimate the overall validity of responses. Consider factors such 
as compliance with the interview, mental status (e.g., problems 
with concentration, comprehension of items, dissociation), and 
evidence of efforts to exaggerate or minimize symptoms. 
27. Global severity 
Estimate the overall severity of PTSD symptoms. Consider 
degree of subjective distress, degree of functional impairment, 
observations of behaviors in interview, and judgment regarding 
reporting style 
CAPS-5 Page 17 
No adver.ie impact 
Mild impact, minimal impairment in occupational/other 
important functioning 
Moderate impact, definite impairment but many 
aspects of occupational/other important functioning 
still intact 
Severe impact, marked impainnent, few aspects of 
occupational/other important functioning still intact 
Extreme impact, little or no occupational/other 
important functioning 
Excellent, no reason to suspect invalid responses 
Good, factors present that may adversely affect 
validity 
Fair, factors present that definitely reduce validity 
Poor, substantially reduced validity 
Invalid responses, severely impaired mental status or 
possible deliberate " faking bad" or "faking good" 
No clinically significant symptoms, no distress and no 
functional impaitment 
Mild, minimal distress or functional impairment 
Moderate, definite distress orfunctlonal impaltment 
but fu nctions satisfactorily with effort 
Severe, considerable distress or functional 
impairment, limited functioning even with effort 
Extreme, marked distress or marked impaitment in two 
or more major areas offunctioning 

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28. Global improvement 
Asymptomatic 
Rate total overall improvement since the previous rating. Rate 
the degree of change, whether or not, in your judgment, it is due 
to treatment 
Considerable improvement 
Moderate improvement 
Slight improvement 
No improvement 
Insufficient information 
Specify whether with dissociative symptoms: The individual's symptoms meet the criteria for posttraumatic stress 
disorder, and in addition, in response to the stressor, the individual experiences persistent or recurrent symptoms 
of either of the following: 
29. (1) Depersonalization: Persistent or recurrent experiences of feeling detached from, and as if one were an outside 
observer of, one's mental processes or body (e.g., feeling as though one were in a dream; feeling a sense of unreality of 
self or body or of time moving slowly). 
In the past month, have there been times when you felt as if you were separated from 
yourself, like you were watching yourself from the outside or observing your thoughts 
and feelings as if you were another person? 
[If no:] (What about feeling as if you were in a dream, even though you were 
awake? Feeling as if something about you wasn't real? Feeling as if time was 
moving more slowly?) 
Tell me more about that. 
How strong is this feeling? (Do you lose track of where you actually are or what's actually 
going on?) 
What do you do while this is happening? (Do other people notice your behavior? What 
do they say?) 
How long does it last? 
Circle: Dissociation = Minimal 
Clearly Present 
Pronounced 
Extreme 
[If not clear:] (Was this due to the effects of alcohol or drugs? What about a 
medical condition like seizures?) [Rate O=Absent if due to the effects of a substance or 
another medical condition] 
How often has this happened in the past month? 
#of times ___ 
_ 
Did this feeling start or get worse after (EVENT)? (Do you think it's related to [EVENT}? 
How so?) Circle: Trauma-relatedness= Definite 
Probable 
Unlikely 
Key rating dimensions = frequen cy I intensity of dissociation 
Moderate = at least 2 X month I dissociative quality clearly present but transient, retains some realistic sense of self 
and awareness of environment 
Severe = at least 2 X week I pronounced dissociative quality, marked sense of detachment and unreality 
0 Absent 
1 Mild I subthreshold 
2 Moderate I threshold 
3 Severe I markedly elevated 
4 Extreme I Incapacitating 

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CAPS-5 Page 19 
30. (2) Derealization: Persistent or recurrent experiences of unreality of surroundings (e.g., the world around the individual 
is experienced as unreal, dreamlike, distant, or distorted) 
In the past month, have there been times when things going on around you seemed 
unreal or very strange and unfamiliar? 
[If no:] (Do things going on around you seem like a dream or like a scene from a 
movie? Do they seem distant or distorted?) 
Tell me more about that. 
How strong is this feeling? (Do you lose track of where you actually are or what's actually 
going on?) 
What do you do while this is happening? (Do other people notice your behavior? What 
do they say?) 
How long does it last? 
Circle: Dissociation = Minimal 
Clearly Present 
Pronounced 
Extreme 
[If not clear:] (Was this due to the effects of alcohol or drugs? What about a 
medical condition like seizures ?) [Rate Q; Absent if due to the effects of a substance or 
another medical condition] 
How often has this happened in the past month? 
#of times ___ 
_ 
Did this feeling start or get worse after (EVENT)? (Do you think it's related to [EVENT]? 
How so?) Circle: Trauma-relatedness; Definite 
Probable 
Unlikely 
Key rating dimensions= frequency I intensity of dissociation 
Moderate = at least 2 X month I dissociative quality clearly present but transient, retains some realistic sense of 
environment 
Severe= at least 2 X week I pronounced dissociative quality, marked sense of unreality 
0 Absent 
1 Mild I subthreshold 
2 Moderate I threshold 
3 Severe I markedly elevated 
4 Extreme I incapacitating 

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CAPS-5 Page 20 
CAPS-5 SUMMARY SHEET 
Name: _______ ID#: ____ Interviewer: _______ Study: _____ Date: __ 
_ 
A. Exposure to actual or threatened death, serious injury, or sexual violence 
Criterion A met? 
0= NO 
1 =YES 
B. Intrusion symptoms (need 1 for diagnosis) 
Past Month 
Sev 
Sx (Sev 2)? 
(1) 81 -Intrusive memories 
0= NO 
1 =YES 
(2) 82 - Distressing dreams 
0 =NO 
1 =YES 
(3) 83 - Dissociative reactions 
0= NO 
1 =YES 
(4) 84 -Cued psychological distress 
0 =NO 
1 =YES 
(5) 85 -Cued physiological reactions 
0= NO 
1 =YES 
B subtotals B Sev= 
#B Sx= 
C. Avoidance symptoms (need 1 for diagnosis) 
Past Month 
Sev 
Sx (Sev > 2)? 
(6) C1 -Avoidance of memories, thoughts, feelings 
0= NO 
1 =YES 
(7) C2- Avoidance of external reminders 
0 =NO 
1 =YES 
C subtotals CSev= 
#C Sx= 
D. Cognitions and mood symptoms (need 2 for diagnosis) 
Past Month 
Sev 
Sx (Sev 2)? 
(8) D1 - Inability to recall important aspect of event 
0= NO 
1 =YES 
(9) D2 - Exaggerated negative beliefs or expectations 
0 =NO 
1 =YES 
(10) D3- Distorted cognitions leading to blame 
0= NO 
1 =YES 
(11) D4- Persistent negative emotional state 
0= NO 
1 =YES 
(12) D5- Diminished interest or participation in activities 
0= NO 
1 =YES 
(13) D6- Detachment or estrangement from others 
0= NO 
1 =YES 
(14) D7- Persistent inability to experience positive emotions 
0= NO 
1 =YES 
D subtotals D Sev= 
#D Sx= 
E. Arousal and reactivity symptoms (need 2 for diagnosis) 
Past Month 
Sev 
Sx (Sev > 2)? 
(15) E1 -Irritable behavior and angry outbursts 
0= NO 
1 =YES 
(16) E2- Reckless or self-destructive behavior 
0 =NO 
1 =YES 
(17) E3- Hypervigilance 
0= NO 
1 =YES 
(18) E4- Exaggerated startle response 
0 =NO 
1 =YES 
(19) E5- Problems with concentration 
0= NO 
1 =YES 
(20) E6- Sleep disturbance 
0 =NO 
1 =YES 
E subtotals E Sev= 
#E Sx= 

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CAPS-5 Page 21 
PTSD totals 
Past Month 
Total Sev 
I 
Total# Sx 
Sum of subtotals (B+C+D+E) 
I 
F. Duration of disturbance 
Current 
(22) Duration of 
1 month? 
0= NO 
1 =YES 
G. Distress or impairment (need 1 for diagnosis) 
Past Month 
Sev 
Cx (Sev 2)7 
(23) Subjective distress 
0= NO 
1 =YES 
(24) Impairment in social functioning 
0 =NO 
1 =YES 
(25) Impairment in occupational functioning 
0= NO 
1 =YES 
G subtotals G Sev= 
#GCx = 
Global ratings 
Past Month 
(26) Global validity 
(27) Global severity 
(28) Global improvement 
Dissociative symptoms (need 1 for subtype) 
Past Month 
Sev 
Sx (Sev 2)? 
(29) 1 - Depersonalization 
0= NO 
1 =YES 
(30) 2- Derealization 
0 =NO 
1 =YES 
Dissociative subtotals Diss Sev = 
#Diss Sx = 
PTSD diagnosis 
Past Month 
PTSD PRESENT- ALL CRITERIA (A-G) MET? 
0= NO 
1 =YES 
With dissociative symptoms 
0= NO 
1 =YES 
(21) With delayed 
6 months) 
0= NO 
1 =YES 

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Appendix 6
Past Week Version of the Clinician-Administered PTSD Scale 
For DSM-5 (CAPS-5)
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CAPS-S Page 1 
National Center for PTSD 
CLINICIAN-ADMINISTERED PTSD SCALE FOR DSM-5 
PAST WEEK VERSION 
Name: 
lntervie\Ner: 
Study: 
ID#: 
Date: 
Frank W. Weathers, Dudley D. Blake, Paula P. Schnurr, 
Danny G. Kaloupek, Brian P. Marx, & Terence M. Keane 
National Center for Posttraumatic Stress Disorder 
May 1, 2015 

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CAPS-S Page 2 
NOTE: This is the PAST WEEK version of the CAPS-5, which should be used only to evaluate PTSD symptom 
severity over the past week. PTSD diagnostic status should be evaluated with the PAST MONTH version of the 
CAPS-5. 
Criterion A: Exposure to actual or threatened death, serious injury, or sexual violence in one (or more) of the 
following ways: 
1. Directly experiencing the traumatic event(s). 
2. Witnessing, in person, the event(s) as it occurred to others. 
3. Learning that the traumatic event(s) occurred to a close family member or close friend. In cases of actual or 
threatened death of a family member or friend, the event(s) must have been violent or accidental. 
4. Experiencing repeated or extreme exposure to aversive details of the traumatic event(s) (e.g., first 
responders collecting human remains; police officers repeatedly exposed to details of child abuse). Note: 
Criterion A4 does not apply to exposure through electronic media, television, movies, or pictures, unless 
this exposure is work related. 
NOTE: Criterion A should already have been evaluated in a prior administration of the PAST MONTH version of 
the CAPS-5. Thus, for most applications of the PAST WEEK version, Criterion A does not need to be re-
evaluated. 
[Administer Life Events Checklist or other structured trauma screen] 
I'm going to ask you about the stressful experiences questionnaire you filled out. First I'll ask you to tell me a 
little bit about the event you said was the worst for you. Then I'll ask how that event may have affected you over 
the past week. In general I don't need a lot of information- just enough so I can understand any problems you 
may have had. Please let me know if you find yourself becoming upset as we go through the questions so we can 
slow down and talk about it. Also, let me know if you have any questions or don't understand something. Do you 
have any questions before we start? 
The event you said was the worst was (EVENT). What I'd like for you to do is briefly describe what happened. 
Index event (specify). 
What happened? (How old were you? How were you involved? 
Who else was involved? Was anyone seriously injured or killed? 
Was anyone's life in danger? How many times did this happen?) 
Exposure type 
Experienced_ 
Witnessed 
Learned about 
Exposed to aversive details_ 
Life threat? 
NO YES [self_ 
other__) 
Serious injury? 
NO YES [self_ 
other__) 
Sexual violence? 
NO YES [self_ other __) 
Criterion A met? 
NO 
PROBABLE 
YES 
For the rest of the interview, I want you to keep (EVENT) in mind as I ask you about different problems it may 
have caused you. You may have had some of these problems before, but for this interview we're going to focus 
just on the past week. For each problem I'll ask if you've had it in the past week. and if so, how often and how 
much it bothered you. 

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CAPS-S Page 3 
Criterion B: Presence of one (or more) of the following intrusion symptoms associated with the traumatic 
event(s), beginning after the traumatic event(s) occurred: 
1. (81) Recurrent, involuntary, and intrusive distressing memories of the traumatic event(s). Note In children older than 6 
years, repetitive play may occur in which themes or aspects of the traumatic event(s) are expressed. 
In the past week, have you had any unwanted memories of (EVENT) while you were 
awake, so not counting dreams? [Rate O=Absent if only during dreams] 
How does it happen that you start remembering (EVENT)? 
[If not clear:) (Are these unwanted memories, or are you thinking about [EVENT] 
on purpose?) [Rate O=Absent unless perceived as involuntary and intrusive) 
How much do these memories bother you? 
Are you able to put them out of your mind and think about something else? 
[If not clear:) (Overall, how much of a problem is this for you? How so?) 
Distress = Minimal 
Clearly Present 
Pronounced 
Extreme 
How often have you had these memories in the past week? 
#of times ___ 
_ 
Key rating dimensions = frequency I Intensity of distress 
Moderate = at least 1 X week I distress clearly present, some difficulty dismissing memories 
Severe = at least 2 X week I pronounced distress, considerable difficulty dismissing memories 
0 Absent 
1 Mild I subthreshold 
2 Moderate I threshold 
3 Severe I markedly elevated 
4 Extreme I incapacitating 
2. (82) Recurrent distressing dreams in which the content and/or affect of the dream are related to the event(s). Note: In 
children, there may be frightening dreams without recognizable content 
In the past week, have you had any unpleasant dreams about (EVENT)? 
Describe a typical dream. (V\Ihat happens?) 
[If not clear:) (Do they wake you up?) 
[If yes:) (What do you experience when you wake up? How long does it 
take you to get back to sleep?) 
[If reports not returning to sleep:) (How much sleep do you lose?) 
How much do these dreams bother you? 
Circle: Distress = Minimal 
Clearly Present 
Pronounced 
Extreme 
How often have you had these dreams in the past week? 
# of times ___ 
_ 
Key rating dimensions = frequency I intensity of dis tress 
Moderate = at least 1 X week I distress clearly present, less than 1 hour sleep loss 
Severe= at least 2 X week I pronounced distress, more than 1 hour sleep loss 
0 Absent 
1 Mild I subthreshold 
2 Moderate I threshold 
3 Severe I markedly elevated 
4 Extreme I Incapacitating 

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CAPS-S Page 4 
3. (83) Dissociative reactions (e.g. , flashbacks) in which the individual feels or acts as if the traumatic event(s) were 
recurring. (Such reactions may occur on a continuum, with the most extreme expression being a complete loss of 
awareness of present surroundings.) Note: In children, trauma-specific reenactment may occur in play. 
In the past week, have there been times when you suddenly acted or felt as if (EVENT) 
were actually happening again? 
[If not clear: I (This is different than thinking about it or dreaming about it- now 
I'm asking about flashbacks, when you fee/like you're actually back at the time 
of [EVENT], actually reliving it.) 
How much does it seem as if (EVENT) were happening again? (Are you confused about 
where you actually are?) 
What do you do while this is happening? (Do other people notice your behavior? What 
do they say?) 
How long does it last? 
Circle: Dissociation = Minimal 
Clearly Present 
Pronounced 
Extreme 
How often has this happened in the past week? 
#of times ___ 
_ 
Key rating dimensions =frequency I intensity of dissociation 
Moderate = at least 1 X week I dissociative quality clearly present, may retain some awareness of surroundings but 
relives event in a manner clearly distinct from thoughts and memories 
Severe= at least 2 X week I pronounced dissociative quality, reports vivid relivino, e.o., with imaqes, sounds, smells 
0 Absent 
1 Mild I subthreshold 
2 Moderate I threshold 
3 Severe I markedly elevated 
4 Extreme I incapacitating 
4. (84) Intense or prolonged psychological distress at exposure to internal or external cues that symbolize or resemble an 
aspect of the traumatic event(s). 
In the past week, have you gotten emotionally upset when something reminded .Y2.!!. of 
0 Absent 
(EVENT)? 
1 Mild I subthreshold 
What kinds of reminders make you upset? 
2 Moderate I threshold 
How much do these reminders bother you? 
3 Severe I markedly elevated 
Are you able to calm yourself down when this happens? (How long does it take?) 
4 Extreme I Incapacitating 
[If not clear:l (Overall, how much of a problem is this for you? How so?) 
Distress = Minimal 
Clearly Present 
Pronounced 
Extreme 
How often has this happened in the past week? 
# of times ----
Key rating dimensions =frequency I Intensity of distress 
Moderate = at least 1 X week I distress clearly present, some difficulty recovering 
Severe = at least 2 X week I pronounced distress, considerable difficulty recoverino 

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CAPS-S Page S 
5. (85) Marked physiological reactions to internal or external cues that symbolize or resemble an aspect of the traumatic 
event(s). 
In the past week, have you had 
reactions when something reminded .l£2.!! 
0 Absent 
of(EVENT)? 
1 Mild I subthreshold 
Can you give me some examples? (Does your heart race or your breathing change? What 
2 Moderate I threshold 
about sweating or feeling really tense or shaky?) 
3 Severe I markedly elevated 
What kinds of reminders trigger these reactions? 
4 Extreme I Incapacitating 
How long does it take you to recover? 
Circle: Physiological reactivity ;; Minimal 
Clearly Present 
Pronounced 
Extreme 
How often has this happened in the past week? 
# of times ----
Key rating dimensions =frequency I intensity of physiological arousal 
Moderate = at least 1 X week I reactivity clearly present, some difficulty recovering 
Severe= at least 2 X week I pronounced reactivity, sustained arousal, considerable difficulty recovering 
Criterion C: Persistent avoidance of stimuli associated with the traumatic event(s), beginning after the traumatic 
event(s) occurred, as evidenced by one or both of the following: 
6. (C1) Avoidance of or efforts to avoid distressing memories, thoughts, or feelings about or closely associated with the 
traumatic event(s). 
In the past week, have you tried to avoid thoughts or feelings about (EVENT)? 
0 Absent 
What kinds of thoughts or feelings do you avoid? 
1 Mild I subthreshold 
2 Moderate I threshold 
How hard do you try to avoid these thoughts or feelings? (Iii/hat kinds of things do you 
do?) 
3 Severe I markedly elevated 
111 not clear: I (Overall, how much of a problem is this for you? How would things 
4 Extreme I Incapacitating 
be different if you didn't have to avoid these thoughts or feelings?) 
Circle: Avoidance= Minimal 
Clearly Present 
Pronounced 
Extreme 
How often in the past week? 
#of times ----
Key rating dimensions =frequency I intensity of avoidance 
Moderate = at least 1 X week I avoidance clearly present 
Severe = at least 2 X week I pronounced avoidance 

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CAPS-S Page 6 
7. (C2) Avoidance of or efforts to avoid external reminders (people, places, conversations, activities, objects, situations) 
that arouse distressing memories, thoughts, or feelings about or closely associated with the traumatic event(s). 
In the past week, have you tried to avoid things that remind 
(EVENT), like 
0 Absent 
certain people, places, or situations? 
1 Mild I subthreshold 
What kinds of things do you avoid? 
2 Moderate I threshold 
How much effort do you make to avoid these reminders? (Do you have to make a plan or 
3 Severe I markedly elevated 
change your activities to avoid them?) 
4 Extreme I Incapacitating 
[If not clear: I (Overall, how much of a problem is this for you? How would things 
be different if you didn't have to avoid these reminders?) 
Circle: Avoidance= Minimal 
Clearly Present 
Pronounced 
Extreme 
How often in the past week? 
#of times ----
Key rating dimensions =frequency I Intensity of avoidance 
Moderate = at least 1 X week I avoidance clearly present 
Severe= at least 2 X week I pronounced avoidance 
8. (01) Inability to remember an important aspect of the traumatic event(s) (typically due to dissociative amnesia and not 
to other factors such as head injury, alcohol, or drugs). 
In the past week, have you had difficulty remembering some important parts of 
(EVENT)? (Do you feel there are gaps in your memory of [EVENT]?) 
What parts have you had difficulty remembering? 
Do you feel you should be able to remember these things? 
[If not clear:] (Why do you think you can't? Did you have a head injury during 
[EVENT]? Were you knocked unconscious? Were you intoxicated from alcohol 
or drugs?) [Rate O=Absent if due to head injury or loss of consciousness or intoxication during event] 
[If still not clear 1 (Is this just normal forgetting? Or do you think you may 
have blocked it out because it would be too painful to remember?) [Rate 
O=Absent if due only to normal forgetting] 
Circle: Difficulty remembering = Minimal 
Clearly Present 
Pronounced 
Extreme 
In the past week, how many of the important parts of (EVENT) have you had difficulty 
remembering? (What parts do you still remember?) 
#of important aspects ___ 
_ 
Would you be able to recall these things if you tried? 
Key rating dimensions =amount of event not recalled I intensity of inability to recall 
Moderate = at least one important aspect I difficulty remembering clearly present, some recall possible with effort 
Severe= several important aspects I pronounced difficulty remembering, little recall even 'Nith effort 
0 Absent 
1 Mild I subthreshold 
2 Moderate I threshold 
3 Severe I markedly elevated 
4 Extreme I Incapacitating 

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CAPS-S Page 7 
9. (02) Persistent and exaggerated negative beliefs or expectations about oneself, others, or the world (e.g., "I am bad," 
"No one can be trusted," "The world is completely dangerous," "My whole nervous system is permanently ruined"). 
In the past week, have you had strong 
about yourself, other people, or o Absent 
the world? 
Can you give me some examples? (What about believing things like "I am bad," "there is 
something seriously wrong with me," "no one can be trusted," "the world is completely 
dangerous"?) 
How strong are these beliefs? (How convinced are you that these beliefs are actually true? 
Can you see other ways of thinking about it?) 
Circle: Conviction = Minimal 
Clearly Present 
Pronounced 
Extreme 
How much of the time in the past week have you felt that way, as a percentage? 
% of time ___ 
_ 
Did these beliefs start or get worse after (EVENT)? (Do you think they're related to 
[EVENT]? How so ?) Circle: Trauma-relatedness = Definite 
Probable 
Unlikely 
Key rating dimensions =frequency I intensity of beliefs 
Moderate = some of the time (20-30%) I exaggerated negative expectations clearly present, some difficulty 
considering more realistic beliefs 
Severe = much of the time (50-60%) I pronounced exaggerated negative expectations, considerable difficulty 
considering more realistic beliefs 
1 Mild I subthreshold 
2 Moderate I threshold 
3 Severe I markedly elevated 
4 Extreme I incapacitating 
10. (03) Persistent, distorted cognitions about the cause or consequences of the traumatic event(s) that lead the 
individual to blame himself/herself or others. 
In the past week, have you blamed yourself for (EVENT) or what happened as a result 
of it? Tell me more about that. (In what sense do you see yourself as having caused 
[EVEN T]? Is it because of something you did? Or something you think you should have done 
but didn't? Is it because of something about you in general?) 
What about 
for (EVENT) or what happened as a result of it? Tell 
0 Absent 
1 Mild I subthreshold 
2 Moderate I threshold 
me more about that. (In what sense do you see [OTHERS] as having caused [EVENT]? Is 
3 severe! markedly elevated 
it because of something they did? Or something you think they should have done but didn't?) 
How much do you blame (YOURSELF OR OTHERS)? 
How convinced are you that [YOU OR OTHERS] are truly to blame for what happened? 
(Do other people agree with you? Can you see other ways of thinking about it?) 
[Rate O=Absent if only blames perpetrator, i.e., someone who deliberately caused the event and intended harm) 
Circle: Conviction = Minimal 
Clearly Present 
Pronounced 
Extreme 
How much of the time in the past week have you felt that way, as a percentage? 
%of time ___ 
_ 
Key rating dimensions = frequency I intensity of blame 
Moderate = some of the time (20-30%) I distorted blame clearly present, some difficulty considering more realistic 
beliefs 
Severe= much of the time (50-60%) I pronounced distorted blame, considerable difficulty considering more realistic 
beliefs 
4 Extreme I incapacitating 

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11 (04) Persistent negative emotional state (e.g., fear, horror, anger, guilt, or shame). 
In the past week, have you had any strong negative feelings such as fear, horror, 
anger, guilt, or shame? 
Can you give me some examples? (\Mlat negative feelings do you experience?) 
How strong are these negative feelings? 
How well are you able to manage them? 
111 not clear: I (Overall, how much of a problem is this for you? How so?) 
Circle: Negative emotions ;: Minimal 
Clearly Present 
Pronounced 
Extreme 
How much of the time in the past week have you felt that way, as a percentage? 
%of time ___ 
_ 
Did these negative feelings start or get worse after (EVENT)? (Do you think they're 
related to {EVENT]? How so?) Circle: Trauma-relatedness = Definite 
Probable 
Unlikely 
Key rating dimensions = frequency I intensity of negative emotions 
Moderate = some of the time (20-30%) I negative emotions clearly present, some difficulty managing 
Severe :::; much of the time (50-60%) I pronounced negative emotions, considerable difficulty managing 
12. (05) Markedly diminished interest or participation in significant activities. 
In the past week, have you been less interested in activities that you used to enjoy? 
What kinds of things have you lost interest in or don't do as much as you used to? 
(Anything else?) 
Why is that? [Rate O=Absent if diminished participation is due to lack of opportunity, physical inability, or 
developmentally appropriate change in preferred activities] 
How strong is your loss of interest? (Would you still enjoy [ACTIVITIES] once you got 
started?) 
Circle: Loss of interest= Minimal 
Clearly Present 
Pronounced 
Extreme 
Overall, in the past week, how many of your usual activities have you been less 
interested in, as a percentage? 
%of activflies ___ 
_ 
What kinds of things do you still enjoy doing? 
Did this loss of interest start or get worse after (EVENT)? (Do you think it's related to 
[EVENT]? How so?) Circle: Trauma-relatedness = Definite 
Probable 
Unlikely 
Key rating dimensions =percent of activities affected I intensity of loss of interest 
Moderate = some activities (20-30%) / loss of interest clearly present but still has some enjoyment of activities 
Severe = many activities (50-60%) I pronounced loss of interest, little interest or participation in activities 
CAPS-S Page 8 
0 Absent 
1 Mild I subthreshold 
2 Modernte I threshold 
3 Severe I markedly elevated 
4 Extreme I incapacitating 
0 Absent 
1 Mild I sub threshold 
2 Moderate I threshold 
3 Severe I m arkedly elevated 
4 Extreme I incapacitating 

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13. (06) Feelings of detachment or estrangement from others. 
In the past week, have you felt distant or cut off from other people? 
Tell me more about that. 
How strong are your feelings of being distant or cut off from others? (Who do you feel 
closest to? How many people do you feel comfortable talking with about personal things?) 
Circle: Detachment or estrangement = Minimal 
Clearly Present 
Pronounced 
Extreme 
How much of the time in the past week have you felt that way, as a percentage? 
% of time ___ 
_ 
Did this feeling of being distant or cut off start or get worse after (EVENT)? (Do you 
think it's related to [EVENT]? How so?) Circle: Trauma-relatedness = Definite 
Probable 
Unlikely 
Key rating dimensions = frequency I intensity of detachment or estrangement 
Moderate = some of the time (20-30%) I feelings of detachment clearly present but still feels some interpersonal 
connection 
Severe= much of the time (50-60%) I pronounced feelings of detachment or estrangement from most people, may 
feel close to only one or two people 
CAPS-S Page 9 
0 Absent 
1 Mild I subthreshold 
2 Modernte I threshold 
3 Severe I markedly elevated 
4 Extreme I incapacitating 
14. (07) Persistent inability to experience positive emotions (e.g., inability to experience happiness, satisfaction, or loving 
feelings). 
In the past week, have there been times when you had difficulty experiencing positive 
feelings like love or happiness? 
Tell me more about that. (What feelings are difficult to experience?) 
How much difficulty do you have experiencing positive feelings? (Are you still able to 
experience any positive feelings?) 
Circle: Reduction of positive emotions = Minimal 
Clearly Present 
Pronounced 
Extreme 
How much of the time in the past week have you felt that way, as a percentage? 
%of time ___ 
_ 
Did this trouble experiencing positive feelings start or get worse after (EVENT)? (Do 
you think it's related to [EVENT]? How so?) Circle: Trauma-relatedness = Definite 
Probable 
Unlikely 
Key rating dimensions = frequency I intensity of reduction in positive emotions 
Moderate = some of the time (20-30%) I reduction of positive emotional experience clearly present but still able to 
experience some positive emotions 
Severe= much of the time (50-60%) I pronounced reduction of experience across range of positive emotions 
0 Absent 
1 Mild I subthreshold 
2 Moderate I threshold 
3 Severe I markedly elevated 
4 Extreme I incapacitating 

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CAPS-5 Page 10 
15. (E1) Irritable behavior and angry outbursts (with little or no provocation) typically expressed as verbal or physical 
aggression toward people or objects. 
In the past week, have there been times when you felt especially irritable or angry and 
0 Absent 
showed it in your behavior? 
1 Mild I subthreshold 
Can you give me some examples? (How do you show if? Do you raise your voice or yell? 
2 Moderate I threshold 
Throw or hit things? Push or hit other people?) 
3 Severe I markedly elevated 
Circle: Aggression = Minimal 
Clearly Present 
Pronounced 
Extreme 
4 Extreme I incapacitating 
How often in the past week? 
#of times ----
Did this behavior start or get worse after (EVENT)? (Do you think it's related to [EVENT]? 
How so?) Circle: Trauma-relatedness = Definite 
Probable 
Unlikely 
Key rating dimensions =frequency I Intensity of aggress ive behavior 
Moderate= at least 1 X week I aggression clear1y present, primarily verbal 
Severe = at least 2 X week I pronounced aggression, at least some physical aggression 
16. (E2) Reckless or self-destructive behavior. 
In the past week, have there been times when you were taking more risks or doing 
0 Absent 
things that might have caused you harm? 
1 Mild I subthreshold 
Can you give me some examples? 
2 Moderate I threshold 
How much of a risk do you take? (How dangerous are these behaviors? Were you injured 
3 Severe I m arkedly elevated 
or harmed in some way?) 
4 Extreme I incapacitating 
Circle: Risk = Minimal 
Clearly Present 
Pronounced 
Extreme 
How often have you taken these kinds of risks in the past week? 
# of times ----
Did this behavior start or get worse after (EVENT)? (Do you think it's related to [EVENT]? 
How so?) Circle: Trauma-relatedness = Definite 
Probable 
Unlikely 
Key rating dimensions = frequency I degree of risk 
Moderate = at least 1 X week I risk clearly present, may have been harmed 
Severe = at least 2 X week I pronounced risk, actual harm or hiqh probability of harm 

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17. (E3) Hypervigilance 
In the past week, have you been especially alert or watchful, even when there was no 
specific threat or danger? (Have you felt as if you had to be on guard?) 
Can you give me some examples? (\Mlat kinds of things do you do when you're alert or 
watchful?) 
[If not clear: I (What causes you to react this way? Do you fee/like you're in 
danger or threatened in some way? Do you feel that way more than most 
people would in the same situation?) 
Circle: Hypervigilance = Minimal 
Clearly Present 
Pronounced 
Extreme 
How much of the time in the past week have you felt that way, as a percentage? 
% of time ___ 
_ 
Did being especially alert or watchful start or get worse after (EVENT)? (Do you think 
it's related to {EVENT]? How so?) Circle: Trauma-relatedness = Definite 
Probable 
Unlikely 
Key rating dimensions =frequency I Intensity of hypeNigilance 
Moderate= some of the time (20-30%) I hypervigilance clearly present, e.g., watchful in public, heightened 
awareness of threat 
Severe = much of the time (50-60%) I pronounced hypervigilance, e.g., scans environment for danger, may have 
safety rituals, exaggerated concern for safety of self/family/home 
18. (E4) Exaggerated startle response. 
In the past week, have you had any 
reactions? 
What kinds of things made you startle? 
How strong are these startle reactions? (How strong are they compared to how most 
people would respond? Do you do anything other people would notice?) 
How long does it take you to recover? 
Circle: Startle = Minimal 
Clearly Present 
Pronounced 
Extreme 
How often has this happened in the past week? 
#of times ___ 
_ 
Did these startle reactions start or get worse after (EVENT)? (Do you think they're 
related to [EVENT]? How so?) Circle: Trauma-relatedness = Definite 
Probable 
Unlikely 
Key rating dimensions =frequency I intensity of startle 
Moderate = at least 1 X week I startle clearly present, some difficulty recovering 
Severe= at least 2 X week I pronounced startle, sustained arousal, considerable difficulty recovering 
CAPS-5 Page 11 
0 Absent 
1 Mild I subthreshold 
2 Modernte I threshold 
3 Severe I markedly elevated 
4 Extreme I incapacitating 
0 Absent 
1 Mild I subthreshold 
2 Moderate I threshold 
3 Severe I m arkedly elevated 
4 Extreme I incapacitating 

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19. (E5) Problems with concentration. 
In the past week, have you had any problems with concentration? 
Can you give me some examples? 
Are you able to concentrate if you really try? 
[If not clear:) (Overall, how much of a problem is this for you? How would things 
be different if you didn't have problems with concentration?) 
Circle: Problem concentrating = Minimal 
Clearly Present 
Pronounced 
Extreme 
How much of the time in the past week have you had problems with concentration, as 
a percentage? 
%of time ___ 
_ 
Did these problems with concentration start or get worse after (EVENT)? (Do you think 
they're related to [EVENT]? How so?) Circle: Trauma-relatedness ; Deflnite 
Probable 
Unlikely 
Key rating dimensions =frequency I intensity of concentration problems 
Moderate = some of the time (20-30%) I problem concentrating clearly present, some difficulty but can concentrate 
with effort 
Severe= much of the time (50-60%) I pronounced problem concentrating, considerable difficulty even with effort 
20. (E6) Sleep disturbance (e.g., difficulty falling or staying asleep or restless sleep). 
In the past week, have you had any problems falling or staying asleep? 
What kinds of problems? (How long does it take you to fall asleep? How often do you 
wake up in the night? Do you wake up earlier than you want to?) 
How many total hours do you sleep each night? 
How many hours do you think you should be sleeping? 
Circle: Problem sleeping = Minimal 
Clearly Present 
Pronounced 
Extreme 
How often in the past week have you had these sleep problems? 
#of times ___ 
_ 
Did these sleep problems start or get worse after (EVENT)? (Do you think they're related 
to [E VE N T] ? How so?) Circle: Trauma-relatedness = Definite 
Probable 
Unlikely 
Key rating dimensions =frequency I intensity of sleep problems 
Moderate = at least 1 X week I sleep disturbance clearly present, clearly longer latency or clear difficulty staying 
asleep, 30-90 minutes loss of sleep 
Severe = at least 2 X week I pronounced sleep disturbance, considerably longer latency or marked difficulty staying 
asleep, 90 min to 3 hrs loss of sleep 
CAPS-5 Page 12 
0 Absent 
1 Mild I subthreshold 
2 Modernte I threshold 
3 Severe I markedly elevated 
4 Extreme I incapacitating 
0 Absent 
1 Mild I subthreshold 
2 Modemte I threshold 
3 Severe I m arkedly elevated 
4 Extreme I incapacitating 

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CAPS-5 Page 13 
Criterion F: Duration of the disturbance (Criteria B, C, D, and E) is more than 1 month. 
NOTE: Items 21 and 22 are not applicable for the PAST WEEK version. They are listed here without prompts only 
to maintain correspondence with item numbering on the PAST MONTH version. Onset and duration of symptoms 
should be assessed with 
21 Onset of symptoms 
22. Duration of symptoms 
Criterion G: The disturbance causes clinically significant distress or impairment in social, occupational, or other 
important areas of functioning. 
23. Subjective distress 
Overall, in the past week, how much have you been bothered 
by these (PTSD SYMPTOMS) you've told me about? [Consider 
distress reported on earlier items] 
24. Impairment in social functioning 
In the past week, have these (PTSD SYMPTOMS) affected 
your relationships with other people? How so? [Consider 
impairment in social functioning reported on earlier items] 
25. Impairment in occupational or other important area of functioning 
[If not clear:[ Are you working now? 
[If yes:] In the past week, have these (PTSD SYMPTOMS) 
affected your work or your ability to work? How so? 
[If no:] Why is that? (Do you feel that your [PTSD 
SYMPTOMS] are related to you not working now? How so?) 
[If unable to work because of PTSD symptoms, rate at least 3=Severe. If 
unemployment is not due to PTSD symptoms, or if the link is not clear, base 
rating only on impairment in other important areas of functioning] 
Have these (PTSD SYMPTOMS) affected any other 
important part of your life? [As appropriate, suggest examples such 
as parenting, housework, schoolwork, volunteer work, etc.] How so? 
None 
Mild, minimal distress 
Moderate? distress clearly present but still manageable 
Severe, considerable distress 
Extreme, Incapacitating distress 
No adverse impact 
Mild impact, minima/Impairment In social functioning 
Moderate Impact, definite Impairment but many 
aspects of social functioning s till intact 
Severe impact, marked impainnent, few aspects of 
social functioning still intact 
Extreme impact, little or no social functioning 
No adverse impact 
Mild impact, minimal impainnent in occupational/other 
important functioning 
Moderate impact, definite impairment but many 
aspects of occupational/other Important functioning 
still intact 
Severe impact, marked impairment, few aspects of 
occupational/other important functioning still intact 
Extreme impact, little or no occupational/other 
important functioning 

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Global Ratings 
26. Global validity 
Estimate the overall validity of responses. Consider factors such 
as compliance with the interview, mental status (e.g., problems 
with concentration, comprehension of items, dissociation), and 
evidence of efforts to exaggerate or minimize symptoms. 
27. Global severity 
Estimate the overall severity of PTSD symptoms. Consider 
degree of subjective distress, degree of functional impairment, 
observations of behaviors in interview, and judgment regarding 
reporting style. 
28. Global improvement 
Rate total overall improvement since the previous rating Rate 
the degree of change, whether or not, in your judgment, it is due 
to treatment 
CAPS-5 Page 14 
Excellent, no reason to suspect invalid responses 
Good, factors present that may adversely affect 
validity 
Fair, factors present that definitely reduce validity 
Poor. substantially reduced validity 
Invalid responses, severely impaired mental status or 
possible deliberate "faking bad" or "faking good'' 
No clinically significant symptoms, no distress and no 
functional impairment 
Mild, minimal distress or functional impalnnent 
Moderate, definite dis tress or functional impairment 
but functions satisfactorily with effort 
Severe, considerable distress or functional 
impainnent, limited functioning even with effort 
Extreme, marked distress or marked impairment in two 
or more major areas of functioning 
Asymptomatic 
Considerable improvement 
Moderate improvement 
Slight improvement 
No improvement 
Insufficient lnfonnation 

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CAPS-5 Page 15 
Specify whether with dissociative symptoms: The individual's symptoms meet the criteria for posttraumatic stress 
disorder, and in addition, in response to the stressor, the individual experiences persistent or recurrent symptoms 
of either of the following: 
29. (1 ) Depersonalization: Persistent or recurrent experiences of feeling detached from, and as if one were an outside 
observer of, one's mental processes or body (e.g., feeling as though one were in a dream; feeling a sense of unreality of 
self or body or of time moving slowly). 
In the past week, have there been times when you felt as if you were separated from 
yourself, like you were watching yourself from the outside or observing your thoughts 
and feelings as if you were another person? 
[If no:] (What about feeling as if you were in a dream, even though you were 
awake? Feeling as if something about you wasn't real? Feeling as if time was 
moving more slowly?) 
Tell me more about that. 
How strong is this feeling? (Do you lose track of where you actually are or what's actually 
going on?) 
What do you do while this is happening? (Do other people notice your behavior? What 
do they say?) 
How long does it last? 
Dissociation = Minimal 
Clearly Present 
Pronounced 
Extreme 
[If not clear: I (Was this due to the effects of alcohol or drugs? What about a 
medical condition like seizures?) [Rate O=Absent if due to the effects of a substance or 
another medical condition] 
How often has this happened in the past week? 
# of times ___ _ 
Did this feeling start or get worse after (EVENT)? (Do you think it's related to [EVENT]? 
How so?) Circle: Trauma-relatedness = Definite 
Probable 
Unlikely 
Key rating dimensions =frequency I Intensity of dissociation 
Moderate = at least 1 X week I dissociative quality clearly present but transient, retains some realistic sense of self 
and awareness of environment 
Severe = at least 2 X week I pronounced dissociative quality, marked sense of detachment and unreality 
0 Absent 
1 Mild I subthreshold 
2 Moderate I threshold 
3 Severe I m arkedly elevated 
4 Extreme I incapacitating 

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CAPS-5 Page 16 
30. (2) Derealization: Persistent or recurrent experiences of unreality of surroundings (e.g., the world around the individual 
is experienced as unreal, dreamlike, distant, or distorted). 
In the past week, have there been times when things going on around you seemed 
unreal or very strange and unfamiliar? 
[If no:] (Do things going on around you seem like a dream or like a scene from a 
movie? Do they seem distant or distorted?) 
Tell me more about that. 
How strong is this feeling? (Do you lose track of where you actually are or what's actually 
going on?) 
What do you do while this is happening? (Do other people notice your behavior? What 
do they say?) 
How long does it last? 
Circle: Dissociation = Minimal 
Clearly Present 
Pronounced 
Extreme 
[If not clear:[ (Was this due to the effects of alcohol or drugs? What about a 
medical condition like seizures?) [Rate O=Absent if due to the effects of a substance or 
another medical condition] 
How often has this happened in the past week? 
# of times ___ 
_ 
Did this feeling start or get worse after (EVENT)? (Do you think it's related to [EVENT)? 
How so?) Circle: Trauma-relatedness = Definite 
Probable 
Unlikely 
Key rating dimensions =frequency I Intensity of dissociation 
Moderate = at least 1 X week I dissociative quality clearly present but transient, retains some realistic sense of 
environment 
Severe= at least 2 X week I pronounced dissociative quality, marked sense of unreality 
0 Absent 
1 Mild I subthreshold 
2 Moderate I threshold 
3 Severe I markedly elevated 
4 Extreme I Incapacitating 

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CAPS-5 Page 17 
CAPS-5 SUMMARY SHEET 
Name: _______ ID#: ____ Interviewer: _______ Study: _____ Date: __ 
_ 
A. Exposure to actual or threatened death, serious injury, or sexual violence 
Criterion A met? 
0= NO 
1 =YES 
B. Intrusion symptoms (need 1 for diagnosis) 
Past Week 
Sev 
Sx (Sev > 2)? 
(1) 81 -Intrusive memories 
0= NO 
1 =YES 
(2) 82- Distressing dreams 
0= NO 
1 =YES 
(3) 83 - Dissociative reactions 
0= NO 
1 =YES 
(4) 84- Cued psychological distress 
0= NO 
1 =YES 
(5) 85- Cued physiological reactions 
0= NO 
1 =YES 
B subtotals BSev= 
#BSx= 
C. Avoidance symptoms {need 1 for diagnosis) 
Past Week 
Sev 
Sx(Sev_::2)? 
(6) C1 -Avoidance of memories, thoughts, feelings 
0= NO 
1 =YES 
(7) C2- Avoidance of external reminders 
0= NO 
1 =YES 
C subtotals CSev= 
#CSx= 
D. Cognitions and mood symptoms (need 2 for diagnosis) 
Past Week 
Sev 
Sx(Sev_::2)? 
(8) 01 - Inability to recall important aspect of event 
0= NO 
1 =YES 
(9) 02- Exaggerated negative beliefs or expectations 
0= NO 
1 =YES 
(1 0) D3- Distorted cognitions leading to blame 
0= NO 
1 =YES 
(11) D4- Persistent negative emotional state 
0= NO 
1 =YES 
(12) D5- Diminished interest or participation in activities 
0= NO 
1 =YES 
(13) D6- Detachment or estrangement from others 
0= NO 
1 =YES 
(14) D7- Persistent inability to experience positive emotions 
0= NO 
1 =YES 
D subtotals DSev= 
#DSx= 
E. Arousal and reactivity symptoms {need 2 for diagnosis) 
Past Week 
Sev 
Sx (Sev > 2)? 
(15) E1 -Irritable behavior and angry outbursts 
0= NO 
1 =YES 
(16) E2- Reckless or self-destructive behavior 
0= NO 
1 =YES 
(17) E3- Hypervigilance 
0= NO 
1 =YES 
(18) E4- Exaggerated startle response 
0= NO 
1 =YES 
(19) E5- Problems with concentration 
0= NO 
1 =YES 
(20) E6- Sleep disturbance 
0= NO 
1 =YES 
E subtotals ESev= 
#ESx= 

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CAPS-5 Page 18 
PTSDtotals 
Past Week 
TotaiSev 
I 
Totai#Sx 
Sum of subtotals (B+C+D+E) 
I 
F. Duration of disturbance 
Current 
(22) 
NOT APPLICABLE 
G. Distress or impairment (need 1 for diagnosis) 
Past Week 
Sev 
Cx (Sev > 2)? 
(23) Subjective distress 
0= NO 
1 =YES 
(24) Impairment in social functioning 
0= NO 
1 =YES 
(25) Impairment in occupational functioning 
0= NO 
1 =YES 
G subtotals GSev= 
#GCx= 
Global ratings 
Past Week 
(26) Global validity 
(27) Global severity 
(28) Global improvement 
Dissociative symptoms (need 1 for subtype) 
Past Week 
Sev 
Sx (Sev > 2)? 
(29) 1 - Depersonalization 
0= NO 
1 =YES 
(30) 2- Derealization 
0= NO 
1 =YES 
Dissociative subtotals Diss Sev= 
#Diss Sx= 

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Appendix 7
Symptoms of Trauma Scale (SOTS)
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1. Re-experiencing 
Chapter 3 
Items, Definitions, and Anchoring Points 
Symptoms of Trauma Scale (SOTS) 
Past Week:__ (If not the past week, specify time frame) 
Lifetime: present or absent (circle one) 
Definition: Involuntary intrusion into present consciousness of memories or memory fragments 
(flashbacks) of past trauma; nightmares, intrusive memories, or feeling that one is reliving the traumatic 
experience. 
1-Absent 
Definition does not apply. 
2-Minimal 
Questionable pathology; may be at the upper extreme of normal limits. 
3-Mild 
Infrequent (twice or less/week) re-experiencing without significant psychological distress 
or physiological reactivity. Does not cause any interference in day-to-day 
functioning. 
4-Moderate 
Either (a) frequent (more than twice a week) re-experiencing without significant 
psychological distress or physiological reactivity or interference in daily activities 
and the person is able to cope/manage successfully; or (b) infrequent (twice or 
less/week) re-experiencing with significant psychological distress or physiological 
reactivity that cause some interference with day-to-day functioning but the person 
is able to cope/manage successfully. 
5-Moderate/ 
Frequent re-experiencing cause distinct 
Severe 
interference with day-to-day functioning and/or sometimes exceed the persons ability to 
cope/manage. 
6-Severe 
Frequent re-experiencing cause severe interference with day to day functioning 
and/or often exceed ability to cope/manage, but do not lead to a life-threatening 
situation to self or others 
7 -Extreme 
Frequent re-experiencing cause complete interference with day-to-day functioning and/or 
completely override ability to cope/manage and/or lead to a life-threatening 
situation to self or others 

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2. Hyperarousal 
Past Week: 
(If not the past week, specify time frame) 
Lifetime: present or absent (circle one) 
Definition Hyperarousal, hypervigilance, increased reactivity or exaggerated startle response. 
1-Absent 
Definition does not apply 
2-Minimal 
Questionable pathology; may be at the upper extreme of normal limits. 
3-Mild 
Infrequent (twice or less/week) hyperarousal, without significant psychological distress or 
physiological reactivity. Does not cause any interference in day-to-day 
functioning. 
4-Moderate 
Either (a) frequent (more than twice a week) hyperarousal without significant 
psychological distress or physiological reactivity or interference in daily activities 
and the person is able to cope/manage successfully; or (b) infrequent (twice or 
less/week) hyperarousal with significant psychological distress or physiological 
reactivity that cause some interference with day-to-day functioning but the person 
is able to cope/manage successfully 
5-Moderate/ 
Frequent hyperarousal causes distinct interference 
Severe 
with day-to-day functioning and/or sometimes exceeds the persons ability to cope/manage. 
6-Severe 
Frequent hyperarousal causes severe interference with day to day functioning 
and/or often exceeds ability to cope/manage, but does not lead to a life-
threatening situation to self or others 
7 -Extreme 
Frequent hyperarousal causes complete interference with day-to-day functioning and/or 
completely overrides ability to cope/manage and/or leads to a life-threatening 
situation to self or others 

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3. Affective Dysregulation 
Past Week: __ (If not the past week, specify time frame) 
Lifetime: present or absent (circle one) 
Definition: Emotions are experienced as overwhelming, too changeable, ego dystonic, or too extreme to 
be tolerable (Does not include episodes that qualify for DSM bipolar disorder manic episodes). 
1-Absent 
Definition does not apply 
2-Minimal 
Questionable pathology; may be at the upper extreme of normal limits. 
3-Mild 
Infrequent (twice or less/week) affective dysregulation, without significant psychological 
distress or physiological reactivity. Does not cause any interference in day-to-day 
functioning. 
4-Moderate 
Either (a) frequent (more than twice a week) affective dysregulation without significant 
psychological distress or physiological reactivity or interference in daily activities 
and the person is able to cope/manage successfully; or (b) infrequent (twice or 
less/week) affective dysregulation with significant psychological distress or 
physiological reactivity that cause some interference with day-to-day functioning 
but the person is able to cope/manage successfully. 
5-Moderate/ 
Frequent affective dysregulation causes distinct 
Severe 
interference with day-to-day functioning and/or sometimes exceeds the persons ability to 
cope/manage. 
6-Severe 
Frequent affective dysregulation causes severe interference with day to day 
functioning and/or often exceeds ability to cope/manage, but does not lead to a 
life-threatening situation to self or others. 
7 -Extreme 
Frequent affective dysregulation causes complete interference with day-to-day functioning 
and/or completely overrides ability to cope/manage and/or leads to a life-
threatening situation to self or others 

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4. Impulsivity 
Past Week: 
(If not the past week, specify time frame) 
Lifetime: present or absent (circle one) 
Definition Inability to regulate, control or manage intense affect that becomes apparent in verbalizing or 
acting out feelings impulsively, or in potentially dangerous ways (such as self-injury, 
aggression!assaultiveness, or behaviors that are high-risk or addictive). 
1-Absent 
Definition does not apply 
2-Minimal 
Questionable pathology; may be at the upper extreme of normal limits. 
3-Mild 
Infrequent (twice or less/week) impulsive behavior, without significant psychological 
distress or physiological reactivity. Does not cause any interference in day-to-day 
functioning. 
4-Moderate 
Either (a) frequent (more than twice a week) impulsive behavior without significant 
psychological distress or physiological reactivity or interference in daily activities 
and the person is able to cope/manage successfully; or (b) infrequent (twice or 
less/week) impulsive behavior with significant psychological distress or 
physiological reactivity that cause some interference with day-to-day functioning 
but the person is able to cope/manage successfully. 
5-Moderate/ 
Frequent impulsive behavior causes distinct 
Severe 
interference with day-to-day functioning and/or sometimes exceeds the persons ability to 
cope/manage. 
6-Severe 
Frequent impulsive behavior causes severe interference with day to day 
functioning and/or often exceeds ability to cope/manage, but does not lead to a 
life-threatening situation to self or others 
7 -Extreme 
Frequent impulsive behavior causes complete interference with day-to-day functioning 
and/or completely overrides ability to cope/manage and/or leads to a life-
threatening situation to self or others 

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5. Avoidance 
Past Week: 
(If not the past week, specify time frame) 
Note: If also assessing lifetime, circle present or absent below 
Lifetime: present or absent (circle one) 
Definition: Avoiding people, places, things, activities, thoughts or conversations related to trauma. 
1-Absent 
Definition does not apply 
2-Minimal 
Questionable pathology; may be at the upper extreme of normal limits. 
3-Mild 
Infrequent (twice or less/week) avoidance, without significant psychological distress or 
physiological reactivity Does not cause any interference in day-to-day 
functioning. 
4-Moderate 
Either (a) frequent (more than twice a week) avoidance without significant psychological 
distress or physiological reactivity or interference in daily activities and the person 
is able to cope/manage successfully; or (b) infrequent (twice or lessJINeek) 
avoidance with significant psychological distress or physiological reactivity that 
cause some interference with day-to-day functioning but the person is able to 
cope/manage successfully. 
5-Moderate/ 
Frequent avoidance causes distinct interference 
Severe 
with day-to-day functioning and/or sometimes exceeds the persons ability to cope/manage. 
6-Severe 
Frequent avoidance causes severe interference with day to day functioning 
and/or often exceeds ability to cope/manage, but does not lead to a life-
threatening situation to self or others 
7 -Extreme 
Frequent avoidance causes complete interference with day-to-day functioning and/or 
completely overrides ability to cope/manage and/or leads to a life-threatening 
situation to self or others. 

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6. Numbing 
Past Week: 
(If not the past week, specify time frame) 
Lifetime: present or absent (circle one) 
Definition Inability or decreased ability to experience a full range of feelings. 
1-Absent 
Definition does not apply 
2-Minimal 
Questionable pathology; may be at the upper extreme of normal limits. 
3-Mild 
Infrequent (twice or less/week) numbing, without significant psychological distress or 
physiological reactivity. Does not cause any interference in day-to-day 
functioning. 
4-Moderate 
Either (a) frequent (more than twice a week) numbing without significant psychological 
distress or physiological reactivity or interference in daily activities and the person 
is able to cope/manage successfully; or (b) infrequent (twice or lessfvveek) 
numbing with significant psychological distress or physiological reactivity that 
cause some interference with day-to-day functioning but the person is able to 
cope/manage successfully. 
5-Moderate/ 
Frequent numbing causes distinct interference 
Severe 
with day-to-day functioning and/or sometimes exceeds the persons ability to cope/manage. 
6-Severe 
Frequent numbing causes severe interference with day to day functioning and/or 
often exceeds ability to cope/manage, but does not lead to a life-threatening 
situation to self or others 
?-Extreme 
Frequent numbing causes complete interference with day-to-day functioning and/or 
completely overrides ability to cope/manage and/or leads to a life-threatening 
situation to self or others 

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7. Attention/Consciousness/Dissociation 
Past Week: __ (If not the past week, specify time frame) 
Lifetime: present or absent (circle one) 
Definition: §l2.!l1 in present consciousness or partial unawareness/blocking out from present 
consciousness: depersonalization, derealization, periods of 'losing time' (amnesia, fugue, shifting into 
different identities/personalities without awareness). 
1-Absent 
Definition does not apply 
2-Minimal 
Questionable pathology; may be at the upper extreme of normal limits. 
3-Mild 
Infrequent (twice or less/week) dissociation, without significant psychological distress or 
physiological reactivity. Does not cause any interference in day-to-day 
functioning. 
4-Moderate 
Either (a) frequent (more than twice a week) dissociation without significant psychological 
distress or physiological reactivity or interference in daily activities and the person 
is able to cope/manage successfully; or (b) infrequent (twice or lessf.Neek) 
dissociation with significant psychological distress or physiological reactivity that 
cause some interference with day-to-day functioning but the person is able to 
cope/manage successfully. 
5-Moderate/ 
Frequent dissociation causes distinct interference 
Severe 
with day-to-day functioning and/or sometimes exceeds the persons ability to cope/manage. 
6-Severe 
Frequent dissociation causes severe interference with day to day functioning 
and/or often exceeds ability to cope/manage, but does not lead to a life-
threatening situation to self or others 
7 -Extreme 
Frequent dissociation causes complete interference with day-to-day functioning and/or 
completely overrides ability to cope/manage and/or leads to a life-threatening 
situation to self or others 

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8. Self Perception 
Past Week: __ (If not the past week, specify time frame) 
Lifetime: present or absent (circle one) 
Definition: Feeling damaged, ashamed, guilty or blaming self for past trauma Can be angry at self for 
lack of ability to stop traumatic event 
1-Absent 
Definition does not apply 
2-Minimal 
Questionable pathology; may be at the upper extreme of normal limits. 
3-Mild 
Infrequently (twice or less/week) feeling damaged, ashamed, guilty or blaming self for 
past trauma without significant psychological distress or physiological reactivity. 
Does not cause any interference in day-to-day functioning. 
4-Moderate 
Either (a) frequently (more than twice a week) feeling damaged, ashamed, guilty or 
blaming self for past trauma without significant psychological distress or 
physiological reactivity or interference in daily activities and the person is able to 
cope/manage successfully; or (b) infrequently (twice or less/week) feeling 
damaged, ashamed, guilty or blaming self for past trauma with significant 
psychological distress or physiological reactivity that cause some interference 
with day-to-day functioning but the person is able to cope/manage successfully. 
5-Moderate/ 
Frequently feeling damaged, ashamed, guilty 
Severe 
or blaming self for past trauma causes distinct interference with day-to-day functioning 
and/or sometimes exceeds the persons ability to cope/manage. 
6-Severe 
Frequently feeling damaged, ashamed, guilty or blaming self for past trauma 
causes severe interference with day to day functioning and/or often exceeds 
ability to cope/manage, but does not lead to a life-threatening situation to self or 
others 
7 -Extreme 
Frequently feeling damaged, ashamed, guilty or blaming self for past trauma causes 
complete interference with day-to-day functioning and/or completely overrides 
ability to cope/manage and/or leads to a life-threatening situation to self or others. 

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9. Interpersonal Relations 
Past Week: __ (If not the past week, specify time frame) 
Lifetime: present or absent (circle one) 
Definition: Lack of trust in other people and/or problems with relating and boundaries. Relationships are 
intense, enmeshed, intrusive and/or unstable, or the person is isolated and/or disconnected from others. 
1-Absent 
Definition does not apply 
2-Minimal 
Questionable pathology; may be at the upper extreme of normal limits. 
3-Mild 
Infrequent (twice or less/week) lack of trust in other people and/or problems with relating 
and boundaries without significant psychological distress or physiological 
reactivity. Does not cause any interference in day-to-day functioning. 
4-Moderate 
Either (a) frequent (more than twice a week) lack of trust in other people and/or problems 
with relating and boundaries without significant psychological distress or 
physiological reactivity or interference in daily activities and the person is able to 
cope/manage successfully; or (b) infrequent (twice or less/week) lack of trust in 
other people and/or problems with relating and boundaries with significant 
psychological distress or physiological reactivity that cause some interference 
with day-to-day functioning but the person is able to cope/manage successfully. 
5-Moderate/ 
Frequent lack of trust in other people and/or 
Severe 
problems with relating and boundaries cause distinct interference with day-to-day 
functioning and/or sometimes exceed the persons ability to cope/manage. 
6-Severe 
Frequent lack of trust in other people and/or problems with relating and 
boundaries cause severe interference with day to day functioning and/or often 
exceed ability to cope/manage, but do not lead to a life-threatening situation to 
self or others 
7-Extreme 
Frequent lack of trust in other people and/or problems with relating and boundaries cause 
complete interference with day-to-day functioning and/or completely override 
ability to cope/manage and/or lead to a life-threatening situation to self or others. 

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10. Alterations in Sexual Relations/Behaviors 
Past Week: __ (If not the past week, specify time frame) 
Lifetime: present or absent (circle one) 
Definition: Changes in sexual thoughts, feelings, behaviors or relations, including hypersexuality (sex 
addiction, promiscuity, sexually high risk behaviors) or extreme disinterest in sexuality or absence of 
sexual feelings and/or avoidance of sexuality/physical touch. 
1-Absent 
Definition does not apply 
2-Minimal 
Questionable pathology; may be at the upper extreme of normal limits. 
3-Mild 
Infrequent (twice or less/week) alterations in sexual relations/behaviors without significant 
psychological distress or physiological reactivity. Does not cause any 
interference in day-to-day functioning. 
4-Moderate 
Either (a) frequent (more than twice a week) alterations in sexual relations/behaviors 
without significant psychological distress or physiological reactivity or interference 
in daily activities and the person is able to cope/manage successfully; or (b) 
infrequent (twice or less/week) alterations in sexual relations/behaviors with 
significant psychological distress or physiological reactivity that cause some 
interference with day-to-day functioning but the person is able to cope/manage 
successfully. 
5-Moderate/ 
Frequent alterations in sexual relations/behaviors 
Severe 
cause distinct interference with day-to-day functioning and/or sometimes exceed the 
persons ability to cope/manage. 
6-Severe 
Frequent alterations in sexual relations/behaviors cause severe interference with 
day to day functioning and/or often exceed ability to cope/manage, but do not 
lead to a life-threatening situation to self or others 
?-Extreme 
Frequent alterations in sexual relations/behaviors cause complete interference with day-
to-day functioning and/or completely override ability to cope/manage and/or lead 
to a life-threatening situation to self or others. 

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11. Sustaining Beliefs 
Past Week:__ (If not the past week, specify time frame) 
Lifetime: present or absent (circle one) 
Definition: Loss of faith, meaning or sustaining beliefs, and/or feeling purposeless. 
1-Absent 
Definition does not apply 
2-Minimal 
Questionable pathology; may be at the upper extreme of normal limits. 
3-Mild 
Infrequent (twice or less/week) loss of faith, meaning or sustaining beliefs without 
significant psychological distress or physiological reactivity Does not cause any 
interference in day-to-day functioning. 
4-Moderate 
Either (a) frequent (more than twice a week) loss of faith, meaning or sustaining beliefs 
without significant psychological distress or physiological reactivity or interference 
in daily activities and the person is able to cope/manage successfully; or (b) 
infrequent (twice or less/Week) loss of faith, meaning or sustaining beliefs with 
significant psychological distress or physiological reactivity that cause some 
interference with day-to-day functioning but the person is able to cope/manage 
successfully. 
5-Moderate/ 
Frequent loss of faith, meaning or sustaining 
Severe 
beliefs cause distinct interference with day-to-day functioning and/or sometimes exceed 
the persons ability to cope/manage. 
6-Severe 
Frequent loss of faith, meaning or sustaining beliefs cause severe interference 
with day to day functioning and/or often exceed ability to cope/manage, but do not 
lead to a life-threatening situation to self or others 
?-Extreme 
Frequent loss of faith, meaning or sustaining beliefs cause complete interference with 
day-to-day functioning and/or completely override ability to cope/manage and/or 
lead to a life-threatening situation to self or others. 

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12. Somatic Dysregulation 
Past Week:__ (If not the past week, specify time frame) 
Lifetime: present or absent (circle one) 
Definition: Physical health problems that are more extensive or severe than can be attributed to a 
physical illness or medical condition or that are exacerbated more than expected by current stressors. For 
example, extreme bodily pain or fatigue, or severe Gl, respiratory, cardiovascular, genito-urinary, 
inflammatory, or auto-immune health problems. 
1-Absent 
Definition does not apply 
2-Minimal 
Questionable pathology; may be at the upper extreme of normal limits. 
3-Mild 
Infrequent (twice or less/week) somatic dysregulation without significant psychological 
distress or physiological reactivity. Does not cause any interference in day-to-day 
functioning. 
4-Moderate 
Either (a) frequent (more than twice a week) somatic dysregulation without significant 
psychological distress or physiological reactivity or interference in daily activities 
and the person is able to cope/manage successfully; or (b) infrequent (twice or 
less/week) somatic dysregulation with significant psychological distress or 
physiological reactivity that cause some interference with day-to-day functioning 
but the person is able to cope/manage successfully. 
5-Moderate 
Frequent somatic dysregulation causes distinct 
Severe 
interference with day-to-day functioning and/or sometimes exceeds the persons ability to 
cope/manage. 
6-Severe 
Frequent somatic dysregulation causes severe interference with day to day 
functioning and/or often exceeds ability to cope/manage, but does not lead to a 
life-threatening situation to self or others 
7 -Extreme 
Frequent somatic dysregulation causes complete interference with day-to-day functioning 
and/or completely overrides ability to cope/manage and/or leads to a life-
threatening situation to self or others. 

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13. Data on Symptoms in General 
13:1) When did symptoms in general first begin? _____ _ 
13:2) When were these symptoms at their worst? 
13:3) How does this compare to the past week? 
_
worse 
_same 
_better 
13:4) What kinds of circumstances increase the intensity of these symptoms? 
13:5) Does the severity fluctuate with everyday stressors not related to the trauma? 
13:6) Does the severity of your symptoms fluctuate with mood changes not related to everyday stressors? 
13:7) Of the symptoms we discussed, which ones have been most disabling? 
13:8) How about during the past week? ________ _ 

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Chapter 4 
Structured Clinical Interview 
for the Symptoms of Trauma Scale (SCI-SOTS) 
Instructions to interviewer: 
The SCI-SOTS is teing administered to assess the presence and severity of trauma symptoms. The SCI-
SOTS should be administered after you have had a chance to familiarize yourself with a previously 
obtained trauma history. The SCI-SOTS asks about symptom severity in the previous week as well as 
anytime in the past The questions below can be asked as written, if appropriate, but most of the time 
should be paraphrased to be syntonic with the setting and people being interviewed. The order of the 
questions can also be modified as long as all infonmation on every question is obtained. You may 
incorporate the patienfs specific trauma in place of the genelic wording "traumatic experience/s." 
While the interview does not revisit the traumatic event(s), if the interviewee feels lhat he/she needs to 
share some information about his/her traumatic experience/(s), use clinical judgment as regards the pros 
and cons. 
Throughout the administration of the interview it is extremely important to respect the subjecf s sensibilities 
and boundaries and maintain an empathic stance. If the person declines to answer a question when you 
first ask, you may want to ask if you could revisit that question later. 
Start the interview by saying the following: 
"He/lo ... my name is 
and I'm going to be asking you questions about some symptoms 
that you may have experienced or are experiencing currently. The symptoms 111 be asking you 
about are related to traumatic experiences that you may have experienced in the past. I will not be 
asking you details about your trauma history, but rather about how it has affected you. However, if 
you feel that you need to share some information about your history in order to answer a question, 
that's fine. 
I will be asxing about a tot of symptoms, but if it feels that 1 am moving too quickly, please let me 
know. Also, if some of the questions stir up difficult feelings let me know when you are feeling 
uncomfortable or having a hard time. 
I want to better understand how each symptom affects you, so I have to ask similar questions 
about each symptom, whiciJ might feel repetitive at times. If any of the words I use or questions I 
ask are unclear, please ask me to explain. If at any time during the interview you feel 
uncomfortable, please Jet me know. By the way, I may make some notes during the interview. Do 
you have any questions tor me before we begin?' 
Item 1: Data on Reexperiencing 
Definition: Involuntary intrusion into present consciousness of memories or memory fragments 
(ftashbacks) of pasl trauma; nightmares, intrusive memories, or feeling that one is reliving the traumatic 
experience. 
1:1) Do you sometines feel that you are reliving a past traumatic experience, or h3ve intrusive memolies, 
ftashbacks, or nightmares related to trauma in the past? 
1.2) How about in the past week? 
1 :3) How did this affect you? Emotionally? Physically? (Instruction to interviewer: Probe for emotional 
symptoms (e.g. feeling afraid, sad, upset or angry) and physical symptoms (e.g. s1aking, sweating, heart 

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racing) 
1:4) In the past week how often has this occurred? 
1:5) Has this (reliving a past traumatic experience or intrusive memories or ftashbacks or nightmares) ever 
interfered with your daily activities or your ability to function? 
1 :6) In what way has this interfered with your daily activities or your ability to functi.on? 
1:7) How about in the past week? 
1 :8) When an unwanted memory or distressing reminder causes you to relive the past trauma, what has 
helped you cope? 
(Instruction to interviewer: Probe for the following coping mechanisms/techniques: remembering that 
the trauma is not happening now; calming body and emotions; making a practical plan that helps the 
subject feel in control, safe, and hopeful.) 
1 :9) How about in the past week? 
1 :10) Has your having an unwanted memory or distressing reminder of the trauma put you or someone 
else in danger? 
(Instruction to interviewer: If yes, probe for seriousness, and, in particular, dangerousness to 
or 
others) 
1:11) Has this occurred in the past week? 
Item 2: Data on Hyperarousa I 
Definition: Hyperarousal, hypervigilance, increased reactivity or exaggerated startle response. 
2:1) Do you sometimes feel 
tense, irritable, jumpy, on guard, or easily startled? 
2:1a) If no, proceed to item 3 
2:1 b) If yes, ask "Is this related to past trauma?" (As the SOTS is NOT a self report instrument, 
the rater may disagree with subject regarding relationship of symptom to past trauma: if this is the 
case, provide a brief written explanation, e.g. on the rating foml ) 
2:2) How about in the past week? 
2:3) How did this affect you? Emotionally? Physically? 
(Instruction to interviewer:Probe for emotional symptoms (e.g. feeling afraid, sad, upset or angry) and 
physical symptoms (e.g. shaking, sweating, heart racing) 
2:4) In the past week how often has this occurred? 
2:5) Have any of these difficulttes (sometimes feel extremely tense, irritable, jumpy, on guard, or easily 
startled) ever interfered with your daily activities or your ability to function? 
2:6) In what way do they interfere with your daily activities or ability to function? 

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2:7) How about in the past week? 
2:8) When you feel extremely tense, irritable, jumpy, on guard, orr easily startled, what has helped you 
cope? 
(Instruction to interviewer: Probe for the following coping mechanisms/techniques: remembering that 
the lmuma is not happening now; calming body and emotions; making a practical plan that helps the 
subject feel in control, safe, and hopeful.) 
2:9) How about in the past week? 
2:10) Has your feeling extremely tense, irritable, jumpy, on guard!, or easily startled ever put you or 
someone else in danger? 
(Instruction to interviewer: If yes, probe for seriousness, and, in particular, dangerousness to self or 
others) 
2:11) Has this occurred in the past week? 
Item 3: Data on Affective Oysregulation 
Definition: Emotions are experienced as overwhelming, too changeable, egodystonic, or too extreme to 
be tolerable (Does not include episodes that qualify for DSM bipolar disorder manic episodes). 
3:1) Do you ever have difficulties controlling your moods? For example, because of the past trauma does 
your mood become overwhelming and out of control at times and/or do you experience mood swings 
and/or have you had intense feelings of anger, sadness, fear or rage? 
3:1a) If no, proceed to item 4 
3:1b) If yes, ask "Is this related to past trauma?" (As the SOTS is NOT a self report instrument, 
the rater may disagree with subject regarding relationship of symptom to past tmuma: if this is the 
case, provide a brief written explanation, e.g. on the rating form) 
3:2) How about in the past week? 
3:3) How did this affect you? Emotionally? Physically? 
(Instruction to interviewer:Probe for emotional symptoms (e.g. feeling afraid, sad, upset or angry) and 
physical symptoms (e.g. shakimg, sweating, heart racing) 
3:4) In the past week how often has this occurred? 
3:5) Have any of these difficulties (mood seeming out of control, experiencing mood swings, or ha\ling 
intense feelings of anger, sadness, fear or rage) ever interfered with your daily activities or your abi lily to 
function? 
3:6) In what way do they interfere with your daily activities or ability to function? 
3:7) How about in the past week? 

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3:8) When you experience mood swings, or have intense feelings of anger, sadness, fear or rage, what 
has helped you cope? 
(Instruction to inter1iewer: Probe for the following coping mechanisms/technique;: remembering that 
the trauma is not happening now; calming body and emotions; making a practical pl3n that helps the 
subject feel in 
safe. and hopeful.) 
3:9) How about in the past week? 
3:10) Have your mood swings, or intense feelings of anger, sadness. fear or rage e\'er put you or 
someone else in danger? (Instruction to interviewer: If yes, probe for seriousness. and. iA particular, 
dangerousness to se for others) 
3:11) Has this occurred in the past week? 
Item 4: Data on Impulse Control 
Definition: Inability to regulate, control or manage intense affect that becomes apparent in verbalizing or 
acting out feelings impulsively, or in potentially dangerous ways (such as self-injury, 
aggression/assaultiveness, or behaviors that are high-risk or addictive). 
4:1) As a resun of the past trauma, have you ever had trouble with controlling your impulses or risk taking 
behaviors? This may include behaviors such as drinking too much or using drugs, d·iving recklessly or 
making risky sexual c.hoices, or acting destructively, including self-destructively. 
4:1a) If no, proceed to item 5 
4:1b) If yes, ask "Is this related to past trauma?" (As the SOTS is NOT a seW report instrument, 
the rater may disagree with subject regarding relationship of symptom to past trauma: if this is the 
case, provide a brief written explanation, e.g. on the rating form) 
4:2) How about in the past week? 
4:3) How did this affect you? Emotionally? Physically? 
(Instruction to Interviewer: Probe ror emotional symptoms (e.g. reeling arra1a, saa, upset or angry) ana 
physical symptoms (e.g. shaking, sweating, heart racing) 
4:4) In the past week how often has this occurred? 
4:5) Have any of these difficulties (trouble with controlling your impulses or risk taking behaviors) ever 
interfered with your d3ily activities or your ability to function? 
4:6) In what way do they interfere with your daily activities or ability to function? 
4:7) How about in the past week? 
4:8) When you experience trouble with controlling your impulses or risk taking behaviors, what has helped 
you cope? 
(Instruction to interviewer: Probe for the following coping mechanisms/technique;: remembering that 
the trauma is not happening now; calming body and emotions; making a practical plan that helps the 
subject feel in control safe. and hopeful.) 

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4:9) How about in the past week? 
4:10) Have your trouble with controlling your impulses or risk taking behaviors, ever put you or someone 
else in danger? 
(Instruction to interviewer: If yes, probe for seriousness, and, in particular, dangerousness to self or 
others) 
4:11) Has this occurred in the past week? 
Item 5: Data on Avoidance 
Definition: Avoiding people, places, things, activities, conversations or thoughts related to trauma. 
5:1) As a resutt of past trauma have you ever found yourself avoiding certain thoughts or situations such 
as places, people, or things that remind you of the traumatic experience? 
5:1a) If no, proceed to item 6 
5:1b) If yes, ask "Is this related to past trauma?" (As the SOTS is NOT a self report instrument, 
the rater may disagree with subject regarding relationship of symptom to past trauma: if this is the 
case, provide a brief written explanation, e.g. on the rating foml) 
5:2) How about in the past week? 
5:3) How did this affect you? 
5:4) In the past week how often has this occurred? 
5:5) Have any of these difficulties (avoiding certain thoughts or situations such as places, people, or 
things) ever interfered with your daily activities or your ability to function? 
5:6) In what way do they interfere with your daily activities or ability to function? 
5:7) How about in the past week? 
5:8) When you experience avoiding certain thoughts or situations such as places, people, or things, What 
has helped you cope? 
(Instruction to interviewer: Probe for the following coping mechanismsltechmiques: remembering that 
the trauma is not happening now; calming body and emotions; making a practical plan that helps the 
subject feel in control, safe, and hopeful.) 
5:9) How about in the past week? 
5:10) Has your avoiding certain thoughts or situations such as places, people, or things ever put you or 
someone else in danger? 
(Instruction to interviewer: If yes, probe for seriousness, and, in particular, dangerousness to self or 
others) 
5:11) Has this occurred in the past week? 

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Item 6: Data on Numbing 
Definition: Inability or decreased ability to experience a full range of feelings. 
6:1) Sometimes people who lilave survived a trauma describe feeling numb or being unable to feel. Have 
you ever experienced feeling numb or thought that your feelings were blunted, .or that you had no feelings 
at all? 
6:1a) If no, proceed to item 7 
6:1b) If yes, ask "Is this related to past trauma?" (As the SOTS is NOT a self report instrument, 
the rater may disagree with subject regarding relationship of symptom to past trauma: if this is the 
case, provide a brief written explanation, e.g. on the rating foml) 
6:2) How ai>Out in the past week? 
6:3) How did this affect you? Emotionally? Physically? 
(Instruction to interviewer:Probe for emotional symptoms (e.g. feeling afraid, sad, upset or angry) and 
physical symptoms (e.g. shaking, sweating, heart racing) 
6:4) In the past week how often has this occurred? 
6:5) Have any of these difficulties (feeling numb or being unaiJie to feel ) ever imterfered with your daily 
activities or your abilrty to function? 
6:6) In what way do they interfere with your daily activities or ability to function? 
6:7) How ai>Out in the past week? 
6:8) When you experience numbness or are unable to feel, what has helped you cope? 
(Instruction to interviewer: Probe for the following coping mechanisms/techniques: remembering that 
the trauma is not happening now; calming body and emotions; making a 
plan that helps the 
subject feel in control, safe, and hopeful.) 
6:9) How ai>Out in the past week? 
6:10) Have your feelings of numbness ever put you or someone else in danger? 
(Instruction to interviewer: If yes, probe for seriousness, and, in particular, dangerousness to 
or 
others) 
6:11) Has this occurred in the past week? 
Item 7: Data on Dissociation 
in present consciousness or partial unawareness or blocking out from present 
consciousness: depersonalization, derealization, periods of 'losing time' (amnesia, fugue, shifting into 
different identities/personalities without awareness). 
7:1) Have you ever left "spaced out." or lett as though you were ·outside your body" observing your lffe as 
it happens or as though events were not real or not really happening to you? Have you lost your memory 

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for a period of time, so that you couldn't remember what you had done, or found yourself in a place without 
knowing how you got there? 
7:1a) If no, proceed to item 8 
7:11l) If yes, ask "Is this related to past trauma?" (As the SOTS is NOT a self report instrument, 
the rater may disagree with subject regarding relationship of symptom to past trauma: if this is the 
case, provide a brief written explanation, e.g. on the rating form) 
7:2) How about in the past week? 
7:3) How did this affect you? Emotionally? Physically? 
(Instruction to interviewer: Probe for emotional symptoms (e.g. feeling afraid, sad, upset or angry) and 
physical symptoms (e.g. shaking, sweating, heart racing) 
7:4) In the past week how often has this occurred? 
7:5) Have any of these difficulties (feeling "spaced out") ever interfered with your daily activities or your 
ability to function? 
7:6) In what way do they interfere with your daily activities or ability to function? 
7:7) How about in the past week? 
7:8) When you feel "spaced our. What has helped you cope? 
(Instruction to interviewer: Probe for the following coping mechanisms/techniques: remembering that 
the trauma is not happening now; calming body and emotions; making a practical plan that helps the 
subject feel in control, safe, and hopeful.) 
7:9) How about in the past week? 
7:10) Has feeling "spaced our ever put you or someone else in danger? 
(Instruction to interviewer: If yes, probe for seriousness, and, in particular, dangerousness to self or 
others) 
7:11) Has this occurred in the past week? 
Item 8: Data on Alteration in Self-Perception 
Definition: Feeling damaged, ashamed, guilfyor blaming self for past trauma. Can be angry at self for 
lack of ability to stop traumatic event. 
8:1) After a traumatic experience some people feel differently about themselves (e.g. guilty, ashamed, 
damaged or dirty, worthy of mistreatment, feeling singled out for victimization, or feeling responsible for 
What happened). Have you ever had any of these feelings? 
8:1a) If no, proceed to item 9 
8:1b) If yes, ask "Is this related to past trauma?" (As the SOTS is NOT a self report instrument, 
the rater may disagree with subject regarding relationship of symptom to past trauma: if this is the 
case, provide a brief written explanation, e.g. on the rating form) 

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8:2) How about in the past week? 
8:3) How did this affect you? Emotionally? Physically? 
(Instruction to interviewer: Probe for emotional symptoms (e.g. feeling afraid, sad, upset or angry) and 
physical symptoms (e.g. shaking, sweating, heart racing) 
8:4) In the past week how often has this occurred? 
8:5) Has feeling differently ever interfered with your daily activities or your ability to function? 
8:6) In what way does it interfere with your daily activities or ability to function? 
8:7) How about in the past week? 
8:8) When you experience feeling differently, what has helped you cope? 
(Instruction to interviewer: Probe for the following coping mechanisms/techniques: remembering that 
the trauma is not happening now; calming body and emotions; making a practical plan that helps the 
subject feel in control, safe, and hopeful.) 
8:9) How about in the past week? 
8:10) Have your feeling differently ever put you or someone else in danger? 
(Instruction to interviewer: If yes, probe for seriousness, and, in particular, dangerousness to self or 
others) 
8:11) Has this occurred in the past week? 
Item 9: Data on Alteration in Interpersonal Relations 
Definition: lack of trust in other people and/or problems with relating and boundaries. Relationships are 
intense, enmeshed, intrusive and/or unstable, or the person is isolated and/or disconnected from others. 
9:1) Sometimes people who've experienced a trauma have difficulties in their relationships with other 
people. For example, they may have trouble trusting or relating to others. They may have 
with 
closeness, either feeling isolated and distant from others, or getting too close too fast. They may have 
frequent conflicts, arguments or misunderstandings with others, or end relationships abruptly. Have you 
ever had any such difficulties? 
9:1a) If no, proceed to item 10 
9:1b) If yes, ask "Is this related to past trauma?" (As the SOTS is NOT a self report instrument, 
the rater may disagree with subject regarding relationship of symptom to past trauma: if this is the 
case, provide a brief written explanation, e.g. on the rating foml) 
9:2) How about in the past week? 
9:3) How did this affect you? Emotionally? Physically? 
(Instruction to interviewer: Probe for emotional symptoms (e.g. feeling afraid, sad, upset or angry) and 

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physical symptoms (e.g. shaking, sweating, heart racing) 
9:4) In the past week how often has this occurred? 
9:5) Have any of these difficulties in relationships ever interfered with your daily activities or your ability to 
function? 
9:6) In what way do they interfere with your daily activities or ability to function? 
9:7) How about in the past week? 
9:8) When you have difficulties in relationships, what has helped you cope? 
(Instruction to interviewer: Probe for the following coping mechanisms/techniques: remembering that 
the trauma is not happening now; calming body and emotions; making a practical plan that helps the 
subject feel in control, safe, and hopeful.) 
9:9) How about in the past week? 
9:10) Have those difficulties in relationships ever put you or someone else in danger? 
(Instruction to interviewer: If yes, probe for seriousness, and, in particular, dangerousness to self or 
others) 
9:11) Has this occurred in the past week? 
Item 10: Data on Alterations in Sexual Retations or Behavior 
Definition: Changes in sexual thoughts, feelings, behaviors or relations, including hypersexuality (sex 
addiction, promiscuity, sexually high risk behaviors) or extreme disinterest in sexuality or absence of 
sexual feelings and/or avoidance of sexuality/physical touch. 
10:1) Sometimes people who have experienced trauma feel distressed or disgusted by sex, or feel the 
need to avoid sexual relationships entirely. Others have difficulty negotiating their needs in a sexual 
relationship. AHematively they may feel preoccupied by or addicted to sex or not know how to handle 
sexuality within relationships. Have you ever had any of these feelings? 
10:1a) If no, proceed to 
11 
10:1b) If yes, ask "Is this related to past trauma?" (As the SOTS is NOT a self report instrument, 
the rater may disagree with subject regarding relationship of symptom to past trauma: if this is the 
case, provide a brief written explanation, e.g. on the rating fom1) 
10:2) How about in the past week? 
10:3) How did this affect you? Emotionally? Physically? 
(Instruction to interviewer: Probe for emotional symptoms (e.g. feeling afraid, sad, upset or angry) and 
physical symptoms (e.g. shaking, sweating, heart racing) 
10:4) In the past week how often has this occurred? 
10:5) Have these feelings or behaviors ever interfered with your daily activities or your ability to function? 
10:6) In what way does interfere 
your daily activities or ability to function? 

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10:7) How about in the past week? 
10:8) When YQU experience these feelings or behaviors, what ha> helped YQU cope? 
(Instruction to interviewer: Probe for the following coping mechanisms/techniques: remembering that 
the trauma is not happening now; calming body and emotions; making a practical plan that helps the 
suiJject feel in control, safe, and hopeful.) 
10:9) How about in the past week? 
10:10) Have these feelings or behaviors ever put you or someone else in danger? 
(Instruction to interviewer: If yes, probe for seriousness, and, in particular, dangerousness to self or 
others) 
10:11) Has this occurred in the· past week? 
ltem11: Data on Loss of Sustaining Beliefs 
Definition: Loss of faith, meaning or sustaining beliefs, and/or feeling purposeless. 
11:1) After experiencing a trauma some people lose faith in beliefs that used to be important to them, or 
feel that their life has no purpose or meaning. Have you ever fell like this? 
11:1a) If no, proceed to item 12 
11 :1b) If yes, ask "Is this related to past trauma?" (As the SOTS is NOT a self report instrument, 
the rater may disagree with subject regarding relationship of symptom to past trauma: if this is the 
case, provide a brief written explanation, e.g. on the ratin-g form) 
11 :2) How about in the past week? 
11:3) How did this affect you? Emotionally? Physically? (Instruction to interviewer: Probe for emotional 
symptoms (e.g. feeling afraid, sad, upset or angry) and physical symptoms (e.g. shaking, sweating, heart 
racing) 
11:4) In the past week how often has this occurred? 
11 :5) Has losing faith in beliefs or that life has no purpose ever interfered with your daily activities or your 
ability to function? 
11 :6) In what way do they interfere with your daily activities or ability to function? 
11:7) How about in the past week? 

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11 :8) When }IOU lose faith or feel that life has no purpose, what has helped you cope? 
(Instruction to interviewer: Probe for the following coping mechanisms/techniques: remembering that 
the trauma is not happening now; calming body and emotions; making a practical plan that helps the 
subject feel in control, safe, and hopeful.) 
11 :9) How about in the past week? 
11 :10) Has losing faith in beliefs or feeling that life has no purpose ever put }IOU or someone else in 
danger? 
(Instruction to interviewer: If yes, probe for seriousness, and, in particular, dangerousness to self or 
others) 
11 :11) Has this occurred in the past week? 
Item 12: Data on Bodily Manifestations of Trauma 
Definition: Physical health problems that are more extensive or severe than can be attributed to a 
physical illness or medical condition or that are exacerbated more than expected by current stressors. For 
example, extreme bodily pain or fatigue, or severe Gl, respiratory, cardiovascular, genito-urinary, 
inflammalory, or aulo-immune health problems. 
12:1) Have }IOU ever experienced any physical symptoms or illness for which no medical basis can be 
found? If so. what are your symptoms? 
12:1a) If no, proceed to Part 2: Data on Symptoms in General 
12:1b) If yes, ask •1s this related to past trauma?" (As the SOTS is NOT a self report instrument, 
the rater may disagree with subject regarding relationship of symptom to past trauma: if this is the 
case, provide a brief written explanation, e.g. on the rating foml) 
12:2) How about in the past week? 
12:3) How did this affect }IOU? Emotionally? Physically? 
(Instruction to interviewer:Probe for emotional symptoms (e.g. feeling afraid, sad, upset or angry) and 
physical symptoms (e.g. shaking, sweating, heart racing) 
12:4) In the past week how often has this occurred? 
12:5) Have those any physical symptoms ever interfered with }lOUr daily activities or }'Our ability to 
function? 
l :l:o) In wnat way oo tney lntertere w11n }lOUr oa11y actiVIties or ability to Tunct1on'! 
12:7) How about in the past week? 
12:8) When }IOU experience tllose physical symptoms, what has helped you cope? 
(Instruction to interviewer: Probe for the following coping mechanisms/techniques: remembering that 
the trauma is not happening now; calming body and emotions; making a practical plan that helps the 
subject feel in control, safe, and hopeful.) 

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12:9) How about in the past week? 
12:10) Has experiencing those physical symptoms ever put you or someore else in danger? 
(Instruction to interviewer: If yes, probe for seriousness, and, in particular, dangerousness to self or 
others) 
12:11) Has this occurred in the past week? 
Part 2: Data on Symptoms in General 
(Instruction to interviewer: Say the following to interviewee:) 
Now 1 wouta liKe ro asK you aoour rnese rrauma re1acea symptoms tn general. 
In general: 
13:1) When did these symptoms first begin? 
13:2) When were these symptoms at their worst? 
13:3) How does this compare to the past week? 
13:4) What kinds of circumstances increase the intensity of these symptoms? 
13:5) Does the severity ftuctuate with everyday stressors not related to the trauma? 
13:6) Does the severity of your symptoms fluctuate with mood changes not related to everyday stressors? 
13:7) Of the symptoms we discussed, which ones have been most disablirg? 
13:8) How about during the past week? 
(Instruction to interviewer: CONCLUDE INTERVIEW WITH A DEBRIEFING SESSION. Say the 
following to interviewee:) 
This concludes our interview. Thank you for participating. How do you feel right now? How did you 
during th@ inte-rvit;.w? Do you have any que.sUons? Is there anything you would like to talk 
about that is related ro the interview but we havenT discussed? (lf.'ndicated) Are you safe to leave 
the interview? Thank you! 

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Appendix 8
Clinical Global Impression - Severity (CGI-S)
Considering your total clinical experience with this particular population, how mentally 
ill is the patient at this time? 
0 = Not assessed
4 = Moderately ill
1 = Normal, not at all ill
5 = Markedly ill
2 = Borderline mentally ill
6 = Severely ill
3 = Mildly ill
7 = Among the most extremely ill patients
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Appendix 9
PTSD Checklist for DSM-5 (PCL-5)
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PCL-5 with Criterion A 
Instructions: This questionnaire asks about problems you may have had after a very stressful experience involving 
actual or threatened death, serious injury, or sexual violence. It could be something that happened to you directly, 
something you witnessed, or something you learned happened to a close family member or close friend. Some 
examples are a serious accident; fire; disaster such as a hurricane, tornado, or earthquake; physical or sexual attack or 
abuse; war; homicide; or suicide. 
First, please answer a few questions about your worst event, which for this questionnaire means the event that 
currently bothers you the most. This could be one of the examples above or some other very stressful experience. Also, 
it could be a single event (for example, a car crash) or multiple similar events (for example, multiple stressful events in 
a war-zone or repeated sexual abuse). 
Briefly identify the worst event (if you feel comfortable doing so): 
How long ago did it happen?-------------- (please estimate if you are not sure) 
Did it involve actual or threatened death, serious injury, or sexual violence? 
Yes 
No 
How did you experience it? 
___ It happened to me directly 
I witnessed it 
__ I learned about it happening to a close family member or close friend 
___ I was repeatedly exposed to details about it as part of my job (for example, paramedic, police, military, or other 
first responder) 
___ Other, please describe 
If the event involved the death of a close family member or close friend, was it due to some kind of accident or 
violence, or was it due to natural causes? 
Accident or violence 
Natural causes 
___ Not applicable (the event did not involve the death of a close family member or close friend) 
PCL-5 with Criterion A (14 August 2013) 
National Center for PTSD 
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Second, below is a list of problems that people sometimes have in response to a very stressful experience. Keeping 
your worst event in mind, please read each problem carefully and then circle one of the numbers to the right to 
indicate how much you have been bothered by that problem in the past month. 
In the past month, how much were you bothered by: 
Not at 
A little 
Moderately 
Quite 
Extremely 
all 
bit 
a bit 
1. Repeated, disturbing, and unwanted memories of the 
0 
1 
2 
3 
4 
stressful experience? 
2. Repeated, disturbing dreams of the stressful experience? 
0 
1 
2 
3 
4 
3. Suddenly feeling or acting as if the stressful experience were 
actually happening again (as if you were actually back there 
0 
1 
2 
3 
4 
reliving it)? 
4. Feeling very upset when something reminded you of the 
0 
1 
2 
3 
4 
stressful experience? 
5. Having strong physical reactions when something reminded 
you of the stressful experience (for example, heart 
0 
1 
2 
3 
4 
pounding, trouble breathing, sweating)? 
6. Avoiding memories, thoughts, or feelings related to the 
0 
1 
2 
3 
4 
stressful experience> 
7. Avoiding external reminders of the stressful experience (for 
example, people, places, conversations, activities, objects, or 
0 
1 
2 
3 
4 
situations)? 
8. Trouble remembering important parts of the stressful 
0 
1 
2 
3 
4 
experience? 
9. Having strong negative beliefs about yourself, other people, 
or the world (for example, having thoughts such as: I am 
0 
1 
2 
3 
4 
bad, there is something seriously wrong with me, 
no one can be trusted, the world is completely dangerous)? 
10. Blaming yourself or someone else for the stressful 
0 
1 
2 
3 
4 
experience or what happened after it? 
11 . Having strong negative feelings such as fear, horror, anger, 
0 
1 
2 
3 
4 
guilt, or shame? 
12. Loss of interest in activities that you used to enjoy? 
0 
1 
2 
3 
4 
13. Feeling distant or cut off from other people? 
0 
1 
2 
3 
4 
14. Trouble experiencing positive feelings (for example, being 
unable to feel happiness or have loving feelings for people 
0 
1 
2 
3 
4 
close to you)? 
15. Irritable behavior, angry outbursts, or acting aggressively? 
0 
1 
2 
3 
4 
16. Taking too many risks or doing things that could cause you 
0 
1 
2 
3 
4 
harm? 
17. Being "superalert" or watchful or on guard? 
0 
1 
2 
3 
4 
18. Feeling jumpy or easily startled? 
0 
1 
2 
3 
4 
19. Having difficulty concentrating? 
0 
1 
2 
3 
4 
20. Trouble falling or staying asleep? 
0 
1 
2 
3 
4 
PCL-5 with Criterion A (14 August 2013) 
National Center for PTSD 
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Appendix 10
Hospital Anxiety and Depression Scale (HADS)
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Hospital Anxiety and Depression Scale (HADS) 
Instructions: Doctors are aware that emotions play an important part in most illnesses. If your doctor knows about these 
feelings he or she will be able to help you more. This questionnaire is designed to help your doctor know how you feel. Read 
each item and circle the reply which comes closest to how you have been feeling in the past week. Don't take too long over 
your replies: your immediate reaction to each item vvill probably be more accurate than a long thought out response. 
I feel tense or 'wound up': 
A 
I feel as if I am slowed down: 
0 
Most of the time 
3 
Nearly all of the time 
3 
A lot of the time 
2 
Very often 
2 
Time to time, occasionally 
1 
Sometimes 
1 
Notal all 
0 
Notal all 
0 
I still enjoy the things I used to enjoy: 
0 
I get a sort of frightened feeling like 
A 
'butterflies in the stomach': 
Definitely as much 
0 
Not at all 
0 
Not quite so much 
Occasionally 
Only a little 
2 
Quite often 
2 
Notal all 
3 
Very often 
3 
I get a sort of frightened feeling like 
A 
I have lost interest in my appearance: 
0 
something awful is about to happen: 
Very definitely and quite badly 
3 
Definitely 
3 
Yes, but not too badly 
2 
I don't take as much care as I should 
2 
A little, but it doesn't worry me 
I may not take quite as much care 
Not at all 
0 
I take just as much care as ever 
0 
I can laugh and see the funny side of things: 
0 
I feel restless as if I have to be on the 
A 
move: 
As much as I always could 
0 
Very much indeed 
3 
Not quite so much now 
Quite a lot 
2 
Definitely not so much now 
2 
Not very much 
Not at all 
3 
Not at all 
0 
Worrying thoughts go through my mind: 
A 
I look forward with enjoyment to things: 0 
A great deal of the time 
3 
A much as I ever did 
0 
A lot of the time 
2 
Rather less than I used to 
From time to time but not too often 
Definitely less than I used to 
3 
Only occasionally 
0 
Hardly at all 
2 
I feel cheerful: 
0 
I get sudden feelings of panic: 
A 
Not at all 
3 
Very often indeed 
3 
Not often 
2 
Quite often 
2 
Sometimes 
Not very often 
Most of the time 
0 
Not at all 
0 
I can sit at ease and feel relaxed: 
A 
I can enjoy a good book or radio or TV 
0 
programme: 
Definitely 
0 
Often 
0 
Usually 
1 
Sometimes 
1 
Not often 
2 
Not often 
2 
Not at all 
3 
Very seldom 
3 
Questions relating to anxiety are indicated by an 'A' while those relating to depression are shown by a 'D'. Scores of 0-7 in respective subscales are considered 
normal, with 8-10 borderline and 11 or over incicating clinical 'caseness' 

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Appendix 11
Emory Treatment Resistance Interview for PTSD (E-TRIP)
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.
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166
E-TRIP 
[EMORY TREATMENT RESISTANCE INTERVIEW FOR PTSD] 
OVERVIEW 
Start theE-TRIP assessment by handing the PTSD Medication Treatment Record and PTSD 
Psychotherapy Treatment Record pages to the patient. The patient should indicate the treatments 
they have previously received by marking the check boxes next to the treatments. Advise the 
patient that their only action on the form is to check the boxes in the white (unshaded) areas; they 
should ignore the rest of the form (these areas can also be covered so as not to confuse patients 
completing the form). 
Medications are grouped by classes for ease of organization, and antipsychotics are included in 
"other agents" to avoid the possible misinterpretation that they may only be used for patients with 
psychotic symptoms. For each efficacious psychotherapy, a single sentence description is provided 
to help patients who may not have been told the specific name of the psychotherapy they received. 
After the patient has completed the Treatment Records, the interviewer collects them and 
administers the semi-structured interview. 
Questions in Bold font should be asked as written. 
within 
provides instructions to the interviewer for how to proceed and how to mark the 
Treatment Record. 
Each shaded gray box (for instance, ._......; _ __, 
Record the instruction corresponds. 
) indicates with which column on the Treatment 
The interview begins by assessing the onset of PTSD and primary symptoms; if this information is 
already known, these questions do not need to be asked, although the relevant information should 
be recorded. Identifying onset of PTSD is crucial for determining treatment resistance, because 
many patients who had episodes of anxiety or depression before experiencing a trauma may record 
on the treatment records that they had received specific treatments, though in fact those 
treatments were administered prior to the onset of PTSD and therefore should not contribute to the 
E-TRIP score. 
Next, the interviewer evaluates the response to the individual treatments. The interview has 
separate sections for medication and psychotherapy treatments. For each individual treatment for 
which the patient has checked the box, the interview er proceeds through the interview, one 
treatment at a time, following the instructions and recording answ ers in the Treatment Record. For 
instance, if a patient had been treated with sertraline and venlafaxine, the interviewer would ask 
questions 3-5 in regards to sertraline, then return to question 3 and assess venlafaxine. This applies 
to psychotherapy treatments as well. 
NOTE: For psychotherapy and medication treatments administered concomitantly, the key 
consideration is whether the patient responded while receiving the treatments. If so, no points for 
resistance will be scored. If the patient did not respond, then points should be scored for both 
treatments, just as if they had been administered separately. 

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167
PATIENTID: 
DATE: 
INTERVIEWER: 
PTSD MEDICATION TREATMENT RECORD 
Have you ever taken a prescription medication for PTSD? 
D No 
D Yes 
If yes, please review the list of medications below and check the box (D) next to any you have taken in the past or are taking now. 
DO NOT WRITE IN THE GRAY-SHADED AREAS 
PATIENT SECTION 
OFFICE USE ONLY 
Generic name 
Trade name 
Check box if 
Start date 
For 
Dose 
Minimum 
Used to 
weeks? 
days/ 
ever taken 
MM/YYVY 
PTSD? 
used 
effective 
augment? 
week? 
dose 
SSRis 
Citalopram 
Celexa 
D 
y 
N 
20 mg/d 
y 
N 
y 
N 
y 
N 
Esc ita lepra m 
Lexapro 
D 
y 
N 
10 mg/d 
y 
N 
y 
N 
y 
N 
Fluoxetine 
Prozac 
D 
y 
N 
20 mg/d 
y 
N 
y 
N 
y 
N 
Fluvoxamine 
Luvox 
D 
y 
N 
50 mg/d 
y 
N 
y 
N 
y 
N 
Paroxet ine 
Paxil (Paxil CR) 
D 
y 
N 
20 mg/d (25) 
y 
N 
y 
N 
y 
N 
Sertraline 
Zoloft 
D 
y 
N 
50 mg/d 
y 
N 
y 
N 
y 
N 
Vilazodone 
Viibryd 
D 
y 
N 
20 mg/d 
y 
N 
y 
N 
y 
N 
SNRis 
• 
Desvenlafaxine 
I Pristiq 
D 
> 
I 
y 
N I 
I 50 mg/d 
y 
N 
y 
N 
I 
y 
N 
Duloxetine 
I Cymbalta 
D 
..... 
I 
y 
N I 
I 40 mg/d 
y 
N 
y 
N 
I 
y 
N 
z 
Venlafaxine 
I Effexor 
D 
0 
I 
y 
N I 
I 75 mg/d 
y 
N 
y 
N 
I 
y 
N 
TCAs 
w. 
Amitriptyline 
Elavil 
D 
"' 
y 
N 
150 mgfd 
y 
N 
y 
N 
y 
N 
Clomipramine 
A nafranil 
D 
::::> 
y 
N 
150 mg/d 
y 
N 
y 
N 
y 
N 
Desipramine 
Norpramin 
D 
w 
y 
N 
150 mg/d 
y 
N 
y 
N 
y 
N 
u 
Doxepin 
Sinequan 
D 
-... 
y 
N 
150 mg/d 
y 
N 
y 
N 
y 
N 
Imipramine 
Tofranil 
D 
... 
y 
N 
150 mRJd 
y 
N 
y 
N 
y 
N 
Nortriptyline 
Pamelo r 
D 
0 
y 
N 
75 mg/d 
y 
N 
y 
N 
y 
N 
MAO Is 
I 
Phenelzine 
I Nardil 
D 
I 
y 
N I 
I 45 mgfd 
y 
N 
y 
N 
I 
y 
N 
Selegiline 
I Emsam 
D 
I 
y 
N I 
I 6 mg/24 hrs 
y 
N 
y 
N 
I 
y 
N 
Tranylcypromine I Parnate 
D 
I 
y 
N I 
I 30 mg/d 
y 
N 
y 
N 
I 
y 
N 
OTHER ANTIDEPRESSANTS 
• 
Bupropion 
W ellbutrin 
D 
y 
N 
300 mg/d 
y 
N 
y 
N 
y 
N 
Mirtazapine 
Remeron 
D 
y 
N 
30 mg/d 
y 
N 
y 
N 
y 
N 
Nefazodone 
Serzone 
D 
y 
N 
300 mgfd 
y 
N 
y 
N 
y 
N 
Trazodo ne 
Desyrel 
D 
y 
N 
300 mg/d 
y 
N 
y 
N 
y 
N 
TURN TO NEXT PAGE 
If adequate 
Pointst 
trial, 
responded? 
y 
N u 
3 
y 
N u 
3 
y 
N u 
3 
y 
N u 
3 
y 
N u 
3 
y 
N u 
3 
y 
N u 
3 
I 
y 
N u I 
0 
I 
y 
N u I 
0 
I 
y 
N u I 
3 
y 
N u 
0 
y 
N u 
0 
y 
N u 
0 
y 
N u 
0 
y 
N u 
2 
y 
N u 
0 
I 
y 
N u I 
2 
I 
y 
N u I 
0 
I 
y 
N u I 
0 
y 
N u 
0 
y 
N u 
0 
y 
N u 
2 
y 
N u 
0 

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Clinical Study Report 331-201-00061
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PTSD MEDICATION TREATMENT RECORD 
PATIENT SECTION 
OFFICE USE ONLY 
Generic name 
Trade name 
Check box if 
Start date 
For 
Dose 
Minimum 
Used to 
If adequate 
Pointst 
ever taken 
MM/YVYY 
PTSD? 
used 
effective 
augment? 
week? 
trial, 
dose 
responded? 
(Y, N,UI 
BENZODIAZEPINES[SEDATIVES 
• 
Clonazepam 
Klonopin 
D 
y 
N 
n/a 
y 
N 
y 
N 
y 
N 
y 
N u 
0 
l orazepam 
Ativan 
D 
y 
N 
n/a 
y 
N 
y 
N 
y 
N 
y 
N u 
0 
Alprazolam 
Xanax 
D 
y 
N 
n/a 
y 
N 
y 
N 
y 
N 
y 
N u 
0 
Diazepam 
Va lium 
D 
y 
N 
n/a 
y 
N 
y 
N 
y 
N 
y 
N u 
0 
Eszopiclone 
Lunesta 
D 
y 
N 
3 mg/d 
y 
N 
*Y 
N 
y 
N 
y 
N u 
1 
Zolpidem 
A m bien 
D 
y 
N 
n/a 
y 
N 
y 
N 
y 
N 
y 
N u 
0 
Zaleplon 
Sonata 
D 
y 
N 
n/a 
y 
N 
y 
N 
y 
N 
y 
N u 
0 
OTHER MEDICATIONS 
• 
A ripiprazole 
Abilify 
D 
> 
y 
N 
n/a 
y 
N 
y 
N 
y 
N 
y 
N u 
0 
Olanzapine 
Zyprexa 
D 
.... 
y 
N 
n/a 
y 
N 
y 
N 
y 
N 
y 
N u 
0 
z 
Q uetiapine 
Seroquel 
D 
0 
y 
N 
n/a 
y 
N 
y 
N 
y 
N 
y 
N u 
0 
Risperidone 
Risperdal 
D 
w 
y 
N 
2 mg/d 
y 
N 
y 
N 
y 
N 
y 
N u 
1 
Prazosin 
Minipress 
D 
"' 
y 
N 
3 mg/d 
y 
N 
y 
N 
y 
N 
y 
N u 
1 
Lam ictal 
::I 
n/ a 
Lamotrigine 
D 
y 
N 
y 
N 
y 
N 
y 
N 
y 
N u 
0 
Levetiraceta m 
Keppra 
D 
w 
y 
N 
n/a 
y 
N 
y 
N 
y 
N 
y 
N u 
0 
u 
Topiramate 
Topamax 
D 
-
y 
N 
100 ml!/d 
y 
N 
y 
N 
y 
N 
y 
N u 
1 
u.. 
Va lproic Acid 
Depakote 
D 
u.. 
y 
N 
n/a 
y 
N 
y 
N 
y 
N 
y 
N u 
0 
Gabapentin 
Neuront in 
D 
0 
y 
N 
n/a 
y 
N 
y 
N 
y 
N 
y 
N u 
0 
Pregabalin 
Lyrica 
D 
y 
N 
n/a 
y 
N 
y 
N 
y 
N 
y 
N u 
0 
Carbamazepine 
Tegretol 
D 
y 
N 
n/a 
y 
N 
y 
N 
y 
N 
y 
N u 
0 
Clonidine 
Catapres 
D 
y 
N 
n/a 
y 
N 
y 
N 
y 
N 
y 
N u 
0 
Guanfacine 
Ten ex 
D 
y 
N 
n/a 
y 
N 
y 
N 
y 
N 
y 
N u 
0 
Propranolol 
lnderal 
D 
y 
N 
n/ a 
y 
N 
y 
N 
y 
N 
y 
N u 
0 
Atenolol 
Tenormin 
D 
y 
N 
n/a 
y 
N 
y 
N 
y 
N 
y 
N u 
0 
UNLISTED (Write in below) 
I 
I 
D 
I 
y 
N 
I 
I n/a 
y 
N 
y 
N 
I 
y 
N 
I 
y 
N u I 
0 
I 
D 
I 
y 
N 
I 
I n/ a 
y 
N 
y 
N 
I 
y 
N 
I 
y 
N u I 
0 
*When eszop1clone IS used for augmentation, 
weeks constitutes an adequate tnal; 8 weeks IS not requ1red. 
MEDICATION TOTAL POINTS: 

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PATIENTID: 
DATE: 
INTERVIEWER: 
PTSD PSYCHOTHERAPY TREATMENT RECORD 
Have you ever received psychotherapy (talk therapy) for the treatment of PTSD? 
D No 
D Yes 
If yes, please review the list of therapies below and check any you have received in the past or are receiving now. If you are unclear about the name of the 
therapy you have received, use the descriptions to identify which seems most like the treatment you received. 
DO NOT WRITE IN THE GRAY-SHADED AREAS 
PATIENT SECTION 
OFFICE USE ONLY 
Check box 
Start 
For 
No. of 
Minimum 
If adequate 
Points 
Form of Psychotherapy 
if you 
date 
PTSD? 
Sessions 
No. of 
trial, 
received 
MM/YYYY 
Sessions 
responded? 
TRAUMA-FOCUSED CBT 
Prolonged Exposure (PE): You repeatedly went over t he memory of t he traumatic event by saying it out aloud 
0 
3 
with the therapist, and possibly by listening to a recording of you saying it while at home. 
y 
N 
6 
y 
N u 
Cognitive Processing Therapy (CPT): You talked with the therapist about the "stuck points" that were the 
0 
3 
aspects of the event that were the most emotionally upsetting to you. 
y 
N 
6 
y 
N u 
Eye Movement Desensitization and Reprocessing (EMDR): You went t hrough the memory of the traumatic 
0 
2 
event while doing something repetitive, like following the therapist's finger from side to side with your eyes. 
y 
N 
6 
y 
N u 
Trauma·Focused Cognitive·Behavioral Therapy (TFCBT): You discussed thoughts about the trauma with the 
0 
3 
therapist and were assigned homework. You described t he trauma aloud to t he therapist. 
y 
N 
6 
y 
N u 
> 
Narrative Exposure Therapy (NET): You described the story of your life to the therapist and all emot ions that 
0 
..... 
2 
went along with the events in your life. 
z 
y 
N 
6 
y 
N u 
0 
Written Exposure Therapy (WET): You were asked to w rite a detailed account of your trauma in each session, 
0 
... 
2 
emphasizing sounds and images as well as thoughts and emotions at the time of the trauma. 
Vl 
y 
N 
5 
y 
N u 
:::l 
Cognitive Restructuring: You identified unhelpful beliefs you have and worked with t he therapist to change 
D 
... 
0 
those beliefs by examining the evidence for and against the beliefs. 
u 
y 
N 
6 
y 
N u 
-
Stress Inoculation Therapy (SIT): You learned co ping skills to manage anxiety related to the t rauma including 
0 
u.. 
u.. 
y 
N 
6 
y 
N u 
0 
tools to change unhelpful thoughts, relaxation exercises, and guided self·talk. 
0 
Dialectical Behavior Therapy for PTSD: You learned skills such as emotion regulation and distress tolerance 
0 
2 
and acceptance. 
y 
N 
6 
y 
N u 
Nightmare Imagery Rehearsai/CBT: You were asked to write down a nightmare related t o t he trauma. You 
0 
0 
then altered the nightmare into a more positive story and rehearsed t his repeatedly. 
y 
N 
6 
y 
N u 
INTERNET-BASED THERAPIES 
lnternet·based Cognitive·Behavioral Therapy: You used a website to communicate wit h a therapist and 
D 
3 
complete assignments. You wrote about your trauma and learned to share your experience with ot hers. 
y 
N 
6 
y 
N u 
TURN TO NEXT PAGE 
1 

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PTSD PSYCHOTHERAPY TREATMENT RECORD 
PATIENT SECTION 
OFFICE USE ONLY 
Check box 
Start date I For 
No. of 
Minimum 
If adequate 
Points 
Form of Psychotherapy 
if you 
MM/YVVV 
PTSD? 
Sessions 
No. of 
trial, 
received 
Sessions 
responded? 
GROUP THERAPIES 
I 
Group Interpersonal Psychotherapy: In a group, you w orked on problems with other people and PTSD such 
D 
5 
3 
as arguments, social difficulties, changing roles, social isolation, and relationship triggers of PTSD symptoms. 
y 
N 
y 
N 
u 
Cognitive-Behavioral Conjoint Therapy: You and your partner went to therapy toget her. The thera pist helped 
D 
you understand how PTSD has affected your relationship and how to identify and prepare for triggers of PTSD 
y 
N 
6 
y 
N 
u 
2 
symptoms, enhance communicat ion with your partner, and approach rather than avoid difficulties. 
Group Cognitive-Behavioral Therapy: In a group with a therapist, you wrote about your trauma and retold 
D 
the details out loud at home. You may have learned mindfulness meditation, muscle relaxat ion, anger 
y 
N 
6 
y 
N 
u 
0 
management, and role playing to improve social skills. 
COMPLEMENTARY AND ALTERNATIVE MEDICINE THERAPIES 
: I 
Mindfulness: You worked on increasing your aw areness and acceptance of t he present moment, focusing on 
D 
z 
2 
your physical sensations, emotions, and t hought s. You may have pract iced yoga or meditation. 
y 
N 
6 
y 
N 
u 
0 
Acupuncture: Needles were placed into carefully chosen parts of your t issue or muscle and moved around by 
D 
w 
2 
the practitioner. 
Ill 
y 
N 
6 
y 
N 
u 
::l 
Healing Touch with Guided Imagery: A trained practitioner performed this gentle no ninvasive touch thera py 
D 
to revitalize your energy and stimulate healing. You listened to a recording that helped you relax and change 
w 
2 
y 
N 
6 
y 
N 
u 
negative emotions about your trauma. 
u -
OTHER THERAPIES 
Resiliency Intervention: You learned about the concept of resilience. You developed skills such as paying 
D 
0 
attention to bodily sensations, cultivating positive emot ions, and building social bonds, and used these skills 
y 
N 
6 
y 
N 
u 
2 
when addressing your trauma. 
Present-Centered Therapy: You learned skills to resolve problems you have in relationships t hat are caused 
D 
0 
by PTSD symptoms. 
y 
N 
6 
y 
N 
u 
Emotional Freedom Techniques: You were asked to rat e the distress level caused by each t raumatic memory. 
D 
You learned to tap your body at various energy centers while repeating positive affirmations about self-love 
y 
N 
6 
y 
N 
u 
2 
and acceptance until the distress diminished. 
Mind-Body Bridging Program for sleep management: You learned to relax your mind and body. You 
D 
2 
identified causes of your sleep difficulties. 
y 
N 
3 
y 
N 
u 
TURN TO NEXT PAGE 
2 

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PTSD PSYCHOTHERAPY TREATMENT RECORD 
PATIENT SECTION 
OFFICE USE ONLY 
Check box 
Start 
For 
No. of 
Minimum 
If adequate 
Points 
Form of Psychotherapy 
if you 
date 
PTSD? 
Sessions 
No. of 
trial, 
received 
MM/YYYY 
Sessions 
responded? 
Supportive Therapy (ex. Rogerian Therapy, Talk Therapy): You talked with your therapist about what was 
D 
going on in your life and the kinds of stresses you were facing. The therapist encouraged and supported you 
y 
N 
6 
y 
N 
u 
0 
and gave advice about how to manage problems. 
Relaxation: You learned and practiced techniques to relax. These may include focusing on your breath, 
D 
0 
muscle relaxation, visualization, o r the repetition of positive messages. 
y 
N 
6 
y 
N 
u 
> 
COMBINATION THERAPIES 
-' I 
Acupoint Stimulation added to Cognitive-Behavioral Therapy: A needle was placed in a specific part of your 
D 
z 
body. A small elect rical charge w as sent t hrough the needle. 
0 
y 
N 
3 
y 
N 
u 
1 
w 
Skills Training in Affective and Interpersonal Regulation (STAIR): You worked on social skills like being more 
D 
"' 
aware, flexible and assertive. You learned techniques to regulate your emotions. You described your trauma 
;::) 
y 
N 
6 
y 
N 
u 
0 
in detail. 
w 
Medication: You were given one of the following medications j ust before or after t he therapy session to make 
D 
u 
the therapy work better. Choose from list below. 
-
y 
N 
n/a 
y 
N 
u 
0 
..... 
. D·Cycloserine (DCS) 
..... 
. Methylene Blue 
D 
0 
y 
N 
n/a 
y 
N 
u 
0 
. Oxytocin 
D 
y 
N 
n/a 
y 
N 
u 
0 
. Yohimbine 
D 
y 
N 
n/a 
y 
N 
u 
0 
. Dexamethasone/Hydrocortisone/Prednisone 
D 
y 
N 
n/a 
y 
N 
u 
0 
. MDMA ("Ecst asy") 
D 
y 
N 
n/a 
y 
N 
u 
0 
. Propranolol (lnderal) 
D 
y 
N 
n/a 
y 
N 
u 
0 
PSYCHOTHERAPY TOTAL POINTS: 
3 

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E-TRIP 
[EMORY TREATMENT RESISTANCE INTERVIEW FOR PTSD] 
PATIENT: 
DATE: 
INTERVIEWER: 
Hand the E-TRIP PTSD Medication Treatment Record and E-TRIP PTSD Psychotherapy Treatment Record 
to the patient. 
INTERVIEW 
1. 
Clarify date of onset of PTSD. 
ASK: When did your symptoms of PTSD begin? 
Provide the patient with examples of PTSD symptoms if they are unsure. 
2. 
Determine primary PTSD symptoms and impairments in functioning that led patient to seek treatment. 
ASK: What kinds of PTSD symptoms were you experiencing that caused you to seek treatment? 
IF PATIENT IS UNCERTAIN, ASK: For example, did you have intrusive memories of the trauma, 
nightmares, or flashbacks? 
o Did you make excessive efforts to avoid thinking about the event or avoid reminders of it? 
o Did you f eel distant from other people or lose interest in activities you once enjoyed? 
o Did you have problems with sleep, concentration, or irritability? 
PROCEED THROUGH NUMBERS 3-5 FOR EACH M EDICATION TAKEN, ONE AT A TIME. 
PROCEED THROUGH NUMBERS 6-8 FOR EACH PSYCHOTHERAPY RECEIVED, ONE AT A TIME. 
PTSD MEDICATION TREATMENT RECORD 
On the PTSD Medication Treatment Record, if the patient checked " No," skip to Page 3 to assess 
psychotherapy treatments. If t he patient checked "Yes," continue below. 
3. Confirm that the medication checked was taken after the date of onset of PTSD. 
ASK: When did you start taking the (MEDICATION NAME)? Record in theE-TRIP PTSD 
Medication Treatment Record. 
If the medication trial began before the onset of PTSD symptoms, circle " N" and do not 
continue to ask about the specific medication; if the medication t rial began after the onset 
of PTSD symptoms, circle "Y" and continue to ask about the medication. 
1 

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E-TRIP [EMORY TREATMENT RESISTANCE INTERVIEW FOR PTSD] 
4. Determine if the medication treatment constituted an adequate trial. For each medicine taken for PTSD: 
.._..-..=01 ASK: What was the highest dose of the (MEDICATION NAME) you took? Record in the 
E-TRIP PTSD Medication Treatment Record. 
r
Minimuml 
effective 
dose 
If the dose reported is less than the minimally effective dose for that medication, do not 
continue to assess the specific medication. If it is greater than or equal to the minimally 
effective dose, continue to assess the medication. 
b. Determine if the medication was used as monotherapy or as an augmentation ("add on") agent. 
ASK: Was this medicine added on to a medicine you were already taking, so that you were taking both 
medicines on the same days? (If yes) Which medicine was it added on to? Record here. _____ _ 
r 
Used to l" 
augment? 
• 
If the patient did not take the medication to augment another medication, circle " N. " 
If the patient did take the medication to augment another medication, look up the point 
value for the medication you recorded in the above blank. 
o If the point value is 0 or 1 points or not listed, do not continue to assess the 
augmentation medication; circle " N.
11 
o If the point value is 2 or 3 points, the add-on medication is considered an 
augmentation agent, so circle "Y" under the Augment column and continue. 
c. Determine the number of weeks that the patient took the medication. 
ASK: For how many weeks in a row did you take that dose of(MEDICAT/ON NAME)? Record 
in the E-TRIP PTSD Medication Treatment Record. 
If the patient took dose for <8 weeks, circle N and do not continue. If the patient took dose 
8 
weeks, circle Y and continue. 
NOTE: When eszopiclone is used for augmentation, 
weeks constitutes an adequate trial; 8 weeks is 
not required. 
d. Determine how many days the patient took the medication each week. 
ASK: When you were taking that dose, did you take your (MEDICATION NAME) at least 
6 days per week? 
Record in table: if the patient did not take the medication for at least 6 days per week, circle " N" and do 
not continue to assess this medication. If the patient did take the medication for at least 6 days per 
week, circle "Y" and continue. This is an adequate trial. 
Patient responses should be confirmed using pharmacy prescription records or physicians' notes 
whenever such records are available. 
2 

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E-TRIP [EMORY TREATMENT RESISTANCE INTERVIEW FOR PTSD] 
5. 
Responded? (Y, N, U) Determine if the patient responded to each treatment. Response to a treatment is 
defined as >30",6 improvement in PTSD svmptomoto/oqv. 
a. 
Assess Symptom Improvement. ASK: Which symptoms that you listed in the beginning of the 
interview (refer to patient's presenting problems on page 1, question 2) improved or did not improve? 
IF STILL UNSURE IF SYMPTOMS IMPROVED, ASK QUESTIONS BELOW: 
What did your family members or friends say about your response to the treatment? 
Did you feel (MEDICATION NAME) made a clear difference in how you felt? Can you give me 
some examples of how it helped you? 
ASK: Considering all of these symptoms together, what percentage do you think your PTSD 
symptoms improved on this medication? 
RECORD: 
D 0-29% improvement: non-response (N) 
D 30-100"/o improvement: response (Y) 
D Unsure of improvement (U) 
NOTE: Patients who initially responded to a treatment, then lost response to the same treatment at a later time 
and never regained response should be scored as having a non-response to that treatment. 
Code response on the E-TRIP PTSD medication treatment record. If the patient's PTSD 
symptoms improved 0-29% while taking the medication, circle "N." If the patient's PTSD 
symptoms improved 30-100% while taking the medication, circle "Y." If it is unclear if the 
patient's PTSD symptoms improved, circle " U." If you circled "N," go to the "Points" column 
for that medication and circle the number listed. 
NOTE: A maximum of TWO failed SSRI treatment trials should be scored, so that the maximum number 
of points for failing to respond to SSRI medications is 6. Additional failed trials of SSRis should not be 
scored. 
REPEAT QUESTIONS 3-5 FOR EACH MEDICATION TAKEN. 
After assessing all medication trials, add total points for non response to adequate trials of medication 
treatments and record at the bottom of theE-TRIP PTSD Medication Treatment Record. 
PTSD PSYCHOTHERAPY TREATMENT RECORD 
On the E-TRIP PTSD Psychotherapy Treatment Record, if the patient checked "No," end the interview. If 
the patient checked "Yes/' continue. 
6. Confirm that the psychotherapy checked was started after the date of onset of PTSD. 
ASK: When did you begin treatment with (PSYCHOTHERAPY NAME)? Record in table. 
r For PTSD?l 
If the psychotherapy began before the onset of PTSD symptoms, circle " N" and do not 
continue to ask about the specific psychotherapy; if the psychotherapy began after the 
onset of PTSD symptoms, circle "Y" and continue to ask about the psychotherapy. 
If the patient checked multiple psychotherapies that occurred in a similar time frame, determine 
whether the separate therapies were actually conducted as part of a more comprehensive treatment 
package (e.g. " Relaxation" performed as part of prolonged exposure). 
3 

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175
E-TRIP [EMORY TREATMENT RESISTANCE INTERVIEW FOR PTSD] 
7. Determine if each treatment constituted an adequate trial. 
ASK: How many sessions of (PSYCHOTHERAPY NAME) did you receive? Record in the E-TRIP PTSD 
Psychotherapy Treatment Record. 
[
Minimum I 
If the patient received less than the minimum number of sessions for that psychotherapy, do 
No. of 
not continue to ask about the psychotherapy. If the patient received greater than or equal 
Senions 
the minimum number of sessions, continue to ask about the psychotherapy. This is an 
8. 
adequate trial. 
Determine if the patient responded to each treatment. Response to a treatment is 
defined as >30",b improvement in PTSD symptomatology. 
a. 
Assess Symptom Improvement. (ASK) Which symptoms that you listed in the beginning of the 
interview (refer to patient's presenting problems on page 1, question 2) improved or did not 
improve? 
IF STILL UNSURE IF SYMPTOMS IMPROVED, ASK QUESTIONS BELOW: 
What did your family members or friends say about your response to the treatment? 
Did you feel (PSYCHOTHERAPY NAME) made a clear difference in how you felt? Can you give 
me some examples of how it helped you? 
ASK: Considering all of these symptoms together, what percentage do you think your PTSD 
symptoms improved over the course of this psychotherapy? 
RECORD: 
D 0-29% improvement: non-response (N) 
D 30-100"/o improvement: response (Y) 
D Unsure of improvement (U) 
NOTE: Patients who initially responded to a treatment, then lost response to the same treatment at a later time and 
never regained response should be scored as having a non-response to that treatment. 
Code response on the E-TRIP PTSD Psychotherapy Treatment Record. If the patient's PTSD 
symptoms improved 0-29% over the course of the psychotherapy, circle " N." If the patient's 
PTSD symptoms improved 30-100% over the course of the psychotherapy, circle "Y." If it is 
unclear if the patient's PTSD symptoms improved, circle "U." If you circled " N," go to the 
"Points" column for that medication and circle the number listed. 
REPEAT QUESTIONS 6-8 FOR EACH PSYCHOTHERAPY RECEIVED. 
After assessing all psychotherapy trials, add total points for non response to adequate trials of 
psychotherapy treatments and record at the bottom of t he E-TRIP Psychotherapy Treatment Record. 
POINTS: 
MEDICATION 
PSYCHOTHERAPY 
TOTAL 
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Appendix 12
Life Events Checklist for DSM-5 (LEC-5)
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00061
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176
LEC·S 
Part 1 
Instructions: List HI be&ow are 
of difficult Of stressful things that 
happen to people. For each 
event check one or more of lhe boxes to the right to lndlc.lte that: (a) tt bippeoed tovou personally:{b)you wttnessed 
.11 happen co $0meone 
(c) you learned about n happening to a dose famBy member oc close frie-nd; (d) you were 
exposed to lt u pan of yO!" tob(forexam,., paramediC, polke, mlltury, or other first resporKier): (e) )'OU'te o,ouw:etf 
It fiu: or(() It dQ!?$nl apoty to you. 
Be sure to conskler your etJIJU.J!k. (growing up as well as adulthood) as you go through the ll.st of events. 
Event 
P•rtof 
N• t 
0 0f'Sn 't 
.... 
it 
• bout it 
my job 
• ppty 
'· 
Nan.ntcf'tUster {fof eQmprlt, Rood. 
2. Firt-or e.xplos.ion 
3. 
.Kddent (for 
Q r 
a«ident. bo.lt 
tr.:tln wre«_ pbnt cr.Mhl 
4, Serious 
0\t WOtk, horne, ot duMg 
r«te<tdoNI a.ctivity 
s. 
to to* subnance 
danQIM)US 
rJdiation) 
6. 
(for 
•nKked. hit. 
sbPPtd, 
up) 
7. 
with" wt,pon 
btCnv 
she)(. $tabbed. thrt.attntdwith • knife, gun, 
bomb! 
•• 
&SJ.)ult (rili)C',I»tt«nptcd 
m!lde to 
perform 
rype or $6WI4et through 
Ot 
thrut of NtM) 
•• OtM-r unwanted or uncom.fottablf' secu.ll 
10. (011\b.nor f'Jiposurf' to a 
(in tht 
militatyOt •s • cMii•n) 
II. C.ptMty (tor t:Qmple, being; k.idn•wed, 
hdd hosugt_ nont1 of vqr) 
12. 
01 injury 
13. 
suffering 
14. 
sulddcl 
IS, 
16. 
17. 
PlEASE COMPLETE PART 2 ON THE FOllOWING PAGE 
UC-5 
(27 Oaobti 2013) 
9•;e I ol 2 

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Part 2: 
A. If yoo 
anythl"9 for 1171n PART 1. briefly ldenUfy the event you wore thinking of: 
B. If you have experienced more than one of the events In PART 1, thtnk about the event you conskle1 the worst event, 
which forthlsquestionnaire means the event that cum>ntly bothe<s you the most. If you have experienced only one 
events In PART I, use that one as the worst event. Please answer the f"lowlng questkms about the worst event 
(check all options that apply): 
t. Brlefty d.scrlbe the wo<St event (fOiexample. what happened. who wa< lnvotved. etc.). 
2. How long ago did It happen? ________ (please estimate If you are not sure) 
3. How did yoo experience k1 
_ 
n happened to me directly 
I witnessed It 
__ ll .. med about It happening to a dose family mom be< 01 clos<> frtend 
__ 1 ,,..s repeateclly exposed to de<alls about It as pan of my jOb (fOiexample. paramedic, pollee. mllkary; or 
other first 
__ Other. ple.,.descnbe: _________________________ _ 
4. Was someone's life In danger? 
__ Yesmyllfe 
__ Yes, someone 
fife 
No 
S. Was someone seriously Injured or ldlled? 
__ Yl'l. l was se<lously Injured 
__ Yes, someone else was seriously InJured or kl.lled 
_No 
6. Old It IO'IOive sexual vtolence? __ Yes __ No 
7. If the ewnt Involved the death of a <lose family member or dose friend. was it due to some kind of accident or 
violence. Ot w.u It due to natural c.auses? 
__ Ac:ident or violence 
__ Natural causes 
__ Not applicable {The event did notlnvotve the death of a dose family m•mbe< or close frtend) 
8. How many Urnes altogether have you experienced a similar event as stressful or nearly as stressful as the worst 
event? 
Just once 
__ More than once (please specify 01 esumatethe total t orumes you have had thiS experience ____j 
U<·S E.xltndtdU7 October 2013) 
NatioNIUntetforPTSO 
POQ<2of 2 

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Appendix 13
Mini International Neuropsychiatric Interview (MINI)
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.
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178
M.I.N.I. 
M INI INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW 
English Version ?.0.2 
For 
OSM-S 
() Copyright 1992·2016 Sheehan OV 
AI riBMs 
No p:.rt of t.hk document m.ay be n:swoduced or 
In .any form, or by 
means, t'Jtrtronlc or 
medl.wtat.. IM:Iudl"$ 
or by .I"'Y InformatiOn 
or rttf\eval s:ystMI, Wl'lhOut 
In 
from Of, 
rts.ea.-e:heu, di!'llcla.M and st\.detiU 
nonprofit Of publlcty owMd s.etli"Ci {lndudl"t 
nonprofit 
and cowrnrrw:nt int.tihJUons) mJV 
C:OPin of a M I.NJ, IMtrumcnt 
their PtrsoOMJ 
.and 
reSC!.Jorch UI)C, tKrt not for lnstltutioMI use-, OJ fot any tin:utdaiDtofit Ct' g<tln. Arry use lnvoJvil\i 
11 
from Ute copyrlcht I'IOICkr .net payment of a f)tt 
k tMe ftt. 
otsa.AlMEit 
Our aim i$ to aislst In the 
and tnclin£ of 
W'fl;h lft'lllcr efficiency .and .ct\lr.acy. Bc:fore .rtlon b t:.ken on any 
daa collect«t 
by thiS procra.m, it s-l»uJd be 
aM 
bv a 
dil'jdat\. 
Tlw$ prQ&fllm k not 
or 
to b: U'$C'd in Uw: pbco of a full 
ltncf p$ythbtrit r:vak.aatlon by a 
It 1$ ll'ltMded Cftlv as a tool to fa<i1itlHI! 
&til (Ofle«loi'IIM'Id 
ot symptom' etk'itfd by 
l)et\OI'IIIft It k not • 
ten. 
M.t.NJ, 7.02 
8, 2016.(8/8/Hi. 

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Clinical Study Report 331-201-00061
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179
Patient Nome: 
Patient Number: 
Dote of Birth: 
Time ll'lfervlew BeQOn; 
Interviewer's Name: 
Time ll'lfervlew 
Dote of Interview: 
TotofTfme: 
MEETS 
PR.IMARY 
MODULES. 
TIMERtAMf 
CRITERIA 
ICD-lO<M 
DIA.GNOSIS 
A 
MAJOR DEPRESSIVE EPISODE 
Current (2 weeksJ 
0 
0 
Recurrent 
0 
MAJOR DEPRESSIVE DISORDER 
Current (2 weeks) 
D 
F3l.ll 
0 
Past 
D 
Fll.ll 
0 
Recurrent 
0 
rn., 
0 
8 
SUICIDAUTY 
Current (Pas.t Month) 
0 
0 
Lifetime attempt 
0 
0 Low 0 Mode.ate 0 Hlgh 
0 
SUICIDE BEHAVIOR DISORDER 
Current 
0 
(1'1 Past Year) 
0 
In early remission 
0 
(1 • 2 'tears Ago) 
0 
MANIC EPISODE 
Current 
0 
Past 
0 
HYPOMANIC EPISODE 
Current 
0 
Past 
0 
0 Not Explored 
BIPOLAR 1 DISORDER 
Current 
0 
F3LO • F31.76 
0 
Past 
0 
F31.0 • f3L76 
0 
BIPOLAR 1 DISORDER WITH PSYCHOTIC FEATURES 
Current 
0 
F3L2/H.S/F31.64 
0 
Past 
0 
FlLU]l.S/F31.64 
0 
BIPOLAR II DISORDER 
Current 
0 
F3L81 
0 
Past 
0 
FlL81 
0 
OTHER SPECIFIED BIPOlAR ANDRE LA TED DISORDER 
Current 
0 
F31.89 
0 
Past 
0 
FlL89 
0 
D 
PANIC DISORDER 
Current (Past Month) 
0 
F41.0 
0 
lifetime 
0 
F40.0 
0 
AGORAPHOBIA 
Current 
D 
F40.00 
0 
SOCIAL ANXIETY DISORDER (Social Phobia) 
Current (Pan Month) 
0 
F40.10 
0 
G 
OBSESSIVE-COMPULSIVE DISORDER 
Current (Pas.t Mooth) 
0 
F42.Z 
0 
H 
POSTIRAUMATIC STRESS DISORDER 
Current (Pas.t Month) 
D 
F43.10 
0 
ALCOHOl USE DISORDER 
Past 12 Months 
0 
Fl0.10/Fl0.20 
0 
SUBSTANCE USE DISORDER (Non-alcohol) 
Past 12 Months 
0 
FlL10/Fll.20 • Fl9.20 
0 
M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16} 
2 

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180
< 
AKY I'$KI10Tl< DQOIIOtl'. 
"--· 
0 
f.bMH-a. 
c 
0 
'10.11-119 
0 
MAJOR 
CtSOftOUt wm1 'SYCHOT'IG fEA TVAU 
0-lrttnt 
0 
f».l/tJJ.J 
0 
"" 
0 
rJUI'U.l 
0 
&IPQC.AR 
WITH PSVCHOnt f(AJURU 
(Ytttfl\ 
0 
na vrn.str:n__e. 
0 
,.,., 
0 
I U lftl U10 l ... 
0 
AHC!t'OOA NUIYOSA 
C\lt*t (P.ol j 
0 
rso.ov.·SI).O: 
0 
M 
8UUMV. Nt:IMlSA 
(PMC l MoniM) 
0 
'""' 
0 
Mi IINGHATINCi 
I (hlC ) Mclnll'ltl 
0 
ISO.U 
0 
• G.ENtMUZED AHXKTY OISOP.OtR 
Cwrrent (P.-.Mon!N) 
0 
r•u 
0 
0 
,... EOKAL ORGAMC. OJIUG CAUU IIUUO OUl 
C Ho 
O Un<ltf'l.lln 
p 
AHTISOCW. PUt$0MAI,.ITY OC$OIIDE1t 
""''"" 
0 
..... 
0 
IDENTIFY THE PRIMARY DIAGNOSIS 8Y CHECKING TlU An1t.OPRIAT£ CHECK 80X. 
j 
(Which probiem troubles you tht most Of dom&Ntes the od'l"rs or ume first In tht 
tlkt«Y?) 
M.I.H.t 7.0.21AucunS. 2016) (t/8}16) 
3 

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Clinical Study Report 331-201-00061
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181
GENERAL INSTRUCTIONS 
The M.I.NJ, wu dd&ne'd ;n: a btltf 
kH tho majof 
dl)oOI'ckr$ In OSM·S and 1(.1).10. 
•nd 
s.t'-"'lc-s ho)yt been 6ont 
the MJ.N.I. to the SCIO.P fOt OSM•lii•R .lind the 001 (a t.l.ru«ured intet'VIew 
by the WoM 
Of1anlution). 
results of 
Sludies show tNt the M.UU. Ms s.lfftltill tdllbilltv and valldllV pcopertlM, 
but gn b4: •dtNnb:tetC'd In .11 mud\ shorter 
of time: {mt:¥' 18.71 11.6 mh.ltts, 
1S 
INn the •bolt¢ 
lns:trumenu.. Clnk:Lam can Uiot' I\. aftet .11 brlltf tnlnlnc $e:l:Sion. Uy 
require mote 
ttalnlns. 
INTtRVI£W: 
In orctcf to k:cc-p thot 
btf.cf IS. 
Inform 
thllt you '"II condUct • clnlc.JIIntcMtw th11t Is more 
.wuctured th.ln uwal. with very pr«ist 
1bout 
probfw:rnS wtlkh rC'qUire a Y'C!" Of no 
GEHERAlFORMAT: 
The M.I.N.I. ii 
Into modules !Mntlfied by 6tltt!tS, Ndl 
tO I 
•At the' 
of eKh di.JCnottk module 
for psychotic diSOfdffs 
screenlnc QuotStiOn(l) contspOtld_,. 
to the mJin <tlterll of the dbo«<er •rc prtsc"ntc-d In a ar•v bo-. 
•At lhe t.:nd ot 
modulot, <Ycnorut box( H) perm II the dinidan to itldicatt: whWW:r 
ore meL 
S.O:ntm«S wrl«tn In • norm•l fon1 • 
be- read euctly n writte-n to the .,..tlc:nc 'n order to 
Ule 
of db:&nOStic 
wrfutn 1t1 • C»>TAU • ihould not bt' rud to tM p:.tienL Thty art lnstt\lttiOt'ts ro. the 
to a:sSist in the 
scorlrc 
alcoflthms.. 
fn • bold • fndbte the time frame bdnc 
The intt:,...,_C'f sh0to11d rc•d 1hcm on often •s 
n«n$;1ty, Otltf symptoms occurrina 
tht time framoo 
should be conslclcrtd in s.corirc tht 
AnSwto" wfrh on orrcw Obclw tMm {• I Indicate thai one o f the crittori.J nc<cnory for tht di-'"JnoSis or 
is not mu. 
In tNs c011e, lM 
sNK..r co to the 
o4 lM module, 
• NO • 
W dillf'OUk boes ind move to lhe 
nc.Kt module, 
When ttfln$ •rc SC'I):Ititod tw a $k1Sit tn lhc int('f'VItwtf $h0to1ld 
only tho$t symptom$ lr:no\\-n to be pr-esent in the 
pai.Jeftt (for uownpfor, 
J2b or (61)). 
RAnNG INSTROCTlOH.S: 
AI Q\lestlons must be r.necl. f'he ratlnc Is done at 
rfe,tl1 of e01<h Quf.::SUOfl by clrdii\C eftl\ef Y£S o. NO. Clmlal Judjtnent 
by th¢ filer should 
In <odiln& tkt tC5pORSCJ, lnttn'lcwcrs nc:ed to be s,c:nsJtiii'C to the dNtf'Soltyof cuh\lral bctids ln 
their .Jdtnintstratkln or quc.Sbatd and r•tina 
The 
ShOuld ad!: for examp5u when n«euarv. to t:nSUrt: 
a<-turate codlnt. Tht: 
should be encow-aitd 10 asli: for dOirifiutioo on any 
that Is not ibsolutdy dear. 
The dil"'idMt s.houJd bt' sure tNt 
dlmf.:tiSlOtl of the Que:stion II ul:tn into account by the p.11Uent (for 
tkne 
fteqt.tef'o(y, SoeYetity, at'ld/« 
Symptoms, betttt 
lor by an 
or by the 
of ;alcOhOl 01 df'UIS Shoukl nOt be <06td pOSitiW in the 
M.I.H.t "The M.I.N.I. h.u quesciom that 
tl\tse issues. 
!'« ano,que:rtlom, 
nftd tor I t...wnc 
W!fCifl'tlatlcNiabou! !lpd'-..s ofthof M.I,H.I .. plc.IW (Ofttlet: 
David 1/ ShHI!...., M.O., M.IA 
Unhotl'l!ty of SoW! Jbida Cot.tto o4 MtdldM 
ra: •I !Jl.9S6.&cl1 
-
•:cbbnhtn!bst!th vat tsfy 
F« llttn.WI .. pcrmhWon$.0f qiiHtfoM, COIUKC 
M.I.N.I. 7.0.2 (AIJIUS' 8, 2016) (8/8/16) 
4 

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182
A. MAJOR DEPRESSIVE EPISODE 
At 
Were 
01 do"'ft. Of ftlt sad, tfi'Ptv oc hopde:$$ 
tnOSl of the day, 
f!WfY 
fo. twO WH\s? 
IJ NO, COOl NOlO Alb: IJYUA.Sk: 
b fgr t"r PW 1w9 Wftb wt'fC yocuStptC'Sk-4 or down, or fdt sad. tmpty or hoPfJc$$ 
MOM of lhe 
Al .a Wertc 
much less intetesttd In tTI«MI tNnp or tnuth teu atilt to 
thlnp you tJSotd 
most of tM time. f« 1wo'Wftb? 
b fn tM uu 'W9'dttkt were ¥'0'1 much less tnttl'ti1ed 11'1 most thln&S ot 
mud'IIHi abk to tn}ov the thlnp YOi.l us-ed to et\JoV. mon of lhf. trme 1 
AJ 
W Alb 011 Alb • YlS: I.Xf\f:Ml lHl cu•Dn N«J ntt MOSJ SYMnOAM:nc I>AST lPGOOl, OTiflawtSt 
If' Al b AHOAl:b • NO:f#\Q«[ OH\ ' n.t MCI)"T$YMII'IOMATC I>ASl 
• 
.. 
.11 
W•s yOur 
<N 
nearlv twty 
Did voor 
wtieht d«rtaSCI: « lncrNse whhollt h'V\na: 
(I.e .. by tS" of 
bocfvwtl&ht or :t81uw J: l.S k&. fOf 1 160 lb/10k;a 
1t month)? 
" vu ro 
coot: n:s.. 
NO 
b Old you 
trO\ible 
nuttyewry nieht 
HO 
(d•fflcul'ty f.MIInca5lec-p, Witlnc l.'P In the mlcklle of the: nief\t. 
taffy mornin& 
or 
e.r«ufvc:lyl? 
c Old V'Oit talk Ot mO¥e 
Slowly 
or weft you tldcefy, u•sUeu 
• 
Ot hiW!c trouble:: $lttfna stiU almo't tvc:rvd•v? Old 
notice thiJ? 
ltYU,.A$11;Jc.UAMP\.U. 
UoiWII.Of 
IUINOIOf GUill, Oil 
01 NUOINO 1\l.<aS.ItMtHf Cit OCWSIQf6 Of omASt 
Of.Ant Oil HIHltJSTlC Ot 
nc 
f+lt 
wmtADE1.1.!510NAliOEA. eurr-t ..... 0Ho 
, ... r--"e 
0No Ovft 
Old you 
dtff"JC-..tltvcona:ntta1ln& thlnk,tnc Of makinc 
NO 
criry day? 
Old you 
thlnltab<wt duth (ru.• OF CJTINGOOUNOl CCXIHT 
NO 
or havre .any lhouJhU of killn1 
cw have any intent 
Of $11111 to kil youtsdf? Did you llllle:l'l'lct 
If m TO flTHU. coor m. 
Old th<HO 
tai.IM: 
or probf.tm• at home. 
NO 
wotlt:. n s.chool. soci.».lly,ln your 
ot In sornt otMI 
w1f'l, and 
thf-1 a 
from yout ptevi<M.I$ funcUoninc? 
M.I.N.I. 7 .0.2 (AlJCU\t 8, 2016} (818/16) 
s 
VIS 
VES 
VES 
VIS 
vtS 
VIS 
NO 
NO 
NO 
NO 
• 
NO 
VES 
NO 
vtS 
NO 
NO 
NO 
NO 
VES 
NO 
VES 
NO 
VES 

Protocol 331-201-00061
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Version 2.0, 7 Jun 2017
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.
Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
183
2 e-I)ISOdtS or depresSion. Clid y01.1 ever N'lf: at1 
ot at 
2 
months. w'hhout .tny sicniftCant df!presston or 
toss of lntctt':st? 
MI. S 
MOitl Am'WUS (Al..U) COOUI YU AHO 15 A4 COOC.Ol'O 
f(* 
TMC IIIAMf? 
...... 
It ASI:!o COOfOWS. coot 'ttS fOIIatC\/UtXr. 
A6 
a How m-ony CpiiJodCS of 
did y01.1 h.we In '(OIIt i fcUme? __ 
MJ,N,I. 7 .0.2 (A\! IUS\ 8, 1016) {8/S/16) 
6 
N/A 
NO 
YES 
NO 
YES 
MAJOR DEPRESSIVE 
EPISODE 
CVRREN1 
PAST 
IUC\JRREHT 
0 
0 
0 

Protocol 331-201-00061
Confidential - Proprietary Information
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Version 2.0, 7 Jun 2017
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.
Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
184
81 
.,. 
.,. 
8l 
83 
.. 
., 
87 .. .. 
810 
811 
8ll 
8. SUICIDAliTY 
In 
pa.st month did V(KI! 
t-Vve •I'IY ac:dden.ttll'li1. indudes takifll too mudl of .,our mediCWM •dderullfV. 
• HOTO 81. SA» TO 82, Ill 'f(S.A)I(81a· 
Ptin Of Intend to hurt VO'!tSC:IC rn -.nv acddent. titl'lef by 110t •voidln.a • rtlc or 
bv (;)Wtc Ule acddtt\l on 
.. .NO 10 81a, Slll> 10 81. ,, \'($,. ASc 81b: 
Intend to d'c IS a rcwlt of any 
Thinl: (own momenl.lrilvl ttt..t vouwould bt bettCf orr 
q, wi$1'1 yew wet"c:ckad or 
to be dc:ld? 
Tl'IW: (twn MOn'W!tlUrllv) about hlltmir\1 or of hunlne ot of lnJuril'IC 
·wht'l at le1.st some Intent or .W<IttnUsthit yov mieht dilt IS • re1ul1 
• Of think ;,bOut 
•bout tfiHncyour$¢11}? 
.-NO ro at • 8l. )41> ro 84, on.O;w4f ...sa:: 
O«.askln.ally 0 
Ofttn 
0 
Vc:ryofte:n 
0 
..... 
0 
Modt'fllt e 
0 
Sc!l.'t'fC: 
0 
Hur a VOic.e Of VOkes relllnc you to \:11 yourSelf or h.lvt drC:aJM with •nv suidd.al 
U 
C 
Thint about a11v tllsk vou would De- to comJ*te btfetf: li'Yint to Ull 
(c.e. WW"lttn& ill wld6o nota) 
Intend to ;Kt on 
of kl llna you..,df? 
F YU. m¥11: etthefor boch: 0 
ctld youll\ttndto an at 
dmt1 
0 
did you ll'ltetld to Kt 111 SOf'Y'Ie tlmt 11'1 W 
lni*nd lOdM! •s a rMUitof a 
• YU. mark either or bolh: 0 
did V'Ot.l lntet'WJ to die by suidde u lhe lime? 
did you intend to die by wi<ide lilt some bme in the Mure? 
NO 
NO 
NO 
NO 
NO 
NO 
NO 
NO 
NO 
NO 
NO 
Ftel 
n«e1 Of impulse toldlfy011f$Cifor «> p&,n to 
5001\CI 
Ulan latCC'? 
NO 
IF-YO.. mMic Cttnet' o r both: 0 
wu this to kill yoursetn 
0 
w.s thl$ to 
to lr.:il 'I'O'IfS4!1f? 
WYN, M:ld .,llMr flor htlth• t'l w•\ thl\ llortlifv 
M 
-
1,_\ prfWI!'Ibotl) 
1!11 ASSl'SSIHG YnlnlllR n ttl WAS WGllY UHPII.I:M::MlOASit: "S mbltes be(OfC 
thb. Impulse-, 
V041 hJVC prtdk ttd K w01.11d occur •t lh.at timer 
HO 10812, S(IIJ to 814. 
M.I.N.I. 7.0.21Aui'JSI8, 2016) (8/81161 
7 
Y£S 
I'(S 
Y£S 
m 
Y£S 
Y£S 
0 
0 
0 
• 
• 
8 
8 
8 
8 
8 
8 
8 

Protocol 331-201-00061
Confidential - Proprietary Information
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Version 2.0, 7 Jun 2017
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.
Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
185
81) 
.,. 
814a 
8l4b 
814C 
815 
••• 
.... 
816b 
816c 
817 
818 
819 
rq-yc Olt11C:UI1y tfli)\l"l lNM: lmpu!S!n t 
NO 
m 
• 
Take 
actM 
to 
f« • sulddt ntempt In wtlkftvou 6Pt<tfd 
Of 
to dlot (lnc!We •"YtNnc done Of CKffpos.cly not clone 
p4.rt YOI.I dostr 
a $Ukide 01U.empt)? lhb 
t.met when yOu were aoln& to lr:iH yowsctr. 
btlt 'ftft tfttttrupttod ot st()9pe(l yours.etl', bfofore hatminC 'fOU/Setf. 
NO 
YES 
• NOto 614.stl"l081S. 
T•tuatvutt9S to 
to kll 
M vou did not stare die! suklde <Jtttmpt? 
NO 
Y£$ 
• 
lakl:•ctlve Sttp:s to pcep:uc to k•voun«lf, b.rt then you $Copped yourselt just befo.-e 
NO 
YES 
10 
hatmtinc. yourself t•;abotted"' •• 
Till:e.aai¥·e 
to pee-pare to kia 
but then s.omeont or somethlnt 
Uopptd you JIJSt bcfOte l\¥mlfW yo..IBC!If 
NO 
YES 
11 
tnjure yoursetf on 
without lnttndlnc to ll!ill 'fO':f5tff7 
NO 
YES 
0 
Attempt s.uldde {to kill 
NO 
YES 
• NOlO 816, SkiP 10817. 
• wkide atwnpt (to \ill yourwtf). but thC!fl yOu d tc&ckd co stOI) 
NO 
YES 
12 
.and did not finish tM oltttmpt1 
St;an • wkide attempt (to lVII yoursetf). but then you were Interrupted 
NO 
YES 
13 
•nd did not finbh the •ttcmpci 
Went throucl\ whh a 
illltt'mPt (to kll 
<ompktely 
tne:iMI\ to1 
NO 
YES 
14 
A. S...rklde Dtttompt means you did somethfrlc where yOu (Otlkf 
bo lnj\lrtd. 
wim •• 
a SI:Jatlt Intent cod it. 
• HOtO Jlk.SllP 10817: 
to be rescue-d/ 'St.W'Vtve 0 
txP«ttod /lntendf!d to die 
0 
TIME Sf'£NT PlR DAY WITH A.HY SUIOOA.liMPUlSES, THOUGHTS OR A.cnOH.S: 
__ ,..... __ mlnutn.. 
aMOI.mt of ti'ne $pta.\ Ptf 
__ '-" __ mlnut<H. 
Most aMOUnt oi time s.pent 
__ ,...,, __ minutes. 
ln your lifetime: 
Old you ewr tNke" wlclcf,t attempt IllY to kll ycuNeff)1 
NO 
YES 
tt YES, hOW many times? 
tt YES, when was the list suldcle- aU.empt? 
Qment: wltHn tl'le 
U months 
0 
In 
remisSion: bc:t·wetn 1l oncf 24 months •eo 
0 
1n reMk$1on: mOt"c thin 24 months aao 
0 
.. A. 
:HtM'Ipt is .anv self inlul1ous behavior, With at least 
(> Otto die ti 11 tesul\ ot the! a<t. £vleltnte that 
the h!Mdual 
to kilt t*"·Of 
at ttut to-some dqru. c•n be explidt Ot Inferred ftMI the beh,..lor 01 
drtumsttnce. f'or txllmplo. fl. I$ deflntd as .a widde mompt tf lt b de: .a,... not an •ccidtnt or If the-tndMcht•l tNnts the 
act C(M.IId be letNI. tvtflthou.&hdoonyina 
(R>A Guld.Mte fOt lnckatty Suitidot Ideation and 
Document 
2012 •nd c.<ASA detlnltlon). 
Ket al Am J Psydllotty 2007; 16' (7): 10lS.104l & 
ODP'l/www te Wl'PDr'95f'R¥USpmp'!C£dmri'S!t'*Wtn 11!re'9ui5'1Snl9")@ nsmt 
How l.ltfy ;are V<M.I to trv to Ull Y'(IUr$df within the 
3 month$ on a sule ol O.lOOK __ ,. 
A'ff L*£LMOOO>O"-OH 8199tOI.A.ON:cootDttS 
NO 
13 
MJ.fU 7.0.2 
8, 2016) (8/8/16) 
8 

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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
186
lta.AOOM 
lMlN6W'UIIo(I14UtocCXJD"'ftS' .t..'G 
l'tOrY nc 
IClOIIII o.n..,."' t!I1CIICA'I o., n.t OMl.-"''IJne ecr 
IIOCAn 'MI« nca tMt tuClCito&.n'r ao..ut..trt (""" UGNllt) Oil, A 
$loiCDl A.TrtMn 
OIIOf'lt ... .....,.,..hit 
Olllft.l.b"toGmMlOl.,ntOf 
• Nl'l 
lillJI'O'iiW: • IJ.t 
llk OINft' r;w SiJ'UO 1'11 117. 
UttfMMilwt • lll oootOYU 
Ullt.•• '"I,...-. fvt\111." IUCDOtDns.. 
Of 
Ni10 111CM fUT\.Il wo:lrAUfY "" M SHCIIIUOW' 
W.f\ the s..tdciM tc.t 
whtn 
wu !'lOt In a 
Of 
cw 
dehttum? 
Wu tM Wlddt11Ct ctotlt' withOut • 
II VU. $1'lOI'Y 
IHC CIGOI.Ollt G OJML-'fi,IN tAAI.Y fi£MtSS.I()H 011. 
1rot H L7 O.l 
lOll) Clll/16a 
9 
NO 
YES 
SUIOOAUTY 
... _..Low 
0 
9--16PO*IU Modtnte 0 
!: 11 pciM(S ....,. 
0 
C\IIWXI 
0 
Uf(TIM( AntMPT 
0 
UK(I. Y I.N .. v.- IVTUit( 0 
NO 
YES 
SUICIDAL BEHAVIOR 
0/SOROCR 
In tM'f remhWon 
In rcmit;slon 
0 
0 
0 

Protocol 331-201-00061
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
187
C. MANIC AND HYPOMANIC EPISODES 
Do yOu 
III'IV familv hiSt ory of 
lllnoeu or bipolar diSotdef, 
or ¥'Y 
me:mbc.r whQ ho1d mood lwlnes ""att'd wl'h • medication IOite bthium, 
socltum v11lproate (Oepi!Wte) <w 
OilS QUtmOH IS I«JJ 
1011 
fOWCNAlt 
Oil. QI'QCW(s 
MOll'! " 
KM llrolM lltSOIIOtA. 
ct • Hlvt vou e\'C"r 
Ptfto6 or thtwt\.tn vou were ffflfnc 
or 'hl&h' cw 1lyper' 
lind so tct.i\oe or hi II of tnctl'f or full of yourse-lf th.)t ycu tot itlto uoublc, • or that 
otMr 
ti'IOusf'lt you 
not 
U:WaJ 
(Do not 
times whtt\ 
lntoxbttd on df'IIJ$ or alcohol.) 
.. PA OI,Ht' 15 
UHCl.lNI AIOUTWMAJ 'fOU MfA'f 
tt''vt' O.'HIGH' 
'"""-l",QMIN AS IOUOWS: 8y'up' or 'hill'' Of 'hyper' 
II"M:an: Nvtna el11tC'd m<IOd; 
tl'lt.tiY or lnueued act.Hity; 
teis .).\Hp; 
r111)1d thou«f''u; 
full Of kkoas; 
bcreue In ptoductMty, rnotl'tatb\ 
att.ltNity, or 
bd'lavlor. pl'lonlncor wortinc excesslvtty or 
mote f'tiOI'Iey, 
.HO.eoofNOtO C1b: 
b An 'fOI'currenov 
'\lp' or 'hllf'' or 'hypf't' or ruu of tMfJY? 
Cl 
• 
Hlvt you 
Ptfsb\«<lly rrrit.abJt. for 
I dii'YS,.lO ttlat you 
Nd -.uments or verbtl « phy)lul fi&h\$. or 
at 
vour family? Haw you or othen nocked t.hlt you hh'e btton MOre lrTitil.bM 
or owr rc.Jcted, 
to other pt09fo. 
W. 
tNt you fch 
'M!til' justifle<l1 
NO 
HO 
NO • 
HO 
(3 
• Q.b Olll C'Zb • YU! !»lOU THl CUIIUtlHT lJ'GOOl lllltST A. "tt tlltH Oil MOST S'I"MPJOMA.TIC PASt tf'tSOOt, 
• Cl,b AltO C2b • NO: 1»1.0*1 
ntC MC»'I' SYMI'TO!AA TIC I>A$1t11$00C 
WWOifXI"llIUHG Oil C\SJUU.Nl lrtSOOl,. PfiEfACt lAOI QUU1lOH AS I-OUOWS: 
ow,, tbe PHt ff!W days lndl.ldlnt 
whttt you felt hlp tnd full ol enern or ltr!Ublil', dkl you: 
rwt tASt ti>I$CCI(.. Net ...a: [A(HQIJUnCIH A>t-OUOWS: 
ow,, • period of • few d.lys tn ltle pu t, When you felt mon N&:h •ncl 
full of M CflV or mon Irritable, did you: 
a F«< that you C04.1'd do thlnC$ othttl coul<fn'\ do, oc 
YOI.I wert 01n 
NO 
imporunt person? • ns. A.SIC KIA txAMPtU. 
nit (li.A.MPU$ AAt CONJ4TtN'I' WI nt A OUUSIONAliOtA.. 
Oln""' tpiM>Oe 0 No 0 
0 No 0 Ya 
M,I. N.I, 
8, 
(8/8,116) 
10 
\'£S 

Protocol 331-201-00061
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
188
C'uuen\ £prlsocfCI 
( 
Talk too tni.ld\wi\hout stoppinc, or fC!It • PfC!UI.n 
ulkinc? 
NO 
• Notkc '(04111 thlxi&:htsaolnc ""rv filtt Of n.mnlnc 
01 
NO 
or movfnc vtry qiJickt( from 
to anoc.hef? 
• 8ec:ome usly 
so that any little 
tould dlsttil« .,.ou? 
NO 
Hive il 
In your MtMtY Ot 
at won;. ilt s;c:hool, 
NO 
soc;i;ly or kXuatlyOf did VOU b«<Mt physklly 01 mcntilllv rCJtle»? 
TNs 
In 
May bt wrth or withOut a 
• 
Wilnt so muth to enMt: In pkiiSUtallk! actMties.lhn you !&noted lhe rtsb Of NO 
cons.equt:I'ICces {f« ex-..mple. 
Sptt:H. r«::dess drMna.oc KI(IJII 
lndiKreUOn$)1 
0 
SUMMNIY: YIHtH lA n..-.c; 
NO 
If Ob 1$ NO, AAt-4 01; 
ClfCOOlOYts? 
II Cl b CS VU. AAc: ) Ofl MOM 0 A.'i$Wtal INQUO..O O f COOC.O 'IU? 
If' (hiS HO.AIIt 4 Ol MOAt' ClA.'GWUIS.II'ICWOIJII(i Clf cootOYU? 
rt (Ia 1$ YU • .Ul ) O«MC)Ite C3AHS'W'lii$1HQUOIHI; Of (:OO(.OYt$? 
IIUlt: W OO'f/WANSNL'U.SS 
O'ol.Y ] Oll'tft 0 
W'91U 
.., 
....... 
tttt O$YM,Ot.tS. 
G4 
WNt i:i the 
tll'nC! \hete 
lmos.t of the d*V MMtyevc:ryday)? 
C1 
ASSUS IH&OIJAAOOH llOM rt« 'IUn'SlMt 10 till VUY tiro Of SYWPlOMS. NOl JVSt tttl rtAL 
a) 3 eons.ecuttW days or 
b) 4. S or6cons«utNt:divs cw more 
e:) 7cON«V1fvt OilY$ or 
Old 
JY'f'lptornsQ\ISCI' 
proble:ms ill home, at 
s.od.fllv. 
In ';'OUt rciJitionsh.IJ)s,at Sd'IOCI orin s.otne olhe-r itnporunt 
NO 
NO 
Wtre 
usoc:l•t«< W'flh 
kt IMvnvtNt you 
HO 
previously fuoc1ioned 'nd 
w"'" diffetent ftom tht-w11v tNt you 
Mt C)WMM.AIIY ANOO NU) ((.4( o-.CSOA(I5 011 N«n'f010t1C fi:AT\M[ IS 1(1 
COOfCWS? 
.... 
IS •lUll OU1 Olt!N«CAU'Sl (02 SUMMM'Yf COOlOYU? 
M.LN.I. 1.0.2 tAIJCUS' 8, 2016) (8/81161 
11 
ru 
m 
m 
YES 
m 
m 
0 
0 
0 
Y!S 
NO 
NO 
NO 
NO 
NO 
NO 
NO 
NO 
NO 
NO 
.,., 
It$ 
.,., 
It$ 
.,., 
ru 
0 
0 
0 
ItS 
ItS 
YES 
MANIC EPISOOE 
CURRENT 
PASt 
0 
0 

Protocol 331-201-00061
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
189
ts () SUMMMT (OOlO Y(S.\HO AM (:5 A"lO (1$ CCOC.O JrfO olo,."lO 0 (00[0 'rU. 
lo.'d:HUitltU CAb Ot (A( COOfOYU1 
... 
& -.uu_ 
(OZ SUMMMYr 
.... 
Mt AU tS'\'OIOTICUATUitts IN Kl tlsiiOIJGH 1(1 Q)O[OMO? 
AU 0 
SUMIAAJ!V AAlO (4a COOlO 'fU AHO IS CS COOUI NO 1 
• YU JOCU!tUHt MA.H1C l'ISOOf OllKWOMk'IC tHOO£. 
nuN COO£ CUUIVIJ ffYJ'OM4.'<11C SYMf'JOMS AS NO. 
• Y!S tO PAS! MA.'<IIC llt$00( OA 'tU 
tn1JOM.4.+41C 
DIUf COOl •ASt H'Y?OMo\.'<IICSYWI'OMSASHOf 
If MA.'<IIC lJ'lSOOt ts I'OSOI'Il '0C t.llltl• OJM!Ml Oil 
Old you ho1vr: 2 or more of tht'Sof: 
r:plsock,.lfstfnc 7 days or mOte (C4<) In '10'1' 
' Jttin'le (ll'lck.ldifta the wnent 
if 
b)W MANlC OA lm'OM.-....c li1SOOl &Nldltwt 'Oil tn.._Q.IM(Hl 
A$11:: 
Old you havr: 2 or more ql thtw (hypomanic) 
4 
or more ((4b) 
1.\ your llfeUrne (lndudln, ltw! WITel'lt epl$0dt)l 
cJ" ntH 
svwroa.u" 
HYPOMANIC EPISODE 
CUAAtNl 0 NO 
0 YES 
PA>T 
0 NO 
0 YES 
0 NOT EXPlORED 
HYPOMANIC SYMPTOMS 
CUMtNT 0 NO 
0 YES 
PA>T 
0 NO 
0 YES 
0 NOT £XPLOREO 
NO '" 
110 '" 
Did yqu have 
hypcwn.anlc s:ymptom.s lutina only 1 to l days (CA.a) 2 or more lime$ 
In your ltfetlme, (iMiudlnc lt'lf: wrrtnt 
110 
V£S 
M.I.H:.l 7.0.2 (Au&ust 8. 2016) (8/8/16} 
12 

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189
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
190
D. PANIC DISORDER 
01 o H.wovou. on 11'1010 thin one occMion. 
S9db or att.cki" when you 
wry frlthtenc<l, uneomforuble <w une•v. cwn In siW.Jtlon,. 
where most people WOIJI6 not 
t.Nt 
.. 
NO 
.. 
NO 
.. 
02 
At 
tlmt 
did 
of 
or attKk.s Comet 01\ 
NO 
oroe<vr In an 
or unprO'o'OArc<l m.Jni'ICf? 
Ol 
tQve yoo 
Nd ont wch .Jtt.adt 
by a month or more of per.slstef\1 
NO 
04 
OS 
.. 
• 
• 
c 
d 
• 
" 
(Qn(Cfn abollt 
Of worricf about 
ol tho attack .. 
«did vou mate 
eN nee In vour beh.rvlot btt:Hse of tht au.aotU te.a ... 
sltwt.ons, 01 r;oldln&lea>Ms your hol.tse Of 
dolnc thin&l 
to avoid Nivfnt • p.Mic llt1.Kk « vi.Sitklc ycur doctor Of t.hl: tmerrencylOOm mote frequently')? 
OUrinc the wof1.\ atudc that you can 
Otcl you Nvc sldpp1na. r«ine oe pooocSna of your htattl 
Old you hlw swntklc or dlmmv hinds? 
trrtnblil'll ()c 
Oid you Nvc shortntss of brt.Jthor dlfflcuhy breathlna or a smolhcrin:c 
Old youl\ive a cholcf.nt s.c!ttUtlon Ot a lump In your throat? 
Did you l'lave 
pain. pressure ct dbcomfan? 
Did you !\ave 
Slomkh prObtc-nu, or sudOM 
Did you fcc:l dauy, 
or 
f•ln'? 
Old J'Oiol N'lt hot l'k.tshft or 
Old 'fOil haW! t1nJ1fnc or M.ll'ftbnt$S In 
ol 'fO\II body? 
Did lhinCJ a1ound you fed s.tra.nce. 
det«.hed or unfamiliar, oc-did 
'f'O'I ff,t>l CXIUiele of or dt>txhed ttom Pitt« all of VCUf' body? 
Did you ft>ilt tNt you 
kKinC (OIIt(Of or p,._, u azy? 
m Old you rear lhlt you were dyu'£? 
Mf tolM D) • .-..'110 4 <*MOlt D4A.'4WUS,.«CC(O'r'U? 
tn tht I)Ht month die! you 
CQnC:Cfn 
•notkt'f 
orwonv about me 
of the 011ttadts, 
01 did you cha,.e VOfJ' btha'llorln •nv 
ol the •tU>cks? 
M.I.H.I.. 7.0.2 (Atlfuil8, 2016) 
13 
NO 
NO 
NO 
NO 
NO 
NO 
NO 
NO 
NO 
NO 
NO 
NO 
NO .. 
NO 
NO 
"ItS 
"ItS 
"ItS 
"ItS 
YfS 
ru 
"ItS 
"ItS 
YfS 
VI:S 
"ItS 
"ItS 
"ItS 
"ItS 
VI:S 
"ItS 
YfS --
"ItS --
....., 

Protocol 331-201-00061
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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.
Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
191
u 
n 
u 
" 
" 
£6 
IIUJtltf_A OS 011 06 coot.O ru? 
NO 
YU 
... 
PANIC OISOROER 
IS "RUU OUI 
(OlSUMMUY)" COOI:Ol'U? 
E. AGORAPHOBIA 
l)oyou 
uneuy ln pla<t!S or $1tu.itklns 
hdp mJahlnol b• 
UF£nME 
aJRR£H1 
Ot 
be dlff!Wit if '(OUI\ad a 1»n1c tattadt 01" JN;nlc.-litt 011 
Symptoms., 
beinC In a crowd.« 
t. aIM {qutue). 
bclna In •n 
or whC":n cronln& J bridp:, 
beiiiC In an e-ndo5cd $p.ace. 
whtn you 
alOne i1WI')I ftom hotM", ot atone at homt. 
• 
« lTfvt:linl in a bus. ttiJn Of C¥ or Y5lnC publlit 
NO 
• 
Mt 2 
MOI:t or flU A.IOVt $.1f\IAT'IOINSW (1 COOlDYU? 
NO 
• 
Oo 
sltu1tlons ahlost a1ways twins on 
or 
NO 
• 
Do yOu tt:tr 
thu.nlons so nwch thAt you 3'V()Id ttw:m, or 
NO 
lhrqh then\. Of nH<J a compW\Ioft to f.Ke them? 
• 
U thb fi!Jr or Jt\ldt>tyt:xcMsNt or out ol proportk)n to the ru1 
11'1 the! 
NO • 
C*l tl'lls ,...oldan«, 
0t al\ldetY P«siSl fOt Jt lea» 6 months? 
NO 
• 
Cl'cf 
t:ymptoms ausc 
dbtrw « prob\cms al hQITit, 
NO 
at work, iOdally, at sdtool or in some other impcHUnt W'f? 
1$ (6<:01)(0YI:S? 
NO 
vts 
vts 
vts 
I'(S 
vts 
I'(S 
CJ 
0 
YES 
AGORAPHOBIA 
CURRENT 
MJ.N,l 7.0.2 {Auaust 8, 2016) (8/8116) 
14 

Protocol 331-201-00061
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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.
Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
192
F. SOCIAl ANXIETY DISORDER (Social Phobia) 
f1 
tn the 
moMh.. did you 
ond slCftlfk.Mt ol\klety at btinc winched, 
belna the focus 
or of btklc hun1o1ll<lteod or 
or rek<te-ct? 
Thls rncluodn 
spe•kinaln PJblc. eatlllJ 1\ 
or wleh oehets, wridnf 
wt111t IOffltOI\t watches,. perfonnlna rn ftont ol othcn or btlr\&ln 
sHuattons. 
OAMPl(S Of" SI.ICM SOCIAl 
fYPICA.UY INCWOl 
C)jt MN.'<YN.WI(f A (OH'411SA,nQ!ol. 
PA.t:TIOPAtiNG lH SMMl GIIOUf'S, 
....... 
!ftMINCi 
AffiNOINGf'AitiKS. 
-·-
tAll'>G IHtiiOHTOf Ol)tUIS, 
la()HIOf Otlt(-s. 
l.lt!NAlWCi IN A NIUCWAStt*)OM, nc, 
Fl 
Ooyau f.t<l' t..hese social sltwoons so muth 
'(04J 11WIId them. or ScJfft:r 
thrOUJ.h lhtm. 
o ComPAnion to f•ce them 1 
fS 
otd thb sotlaJ 
or anxietv 
f01 ot lean 6 months? 
f6 
Ofd these sodal 
<;aose 
dhtres.s Of lnl*rfere with fO'.jr ability 
to funulon at wort;. atKhool Ot $0Ciii'(Of ln your rti•Uonshlps Of 
In SOn'le otMr lmportMt wav1 
tsf6cootom ? 
..... 
t5 .,.uu_ out OIIGNOC c.wst (01 SOMM».Vr COOlO ns? 
f«)tl tO 
I'UAS( 5't0fY_, M SUlllO"SHAASMf JtUlacJtOtOSitMiNG 
l'lt P\IMJC. 
M I.N.L 7.0.2 (Aupt 8, 2016) {8/8/16) 
lS 
NO 
• 
NO 
• 
NO 
• 
NO 
• 
NO 
• 
NO 
• 
NO 
vrs 
ru 
YfS 
rrs 
"' 
vtS 
YES 
SOCIAL ANXIETY 
DISORDER 
tsodotPJtoblo) 
CURRENT 
RtS1RICTt0 TO PUFOAMAHct 
0 

Protocol 331-201-00061
Confidential - Proprietary Information
192
Version 2.0, 7 Jun 2017
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.
Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
193
Gl• 
Gil> 
G2 
G. OBSESSIVE-COMPULSIVE OISOROER 
In the PMt month. 
you been bothere-d by 
thOuChf.J. 
or 
IMip!i tNt 
(For 
ltle 
th" you were dirtY, 
or hid lt'fi'M. or ftc¥ of 
Of fur of Nrmlna somf'OAt 
lhouch h db-t1.14'bsor dbUaWJ 
yOu, or 
you would att on some impube. or fl!ar oc 
th.lt 
few Lhll'lf.S tolna Wf'OOI. or obseisiom 
01 itnp(,lhti, Qt rc:IIPoc,ls ob$cSslon.S.} 
In the 
month, dkt you tty to 
these tt'IOIJ&h\S,Im.PU'Isrei• Of 
II'I'WIIft or to 
or to rtdu« them Wtttl KlmC! odw!r 
Of .cllon? 
UFtl'tiOIIltM:S. OOH01 
l-.QUOC: 
$G<t 
llOO't 
DI50M)UI, UllNG 0601U)fflS.,SI.XUAl OMAnot6. 
IKCAIJU nt1 PATUHt tAU 
()(1M. 
IIIIOM 11CACM'Y 4.'10 MAYWIJ(f 10 
(Ill 
11S ktGAJM 
Did 
ttoep 
blck il'ltO '((Kit mitd ewf\ wtlen you ttit'd to ilnore Ot 
set rid of 
1 
In lht pas-t MOJ'Itf\ did y(IU ftfl ct.iven 
In 
to an 
obsf:ssion Ot In 
to 1 riJ:Id nh,lib w.as.hina Of 
or 
d'ltd:lnl thii'IJ$ 0'/tr and ovk, or repeatint or arun&lnJ 
ot 
G3b 
Alt:thHe tftuab done 
or 
a.niletyor dl!tr!US or to 
bad from htppen)l'lf 
<lre lhey Vttes.slw! ot 
G.tl 
tn the pus month, did thnct ofmossr..-e thol.l&hu 
bch.rvlotl 
cause iolp<lirk.ant distrM.S, otlnurle-e with .,.cur l)biiiW to funttiGn 
at work, at 
sd'IOOI ot 
In you.r rttltionshi!M Of' ir\ sotl'le othef wporunt 
or dkt they 
t.a!.:e mor• thin one hour 
5 ·NJU.OI./1 OI'GA.-.c: (.MIS( co2 
COOfom ? 
(CHIO: fOil AK1 01$U.1Nt C0MPUU1V1 SYWtOMi 
'M'MN l WU:lS Of AH 1'4rtCTIOH) 
M.lJ'U. 7.0.2 (Au,UU3, 2016) (8/8116) 
16 
NO 
ns 
J. 
NO 
J. 
NO 
NO 
'ItS 
'ItS 
'ItS 
"'' 
I 
I 
.. 
NO 
'ItS 
NO 
YES 
o.c.o. 
CURRENT 
INSIGHT: 
GOOO Oil fAIR 
0 
POOtl 
0 
AIISrnT 
0 
DElUSIONAl 
0 
TlC·REl.ATED 
0 

Protocol 331-201-00061
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
194
H. POSTIRAUMATIC STRESS OISOROER 
{• M(NfS: GO 10 fH[ Ol.tt4NOSnc 100(, OflW NO, A!C> MOVl TO 1'Hf NlXf MOOt.IU) 
• 
HI 
Hlw you ev-er e.Kpetie:nc:edor w•tnessed ot had todtal with an 
uaumotic 
NO 
YES 
tl'lit lnduc:lt<S adull or 
dt.uh cw M'riou$ll*'rv or so.m 
to vw Of KHT!tone dMt? 
,. 
AnAO:. OUHO 
eocw, w"'-
Olt+IAt\IIIIAl 
'Milit'WHG lltl.\IIOU.Hf Ol suootHOfATMOF SOMfONfQ.QS( fO'YOO, 
OIAtlll fltMAJOII!iGUHUS. 
• 
H2 
Statttnc: aJttf W 
dld you 
t.ht event 
NO 
YES 
In an Ul'fW'anted mcnt.ly 
{wth ;u. in 
rdatod to tho CVM\ 
inttnst rt'COIMioruor 
0t 
trw: evetlt W):l f('(vtr.,.) c.r did you 
intense physical 
rean!lons when V(k.l wtrt reminded aboUt !he 
t'Yt'f\t or 
to a 
ewnt 1 
H) 
In the pa:n "*'th: 
• 01\d V(kl persistently try to avoid thW:itll <lbot.lt « remembMntdiSltes.slfll dtUIS 
NO 
YES 
orf«Unp 
to the cvtnt? 
• Did vou p.e,r$1sttmly 1fY to 
situatiO(IS, 
NO 
YES 
k-tiviCJn or thlf\&i th.a:t brina bKk dest.rt"Uinl recolle<tlons of ttlc event? 
• 
Mf: 1 01 MQlltC t4) 
CO«O YU? 
NO 
YES 
.. 
In the pMt month: 
• Did vou Nvc uouble tK.illlf'll S04"nnt ...,pottant 
ot the lt au Mil? 
NO 
YES 
(bill 
of Of r$ttd tO 
illcohot Of drvp), 
• Were 'f(WCOMUntfV and unte<floOnably 
vouu.ctf 01 others or thct WOfl6? 
NO 
YES 
< Old VO\I con:st;tntlv 
yourwtt or olhc:n In 
waY$ lOt ll'wt 
NO 
YES 
• Were '(04Ir f«:fn&$ 
ne:pti\o'C twth .» 
horrQf, ;tllJC:t.i\lat or V!01mc)? 
NO 
YES 
• 1-Qvc you b«omc much ln1 
in 
in Ole""""'"' tNt 
NO 
YES 
•re-me.mintful to you betOfe? 
fed det.xhed Of 
fromothcn? 
NO 
YES 
• 
Were you 
""'Y &ood 
(wch a1 hOlppin.q», AtJ$faction 
NO 
YES 
Of Iewin& ftt'lit\IS}? 
• 
NO 
YES 
M.t.N.I. 7.0.2 !Autv"S. 2016) (8/S/16} 
17 

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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
195
H1 
c Were you mort MI'YOU.S or «M''St.tt\llyoo your cu¥cf? 
t 
Okl you Mvt more difflc.uhy 
the 
month, did 
c•11se $ianlfkint dlstrtiS. 
M 
your ability lO luntllon 31l I'IOnle,llt wed::, at 
SChool e. sodaltv 
your rdltlonshtps Of ln some otl'ltr ltnpottant 
S'tOI'Y ¥1 t!¢ CONontON IS 
ttO wnM OU(II:$0""'--'CAliOH, 
011 
WITH DUAYlO 
M.I.N:,I. 7,0..2 (AIIJU.St 8, 2016) {8/8/16) 
18 
"" 
\'[5 
"" 
Y[S 
"" 
Y[5 
"" 
Y[5 
"" 
vts 
"" 
vts 
.. 
"" 
vts 
.. 
"" 
Y[S 
NO 
YES 
POSTTRAUMATIC 
STRESS DISORDER 
CURRENT 
WITH 
DEPERSONAUZATK>N 
0 
0 
0£t.A't't0 EXPft£SSION 
0 

Protocol 331-201-00061
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195
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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.
Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
196
II 
I. ALCOHOL USE DISORDER 
In the pM t 12 monthJ. hfve 
3 or mort 
... wfl.hln ;a 
ll)(lt.W' per10d, ·on l M more cx:!Usi(mS? 
12 
In the pa« ll 
a Ol.wlnt the times 
vw 
•kotlot. did you end up drinkina more than 
you pUnned •'hen vou mrttdl 
b 
Wlnt to rtdU<e or con.lrol your *ohol u$C? 
Did you try ton.t dowl'l ot ('()f'ltrOI 't(klr akohOI uSC!-, but failtod? 
IF YU ro tri'MUI., COOl 'I'U, 
( 
On UM) d,yJ 
you cfnn);. die! )'011 
tlnw: obla!Mit 
*OhOI. drinklnc, Of rt(OWririC from the ttf.ets of akohol? 
t 
OW you Sl)t:nd leu Umoe 
'fOUl" 
work. 011 Khool. 
or •t homo, bcu1o11-e or your 
drrntil\a? 
H yOuf drlntlnc 
whhyow 
o.. otMt peop$e. 
did you stJI kft'P on 
1 Wert youintoxie.ateod MO«' thin Cl(l(f. itltlny 
you 0t oWrs wtfe 
ot risk, fOf 
drivff'IC a c.ar, r$dlnf: •motetb!U, usq mathintry, b\Ntlnt.. etc.? 
h Did ycu 
to use :.lcOhot. evton thoutfllt w;u deat th.lt the okOhol 
h.cl Qwstd or worst:Md psydloloalul 0t PhYsical PtObltms? 
Old 'f(lu redote 0t .,W up lfnCIO!tant wol'k, s.odal Of tffleallonal 
beuuse or your drinklnC;? 
Did you illltt'd to drink 
more rt.«det to cet tht satM- efttct 
yw tot when vou r.-n 
mttf!d dtlnldnc or did VCHJ 
much less effect with 
use of lht Unw! 
k! WMn '((IU cut down on 
Cit 
dtinldntdld vou Nove any of the fOIIowinf: 
l. inw:ast'd 
0 
2. hoM'Id trvnor or "'the 
0 
J. ttOtlble skepln1 
0 
4, 
or vomiUrc 
0 
s. heolrifll oc 
thlnf) otMt 
tould not stoe or hear 
Of Nvlna Knution.s M\your skin f.ot no 
rt.Hon 
0 
0 
7 . ..Werv 
0 
8. seilUtei 
0 
M.l NJ. 
8. 2<)16) (8/8/161 
19 
• 
If() 
If() 
If() 
If() 
If() 
NO 
NO 
NO 
'ItS 
'ItS 
'ItS 
'ItS 
'ItS 
'ItS 
YES 
YlS 
YlS 
n:s 
YlS 
YlS 

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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
197
Mt 2 01 
JZ• 
••ru 
10Cilt'Mlllcovon MCHL 
2-3 01 nc 12 $'I'W'IOtoiJ 
MOCIO.oltt .. 4-5 Of • a f"WWIMl 
wvut• 6011..-.0f Dlt Q 
lflllAIU 
• am:at. 'lOT WJIOIWfWlOI) Sl UCifll"16. 
.. SUStMCD llllJoMSICJIIII • OI'UM NOt 1C1 • 
1ZloiON'1160l WO... 
CJOnj wmt l'llllliCI"ttiftC. CM1JIOirj. CCM"""tAIIIM , 
M.I.N.I. 7,0.2 V<lJpt &,. 2016t (1/1/16) 
20 
HO ... 
NO 
YES 
ALCOHOL VSE DISORDER 
PAST 12 MONTHS 
SP£0FYIF: 
0 
0 
0 
0 
0 
tNACONTJIOU(OlNVHIIOtW[Hl 0 

Protocol 331-201-00061
Confidential - Proprietary Information
197
Version 2.0, 7 Jun 2017
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
198
J. SUBSTANCE USE DISORDER (NON ·ALCOHOL) 
(• MtAHS: GOlOTHtOIAGMOSJIC IOX,.CMCI.f NOAAOMOVtTOn« NOOMOOULI) 
Now I am &<JII'I& to $hOW you I rucf to you • liM of stffl:t dNP or medicines. 
n 
"' 
1ft 
12 months. dfctvw t.ake 1nyof\hne dNP mOlt than on«:. 
lD lt't hilt\. to IH:I 
to ce-t 
butt'" ot to d'laf'ltt. yow MOOd? 
OIIICU tAOI CNlUG I AJt(."i': 
Stlmul.fnts: 
"spetd", c:rysUil me-tl\, •cranl(', Duedtint, 
snottinc. rv. freeblse, u<Kk, 
• 
NO 
VES 
htro&n. motpti{M, ChbudJcl, opium, Oemerol, mtth.aclone, 
codeiM, 
Vlcodln, Oxyeontin. 
HaltudnoJtMo LS-D ('"add•t, f'ne:S(tlil'le, peyote, piilocyt)in.. STP, "tnuShrOOti\S"', •e<s.tuy-, MDA, M!>Mo\.. 
OiuocUtfvoe Orv.Jt: PCP (Phtflcydidinc :·Anld CMt", 
Pir, "'Has'"), or kc-LHnlnt 
K·). 
lnhl:t•ntl: '"&lut•, tthyt d\loridt, "rush"', niltO\.IS. oxide ("buaNna &aS"), Omyt 9C 
nltQtO 
C:anrw.bls: 
THC. "pot'", •lril»", 
Stdiltlw:S, HypnotJts or Allxlolydo: Qvilillude.,. Sc!<on.JI t•rtd$"), 
)YnM, Ubdum, AtMn. 
b¥blturJt6, 
Rooflno&. "Roofles"'. 
MlscellantOVs:: steroid'S.. nonpresaipdoo 
or dltt plh. Coulf\ Medicine? Any othtts? 
____________________ 
_ 
MIIGGfSl Pfloet.tMS? -----------------
t'Ht CllfTtl!A enowrO.lHtOIIUCIQASSCAIISINO M SIGGcst NOaUWA.-..OnU DHf MOSt um\' f0Mfr1UITr.b 
I.ISl OtSOMOta. 0' SCVI'MI.Oitt,IO c:v.$SUkAYt: I((NM$,$(0, 0:1'\.C*C ASMAH'I'Cl'IAS fEW Ailti.Qt.IIR(Ot'f nt( il'ttOIOCOI.. 
J2 
Comid«incvour use of (NAMtOfOfiUC/a.ullQAU.stUCTto}, in the 
11 months: 
:. 
Du.rirc the t.-nes 
you us.td 
did yoy end wp 
more 
NO 
'f'£S 
(HAMt Of OWG/OWG cw.s SUKJto) tNn you l)llnned when you sta.rted? 
b Old you reputedly 
to reduce <w conuol 
(JWM or O«UG I a.:oG CLAS.UtlfcttO} us-e 7 
NO 
vrs 
Old vou try to cutdown Of toniJolyour 
OIIOCi/OIUJGCW.SSlUctto)\lse, but 
rl· YU tO (JJW( .. COOC YU. 
c On thctd.:.'f' lhlt you 
(N.WCQII 
wtm.lnlbl 
NO 
YES 
time ObYil'lii'II(Mo\Mf Of OIIIJG/ flltl!GaASSSEUctt:O}, u$ina 
ot 
from \he its 
d 
Old 
Or 
a Stront6e$hOt urte tO Ut.t! 
DkUCICI.AS.SSULCif.O)? 
NO 
VES 
e Old you $tX'nd kts time 
your rewonsibllitlti at WOtk, .at school. or .at homt, 
NO 
'l'ts 
of 'f(Mif repeated 
OfWG /ORooo..msw:crm) use? 
tryour(I'IAMf.Of OltOCI/OlUCICI.ASS$lltCno) use tl:IU$ed proNetns wrth 'fOUf '"ml..,or 
NO 
V£S 
other people, did you .st\.1 keep on usint h? 
1 Old you use the drut more tNn once In .nv sltu.atkln 
vou or others were 
NO 
V($ 
.at risk. for CQmplo, drMns a c.•r. rldlna motcwblkt-. Vlinc rN(hincry, 
etc.. 1 
h 
019 'fO'Iol Wo!'\ln..,. to \IS. (lrW-01 Of> 
• ..,..,. 
It 
NO 
VU. 
tNt the (HAM( or 
tiM 
or worsenfod psydiOIOCiCM 
problems? 
M,I,N,I, 1.0.2 (MIIUst 8, 2016} {818/16) 
21 

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Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
199
• 
Old vou 
atvcup 
work,. 
bcoc .. 
of your ((YlMl ut l/lfllllll.i> I VAAJU UA)) )lU\.U.u} uw? 
Old you need to t.rSe 
Of OllJIJ I DRUG (!.AU $&UC1l0. II lot n-.orc In 
t:o aet tht 
same efft<l Wt 'fOil 
.,.ou first 
usina: h or cl.cf you ett 
effect 
with 
use of the satM amol.lnt? 
HO 
HO 
tHI!.CMftiiON ISCOOI:O ..,. 1 .. 
Mto.tAL 
U When vou cut down on heavy or prolonc«< \M of U'lf: df\11 did you haw anv of 
followlnc wlthdr-.-wal svmptonu: 
HO 
II YU tOtHfl:tctutfltOHUM!ItAOfWfn101lAWAI. 
coot J2kl AS 'ttS. 
sedatfv.e:s, Hypnotks 0t Andolytlcs (2 or mote wttMnw-'1 syM-J)LOM$) 
1. 
or lnc:reMotd 
rate 
0 
2. h-and ttetn« Of "'the shllkt-s"' 
Ci 
3. 
skepfna 
0 
4. 
or votnillnc 
0 
S. hearlna or s.«ln& thln&sotMf 
could 
or hear 
« 
in your stan for no app.atent rea 
0 
6. >aitollon 
Cl 
7.anxlery 
0 
a. $ei:wes 
Cl 
Opiates (3 Of moteW'Jlhdrawal symptoms) 
1. 
o 
1. NVMIII or vomillna 
0 
3. n'IUS<k ICheS 
0 
4, N-fWYV noM or tcatv em 
0 
S, dilated l)tJpih. 
bUMC)i Of hlir Stllt\dil'lf Of'l «<d 
Ofswutlna 
a 
0 
7.yawnlnc 
0 
a. hOt ftashei 
0 
9. ttouble sA«plna 
0 
Stlmvt.ntsand Coulne(Z 01 mote wllhdrwwlll svmptOI'ftSI 
l btitue 
0 
2. 'o'Md « unl)!euant drums 
a 
l. crcrr.wttv 
too much 
IJ 
4.1nututd iiPPt-tatC! 
0 
S. 
Of loot5n& phvSit.,lty or 
$IOWINI down 
0 
C.nnabJ1o (l Of rnOfC! withdrawal wmptem1o) 
1. .. ritablity, 
or a.gressi<M'I 
0 
2. tW!NttuSnoC!U 01 andety 
0 
l. ttOI.oble SSHpitll 
0 
4. app¢tite or wc:icht IOU 
0 
S. restiC!SVICSS 
Cl 
6. fMina 6epttued 
D 
7. siJnltkant diKOI'I'IfOI'\ from OM of the> fellowlnc: 
pain". trtn\011o or 
)WCIItlng. hot lla$hcs, 
<Nib. 
0 
HO 
M.I.N.I, 7..0.2 V\AiiUS\ 8, 2016) (8/B/16) 
22 
YES 

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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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16.1.1 Protocol and Protocol Amendments
200
AAt 2 OllMOilt JZ A.HSV.USIIIOM J2a ntiiOIJGil, JlkSUMMNlYCOOlOYU? 
(Jlkl 
12:k2 T'C)C;CTlft.t COUNt A$ Of.it AMONG llltsf OOCU,) 
MAD• l ·) Of n41Jl SYW'IOM$ 
MOOCAAn • 4-S OI 
Sl'VUI£ • 6 Oil MOIU' Of ntlll 
l'l tAAt'tii(MISSIOH • Ol'tllllAif01 r.ttf fOillffWtlN 3 & UMONtlCS. 
l!f WSl'AIH(O ltt.Ml$SION • CAJT£1'1A HOt MCf 101l12 MONU«J Ot MOU, 
{IIOTM wmt n1E C:xa:moNor CJiiii'TtiiiOH d· (CMW«i)J«WL) 
M,l,N,I, ?,0,2 (AIISVS' 8, 2016) (818/16) 
23 
vts 
NO 
YES 
SUBSTANCE 
(Drog or Drug Goss Nome} 
USE DISORDER 
PAST 12 MONTHS 
SPECIFY IF: 
MILD 
MODUlATE 
SEVERE 
W EARLY ReMISSION 
0 
0 
0 
I P<l SU$1 A!H[ 0 REMIS-SIO-N 
0 
0 
IN ACONTROU£DENVIRONMEHT 0 

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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.
Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
201
K. PSYCHOTIC DISORDERS AND MOOD DISORDER WITH PSYCHOTIC FEATURES 
ASIC JOA A."f OCAMPU or U.CH Q.l'ts1lON AN\-.ulO POSITM:l'f. ooot W.S OHl't IF Plf. UAMJti.U CUAAI.V 
otSTOII.TlO!'t Of OIOUGifl Ol Of 
PUUI'flOH 01: • lHtv Ml HOI CUltuAA£1. \' AI'NOfiiQA rt. n4t 'IJIIPCm. OJ OIG MOOUlt liS 10 (IOQ.Uot PATIL'fn WITH 
OISOIWU$. THIS MOOUU 
Dftltl(NQ. 
Kl 
.a Haw you ever 
tt\.)t 
wtte '9"'"' on you, Of tl'l:at 
.-c.alnst vou. or Wnc to hurt you? 
NOl'l; 
fOIWU OUf ACT\IM STAIJONG. 
KZ 
.a tQvc you C"Ytt 
J.Omcone wu 
mind or 
.. , 
yOUt tMuahti, Of thJit yOu cOUSd utualty reM S4mec>nt's mWI or he# wf\.at 
anolhtr penon won tNnlif'IC? 
Kl 
a Have 
belie-ved th.Jt someone« some fOrce outside: of 
Pill thovehu In your mind lhlll W«e 110t your own. or tnadoC! you act 1n a 
tNt WfS not 
'fOt.l cwr fc:tt ttl .at vou wtrc 
,........,, 
QJNICWI! 
OISCOU-'i"l A.'OY 'I'HA1 AAl HOI nrotOTK. 
lt4 
.a 
Hi'/4! you cover 
vou 
spced.al 
lhtoulh 
the TV. Qdlo, lntemct. 
bookl. or m.q"lnc$ or cNt <1 pct':$On 
yOU did not 
kno¥.' wu partkutotty tnterMted in you? 
KS 
.a 
yout rel.at!Yts or friends ewr 
of your bc!lkfs odd 
01' UI'IU$U,11i' 
QJNICIAH: A.SIC rOAIXAMI'U$. 0...'((00( 'I'U. Oil t:X.\Mo'I.Uo\IU" QUAl\' 
DC.WSO'W. IDf.loSNOI (J(PU)UOIN QUlSl10N'S KJ 10 U , fOII t'.fAWU.Q:IJCiiOUS,. OlAI"-
DG(A$( 
DlUISIONS<W 
011 Of 
t MLIII. INA!lt®N:t, IWN, Oil OUT11UTICIH, OIIIIIIHIU!StJC t>UI.I5.oNS, 
If 'ft'S TO VOICl tW.l.I.JCII(AT'IOH: W.U 
voke COMI'tlentint Oft 'f(NithOuiMS 
or 
<W did V'O" 
two or 
tilfldna to 
b 
WYUfOK6a: h.weyou ht:ttd 
in li'H! 
month? 
If' YU TO VOKl tW.WCIIIA 
\V.U lht> \rOICit COMITIItfttlnf on 'r'C'K thOUI}KS 
or bt:h .... lor or did '((KI 
two or mornolccs Glklnc to cachothtf? 
M,UtJ, 1.0.2 {AIJ&W: 8, 2016) (8/81161 
24 
NO 
VES 
NO 
YES 
NO 
YES 
NO 
NO 
m 
NO 
YES 
NO 
Y!$ 
NO 
YES 
NO 
NO 
YES 
NO 
NO 
NO 
YES 
NO 
Y!S 

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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
202
K7 
;a 
vov CM!:f had visions \\'t\l!ft you weto 
Ot h.IVC! yov evtn" s.«n Uwles, 
Oltw:t pcop1e: c:ouldn't Sct1 
QJNt(IAH"S J.UOGM[NT 
1(8 
a 
010 niE .,UI(Nl t:\UII!t Uif I'ASt t»tffft otSOIIGAHlliO, INCIOMtlfHT 011 tlUM.lO 
Sl'(tCH,OII: "'-.AIII[O I.OOSl.NING Of ASSOClATIOm? 
k! 
b e 
•.r.tJC N'f OJU.tNtLY tl01111'11'-IG IHCOiiUio.tt. 
CM 
VUCH, Oil 
MSOOAllOHS? 
K9 
;a 
010 1H( H.JI{N1 
IH(I'AS'tODtlltrOISOIIGAI'ftltOOI:(AlAl"ONIC 
KHA\1CIIU 
K9 
b 
G n.t•.r.-.N'f 
CliS<liiGA!'«<'EDCM (AJATQMC 
•HA.v.c»? 
Q O It 010 tHf fA llt:HT fVU l!'i flol[ .AST tfl.vt HtGAtM SYMPfQMS,.l.G. SIGWlCAH'lltmuctlONOJ 
tMOIIONAl 
OIN,(CIM "-Ant,.,'l.."'lti, POWIITYOf S'((Of 
A 'I INAaitl1'f 10 INfTIAl( Olltlt$lSlllf GQN.•OIIIIfC'1l0 ICMnl'S (AVOUIW0..)7 
K.10 b Ml NtG\I"M SYMI"l'OMSOf-sot:llOPI«I.MA, t.G. SIGNIFJIC#.H1 .._oucntlNO' tMOJIONA&. 
IU.ntNIHG, P'OVtiiNOIS'ltCM 
O&A.'IIHAMirY 
fO tt.lln.t.tt OII.[*SISIIH GON. •l*tC'IlO ACtMIIU (AvotmOH), HIIOMINlHI OUII.-.G 
MIHTUMtW? 
A.HO ISlflMOI: 
UtSOOl, (CUitUNT, •to.Mfii.HJ Oil tASl) 
.. 
MMIC Olllt'J?OMA.'« [MOO(, (OJM.l 'If 01 ,loSt) COOtOYU 1' 
ttOW lONG tiA) nil MOOO tftSOOt wrto? -;,;:==-
HOW t,ONG: "-')ttl( I'SYOtOnC li'UOOf Wlto7 
• SUCH A MOOO lH!OellS Nf.SlHT, UIOC m TO Klla O!ii.Y• flilMOOOOISfUUAHa t5Nf.5Ut1' 
rOll 00 MAJOIU'I'I' Of IHliO'I Al OUIIA 
Of ntl ACtlVl NID ltt.SIOUAL fiUIIClOS Of Dlt 
'S't'OtOriC $VMPl0MS. 
¢00( NQ, 
• NO 10 Klla A. 'lOtH[ 101A.LOUIAJIIOH OffM[ 
15 U$S ftiA.N IHt 
Of Pit PS'I"CMMnc: tNS00t. ottN CKU NO IN IIOlH 'MODO OISOIDU WitH PSYCHOTIC ftAru«U' 
lOW A.'«< MOVt.IO Kl). 
M-UU. 1.0.2 
8, 2016) (8/8116) 
25 
'ItS 
'ItS 
NO 
'ItS 
NO 
'ItS 
'It$ 
'ItS 
ns 
V£$ 
'It$ 

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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.
Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
203
II 
1410 me C«<ICf ll\l' ¥01i IWCI Ptftodti}whe'" YO'rol ltn 
Wtt• 
Mid 
ct«Ktibcd 
• M 
l'41t.OA 'UIOOOf AIU.Ut ZWU'll:it:/6 II.AVI..; nc.sc: leW'S 
..... 
-
M.UOIOI"Hili&M ll'liOOI: ta..:m• 
.. 
.,..,, • 
(OIMNl)cootom ? 
If 1'14lloMSW\•15m TO nil5 CltfiC*IIICU'rTIMI: OI.CUIIJIOtt].OICU 1110 to KU NO KJCA->10 
fO '"'NOn' tM)OUU 
M& 2 011: MOll& • b •QUUfiO'oiS (llt0M • 1b lO KlOb, ColiOt:OYU} 
... 
U C 
e KU CootoYU? 
.. 
WI& l CMI MOlt • a • C»,,l'm0*6 ftiiOM Kh fO Kh. COOlO m ? 
---
26 
NO 
YES 
MOOO DISOfCDEft W"H 
PSYCHOTIC FEA TVRES 
Uf£nM£ 
NO 
YES 
MOOO OISOitDllf WITH 
PSYCHOTIC FEA TV RES 
CURRENT 
NO 
YES 
PSYCHOTIC DiSORDER 
CURRENT 
NO 
YES 
PSYCHOTIC OISOitOER 
UfETIME 

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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
204
L. ANOREXIA NERVOSA 
C. IJPAOU«'S WUGW'I (QUAi_ 
tO 
CRt JAtiA N.LOW,) 
L4 
a Have you 
too bll/lat or that p.1n or yout body was toob41/ tal? 
HlJGHT / WOGHTTA6U 
.. 8MI ntltESHOlD 0t 17.0@/Ml 
...,._.,. 
Mn ... 
.... 
4'11 , . ,., ,., ,., ,., .. ... 
, 
" .. 
., .. .. .. .. 
.• , ... 
.. 
lAS 
"' 
ISO "' "' 
lS& . 
.. .. .., ... 
.. " 
" 
.... ,., .. 
.... .... .. .. .... .. 
Hotlc:MIW•IcM 
Mn $' 11 ... 
•• 
.. , .., 
b 
"' 
Ill "' 
U) ... 
.. ... . .. 
"'' ... ••• 
.. " " 
,_, .. " 
,., ... .,. .. 
o.o o, .. 
0 OOcm 
0 oo,. 
0 0 o .. 
.. 
NO 
YES 
.. 
NO 
m 
.. 
NO 
Y!S 
NO 
Y!S 
NO 
YES 
HO 
vts 
.. 
NO 
ru 
NO 
YE.S 
ANOREXIA NERVOSA 
CURRENT 
,., 
s·to 
"' 
liS ... 
"' 
175 
"' 
5I 
" .. 
TM -cht lbusbokh 1bavnre 
us1nc 1 boat mus ln6e11 (8MIJ 
to or bttow I 7.0 q/m tor tlw p1'!lltnt"s IMIIcht uW11 tbe CIHitiH o! 
DIU' 
COf'ittol& 
eMI c.Jcu&atot. ibOI h; tl\ot t.hrHhold culcleflht Odow wtlktl I pt-n.OI'I h 
unci-'Ct!t b'f tl\ot OSM.S fot 
Anot"ed.Het'WW. 
M,I,N.I. 1 A2 (AI.ICIJS.t 8, 2016) (8/8/16, 
27 

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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
205
M. BULIMIA NERVOSA 
(• 
GOiO TlC OtAGNOSnc: IOXD, C.U NO 1M TH[) ISUUMA SllCTIOH OIA.GHOSllC.O.XU.. AAOMOYt TO IIHGl f.ATVOG OISOROtJI) 
Ml 
M2 
M> 
M4 
MS 
M6 
M1 
In the 
three months.. did you howe ea tll'll blnles or tlme'S when you ilte 
of food 
a 2•hololr period? 
Did '(04J do •n'(lhiftt to 
for. or to prevent a weiJht prn., 
like W>mkin&. f.ullnc. 
or uldflc 
Mem.S.dluretks: 
(ftuld pitts.), « otht!f mfl'dlu'Uons? Old you do lhls •s often as once 01 wec:.k 1 
00 tht'W! t*lces O<Wf only when you <Iff, \lndtr ( __ 
CIJNICW.: Wlltl'l 1.'11ti( AIOVt 
n.c J)IUSHQI.OwtQn 
,A.tll'H!"$ 
HllGHl riiOM MtWGiff I wtiGtft 1AIU tt'lltlAHOII.'fn4HOVOSAMOOULL 
M8 
ISM S COOlOttSAHOSlnl*lM6 01t M7oootONO? 
ISM7cootoru? 
M.I.N.I. 7.0.2 (.\uCUS{ 8, 2016) (8/8/16} 
28 
NO 
• 
.., 
• 
.., 
• 
.., 
• 
.., 
• 
.., 
.., 
l 
"'' 
YlS 
YlS 
Skip to M8 
.., 
vtS 
YES 
BULIMIA NERVOSA 
CURRENT 
NO 
YES 
ANOREXIA NERVOSA 
Binge Eating/Purging Type 
CURRENT 

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Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
206
M81 
M82 
M8l 
MB4 
Mil$ 
MB6o 
M86b 
M86< 
MB6d 
M86< 
00 Ttl( tAf'C(f"$ SYM""OM$ MID Cli'IU:U. f(ll ANOUltiA 
.... 
lSM'l OlM4 cootOHO? 
&I«»>UOf 
ClOW'CJ4A1()11rf IC."k4VIOII$ 
MOOUAJt "'4•7 ltiSOOUCW 
COMP'r."iiS.AlOft'f .JIAV!Citi 
$lVUl a 8·13 tPCsootSOf 
lOlA VIOlS 
lXfUM( • 14 0l M¢«1: t;fi'ISOOtl 01 
MB. BINGE EATING DISORDER 
00 f1olf • AI'I(HT'S SYM•TOMS lllttr WlU!IliOl AHOittlOA NUIYCI&A? 
00 flU PAtblr'S 
..U: f 0111.-I'OAtwMIA .'\'i.J.VOSA.? 
ISM1 COOl;DYtS1 
1$> Ml coot ova 7 
1$M4COO(OYCS? 
In the I.-it 3 mont hs durin1 the blnJinJ did you: 
tat mote 
th.ln nomun 
Eat 
you ftft uncom.fo«•ly full7 
tat laflt: a.mounu of food when you 
t10t 
tat :.tooe because you rttt 
abOut how mud\ you 
e:.ti"'? 
feel cvaw. depresse-d 01" dlseumd with yowsel:f 
binclnc? 
.W 3 OliiiOflf M86 QUUl'IOHS COO(D 'I'U? 
M.UU 7 .0.2 (lo.uaust 8. 2016l {8/8/16) 
29 
NO 
YES 
ANOREXIA NERVOSA 
CURRENT 
SPECIFY IF: 
Ml'-0 
[J 
MOOERAU 
[J 
SEVEII£ 
[J 
EXtREME 
[J 
• 
NO 
YES 
• 
NO 
Y£S 
• 
NO 
YES 
• 
NO 
YES 
• 
NO 
'ItS 
NO 
YES 
NO 
YES 
NO 
YES 
NO 
YES 
NO 
'ItS 
.. 
NO 
YES 

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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
207
1$M 81 (IO()(O'IU1 
MCIO(M1{ . .... , l'GOOU 01 ........ "'"'"' ...... . 
SINlM • a.u 
01 ll*llAfliiO ... ., o: 
otnfMl a l CO....,_lftSOOUOf III'CillAfliiiCi 'til WI h . 
M.lN.l 7.0.2 fAuaust 8.1016) tl/1116) 
30 
• 
H() 
NO 
YES 
SJNGl·EATING OISORO£R 
CURRENT 
SI'EOFY IF: 
... lO 
0 
MC)O(AA,T[ 
0 
S(Y(JI( 
0 
OOOLMl 
0 

Protocol 331-201-00061
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
208
., . 
• 
Nl 
N. GENERAliZED ANXIETY DISORDER 
t!lCtt:Wvtfy tn,dot:ttor wOtritd about st-vtr".al routine t.hJrCt, 
ovtt the p.st 6 monthS? 
.,- OC , AfiL-n'tS UNO.tAA AMJ4ffVMot.J W)U 
JliliOtt 
tDoothets thil\k thlt you lilt • woniH« a 
Are tht..seanxldie:s W 'wOttio!t ptf!setlt most d,ws? 
Ml TMt M"MH'I'SA.t(IO(.'IY A."'I 
UQ.USMU' 
ro,C»t(lTtl.t:tltA!NrDI'I', A.'(¥ 
Ooyou find It difficult to control the WOttie:s? 
tO 
I Oil. M fOUOWIHG, COO£ NO W tttr SYWfOM:S Nil CO"''IN[O lO 
A..'fY 
IOOIISJIOIH'f. 
.a Fttl fe$1Je:ls, J:tytcl up« on 
b !Qve 
te:n51on? 
e I'C't'llmt.atlla? 
H".lvt d•ffiwtl.y 
(dlfflcufty Cill"' a$okt9, wildrc up In thct mkldk! 
of lhe nl&hl. earty mo.-nltll wamlns or 
exceu1Yety)1 
AAt l O.UOIU' 
N.t 
Oo 
an:detiei 
worrid Ji&tiiUeantlydbtupt yolJf .tbillry tO WO(Ic, 
to f\.ll'lrtion sodaltv or ln 
telnioi'«Shfps Of In otMr lmpottant arus oC 
your life or Quit YOI.I $icniftttnt 
NO 
.. 
110 
.. 
110 
NO 
.. 
"" 
"" 
NO 
,.., 
NO 
NO 
1<0 
.. 
110 
'" 
"' .. 
vts 
"' "' 
vts 
n:s 
vts 
l'tS 
l'tS 
YES 
GENERALIZED ANXIETY 
0/SOROER 
CURRENT 
0. RULE OUT MEDICAl, ORGANIC OR DRUG CAUSES FOR All DISORDERS 
Just bof«e these sympton» bcJ;J;n: 
Ola WHt: .,.ou U.kil'll anyd•UC" o.. mt'dk-lnes or in wfthdrllwill fr0tr1 My of 
Ol b 
Old 
•"Y 
O l 
It O l a 011 Olb ISCO«OvtS, I'll ntfQJ!«:W{SJOOGMtNl, tSlmlUUUtV tO. AerttCf 
CAlM OF lHl PA ntNf'l OGOIDUi l If MCUSAAY, A,!.Jt AOOmO!rW. CJPtlHMotO 
0 Ho 0 Yd 0 Unc:ttUin 
0 No 
0 Yts 0 
0 No 0 Yes C Ut'ICA!nlln 
/MlOICAL/OWGiliAflOCAU:SUttHiti.UOOUll 
0 No c 
a 
UMe,Uift 
If 01 1$ YU, f"UI 02 WMMAni:SitO •• OZ 
TlllN 02 $Ul.UoCAA'f IS 'I'U. 
n G \I'NICllllAIN 
M.J.N.I. 7.0.2 
8, 2016) {818116) 

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Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
209
P. ANTISOCIAL PERSONAUTY DISORDER 
Pl 
S.for. 
W'tr• 1.5 yun Old, did you:: 
• 
repeatedly stlp schoOl or nm 
home ovt:l'l"'feht or suV't(l out 
at nleht •a.m.n your par'enl's tutti? 
d df'J!Mratety dewov Lhlfl&i Of start llres? 
a done- lhlncs that are •et•J ot would be crounds to 
atresttd, 
If 'fOtl didn't 
&tt QU&f\t (fOf 
dntroylne propertY, shopl(fdne. "ulilnio stllint 
or committfi'C a felony)? 
b often littd 01 
otfler peQ9tre to aet montY or ple•wre, or tltd J1.1$t 
for fun? 
d bHn an physlcltl fl&hts 
usautttd othe-rs (intludlnc l)hysktt flctlts 
with V0411 Spot,IM Of children)? 
,.pcattdly bthflf9d Ina way 
consldt-r 
lite 
to p.ty for tNrcs 
beW. 
or delMfatt(y 
not worklnc to wppott 'r'f)Uts.elf? 
t: feit no CUilt after hurt Ina. mtweatfllc. tylna to, cr sualirc fr<wn others, or 
aft« dil'l"'lJI"' propMy? 
NO 
NO 
NO 
NO 
NO 
NO .. 
NO 
NO 
NO 
NO 
NO 
NO 
NO 
NO 
NO 
vts 
rtS 
vts 
rtS 
ru 
YES 
ru 
m 
YES 
yt$ 
m 
VES 
ANTISOCIAL PERSONALITY 
DiSORDER 
LIFEnME 
( 
ADDITIONAL OPTIONAL INTERVIEW ASSESSMENTS ON PAGES 36 & 37 
M.I.NJ. 7.0 .2 (AuJint 8, 2016) (8./8/16) 
32 

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Clinical Study Report 331-201-00061
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210
MOOD DISORDERS: DIAGNOSTIC AlGORITHM 
Consuh McduloH: 
A 
( 
M*r 
Episode 
MODULE K: 
lol 
1b 
Gtcl2HootOYU? 
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1 
0 
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b 
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( 
GMA.JO«ot.JittlSSl\1: £PtSOOt COOlO 'l't.S (CUUt.-.,JOII PAST)? 
... 
IS MANIC IMOOlCOOfO NO(C\IM!Hl ANl>PAS1)l 
... 
GW'I'POMA.'"l( lMOOl COO(o NO (OJ«I.L'H A."O P"-P)? 
... 
a -..u: 
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\\11'H I'SYOIOIIC fUIUIUSPASI: If la 
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MJ.tU 7.0,2 (Autt.rSl8,10161 (8/8/16, 
33 
HO 
HO 
Currtnt 
VES 
'itS 
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..... 
'itS 
'itS 
MOO 
MAJOR DfPitCSSNE 
OISO"DlR 
Wirb h'f(h<Jrk f«tiJfn 
0 
Put 
o 

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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
211
1'1 "_,..,. '""""" N'rNfl ..,. 
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Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
212
6 """"""' WHl»rit: t.ruOOt ((li,)(0 NO (CuUU.J AI'P' 
f 
... 
IS MANIC £l'rSOOl COOlDifO(CUIW:Nl 
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.... 
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n'-'C rM.Mt? 
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3S 
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ANO RElATEO Ot$0/fOCR 
Olhct S9«ifl«< 
8ipobr 
Rcbted 
Disorder 

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16.1.1 Protocol and Protocol Amendments
213
OPTIONAL ASSESSMENT MEASURES TO TRACK CHANGES OVER TIME 
A: CROSS CUTTING MEASURES 
SEVERITY OF SYMPTOM 
Use this scale to rate the severity of your symptom In the score column in the table below: 
Wild 
...... 
Extn!.me 
. 
,. 
........... . 
"''"'" \ 
svmotom Name 
SCore 
1 
Oef?!ession 
2 
AnJer 
3 
Mania {feeling up or high or ttvper or full of energy with rad!\J thoughts) 
-
4 
Anxiety 
---
---
s 
Ph:eical isomaticJ S:(!!!Etoms 
6 
Sukidal 
Impulses, plans. intent, (ANY thotJght:s of killing yoursetf), or 
-
any preparadons to kiiJ yourself Of ANY attempt to k111 yout$eff 
Hearing sounds or voices others can't hear or fearing someone tan hear or read 
7 
your thoughts or believil\8 things others don't accept as true e.g. that people 
are spyl!!& on you or 
agalrut 
01 talking about you {Psychosis) 
8 
Sleep problems 
9 
Memo_,ry problems 
---to 
or obsessiw thoughts or compulsive behaviors 
11 
Feeling things around you are strange, unreal, detached or unfammar, or 
feeling outside or detached from part or all of your body (Oissodation) 
12 
Abilitv to funcdon at work. at home tn vour fife or In vour relationshlos 
13 
Overusing alcol\ol or drugs 
MJ.H.I. 7.0.2 (AuJUSl 8, 2016) (8/8/16) 
36 

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Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
214
1 
2 
3 
4 
5 
6 
7 
8 
9 
11 
l2 
8 ; DISABILITY/ FUNCTIONAL IMPAIRMENT 
SEVERITY Of DISABILITY / IMPAIRMENT 
Use this s.ta.le to rate In the score column of the tabSe below, how much your s.ymptoms 
have disrupted your ability to function in the following areas of your life: 
Nolpresenl 
.... 
...... 
• 
' 
' 
, 
• 
" 
Assessment of Impairment of Functioning /Disability 
Domain Name 
Score 
Wolit or school wort 
Social life O<iofsure activities (like hobbles or 
do lor enjoyment) 
Family rife and I or home responsibilities 
Ability to get 
with people 
Personal and soc&at relationships 
Ability to understand and to communk:.ate with others 
Ability to take care of yourself (washing. showering, bathing. dressing properly1 
brushin< teeth.launclrv. combln</ brushi!'_B hair, eatlns 
Made 
disruptive or aggressive towards others 
Financially {ability to manage vour mo,!!!)') 
1-
Ability to 'et 
1 
or religious life 
How much did your condj(lon have an impact on other people In your fam1ty? 
M,I,H.I. 7.0.1 
8, 2016) {818/16) 
37 

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Clinical Study Report 331-201-00061
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215
REFERENCES 
1. 
OV,leuubttr Y, 
I(,Amorfm P, J.an.wsJ, Wt'illt:r £. Hetaueta T, &.leer ft., Dunbar G: The 
NevfOi,YS'i(hiltri(: lntCfVI!tW (MJ.N.I,}; The Development •nd Validltion Of a StN(\Ured OiaJno>tiC Pl'Vdllatrit Interview, J. (r'ft 
Piyctli•try, 1998;S9(rup1)120}: 22·33. 
2. Sb«h_.. OV, LtcrubiCI'C' Y, 
IC, 
J, Wtlle:t E, eon..ra U. Kcitinef A. Sdlin-':.1 J, k.Npp t, $hofhQI'I MF-, Ovnbar 
GC. Rdiabllrity and V:lliddy or the MJNI 
Ntuf'OpSyd'liatric lnter&w (MJ.N.q: Atconllrti to the S(II).P. 
Psydli.atry. 1997; 12:1l2·24iL 
), lecrublt:r V, Shethan 0, Weller E, Amorim P, Booor-• I, Sheetwl 
J,Ounb;tr G. "T'ht MIH/IntHn.atlonal 
lntti'W!w (MJ.N.t) A Shoft Dlaanostlc 
Rellabllltv and ValiditY Ac:cord•nc to tM 001. (urC)9otan PsvcN•uv. 
1997: U: 224·2'!1. 
<4. Amorim P, l fO'Ublet V, Wtillf:r £, »trtutta T, Shotehan 0:. Os:M·IIJ.-ft P!'((hotit (Morden: procedunl validity of tilt! Mini 
lntcrn;rtionoll 
Interview (M.I.HJ.). Concord¥t<C and 
for dCKordinc.e wi'lh lht ClOt. 
PsvcNitty. 
1998; tl:26-l4. 
ACKNOWlEDGEMENTS 
1. Yves 
my clo$e colllbor•tor (now dect;a.secn on the iniWI Oewtopment of the MINI roc OSM IIS.«.Ihe OSM N •nd KD-10. 
2. Jurls 
£m.nudle WelltH, Chtk.tet Allul•ndet, K.tthv H•men·SI\eoehM\, RoJ<r 
MkhHt 
Ctwh Gr•y. Tlliefty 
HefiUt't•. N, Kidri, O...,ld &ildwln, (hrlsn.n (vtn, tlowrlo Hidlleo, Mlrdli Soto-Colon. Oswn» Osm.n. 
l.P,)Irida Amorim for het" ellttNIV<e wad( on Ule dcYdoPmtnt of the exp.anded V('rSion of 11\e Psytholic OiSOrdC'tS M<ldule •nd 
atcorithms for DSM 111-R. we 
evol\red Mf model funl\et In the MINI fOt Psychollc Otsorders 7 and k\ W MINI Plus 7 f« OSM· 
s. 
4 b«uwe 
for thctMINI6.0.0 for OSM•IV: 
Chrl.saer Altculifldef, Stoc:kholm, SWeden 
A. Carlo AfumutJ, 
n-,ty 
Cynl Hos.ctd, Praha, Cleeh Republic 
Geot&t P.padlmltrlou, Athens., 
H.lns A,ren, G6ttbofl,. 
Hlni·.IOracn M611e-r, Milnthtn. Gtrmanv 
HIM·Uirkh Whtd'ltC\ OresdM. Gernunv 
IstvAn Bltttf, BudiPHt.. Huncarv 
k•n-Picnc Ltplnc, P•rb, FtJntc 
Zurich, SwiUt'tla-M' 
JuJio &obc!s. 
LUCI.lno Conti, Piw, lt•ly 
M.kdll CCIIM·SOtO MD, Pu«tc> RiCO, United 
Mlc.h•ct V•n Atnfflneen MO. TOtonto, C.n.ct. 
Ro$liM Hldalao .MO, Tamp.IJ, United States 
Sl:.eeffied IC.aSf)et. Vlenn•. A.uWII 
Thom.s 
eonn, Germ#l'!'y 
5. 
•nd the m.anv 
tr.m&ation 
lntcrnDtioMiy who coB:Iborat.td in en'hH'U'If that 
tratulotlont; beome 
;)vailAtJI,e l" oYC'f 70 
Of lolntuaae variants. M.lpi lhttp:l/www.m:!()!srouo.coml Is now 
offid.ll 
one! 
llnf;Uis.tk Yflld.atkwl stc'Yke fOf all vi.rl.nts of the Mutt 
and patitnh who over 
ye¥S m.ctecOIIfttk» 
to help Improve the .loC.Cur.cy .tnd dlnlwlv•k.le co 
lhe MINI: JM 
fOI Mt' 
CM'I tht Mttfl 7 vtnJoft o l tM StlkJdaity Olsorderi Module, Dr. 
Vo1n Ametln&en for 
IUiitoW\U with the ADHO mod uSe, if\d Of P1ui ne Powers foe boer acMc:e on the mocfuk!1 Ofl 
ood Bulimloi. 
1. 
studies of the M INI wtrc: 
pouibtt, In Htt. by lfiJfl\s from SmithiOintlkc:<hlm and lhC' 
Comml:»lon. 
M.I.N.l7.0.2 (Aups18, 2016) (8/8/16) 
38 

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Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
216
M ,I.N,I, PlUS 
1M sNdtd n'l(ldults 
<lddttlona.l 
In tM MINI PlUS btoyond wMt 1' i'\'dbte 
sund•rd MJNL 
mO<Uo$ 
tilt: In 
StM'IdirO MINI, 
Thtif: MINI PUJS modlks 
be 
Into 
tn 
of thct 
MINI modu'es. as 
by the 
netds of •nv 
MOO V!.'mt MlXlO flATt.M£$ 
MOOUW 
MOO V!.'fTH MEI.AHCHOUC ff.A TVIIU 
MOOWfTH(ATATON14 
MOO WITHSf.ASOtW. rATTE!U-1 
IMX)R O(HIESSJvt: DISO.D(a WITH PSY(HOTlC fEA TURU 
etP()tAR IOIS()I!DfR 
IIPOtARaOISOAO£A. 
C.,.,.,M(2Wftbt 
( t,ltNM (2 ""ttbl 
CiltNM (2 WMbl 
( .....,., (2 ,...q. 
(:Utff,"' f2 
....... 
.... 
(urr.nt (2 WC!t'b • 
... 
(Pnlt.&ontt!) 0 
Utetft•tt•mpc 
0 Ot.w U""'*'I'W: Oto¥ 
(utl1!rrt 
0 (In Put Ye..r) 
lnHrfrt'ttrniuiCII'I 
0 U· 2'1'u'"'AcOI 
0 (> 1YUf1A(o. 
c.. .... 
.... 
SUISTAHGl·/ 
&lf'IOC.MOI$0R.CfA AHO REI.ATtO O«SSRRER 
C"""' (2 Wftb • 
.... 
M.tN.t 1.0.2 
a. 
(8/81161 
39 

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Clinical Study Report 331-201-00061
16.1.1 Protocol and Protocol Amendments
217
&II'C)(AR Ol$0fi0U AHO RUA TtO DISOJIOOI OUE TO A GlHf:IW. MfOKAl CONOffiON '-"rrtM f1 . 
.., 
UNSnCiflEDIIPOlAAAHO RnATtO OIS()ftll(R 
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OU( TO ANOTHER MEOICAI. CONOfflOt4 
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....... 
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Ct.lrrent 
Li!tlfme 
?.0.2 {At.rl'U'U 8, 2016) (8/8/16) 
40 

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16.1.1 Protocol and Protocol Amendments
218
UWfOfUOSO«ZOPtiJilHIA SPfCTIWM AHO OTHlJI PSYCHOTIC 015011.0£1t 
ANOWIA N{JIVOSA 
ANQRO!IA Nt.fiVO$A. 81NGl tATING/PURGIHG 1'VJ't 
ANOillXJA N:UIVOSA. M$TIIKTWG TY'Pf 
M 8UUMIA N(JIVOS4 
MIJ 81HGl.£A TI:HG OfSOaOER 
H 
GEtWW.I!(0AHXJt1Y 01$01t0Eit(GAOJ 
$V8:$TAHC£·/ 
GAO DUE TO AHOTHUt MEOICAt COHDIT'ON 
S 
CONOUCT DISORDER. 
T 
AMHnOHDt:nCIT/ tM'UAOMTYDCSOAOlA 
ADHO C'OM81Nf0 ... 
AOfiD f>JI(DOMWAHflY INA ntHll\ll Pki$EHTA OON 
0 
0 
ADHQ PREOOMINAN'T\Y HVP£AAClM / tMi'UUivt PRE$EHT A TION 0 
TA AntNT10H DI!FICrt/KYPUACTMTY DCSc)ROlA 
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X 
MlDfCAt.. 
OIIUG CAUSI: llUI.£0 OUT 
0 
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""""' 
""""' 
IPM' .J MOM"'· 
Curr•m 
.J Monthi) 
Cutrem jP'a-n 4 Montll.s) 
CurrtM 
CUrttM 
""""' 
CUrrent 
"'"""" 
For Schb:ophrenta and psychotk disorder studies and for psychotic disorder subtypln& In c6nlcat settings. use the MINI 
P$y<:hocic: Disorders in.ntad of the 
MINI, For m1t1y dinic:<al sttt1nss this level of p.sy<:hotie disorder subtypift& 
detall is not necessary and the standard MINI is suffldent. 
For c:hlldrt::n 3nd 
us.t the MINI Kld or tht MINilUd 
of the MIN Kid for P$ythotk: Disorders, 
A c:omputeru.ed version of the MINI I:s wallable. Forlnfortn3tkln on th.e avallabiWty and IJcenslna of llny version of the 
MINI, 
Ot 
I pdf versions, 
01v.d Shee-hfn MD M8A 
davlctvsheehanO&mall,c:om 
M ,LN,I, 7,0.Z (AIIIVM-6, ZOl(l) (a/1(16) 
41 

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Version 2.0, 7 Jun 2017
Appendix 14
Ohio State University Traumatic Brain Injury Identification 
Method (OSU TBI-ID)
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.
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219

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16.1.1 Protocol and Protocol Amendments
220
Name: _______________________________ _ 
Current Age: _____ 
Interviewer Initials: 
Date: ______ _ 
Ohio State UniversityTBIIdentification Method -Interview Form 
Step 1 
Ask questions 1-5 below. Record the cause of each reported InJury 
and any deta1ls provided spontaneously m the chart at the bottom 
of this page. You do not need to ask further about loss of 
consciousness or other m)urydeta1/s durmg th1s step. 
I am going to ask you about injuries to your head or 
neck that you may have had anytime in your life. 
1 .In your lifetime, have you ever been hospitalized or 
treated in an emergency room following an injury to 
your head or neck? Think about any childhood injuries 
you remember or were told about. 
D No D Yes-Record cause in chart 
2. In your lifetime, have you ever injured your head or 
neck in a car accident or from crashing some other 
moving vehicle like a bicycle, motorcycle or ATV? 
D No D Yes-
Record cause in chart 
3. In your lifetime, have you ever injured your head or 
neck in a fall or from being hit by something (for 
example, falling from a bike or horse, rollerblading, 
falling on ice, being hit by a rock)? Have you ever 
injured your head or neck playing sports or on the 
playground? 
D No D Yes-Record cause in chart 
4. In your lifetime, have you ever injured your head or 
neck in a fight, from being hit by someone, or from 
being shaken violently? Have you ever been shot in 
the head? 
D No D Yes-Record cause in chart 
5. In your lifetime, have you ever been nearby when an 
explosion or a blast occurred? If you served in the 
military, think about any combat- or training-related 
incidents. 
D No D Yes-Record cause in chart 
Interviewer instruction: 
If the answers to any of the above questions are "yes," go to 
Step2. If the answers to all of the above questions are "no/' 
then proceed to Step 3. 
Step2 
Interviewer instruction: If the answer is "yes" to any of the 
questions in Step 1 ask the following additional questions 
about each reported Injury and add details to the chart below. 
Were you knocked out or did you lose consciousness 
(LOC)? 
If 
how long? 
If no, were you dazed or did you have a gap in 
your memory from the injury? 
How old w ere you? 
Step2 
Step 3 
Interviewer mstruct1on Ask the followmg quest1ons to help 
1dent1fy a h1story that may mc/udemultlplemlld TB/s and 
complete the chart below. 
Have you ever had a period of time in which you 
experienced multiple, repeated impacts to your head 
(e.g. history of abuse, contact sports, military duty)? 
If yes, what was the typical or usual effect--were you 
knocked out (loss of Consciousness - LOC)? 
If no, were you dazed or did you have a gap in your 
memory from the injury? 
What w as the most severe effect from one of the times 
you had an impact to the head? 
How old were you when these repeated injuries began? 
Ended? 
Loss of consciousness (LOC)/knocked out 
Dazed/Mem Gap 
Age 
:_< 
hrs:;; :=> 24 hrs= 
Yes 
No 
Adapted with permission from the Ohio State University TB/Identification Method (COITigan,J.D., Bogner, J.A. (2007). Initial reliability and validity of theOSU TBI/dentification Method. J Head Trauma Rehabil22(6):318-329. 
© Reserved 2007, The Ohio Valley Center for Brain lnjwy Prevencionand Rehabilitation 

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(Continuation from reverse side if needed) 
Current Age: 
Interviewer Initials: 
Step2 
Loss of consciousness (LOC)/knocked out 
Dazed/Mem Gap 
Age 
No LOC 
< 30 min 
30 mm-24 hrs 
> 24 hrs 
Yes 
No 
If more injuries with LOC: How many? ____ Longest knocked out? _____ How many<:: 30 mins.? ____ Youngest age? ____ _ 
Step 3 
Typical Effect 
Most Severe Effect 
Age 
Dazed/ 
Dazed/ 
LOC 
LOC 
LOC 
Cause of repeated injury 
LOC 
< 30 m1n 
> 24 hrs. 
Began 
Ended 
Interpreting Findings 
A person may be more likely to have ongoing 
problems if they have any of the fo llowing: 
·WORST 
One moderate o r severe TBI 
·FIRST 
TBI wit h loss of consciousness before age 15 
· MULTIPLE 
2 or more TBis close together, including a period 
of t ime when t hey experienced multiple blows 
to the head 
· RECENT 
A mild TBI in the last weeks or a more severe TBI 
in the last months 
· OTHER SOURCES 
AnyTBI combined with anot her way that their 
brain function has been impaired 
For more information about TBI 
or the OSU TBIIdentification 
Method visit: 
· Ohio Valley Center at OSU 
www.ohiovalley.org/ informationeducation 
Brainline.org 
www.brainline.org 
(Updated July 2013) 

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Appendix 15
Abnormal Involuntary Movement Scale (AIMS)
Movement ratings: rate highest severity observed. Rate 
movements that occur upon activation one less than those 
observed spontaneously.
Code for items 1-7:
0 = None
1 = Minimal, may be extreme normal
2 = Mild
3 = Moderate
4 = Severe
(Circle One)
FACIAL AND
ORAL
MOVEMENTS:
1.
MUSCLES OF FACIAL EXPRESSION e.g. 
movements of forehead, eyebrows, periorbital area, 
cheeks; include frowning, blinking, smiling, 
grimacing
0
1
2
3
4
2.
LIPS AND PERIORAL AREA e.g. puckering, 
pouting, smacking.
0
1
2
3
4
3.
JAW e.g. biting, clenching, chewing, mouth 
opening, lateral movement.
0
1
2
3
4
4.
TONGUE Rate only increase in movement both in 
and out of mouth, not inability to sustain 
movement.
0
1
2
3
4
EXTREMITY 
MOVEMENTS:
5.
UPPER (ARMS, WRISTS, HANDS, FINGERS) 
include choreic movements (i.e. rapid, objectively 
purposeless, irregular, spontaneous), athetoid 
movements (i.e. slow, irregular, complex, 
serpentine). Do not include tremor (i.e. repetitive, 
regular, rhythmic).
0
1
2
3
4
6.
LOWER (LEGS, KNEES, ANKLES, TOES) e.g. 
lateral knee movement, foot tapping, heel dropping, 
foot squirming, inversion and eversion of foot
0
1
2
3
4
TRUNK 
MOVEMENTS:
7.
NECK, SHOULDERS, HIPS e.g. rocking, 
twisting, squirming, pelvic gyrations
0
1
2
3
4
GLOBAL 
JUDGMENTS:
8.
Severity of abnormal movements
None, normal
0
Minimal
1
Mild
2
Moderate
3
Severe
4
9.
Incapacitation due to abnormal movements
None, normal
0
Minimal
1
Mild
2
Moderate
3
Severe
4
10. Patient's awareness of abnormal movements
Rate only subject’s report.
No awareness
0
Aware, no distress
1
Aware, mild distress
2
Aware, moderate distress
3
Aware, severe distress
4
DENTAL
STATUS:
11. Any current problems with teeth and/or dentures?
No
0
Yes
1
12. Does patient usually wear dentures?
No
0
Yes
1
Guy W. ECDEU Assessment Manual for Psychopharmacology. US Department of Health, Education, 
and Welfare publication (ADM) 76-338. Rockville, MD: National Institute of Mental Health; 1976.
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Appendix 16
Barnes Akathisia Rating Scale (BARS)
Instructions
Patient should be observed while they are seated, and then standing while engaged in 
neutral conversation (for a minimum of 2 minutes in each position). Symptoms observed 
in other situations, for example while engaged in activity on the ward, may also be rated. 
Subsequently, the subjective phenomena should be elicited by direct questioning.
Objective
0
Normal, occasional fidgety movements of the limbs
1
Presence of characteristic restless movements: shuffling or tramping movements 
of the legs/feet, or swinging one leg while sitting, and/or rocking from foot to foot 
or "walking on the spot" when standing, but movements present for less than half 
the time observed
2
Observed phenomena, as described in (1) above, which are present for at least 
half the observation period
3
Patient is constantly engaged in characteristic restless movements, and/or has the 
inability to remain seated or standing without walking or pacing, during the time 
observed
Subjective
Awareness of restlessness
0
Absence of inner restlessness
1
Non-specific sense of inner restlessness
2
The patient is aware of an inability to keep the legs still, or a desire to move the 
legs, and/or complains of inner restlessness aggravated specifically by being 
required to stand still
3
Awareness of intense compulsion to move most of the time and/or reports strong 
desire to walk or pace most of the time
Distress related to restlessness
0
No distress
1
Mild
2
Moderate
3
Severe
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Global clinical assessment of akathisia
0
Absent. No evidence of awareness of restlessness. Observation of characteristic 
movements of akathisia in the absence of a subjective report of inner restlessness 
or compulsive desire to move the legs should be classified as pseudoakathisia
1
Questionable. Non-specific inner tension and fidgety movements
2
Mild akathisia. Awareness of restlessness in the legs and/or inner restlessness 
worse when required to stand still. Fidgety movements present, but characteristic 
restless movements of akathisia not necessarily observed. Condition causes little 
or no distress
3
Moderate akathisia. Awareness of restlessness as described for mild akathisia 
above, combined with characteristic restless movements such as rocking from 
foot to foot when standing. Patient finds the condition distressing
4
Marked akathisia. Subjective experience of restlessness includes a compulsive 
desire to walk or pace. However, the patient is able to remain seated for at least 
five minutes. The condition is obviously distressing
5
Severe akathisia. The patient reports a strong compulsion to pace up and down 
most of the time. Unable to sit or lie down for more than a few minutes. Constant 
restlessness which is associated with intense distress and insomnia
Reproduced from: A rating scale for drug-induced akathisia. T.R.E. Barnes, British Journal of Psychiatry 
(1989), 154, 672-676.
© 1989 The Royal College of Psychiatrists.
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Appendix 17
Simpson-Angus Scale (SAS)
Circle the appropriate score for each item:
1.
GAIT
The patient is examined as he walks into the examining room; his gait, the swing of arms, his 
general posture; all form the basis for an overall score for this item. This is rated as follows:
0
Normal
1
Mild diminution in swing while the patient is walking
2
Obvious diminution in swing suggesting shoulder rigidity
3
Stiff gait with little or no arm swing noticeable
4
Rigid gait with arms slightly pronated; or stooped-shuffling gait with propulsion and retropulsion
2.
ARM DROPPING
The patient and the examiner both raise their arms to shoulder height and let them fall to their sides, 
in a normal subject a stout slap is heard as the arms hit the sides. In the patient with extreme 
Parkinson's syndrome, the arms fall very slowly.
0
Normal, free fall with loud slap and rebound
1
Fall slowed slightly with less audible contact and little rebound
2
Fall slowed, no rebound
3
Marked slowing, no slap at all
4
Arms fall as though against resistance; as though through glue
3.
SHOULDER SHAKING
The subject's arms are bent at a right angle at the elbow and taken one at a time by the examiner
who grabs one hand and also clasps the other around the patient's elbow. The subject's upper arm is 
pushed to and from and the humerus is externally rotated. The degree of resistance from normal to 
extreme rigidity is scored as follows:
0
Normal
1
Slight stiffness and resistance
2
Moderate stiffness and resistance
3
Marked rigidity with difficulty in passive movement
4
Extreme stiffness and rigidity with almost a frozen joint
4.
ELBOW RIGIDITY
The elbow joints are separately bent at right angles and passively extended and flexed, with the 
subject's biceps observed and simultaneously palpated. The resistance to the procedure is rated.  
(The presence of cogwheel rigidity is noted separately.)
0
Normal
1
Slight stiffness and resistance
2
Moderate stiffness and resistance
3
Marked rigidity with difficulty in passive movement
4
Extreme stiffness and rigidity with almost a frozen joint
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5.
WRIST RIGIDITY
The wrist is held in one hand and then the fingers held by the examiner's other hand with the wrist 
moved to extension, and both ulnar and radial deviation. The resistance to this procedure is rated:
0
Normal
1
Slight stiffness and resistance
2
Moderate stiffness and resistance
3
Marked rigidity with difficulty in passive movement
4
Extreme stiffness and rigidity with almost a frozen joint
6.
HEAD ROTATION
The patient sits or stands and is told that you are going to move his head from side to side, that it 
will not hurt and that he should try and relax. (Questions about pain in the cervical area or difficulty 
in moving his head should be obtained to avoid causing any pain.) Clasp the patient's head between 
the two hands with fingers on back of the neck. Gently rotate the head in a circular motion 3 times 
and evaluate the muscular resistance to the movement.
0
Loose, no resistance
1
Slight resistance to movement although the time to rotate may be normal
2
Resistance is apparent and time of rotation is slowed
3
Resistance is obvious and rotation is slowed
4
Head appears stiff and rotation is difficult to carry out
7.
GLABELLA TAP
Subject is told to open his eyes and not to blink. The glabella region is tapped at a steady, rapid
speed. The number of times patient blinks in succession is noted:
0
0-5 blinks
1
6-10 blinks
2
11-15 blinks
3
16-20 blinks
4
21 and more blinks
8.
TREMOR
Patient is observed walking into examining room and then is examined for this item.
0
Normal
1
Mild finger tremor, obvious to sight and touch
2
Tremor of hand or arm occurring spasmodically
3
Persistent tremor of one or more limbs
4
Whole body tremor
9.
SALIVATION
Patient is observed while talking and then asked to open his mouth and elevate his tongue. The 
following ratings are given:
0
Normal
1
Excess salivation so that pooling takes place if the mouth is open and the tongue raised
2
Excess salivation is present and might occasionally result in difficulty in speaking
3
Speaking with difficulty because of excess salivation
4
Frank drooling
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10.
AKATHISIA
Patient is observed for restlessness. If restlessness is noted, ask: "Do you feel restless or jittery 
inside; is it difficult to sit still?" Subjective response is not necessary for scoring but patient report 
can help make the assessment.
0
No restlessness reported or observed
1
Mild restlessness observed
2
Moderate restlessness observed
3
Restlessness is frequently observed
4
Restlessness persistently observed
Adapted and used with permission.  Reference:  Simpson GN, Angus JW. A rating scale for 
extrapyramidal side effects. Acta Psychiatrica Scandinavica. 1970;45(suppl 212):11-9.
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Appendix 18
Baseline Columbia-Suicide Severity Rating Scale
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COLUMBIA-SUICIDE SEVERITY 
RATING SCALE (C-SSRS) 
Baseline/Screening Version
Version 1/14/09
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; 
Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J.
Disclaimer:
This scale is intended  to be used by individuals who have received training in its administration.  
The questions contained in the Columbia-Suicide Severity Rating Scale are suggested probes. 
Ultimately,  the determination  of the presence of suicidal ideation or behavior depends on the 
judgment of the individual administering the scale.
Definitions of behavioral suicidal events in this scale are based on those used in  
The Columbia Suicide History Form, developed by John Mann,  MD and Maria 
Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051  Riverside Drive, New 
York, NY, 10032.  (Oquendo M. A., Halberstam B. & Mann J. J., Risk factors for 
suicidal behavior: utility and limitations of research instruments. In M.B. First [Ed.] 
Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.)
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State 
Psychiatric Institute, 1051  Riverside Drive, New York, New York, 10032;  
inquiries and training requirements contact posnerk@nyspi.columbia.edu
© 2008 The Research Foundation for Mental Hygiene, Inc.
SUICIDAL IDEATION
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Ask questions 1 and 2. If both are negative, proceed to “Suicidal Behavior”
section. If the answer to
question 2 is “yes”, ask questions 3, 4 and 5. If the answer to question 1 and/or
Lifetime: Time 
He/She Felt 
Most Suicidal
Past
90 Days
1. Wish to be Dead
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and
not wake up.
Have you wished you were dead or wished you could go to sleep and not wake up?
If yes, describe:
Yes
No
□
□
Yes
No
□□
2. Non-Specific Active Suicidal Thoughts
General non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought
about killing myself”) without thoughts of ways to kill oneself/associated methods, intent, or plan
during the assessment period.
Have you actually had any thoughts of killing yourself?
If yes, describe:
Yes
No
□
□
Yes
No
□□
3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
Subject endorses thoughts of suicide and has thought of at least one method during the assessment
period. This is different than a
specific plan with time, place or method details worked out (e.g.  thought of method to kill self but
not a specific plan). Includes person who would say, “I thought about taking an overdose but I
never made a specific plan as to when, where or how I would actually do it…and I would never go
through with it.”
Have you been thinking about how you might do this?
If yes, describe:
Yes
No
□
□
Yes
No
□□
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such
thoughts, as opposed to “I have the thoughts but I definitely will not do anything about them.”
Have you had these thoughts and had some intention of acting on them?
If yes, describe:
Yes
No
□
□
Yes
No
□□
5. Active Suicidal Ideation with Specific Plan and Intent
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some
intent to carry it out.
Have you started to work out or worked out the details of how to kill yourself? Do you intend to 
carry out this plan?
If yes, describe:
Yes
No
□
□
Yes
No
□□
INTENSITY OF IDEATION
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The following features should be rated with respect to the most severe type of ideation 
(i.e.,1-5 from above, with 1 being the least severe and 5 being the most severe ). Ask about 
time he/she was feeling the most suicidal. 
Lifetime -           Most Severe Ideation: ________
_______________________
Type # (1-5)
Description of  Ideation
Past 6 Months - Most Severe Ideation:  ________
________________________
Type # (1-5)                 Description of  Ideation
Most
Severe
Most
Severe
Frequency
How many times have you had these thoughts?
(1) Less than once a week   (2) Once a week  (3) 2-5 times in week   (4) Daily or almost
daily  (5) Many times each day
Duration
When you have the thoughts, how long do they last?
(1) Fleeting - few seconds or minutes            (4) 4-8 hours/most of day
(2) Less than 1 hour/some of the time            (5) More than 8 hours/persistent or continuous
(3) 1-4 hours/a lot of time
Controllability
Could/can you stop thinking about killing yourself or wanting to die if you want
to?
1) Easily able to control thoughts                       (4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty    (5) Unable to control thoughts
(3) Can control thoughts with some difficulty   (0) Does not attempt to control thoughts
Deterrents
Are there things - anyone or anything (e.g., family, religion, pain of death) -
that stopped you from wanting to die or acting on thoughts of committing
suicide?
(1) Deterrents definitely stopped you from       (4) Deterrents most likely did not stop you 
attempting suicide   
(2) Deterrents probably stopped you                 (5) Deterrents definitely did not stop you 
(3) Uncertain that deterrents stopped you         (0) Does not apply
Reasons for Ideation
What sort of reasons did you have for thinking about wanting to die or killing
yourself? Was it to end the pain or stop the way you were feeling (in other words
you couldn’t go on living with this pain or how you were feeling) or was it to get
attention, revenge or a reaction from others? Or both?
(1) Completely to get attention, revenge or (4) Mostly to end or stop the pain (you 
a reaction from others
couldn’t go on living with the pain or
(2) Mostly to get attention, revenge or a 
how you were feeling).
reaction from others.
(5) Completely to end or stop the pain (you
(3) Equally to get attention, revenge or a 
couldn’t go on living with the pain or  how
reaction from others and to end/stop
you were feeling).
the pain.
(0) Does not apply
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SUICIDAL BEHAVIOR
(Check all that apply, so long as these are separate events; must ask about all types)
Lifetime 
Past 1 
year
Actual Attempt:
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was 
in part thought of as method to kill oneself. Intent does not have to be 100%.  If there is any intent/desire 
to die associated with the act, then it can be considered an actual suicide attempt. There does not have 
to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in 
mouth but gun is broken so no injury results, this is considered an attempt.  
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the 
behavior or circumstances. For example, a highly lethal act that is clearly not an accident so no other intent 
but suicide can be inferred (e.g., gunshot to head, jumping from window of a high floor/story). Also, if 
someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred. 
Have you made a suicide attempt?
Have you done anything to harm yourself?
Have you done anything dangerous where you could have died?
What did you do?
Did you______ as a way to end your life? 
Did you want to die (even a little) when you_____? 
Were you trying to end your life when you _____?
Or did you think it was possible you could have died from_____?
Or did you do it purely for other reasons / without ANY intention of killing yourself (like 
to relieve stress, feel better, get sympathy, or get something else to happen)? (Self-Injurious 
Behavior without suicidal intent)
If yes, describe:
Has subject engaged in Non-Suicidal Self-Injurious Behavior?
Yes      No
□   □
Total # of
Attempts
______
Yes    No
□   □
Yes      No
□   □
Total # of
Attempts
______
Yes    No
□   □
Interrupted Attempt:  
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act
(if not for that, actual attempt would have occurred).
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes 
an attempt rather than an interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken 
away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, even if 
the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from 
ledge. Hanging: Person has noose around neck but has not yet started to hang - is stopped from doing so.
Has there been a time when you started to do something to end your life but someone
or something stopped you before you actually did anything?
If yes, describe:
Yes      No
□   □
Total # of 
interrupted
______
Yes      No
□   □
Total # of 
interrupted
______
Aborted Attempt:  
When person begins to take steps toward making a suicide attempt, but stops themselves before they 
actually have engaged in any self-destructive behavior. Examples are similar to interrupted attempts, 
except that the individual stops him/herself, instead of being stopped by something else.
Has there been a time when you started to do something to try to end your life but you 
stopped yourself before you actually did anything?
If yes, describe:
Yes      No
□   □
Total # of
aborted
______
Yes      No
□   □
Total # of
aborted
______
Preparatory Acts or Behavior:
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a 
verbalization or thought, such as assembling a specific method (e.g., buying pills, purchasing a gun) or 
preparing for one’s death by suicide (e.g., giving things away, writing a suicide note). 
Have you taken any steps towards making a suicide attempt or preparing to kill 
yourself (such as collecting pills, getting a gun, giving valuables away or writing a 
suicide note)?
If yes, describe:
Yes      No
□   □
Yes      No
□   □
Suicidal Behavior:
Suicidal behavior was present during the assessment period?
Yes      No
□   □
Yes      No
□   □
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Answer for Actual Attempts Only
Most Recent 
Attempt Date:
Most Lethal 
Attempt Date:
Initial/
First Attempt 
Date:
Actual Lethality/Medical Damage:  
0.  No physical damage or very minor physical damage (e.g., surface scratches).
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; 
sprains).
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, 
somewhat responsive; second-degree burns; bleeding of major vessel).
3.  Moderately severe physical damage; medical hospitalization and likely intensive 
care required (e.g., comatose with reflexes intact; third-degree burns less than 
20% of body; extensive blood loss but can recover; major fractures).
4.  Severe physical damage; medical hospitalization with intensive care required 
(e.g., comatose without reflexes; third-degree burns over 20% of body; 
extensive blood loss with unstable vital signs; major damage to a vital area).
5.  Death
Enter Code
_________
Enter Code
_________
Enter Code
_________
Potential Lethality: Only Answer if Actual Lethality=0
Likely lethality of actual attempt if no medical damage (the following examples, 
while having no actual medical damage, had potential for very serious lethality: put 
gun in mouth and pulled the trigger but gun fails to fire so no medical damage; 
laying on train tracks with oncoming train but pulled away before run over).
0 = Behavior not likely to result in injury
1 = Behavior likely to result in injury but not likely to cause death
2 = Behavior likely to result in death despite available medical care 
Enter Code
_________
Enter Code
_________
Enter Code
_________
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Appendix 19
Since Last Visit Columbia-Suicide Severity Rating Scale
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COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Since Last Visit 
Version 1114/09 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; 
Fisher, P.; Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J. 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The 
questions contained in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, 
the determination of the presence of suicidal ideation or behavior depends on the judgment of the 
individual administering the scale. 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia 
Suicide History Form. developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the 
Neuroscience of Mental Disorders (CCNMD), New York State Psychiatric Institute, 1051 Riverside 
Drive, New York, NY, 10032. (Oquendo M.A., Halberstam B. & Mann J. J., Risk factors for suicidal 
behavior: utility and limitations of research instruments. In M.B. First [Ed.] Standardized Evaluation 
in Clinical Practice, pp. 103 -130, 2003.) 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 
Riverside Drive, New York, New York, 10032; inquiries and training requirements contact 
posnerk@childpsych.columbia.edu 
© 2008 The Research Foundation for Mental Hygiene, Inc. 

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SUICIDAL IDEATION 
Ask questions I and 2. If both are negative, proceed to "Suicidal Behavior" section. If the 
answer to question 2 is "yes", ask questions 3, 4 and 5. If the answer to question I and/or 2 
Since Last 
is ''yes", complete "Intensity of Ideation" section be low. 
Visit 
1. Wish to be Dead 
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up. 
Yes 
No 
Have you wished you were dead or wished you could go to sleep and not wake up? 
D 
D 
If yes, describe: 
2. Non-Specific Active Suicidal Thoughts 
General, non·specific thoughts of wanting to end one's life/commit suicide (e.g., "I've thought about killing myself') 
Yes 
No 
without thoughts of ways to kill oneself/associated methods, intent, or plan during the assessment period. 
D 
D 
Have you actually had auy thoughts of killing yourself? 
If yes, describe: 
3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is 
Yes 
No 
different than a specific plan with time, place or method details worked out (e.g., thought of method to kill self but 
D 
D 
not a specific plan). hlcludes person who would say, "I thought about taking an overdose but I never made a specific 
plan as to when, where or how I would actually do it ..... Wld I would never f{O through with it. " 
Have you been thinking about how you might do tJtis? 
If yes, describe: 
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts as opposed 
Yes 
No 
to "I have the thoughts but I definitely will not do anything about them." 
D 
D 
Have you had these thoughts and had some intention of acting on them? 
If yes, describe: 
5. Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it 
Yes 
No 
out. 
D 
D 
Have you started to work out or worked out the details of how to kill yourself? Do you inte11d to cany out tJtis 
plan? 
If yes, describe: 

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INTENSITY OF IDEATION 
The followingfoatures should be rated with respect to the most severe type of ideation (i.e., 1-5 from 
above, with 1 being the least severe and 5 being the most severe). 
Most 
Most Severe Ideation: 
Severe 
--
Type# (1-5) 
Description of Ideation 
Frequency 
How many times have you had these til oughts? 
--
(I) Less than once a week (2) Once a week (3) 2-5 times in week (4) Daily or almost daily 
(5) Many times each day 
Duration 
Wilen you have the thoughts, how long do they last? 
(1) Fleeting- few seconds or minutes 
(4) 4-8 hours/most of day 
--
(2) Less than I hour/some of the time 
(5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot oftime 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(I) Easily able to control thoughts 
(4) Can control thoughts with a lot of difficulty 
--
(2) Can control thoughts with little difficulty 
(5) Unable to control thoughts 
(3) Can control thoughts with some difficulty 
(O) Does not attempt to control thoughts 
Deterrents 
Are there things- anyone or anything (eg.,family, religion, pain of death)- that stopped you 
from wanting to die or acting on til oughts of committing suicide? 
(I) Deterrents definitely stopped you from attempting suicide 
(4) Deterrents most likely did not stop you 
--
(2) Deterrents probably stopped you 
(5) Deterrents definitely did not stop you 
(3) Uncertain that deterrents stopped you 
(0) Does not apply 
Reasons for Ideation 
What sort of reasons did you llavefor thinking about wanting to die or killing yourself? Was it 
to end tile pain or stop tile way you were feeling (in other words you couldn't go on living with 
this pain or how you were feeling) or was it to get attention, revenge or a reaction from others? 
Or both? 
(1) Completely to get attention, revenge or a reaction from others. 
(4) Mostly to end or stop the pain (you 
(2) Mostly to get attention, revenge or a reaction from others. 
couldn't go on living with the pain or 
--
(3) Equally to get attention, revenge or a reaction from others 
how you were feeling). 
and to end/stop the pain. 
(5) Completely to end or stop the pain 
(you couldn't go on living with the 
pain or how you were feeling) . 
(0) Does not apply 

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SUICIDAL BEHA VJOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Actual Attempt: 
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part 
thought of as method to kill oneself. Intent does not have to be 100%. If there is any intent! desire to die associated 
with the act, then it can be considered an actual suicide attempt There does not have to be any injury or 
Jzarm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no 
injury results, this is considered an attempt. 
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or 
circumstances. For example, a highly lethal act that is clearly not an accident so no other intent but suicide can be 
inferred (e.g., gunshot to head, jumping from window of a high floor/story). Also, if someone denies intent to die, 
but they thought that what they did could be lethal, intent may be inferred. 
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything da11gerous where you could have died? 
What did you do? 
Did you ___ as a way to e11d your life? 
Did you waul to die (even a little) when you __ ? 
Were you trying to end your life when you __ ? 
Or did you think it was p ossible you could have died from __ ? 
Or did you do it purely for other reasons I without ANY intention of killing yourself (like to 
relieve !\lre.ft.'i:, feel better, get .flympathy, or get .flom£thing elfle to happen)? {Self-Tnjnrions 
without suicidal intent) 
If yes, describe: 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
Interrupted Attempt: 
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious ad (if not for 
thai, actual aJtempt would have occu11'ed) . 
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this becomes an 
attempt rather than an interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken away by 
someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, even if the gun fails to fire, it 
is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose 
around neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or 
something stopped you before you actually did auything? 
If yes, describe: 
Aborted Attempt: 
When person begins to take steps toward making a suicide attempt, but 
themselves before they actually have 
engaged in any self-destructive behavior. Examples are similar to interrupted attempts, except that the individual 
stops him/herself, instead of being stopped by something else. 
Has there been a time when you started to do something to try to end your life but you 
stopped yourself before you actually did anything? 
If yes, describe: 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization 
or thought, such as assembling a specific method (e.g., buying pills, purchasing a gun) or preparing for one's death 
by suicide (e.g., giving tl1ings away, writing a suicide note). 
Have you taken auy steps towards making a suicide attempt or preparing to kill yourself (such 
as collecting pills, getting a gun, giving vahtables away or writing a suicide note)? 
If yes, describe: 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Completed Suicide: 
Since Last 
Visit 
Yes 
No 
0 
0 
Total # of 
Attempts 
Yes 
No 
0 
0 
Yes 
No 
0 
0 
Total # of 
interrupted 
Yes 
No 
0 
0 
Total # of 
aborted 
Yes 
No 
0 
0 
Yes 
No 
0 
0 
Yes No 
0 
0 

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Answer for Actual Attempts Only 
Most Lethal 
Attempt 
Date: 
Actual Lethality/Medical Damage: 
Enter Code 
0. No physical damage or very minor physical damage (e.g., surface scratches). 
1. M inor physical damage (e.g., lethargic speech; first-degree bums; mild bleeding; sprains). 
2. Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-
degree bums; bleeding of major vessel). 
3. Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g ., comatose 
with reflexes 
third-degree burns less than 20% of body; extensive blood loss but can recover; major 
fractures). 
4. Severe physical damage; medical hospitalization w ith intensive care required (e.g ., comatose without reflexes; 
third-degree burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital 
area). 
5. Death 
Potential Lethality: Only Answer if Actual Lethallty-0 
Enter Code 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical 
damage, had potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no 
medical damage; laying on train tracks with oncoming train but pulled away before run over) . 
0 =Behavior not likely to result in injury 
1 =Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care 

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Appendix 20
Protocol Amendment(s)/Administrative Change(s)
Amendment Number:
1
Issue Date:
7 Jun 2017
PURPOSE:
The sponsor has determined the need for a formal amendment to the original protocol 
approved on 29 Sep 2016 to:

Specify the trial treatment dosing schedule and dosing rules.

Clarify index traumatic event and traumatic brain injury exclusion criteria.

Clarify the date for calculation of medical history exclusions and concomitant 
medication washout.

Add exclusion for history of bariatric surgery, due to concern for pharmacokinetic 
effects.

Clarify the requirement for contact with the medical monitor in cases of obesity.

Exclude the males who refuse to abstain from donating sperm during the trial and 
for 30 days after the last dose of IMP.

Provide for additional extensions of the screening period.

Clarify the visit windows in the Schedule of Assessments.

Add review of birth control methods to Schedule of Assessments.

Change start of wearable device from Screening Visit to Baseline (Day 0) Visit.

Clarify that first dose is to be given on the day after the Baseline (Day 0) Visit.

Clarify process for review of electronic report of labs and ECG.

Clarify/add/update lab sample collection.

Include prazosin in list of restricted concomitant medications.

Clarify follow-up requirements for adverse events and IREs.

Add the collection of FBR sample.
In addition, changes to text to enhance readability and consistency and to correct 
typographical, punctuation, and formatting errors.  These changes were minor and do not 
change the design or content of the protocol, and therefore, are not summarized in this 
appendix.
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BACKGROUND:
This amendment was introduced to correct various administrative errors, to clarify 
language that proved to be unclear and to add lab tests to be consistent with other 
brexpiprazole trials past and ongoing.
MODIFICATIONS TO PROTOCOL:
General Revisions:
Following global changes were made to the protocol:

Replaced all occurrences of interactive voice response system 
(IVRS)/interactive web response system (IWRS) or equivalent with 
interactive response technology (IRT).

Added DNA, FBR, LDL, HDL, and IRT to the list of abbreviations and 
deleted IVRS/IWRS.

Removed registering the trial site visits and blister card assignments using 
IRT from Screening, Baseline (Day 0), Week 1, Week 2, Week 3, Week 4, 
Week 6, Week 8, Week 10, and End of Week 12/ET, as applicable.

Revised to provide wearable device at the Baseline (Day 0) Visit, not at the 
Screening Visit.

Prolactin “which is part of serum chemistry” is the only blinded clinical 
laboratory test. Therefore, it was parted from other tests using a square 
bracket:  “Serum chemistry [including blinded prolactin]”.

Added future biospecimen research sample collection to Week 6 Visit.

Revised Appendix 7 to add Chapter 4 for SOT.

Revised Appendix 12 to add LEC-5 extended version.

Revised Appendix 13 to add M.I.N.I. Version 7.0.2.

Revised Appendix 18 to add Past 90 days and Past 1 year in the right hand 
column.
Sectional Revisions:
Location
Old Text
Updated Text
Synopsis, 
Trial design
Screening Phase:  The screening period 
will be 14 days and will begin when 
consent has been obtained.  An extension of 
up to 14 additional days (28-day maximum 
total) can be requested from the medical 
monitor, if needed to meet eligibility 
requirements.  An interactive voice 
response system (IVRS)/interactive web 
response system (IWRS) will be used to 
obtain an identification (ID) number for 
each subject with documented consent.
[not consecutive]
Screening Phase:  The screening period 
will be up to 14 days and will begin when 
consent has been obtained.  Additional
extension(s) of up to 14 additional days can 
be requested from the medical monitor, if 
needed to meet eligibility requirements.  An 
eSource method will be used to obtain an 
identification (ID) number for each subject 
with documented consent.
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Location
Old Text
Updated Text
Follow-up:  If any subject discontinues the 
trial early, every effort should be made to 
complete the Week 12/early termination 
(ET) evaluations as soon as possible and 
whenever possible prior to starting any new 
medication or treatment.  All subjects 
(completers and early withdrawals) will be 
contacted to monitor for safety events via 
telephone or clinic visit for 14 (+ 2) days 
after the last dose of investigational 
medicinal product (IMP).  Any subject who 
withdraws because of a serious adverse 
event (SAE) should be seen in the clinic, if 
possible.
[not consecutive]
Follow-up:  If any subject discontinues the 
trial early, every effort should be made to 
complete the Week 12/early termination 
(ET) evaluations as soon as possible and 
whenever possible prior to starting any new 
medication or treatment.  All subjects 
(completers and early withdrawals) will be 
contacted to monitor for safety events via 
telephone or clinic visit, 14 (+ 2) days after 
the last dose of investigational medicinal 
product (IMP).  Any subject who 
withdraws because of a serious adverse 
event (SAE) should be seen in the clinic, if 
possible.
Synopsis, 
Inclusion/
Exclusion 
Criteria
Key Exclusion Criteria:
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.
5)    Initial onset of trauma occurred before 
age 16.
14)  Subjects who have a history of 
moderate or severe head trauma as 
assessed by the Ohio State University 
Traumatic Brain Injury Identification 
Method (OSU TBI-ID) or other 
neurological disorders or systemic 
medical diseases that are, in the 
investigator’s opinion, likely to affect 
central nervous system functioning.
15)  Subjects who have experienced a 
traumatic event with 3 months of 
screening
17)  Subjects with hypothyroidism or 
hyperthyroidism (unless condition has 
been stabilized with medications for at 
least the past 90 days).
18)  Subjects who currently have clinically 
significant neurological, hepatic, renal, 
metabolic, hematological, 
immunological, cardiovascular, 
Key Exclusion Criteria:
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.
5)    The index traumatic event occurred 
before age 16.
14)  Subjects who have a history of 
moderate or severe head trauma as 
assessed by the Ohio State University 
Traumatic Brain Injury Identification 
Method (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 patient 
safety, in the investigator’s opinion.
15)  Subjects who have experienced a 
traumatic event within 3 months of 
screening.
17)  Subjects with hypothyroidism or 
hyperthyroidism (unless condition has 
been stabilized with medications for at 
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Location
Old Text
Updated Text
pulmonary, or gastrointestinal 
disorders, 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 × the upper limit of 
normal [ULN]).  Medical conditions 
that are minor or well‑controlled may 
be considered acceptable if the 
condition does not expose the subject 
to an undue risk of a significant 
adverse event (AE) or interfere with 
assessments of safety or efficacy 
during the course of the trial.  The 
medical monitor should be contacted in 
any instance where the investigator is 
uncertain regarding the stability of a 
subject’s medical condition(s) and the 
potential impact of the condition(s) on 
trial participation.
least the past 90 days prior to the 
Baseline [Day 0] Visit).
18)  Subjects who currently have clinically 
significant neurological, hepatic, renal, 
metabolic, hematological, 
immunological, cardiovascular, 
pulmonary, or gastrointestinal 
disorders, 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 × the 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 adverse event (AE) or 
interfere with assessments of safety or 
efficacy during the course of the trial.  
The medical monitor should be 
contacted in any instance where the 
investigator is uncertain regarding the 
stability of a subject’s medical 
condition(s) and the potential impact 
of the condition(s) on trial 
participation.  
Synopsis, 
Criteria for 
Evaluation
Safety Endpoints:  Standard safety 
variables will include AEs, clinical 
laboratory tests (hematology, serum 
chemistry [including blinded prolactin and 
HbA1c], and urinalysis), physical 
examinations, vital sign measurements, and 
ECGs.  Body weight, height, and waist 
circumference will also be measured.
Safety Endpoints:  Standard safety 
variables will include AEs, clinical 
laboratory tests (hematology, serum 
chemistry [including blinded prolactin],
HbA1c, and urinalysis), physical 
examinations, vital sign measurements, and 
ECGs.  Body weight, height, and waist 
circumference will also be measured.
Section 3.1 
Type/Design 
of Trial
Screening Phase:  The screening period 
will be 14 days and will begin when 
consent has been obtained.  An extension of 
up to 14 additional days (28-day maximum 
total) can be requested from the medical 
monitor, if needed to meet eligibility 
requirements.  An interactive response 
system (IVRS)/interactive web response 
system (IWRS) will be used to obtain an 
identification (ID) number for each subject 
with documented consent.  Subjects will be 
between 18 and 65 years of age, inclusive, 
at the time of screening and will have a 
diagnosis of PTSD as defined by DSM 5 
Screening Phase:  The screening period 
will be up to 14 days and will begin when 
consent has been obtained.  Additional 
extension(s) of up to 14 additional days can 
be requested from the medical monitor, if 
needed to meet eligibility requirements.  An 
eSource method will be used to obtain an 
identification (ID) number for each subject 
with documented consent.  Subjects will be 
between 18 and 65 years of age, inclusive, 
at the time of screening and will have a 
diagnosis of PTSD as defined by DSM-5
criteria.
All subjects must agree to discontinue all 
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Location
Old Text
Updated Text
criteria.
All subjects must agree to discontinue all 
prohibited medications during the screening 
period in order to meet the protocol-
specified washout periods.
Follow-up:  If any subject discontinues the 
trial early, every effort should be made to 
complete the Week 12/early termination 
(ET) evaluations as soon as possible and 
whenever possible prior to starting any new 
medication or treatment.  All subjects 
(completers and early withdrawals) will be 
contacted to monitor for safety events via 
telephone or clinic visit for 14 (+ 2) days 
after the last dose of investigational 
medicinal product (IMP).  Any subject who 
withdraws because of a serious adverse 
event (SAE) should be seen in the clinic, if 
possible.
prohibited medications during the screening 
period in order to meet the protocol-
specified washout periods.
Follow-up:  If any subject discontinues the 
trial early, every effort should be made to 
complete the Week 12/early termination 
(ET) evaluations as soon as possible and 
whenever possible prior to starting any new 
medication or treatment.  All subjects 
(completers and early withdrawals) will be 
contacted to monitor for safety events via 
telephone or clinic visit, 14 (+ 2) days after 
the last dose of investigational medicinal 
product (IMP).  Any subject who 
withdraws because of a serious adverse 
event (SAE) should be seen in the clinic, if 
possible.
Section 3.2 
Trial 
Treatments
During the double-blind treatment phase, 
subjects will receive IMP, consisting of 
brexpiprazole monotherapy, 
brexpiprazole + Zoloft (sertraline), Zoloft 
(sertraline) monotherapy, or placebo,
depending on the subject’s treatment 
assignment.
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.
During the first 3 weeks of the trial, 
subjects will be titrated according to the 
blinded titration schedule, based on the 
treatment group to which they will be 
randomized.  Per this schedule, at Week 
3, subjects will receive:
1)
Brexpiprazole monotherapy 
2 mg/day; or
2)
Brexpiprazole 2 mg/day + Zoloft
(sertraline) 150 mg/day; or
3)
Zoloft (sertraline) monotherapy 
150 mg/day; or
4)
Placebo.
No dose adjustments are allowed during 
the 3 week titration period, thus any 
subject unable to tolerate the assigned 
dose of IMP during the titration period 
must be withdrawn from the trial.
Once the subject takes the first dose 
following the forced titration period, the 
dose of IMP can be adjusted to optimize 
efficacy and safety/tolerability according 
to the following rules: 

Dose increases can occur only at 
the Week 4 visit. 

Dose decreases can occur at 
scheduled or unscheduled visits 
starting after the first dose 
following Week 3 and are not 
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allowed after the Week 6 visit.  

Dose may be maintained, 
decreased (if not decreased 
already) or increased at the 
Week 4 visit.  No further dose 
increases are permitted after 
Week 4.

Dose decreases will be allowed 
between Week 3 (following the 
first post-visit dose as above) 
and Week 6, if there are 
tolerability issues.

Dose must be maintained for the 
remainder of the treatment 
period after Week 6.

If subjects are unable to 
maintain the Week 6 dose due to 
tolerability issues, the subject 
must be withdrawn from the 
trial.
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.  
Section 3.3.2 
Subject 
Selection and 
Numbering
At screening, subjects will be assigned a 
unique subject ID number upon completion 
of the consent process based on sequential 
enrollment in the trial.  Subjects will be 
assigned a unique subject number upon 
enrollment/randomization.
At screening, subjects will be assigned a 
unique subject ID number upon completion 
of the consent process based on sequential 
enrollment in the trial.  
Section 3.4.3 
Exclusion 
Criteria:
Table 3.4.3-1 Exclusion Criteria
Sex and Reproductive Status
1)    Sexually active males or 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.  
Table 3.4.3-1 Exclusion Criteria
Sex and Reproductive Status
1)    Sexually active males or 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 
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Target Disease
5)    Initial onset of trauma occurred before 
age 16.
14)  Subjects who have a history of 
moderate or severe head trauma as 
assessed by the Ohio State University 
Traumatic Brain Injury Identification 
Method (OSU TBI-ID) or other 
neurological disorders or systemic 
medical diseases that are, in the 
investigator’s opinion, likely to affect 
central nervous system functioning.
15)  Subjects who have experienced a 
traumatic event with 3 months of 
screening.
Medical History and Concurrent Diseases
17)  Subjects with hypothyroidism or 
hyperthyroidism (unless condition has 
been stabilized with medications for at 
least the past 90 days).
18)  Subjects who currently have clinically 
significant neurological, hepatic, renal, 
metabolic, hematological, 
immunological, cardiovascular, 
pulmonary, or gastrointestinal 
disorders such as any history of 
ischemic heart disease, myocardial 
infarction, congestive heart failure 
(whether controlled or uncontrolled), 
angioplasty, stenting, or coronary 
artery bypass surgery, HIV 
seropositive status/acquired 
immunodeficiency syndrome, chronic 
hepatitis B or C (defined as positive 
serology and AST or ALT elevated to 
> 2 × ULN).  Medical conditions that 
are minor or well‑controlled may be 
considered acceptable if the condition 
does not expose the subject to an 
undue risk of a significant AE or 
interfere with assessments of safety or 
efficacy during the course of the trial.  
The medical monitor should be 
contacted in any instance where the 
investigator is uncertain regarding the 
stability of a subject’s medical 
condition(s) and the potential impact 
of the condition(s) on trial 
participation.  Subjects who are 
severely obese, as confirmed by a 
and for 30 days after the last dose of 
IMP.
Target Disease
5)    The index traumatic event occurred 
before age 16.
14)  Subjects who have a history of 
moderate or severe head trauma as 
assessed by the Ohio State University 
Traumatic Brain Injury Identification 
Method (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 patient 
safety, in the investigator’s opinion.
15)  Subjects who have experienced a 
traumatic event within 3 months of 
screening.
Medical History and Concurrent Diseases
17)  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).
18)  Subjects who currently have clinically 
significant neurological, hepatic, renal, 
metabolic, hematological, 
immunological, cardiovascular, 
pulmonary, or gastrointestinal 
disorders such as ischemic heart 
disease, myocardial infarction, 
congestive heart failure (whether 
controlled or uncontrolled), 
angioplasty, stenting, or coronary 
artery bypass surgery, HIV 
seropositive status/acquired 
immunodeficiency syndrome, chronic 
hepatitis B or C (defined as positive 
serology and AST or ALT elevated to 
> 2 × 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 
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corresponding high BMI, need to be 
reviewed and discussed with the 
medical monitor.
[not consecutive]
Nonchildbearing potential is defined as 
male and female subjects who are 
surgically sterile (ie, male subjects who 
have undergone bilateral orchidectomy and 
female subjects who have undergone 
bilateral oophorectomy and/or 
hysterectomy) and female subjects who 
have been postmenopausal for at least 12 
consecutive months.
[not consecutive]
Screen failures excluded may be rescreened 
at any time if the exclusion characteristic 
has changed.  In the event that a subject 
cannot be randomized prior to expiration of 
the 14-day screening period, a 14-day 
extension of screening (28-day maximum 
total) may be requested from the medical 
monitor.  This extension should be 
requested prior to the expiration of the 14-
day screening period.  If no extension is 
granted, a new ICF must be signed, a new 
screening number assigned, and all 
screening procedures repeated.  Subjects 
may be rescreened twice for this trial.
in any instance where the investigator 
is uncertain regarding the stability of a 
subject’s medical condition(s) and the 
potential impact of the condition(s) on 
trial participation.  Subjects who are 
severely obese, as confirmed by a 
corresponding high BMI 
(BMI ≥40 kg/m2), need to be 
reviewed and discussed with the 
medical monitor.
[not consecutive]
Nonchildbearing potential is defined as 
male and female subjects who are 
surgically sterile (ie, male subjects who 
have undergone bilateral orchidectomy and 
female subjects who have undergone 
bilateral oophorectomy and/or 
hysterectomy) and female subjects who 
have been postmenopausal for at least 12 
consecutive months with no menses 
without an alternative medical cause.
[not consecutive]
Screen failures due to exclusionary 
criteria may be rescreened at any time if 
the exclusion characteristic has changed.  In 
the event that a subject cannot be 
randomized prior to expiration of the 
14-day screening period, additional 14-day 
extension(s) of screening may be requested 
from the medical monitor.  Any extension 
should be requested prior to the expiration 
of the previous extension or screening 
period, as applicable.  If no extension is 
granted, a new ICF must be signed, a new 
screening number assigned, and all 
screening procedures repeated.  Subjects 
may be rescreened twice for this trial.
3.5.3 Safety 
Endpoints
Standard safety variables will include 
adverse events (AEs), clinical laboratory 
tests (hematology, serum chemistry
[including blinded prolactin glycosylated 
hemoglobin (HbA1c)], and urinalysis), 
physical examinations, vital sign 
measurements, and electrocardiograms 
(ECGs).  Body weight, height, and waist 
circumference will also be measured.
Standard safety variables will include 
adverse events (AEs), clinical laboratory 
tests (hematology, serum chemistry
[including blinded prolactin], glycosylated 
hemoglobin [HbA1c], and urinalysis), 
physical examinations, vital sign 
measurements, and electrocardiograms 
(ECGs).  Body weight, height, and waist 
circumference will also be measured.
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Old Text: Table 3.7-1 Schedule of Assessment
Table 3.7-1
Schedule of Assessments
Assessment
Screeninga
(Day −14 to 
Day −3) 
Baseline
(Day 0)
Week 1
Visit
Week 2 
Visit
Week 3
Visit
Week 4
Visit
Week 6
Visit
Week 8
Visit
Week 10
Visit
Week 12/
ETb Visit
Post-
treatment 
Follow-upc
ENTRANCE CRITERIA
Informed Consent
X
Inclusion/exclusion criteria
X
X
Demography
X
Medical history
X
Psychiatric history including 
PTSD history
X
MINI 
X
PTSD treatments: 
pharmacological and non-
pharmacological and E-TRIP
X
Prior medication washoutd
X
LEC-5
X
OSU TBI-ID
X
HIV, HBsAg, and anti-HCV
X
EFFICACY
CAPS-5e
X
X
X
X
X
X
X
SOTS
X
X
X
CGI-S
X
X
X
X
X
X
X
X
X
PCL-5
X
X
X
X
X
X
HADS
X
X
X
X
X
X
Wearable devicef
X -------------------------------------------------------------------------------------------------------------------- X
SAFETY
Assess need for double-blind 
IMP dose modification
X
X
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Table 3.7-1
Schedule of Assessments
Assessment
Screeninga
(Day −14 to 
Day −3) 
Baseline
(Day 0)
Week 1
Visit
Week 2 
Visit
Week 3
Visit
Week 4
Visit
Week 6
Visit
Week 8
Visit
Week 10
Visit
Week 12/
ETb Visit
Post-
treatment 
Follow-upc
Physical examinationg
X
X
Vital signsh
X
X
X
X
X
X
X
X
X
X
12-lead ECGi
X
X
X
Clinical laboratory tests 
(hematology, serum chemistry, 
urinalysis), including blinded 
prolactin and TSHj
X
Xk
X
X
HbA1c
X
X
Urine drug screen/blood 
alcoholl
X
X
Urine pregnancy testm
X
X
X
X
X
C-SSRSn
X
X
X
X
X
X
X
X
X
X
SAS
X
X
X
X
AIMS
X
X
X
X
BARS
X
X
X
X
Adverse eventso
X
X
X
X
X
X
X
X
X
X
X
Concomitant medicationsp
X
X
X
X
X
X
X
X
X
X
OTHER
Register visit in IVRS/IWRS
X
X
X
X
X
X
X
X
X
X
Drug dispensing
X
X
X
X
X
X
X
X
Drug accountability
X
X
X
X
X
X
X
X
Pharmacokinetic and Pharmacogenomic Sampling
PK sampleq
X
X
Pharmacogenomic sampler
X
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anti-HCV = antibodies to hepatitis C virus; E-TRIP = Emory Treatment Resistance Interview for PTSD; HBsAg = hepatitis B surface antigen; LEC-5 = Life 
Events Checklist for DSM-5; TSH = thyroid-stimulating hormone.
aScreening begins upon completion of the consent process.  Although the screening period takes place between Day −14 and Day −3 prior to enrollment, 
subjects will participate in screening activities for a minimum of 3 days.  Therefore, screening procedures should be initiated immediately.  In the event that 
a subject cannot be randomized prior to expiration of the 14-day screening period, a 14-day extension of screening (28-day maximum total) may be 
requested from the medical monitor.  This extension should be requested prior to the expiration of the 14-day screening period.  
bIf a subject discontinues early, every effort should be made to complete the “End of Week 12/ET” evaluations as soon as possible and whenever possible 
prior to starting any new medication or treatment.
cTelephone contact or clinic visit (investigator’s discretion) for evaluation of safety.
dWashout of prohibited medications begins after completion of the consent process and must comply with the required washout periods in Section 4.1.
eThe CAPS-5 Past Month version will be completed for all subjects at screening to determine eligibility and 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.  The CAPS-5 Past Week version will also be completed at all visits 
after the Baseline (Day 0) Visit when the assessment is scheduled for collection.
fAfter completion of the consent process during the Screening Visit, the wearable device will be put on the subject’s nondominant wrist, whenever possible, 
and worn daily until Week12/ET.
gTo include measurement of height (at screening only) and waist circumference.
hVital sign measurements include body weight, body temperature, SBP, DBP, and heart rate.  Blood pressure and heart rate will be measured in the following 
order:  supine and standing after the subject has been in each position for at least 3 minutes.
iStandard 12-lead ECGs will be performed after the subject has been supine and at rest for 5 minutes prior to the ECG.  Electrocardiogram results will be 
evaluated at the investigational site to determine the subject’s eligibility and to monitor safety.  Any screening ECG with abnormal result(s) considered to 
be clinically significant should be repeated in triplicate to confirm the finding(s) before excluding the subject from the trial (see Section 3.7.3.4).  A central 
ECG service will be utilized to review all ECGs in order to standardize interpretations for the safety analysis.
jBlood samples for clinical laboratory tests should be drawn after a minimum 8-hour fast and should be drawn after a minimum 8-hour fast at screening, if 
possible.
kIf a fasting blood sample was obtained at the Screening Visit and less than 10 days have elapsed since the Screening Visit, clinical laboratory tests 
(hematology, serum chemistry, and urinalysis) do not need to be repeated at the Baseline (Day 0) Visit.
lA urine drug screen and a blood alcohol test are required at the designated times, but either or both can be conducted at any time during the trial at the 
discretion of the investigator (Section 4.2.2.2).  See Section 3.4.3 for exclusions based on urine drug screen and blood alcohol tests at screening and 
baseline requirements based on urine drug screen and blood alcohol results.
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mFor women of childbearing potential only (WOCBP).  All positive urine pregnancy test results must be confirmed by a serum test. Pregnancy tests can be 
performed at any point during the trial if pregnancy is suspected.
nThe “Baseline/Screening” C-SSRS form will be completed for all subjects at screening to determine eligibility and the “Since Last Visit” C-SSRS form will 
be completed at the Baseline (Day 0) Visit to assure that the subject continues to qualify for the trial.  The “Since Last Visit” C-SSRS form will also be 
completed at all visits after the Baseline (Day 0) Visit.
oAdverse events will be recorded starting after the subject completes the consent process.
pAll prescription and non-prescription medications taken during the trial will be recorded.  Details of prohibited medications are provided in Section 4.
qA PK sample will be collected at the same time of collection of clinical labs. Time of last 3 doses will be recorded at the time of PK sampling.
rA pharmacogenomics sample to assess the CYP2D6 metabolism status will also be collected.
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New Text: Table 3.7-1 Schedule of Assessment
Table 3.7-1
Schedule of Assessments
Assessment
Screeninga
(Day −14 to 
Day −3) 
Baseline
(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
(2 days)
Week 8
Visit
(2 days)
Week 10
Visit
(2 days)
Week 12/
ETb Visit
(2 days)
Post-
treatment 
Follow-upc
(+ 2 days)
ENTRANCE CRITERIA
Informed Consent
X
Inclusion/exclusion criteria
X
X
Demography
X
Medical history
X
Psychiatric history including 
PTSD history
X
MINI 
X
PTSD treatments: 
pharmacological and non-
pharmacological and E-TRIP
X
Prior medication washoutd
X
LEC-5
X
OSU TBI-ID
X
HIV, HBsAg, and anti-HCV
X
Review of birth control 
methods
X
X
X
X
X
X
X
X
X
X
X
EFFICACY
CAPS-5e
X
X
X
X
X
X
X
SOTS
X
X
X
CGI-S
X
X
X
X
X
X
X
X
X
PCL-5
X
X
X
X
X
X
HADS
X
X
X
X
X
X
Wearable devicef
X
X
X
X
X
X
X
X
X
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Table 3.7-1
Schedule of Assessments
Assessment
Screeninga
(Day −14 to 
Day −3) 
Baseline
(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
(2 days)
Week 8
Visit
(2 days)
Week 10
Visit
(2 days)
Week 12/
ETb Visit
(2 days)
Post-
treatment 
Follow-upc
(+ 2 days)
SAFETY
Assess need for double-blind 
IMP dose modification
X
X
Physical examinationg
X
X
Vital signsh
X
X
X
X
X
X
X
X
X
X
12-lead ECGi
X
X
X
Clinical laboratory tests 
(hematology, serum chemistry
[including blinded 
prolactin], urinalysis), TSHj
X
Xk
X
X
HbA1c
X
X
Insulin
X
Xk
X
Urine drug screen/blood 
alcoholl
X
X
Urine pregnancy testm
X
X
X
X
X
C-SSRSn
X
X
X
X
X
X
X
X
X
X
SAS
X
X
X
X
AIMS
X
X
X
X
BARS
X
X
X
X
Adverse eventso
X
X
X
X
X
X
X
X
X
X
X
Concomitant medicationsp
X
X
X
X
X
X
X
X
X
X
OTHER
Drug dispensingq
X
X
X
X
X
X
X
X
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Table 3.7-1
Schedule of Assessments
Assessment
Screeninga
(Day −14 to 
Day −3) 
Baseline
(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
(2 days)
Week 8
Visit
(2 days)
Week 10
Visit
(2 days)
Week 12/
ETb Visit
(2 days)
Post-
treatment 
Follow-upc
(+ 2 days)
Drug accountability
X
X
X
X
X
X
X
X
Pharmacokinetic and Pharmacogenomic Sampling
PK sampler
X
X
Pharmacogenomic samples
X
FBR samplet
X
anti-HCV = antibodies to hepatitis C virus; E-TRIP = Emory Treatment Resistance Interview for PTSD; FBR = future biospecimen research; 
HBsAg = hepatitis B surface antigen; LEC-5 = Life Events Checklist for DSM-5; TSH = thyroid-stimulating hormone.
aScreening begins upon completion of the consent process.  Although the screening period takes place between Day −14 and Day −3 prior to enrollment, 
subjects will participate in screening activities for a minimum of 3 days.  It is requested to complete screening as quickly as possible.  In the event that a 
subject cannot be randomized prior to expiration of the 14-day screening period, additional 14-day extension(s) of screening may be requested from the 
medical monitor.  Any extension should be requested prior to the expiration of the previous extension or screening period, as applicable.  
bIf a subject discontinues early, every effort should be made to complete the “End of Week 12/ET” evaluations as soon as possible and whenever possible 
prior to starting any new medication or treatment.
cTelephone contact or clinic visit (investigator’s discretion) for evaluation of safety.
dWashout of prohibited medications begins after completion of the consent process and must comply with the required washout periods in Section 4.1.
eThe CAPS-5 Past Month version will be completed for all subjects at screening to determine eligibility and 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.  The CAPS-5 Past Week version will also be completed at all visits 
after the Baseline (Day 0) Visit when the assessment is scheduled for collection.
fThe wearable device will be put on the subject’s nondominant wrist, whenever possible, at the Baseline (Day 0) Visit and worn daily until Week12/ET.  The 
trial site will download Actigraphy data during each subject visit.
gTo include measurement of height (at screening only) and waist circumference.
hVital sign measurements include body weight, body temperature, SBP, DBP, and heart rate.  Blood pressure and heart rate will be measured in the following 
order:  supine and standing after the subject has been in each position for at least 3 minutes.
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iStandard 12-lead ECGs will be performed after the subject has been supine and at rest for 5 minutes prior to the ECG.  Electrocardiogram results will be 
evaluated at the investigational site to determine the subject’s eligibility and to monitor safety.  Any screening ECG with abnormal result(s) considered to 
be clinically significant should be repeated in triplicate to confirm the finding(s) before excluding the subject from the trial (see Section 3.7.3.4).  A central 
ECG service will be utilized to review all ECGs in order to standardize interpretations for the safety analysis.
jBlood samples for clinical laboratory tests should be drawn after a minimum 8-hour fast at the Baseline (Day 0) Visit and should be drawn after a minimum 
8-hour fast at screening, if possible.  If blood draws are not part of the site’s SOP, the subject should not be asked to fast for the study prior to 
signing the ICF.  
kIf 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], TSH with reflex to T4 if the result for TSH is abnormal, insulin, and urinalysis) need 
to be repeated at the Baseline (Day 0) Visit.
lA urine drug screen and a blood alcohol test are required at the designated times, but either or both can be conducted at any time during the trial at the 
discretion of the investigator (Section 4.2.2.2).  See Section 3.4.3 for exclusions based on urine drug screen and blood alcohol tests at screening and 
baseline requirements based on urine drug screen and blood alcohol results.
mFor women of childbearing potential only (WOCBP).  All positive urine pregnancy test results must be confirmed by a serum test. Pregnancy tests can be 
performed at any point during the trial if pregnancy is suspected.
nThe “Baseline/Screening” C-SSRS form will be completed for all subjects at screening to determine eligibility and the “Since Last Visit” C-SSRS form will 
be completed at the Baseline (Day 0) Visit to assure that the subject continues to qualify for the trial.  The “Since Last Visit” C-SSRS form will also be 
completed at all visits after the Baseline (Day 0) Visit.
oAdverse events will be recorded starting after the subject completes the consent process.
pAll prescription and non-prescription medications taken during the trial will be recorded.  Details of prohibited medications are provided in Section 4.
qThe subject will be instructed to take their first dose the day after the Baseline (Day 0) Visit (see Section 3.7.1.2).
rA PK sample will be collected at the same time of collection of clinical labs. Time of last 3 doses will be recorded at the time of PK sampling.
sA pharmacogenomics sample to assess the CYP2D6 metabolism status will also be collected.
tFBR sample will be collected if subject consent is received and if allowed by IRB/IEC (see Section 3.7.5).
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Section 
3.7.1.1 
Screening
The screening period begins after consent 
has been obtained.  Although the screening 
period takes place between Day −14 and 
Day −3, subjects will participate in 
screening activities for a minimum of 
3 days. In the event that a subject cannot 
be randomized prior to expiration of the 14-
day screening period, a 14-day extension of 
screening (28 day maximum total) may be 
requested from the medical monitor.  This 
extension should be requested prior to the 
expiration of the 14-day screening period.  
After a subject has provided consent, sites 
will obtain a subject ID number for the 
subject by accessing the IVRS/IWRS or 
equivalent.  Completion of screening 
activities may require more than one visit; 
however, only the initial visit will be 
registered in the IVRS/IWRS or equivalent.  
Screening evaluations will include the 
following:
[not consecutive]
Blood samples for clinical laboratory 
tests (hematology and serum chemistry, 
including blinded prolactin, HbA1c, and 
thyroid-stimulating hormone [TSH] with 
reflex to free thyroxine [T4] if the result 
for TSH is abnormal) should be drawn 
after a minimum 8 hour fast at screening.  
See Table 3.4.3-1 for exclusions based on 
outcome of screening clinical laboratory 
tests.  
The screening period begins after consent 
has been obtained.  Although the screening 
period takes place between Day −14 and 
Day −3, subjects will participate in 
screening activities for a minimum of 
3 days.  It is requested to complete 
screening as quickly as possible.  In the 
event that a subject cannot be randomized 
prior to expiration of the 14-day screening 
period, additional 14-day extension(s) of 
screening may be requested from the 
medical monitor.  Any extension should be 
requested prior to the expiration of the 
previous extension or screening period, as 
applicable.  After a subject has provided 
consent, sites will obtain a subject ID 
number for the subject by accessing 
eSource.  Completion of screening 
activities may require more than one visit; 
however, only the initial visit will be 
registered in the eSource.  Screening 
evaluations will include the following:
[not consecutive]
Blood samples for clinical laboratory 
tests (hematology, serum chemistry 
[including blinded prolactin], HbA1c, 
thyroid-stimulating hormone [TSH] with 
reflex to free thyroxine [T4] if the result 
for TSH is abnormal, insulin, and 
urinalysis) should be drawn after a 
minimum 8-hour fast at screening.  See 
Table 3.4.3-1 for exclusions based on 
outcome of screening clinical laboratory 
tests.  
Section 
3.7.1.2 
Baseline (Day 
0) Visit
If a fasting blood sample was obtained at 
the Screening Visit and more than 10 
days have elapsed since the Screening 
Visit, blood samples for clinical 
laboratory tests (hematology and serum 
chemistry, including blinded prolactin, 
HbA1c, and TSH with reflex to T4 if the 
result for TSH is abnormal) should be 
drawn after a minimum 8-hour fast at 
Baseline (Day 0).
[not consecutive]
Trial personnel will access the 
IVRS/IWRS or equivalent to register the 
visit and to obtain blister card 
assignment(s) for double-blind IMP.  The 
assigned IMP will be dispensed to the 
If a fasting blood sample was not
obtained at the Screening Visit and if 
more than 10 days have elapsed since the 
Screening Visit, blood samples for 
clinical laboratory tests (hematology and 
serum chemistry [including blinded 
prolactin], TSH with reflex to T4 if the 
result for TSH is abnormal, insulin, and 
urinalysis) should be drawn after a 
minimum 8-hour fast at Baseline (Day 0) 
Visit.
[not consecutive]
The assigned IMP will be dispensed to 
the subject. The subjects should be 
instructed to take their first dose the 
day after the Baseline (Day 0) Visit.
The wearable device will be put on 
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subject.
The wearable device will be taken off and 
the data will be downloaded to the 
computer, prior to putting the device back 
on to continue recording.
subject’s nondominant wrist.  The 
wearable device will be worn 
continuously throughout the double-
blind treatment period.
Section 
3.7.1.7 
Treatment 
Phase -
Week 6
[not consecutive]
Blood samples for clinical laboratory tests 
(hematology and serum chemistry, 
including blinded prolactin) should be 
drawn after a minimum of 
8-hours fasting.
[not consecutive]
Blood samples for clinical laboratory tests 
(hematology, serum chemistry [including 
blinded prolactin], TSH with reflex to T4
if the result for TSH is abnormal, and 
urinalysis) should be drawn after a 
minimum of 8-hour fasting.
Section 
3.7.1.10 End 
of Week 
12/Early 
Termination
[not consecutive]  
Blood samples for clinical laboratory tests 
(hematology, HbA1c, and serum chemistry, 
including blinded prolactin) and blood 
alcohol testing should be drawn after a 
minimum 8-hour fast at Week 12/ET.
[not consecutive] 
Blood samples for clinical laboratory tests 
(hematology, HbA1c, serum chemistry 
[including blinded prolactin], TSH with 
reflex to T4 if the result for TSH is 
abnormal, insulin, and urinalysis) and 
blood alcohol testing should be drawn after 
a minimum 8-hour fast at Week 12/ET.
Section 
3.7.1.11 Post-
Treatment 
Follow-up 
Period
Subjects will be contacted to monitor for 
safety events via telephone contact or clinic 
visit (investigator’s discretion) for 14 (+ 2) 
days after the last dose of IMP.  Adverse 
events and concomitant medications will be 
recorded. This contact also applies to 
subjects withdrawn prematurely from the 
trial.
Subjects will be contacted to monitor for 
safety events via telephone contact or clinic 
visit (investigator’s discretion),
14 (+ 2) days after the last dose of IMP.  
Adverse events and concomitant 
medications will be recorded.  This contact 
also applies to subjects withdrawn 
prematurely from the trial.
Section 
3.7.2.6 
Wearable 
Device
The wearable device should be put on the 
subject’s nondominant wrist, whenever 
possible.  The wearable device will be worn 
continuously throughout the double-blind 
treatment period.  At each trial visit, the 
wearable device is taken off and the data 
will be downloaded to the computer.  At the 
Week 12/ET Visit, the wearable device 
monitoring will be stopped.
Use of the wearable device is optional 
and does not require a separate consent 
form.  If the subject agrees to its use, the 
wearable device should be put on the 
subject’s nondominant wrist at the 
Baseline (Day 0) Visit.  The wearable 
device is to be worn continuously 
throughout the double-blind treatment 
period.  At each trial visit, the wearable 
device is taken off, the data will be 
downloaded to the computer and the 
device will be placed back on the 
subject’s nondominant wrist.  At the 
Week 12/ET Visit, the wearable device 
monitoring will be stopped and the 
device returned to the trial site.  All data 
from device should be transferred to 
Phillips by the conclusion of the Week 
12/ET Visit.
Section 
3.7.3.2 
Clinical 
Laboratory 
Assessment
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 
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 
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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 
obtained at the Screening Visit and less 
than 10 days have elapsed since the 
Screening Visit, clinical laboratory tests 
(hematology, serum chemistry, and 
urinalysis) do not 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 should be filed 
with the source documents for each subject.  
The central laboratory will provide 
laboratory results to the sponsor 
electronically.
[not consecutive]
The total volume of blood to be collected 
during the trial is expected to be 
approximately 160 mL.
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, insulin, 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.
[no consecutive]
The total volume of blood to be collected 
during the trial is expected to be 
approximately 100 - 115 mL.
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Old Text: Table 3.7.3.2-1 Clinical Laboratory Assessment
Table 3.7.3.2-1
Clinical Laboratory Assessments
Hematology:
Hemoglobin
MCHC
MCV
RBC count
WBC count with differential 
Urinalysis:
Appearance
Color 
Blood
Glucose
Microscopic analysis, WBC/RBC counts per high 
powered field
pH
Protein
Specific gravity
Additional Tests (screening only):
HIV
HBsAg
Anti-HCV
Serum Chemistry:
ALP
ALT
AST
Bilirubin, total 
BUN
Calcium
Cholesterol
CPK
Creatinine
GGT
Glucose
LDH
Potassium
Prolactina
Protein, total 
Sodium
Triglycerides
Additional Tests:
Urine pregnancy for WOCBP
TSH
HbA1c
ALP = alkaline phosphatase; BUN = blood urea nitrogen; GGT = gamma glutamyl transferase; 
LDH = lactic dehydrogenase; MCHC = mean corpuscular hemoglobin concentration; MCV = mean 
corpuscular volume; RBC = red blood cell; WBC = white blood cell.
aProlactin results will be blinded to the investigators and trial staff.
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New Text: Table 3.7.3.2-1 Clinical Laboratory Assessment
Table 3.7.3.2-1
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
Insulin
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 = lactic 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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Section 
3.7.3.4 
Electrocardi-
ogram 
Assessments
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.  
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.
Section 
3.7.3.5.4 
Columbia-
Suicide 
Severity 
Rating Scale
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 with 
active suicidal ideation within the last 6 
months, suicidal behaviors within the last 2 
years, or who in the clinical judgment of 
the investigator presents a serious risk of 
suicide should be excluded from the trial 
(Table 3.4.3-1).  The “Since Last Visit” C-
SSRS form will also be completed at all 
visits after screening.  Copies of the C-
SSRS forms are provided in Appendix 18 
and Appendix 19.
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 (Table 3.4.3-1).  
The “Since Last Visit” C-SSRS form will 
also be completed at all visits after 
screening.  Copies of the C-SSRS forms are 
provided in Appendix 18 and Appendix 19.
Section 
3.7.3.5.5
Pharmacogenomic Testing
A pharmacogenomics sample to assess the 
CYP2D6 metabolism status will be 
collected at Week 6.  All samples will be 
shipped to the pharmacogenomics 
laboratory.  Detailed handling and shipping 
instructions are provided in Appendix 1.
Deoxyribonucleic Acid (DNA) Blood 
Samples for Pharmacogenomic Testing
A blood sample will be collected at the 
time point presented in the Schedule of 
Assessments (Table 3.7 1) in order to 
extract deoxyribonucleic acid (DNA) and 
determine genotypes and related 
phenotypes for CYP2D6.  The method 
used to determine these genotypes also 
generates genotype data for additional 
genes related to absorption, distribution, 
metabolism, and excretion (ADME) of 
the compound.  Phenotyping of these 
additional genes is not currently planned 
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but may be considered in the future.  All 
samples will be shipped to the central lab 
provided in Appendix 1.
Section 3.7.5 
Future 
Biospecimen 
Research
New section for this amendment. Hence the previous Section 3.7.5 End of Trial is now 
Section 3.7.6.
A blood sample will be collected at the time point presented in the Schedule of 
Assessments (Table 3.7 1) from consenting subjects, and if allowed by the IRB/IEC.  
Research performed on this sample may include genetic analyses (DNA), gene expression 
profiling (ribonucleic acid [RNA]), proteomics, metabolomics and/or the measurement of 
other analytes.  Such research is for biomarker testing to address emergent questions not 
described elsewhere in the protocol (as part of the main trial) and will only be conducted 
on specimens from appropriately consented subjects.  The objective of collecting 
specimens for FBR is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments.
Processing, storage, and shipping instructions for FBR samples are provided in 
Appendix 1.
Section 
3.8.3.3
Documenting 
Reasons for 
Treatment 
Interruption/
Discontinuati-
on

Withdrawal of informed consent 
(complete written withdrawal of consent 
form)

Withdrawal of informed consent
Section 3.9 
Screen 
Failures
Screen failures excluded may be rescreened 
at any time if the exclusion characteristic 
has changed.  In the event that a subject 
cannot be randomized prior to expiration of 
the 14 day screening period, a 14-day 
extension of screening (28-day maximum 
total) may be requested from the medical 
monitor.  This extension should be 
requested prior to the expiration of the 14-
day screening period.
Screen failures due to exclusionary 
criteria may be rescreened at any time if 
the exclusion characteristic has changed.  In 
the event that a subject cannot be 
randomized prior to expiration of the 14 
day screening period, additional 14-day 
extension(s) of screening may be requested 
from the medical monitor.  Any should be 
requested prior to the expiration of the 
previous extension screening period, as 
applicable.
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Old Text: Table 4.1-2 List of Medications Prohibited/Restricted During the Trial
Table 4.1-2
List of Medications Prohibited/Restricted During the Trial
1.
All psychotropic agents including, but not limited to, the following:
a) Antipsychotics, including depot or long-acting injectable formulations
b) Anticonvulsants
c) Antidepressants 
d) Mood stabilizers (ie, lithium)
e) Benzodiazepines, except when used to manage TEAEs such as agitation and anxietya
f)
Hypnotics, including ramelteon and other non-benzodiazepine sleep aids, except for specific 
medications when used to manage TEAEs related to insomniab
g) Stimulants and atomoxetine – allowed if currently being taken for an appropriate indication at a 
stable dose for at least 14 days prior to screening.  Should be continued throughout trial 
participation.
h) Opioid analgesics, unless approval is obtained from the medical monitor.  Approval for opioid 
use may be considered for a documented and clinically appropriate indication (eg, episodic pain 
condition, tooth extraction) if prescribed at a medically appropriate dose and frequency.
i)
Nutritional supplements and non-prescription herbal preparations with central nervous system
effects (eg, St. John’s Wort, omega-3 fatty acids, kava extracts, gamma-aminobutyric acid 
supplements, etc)
j)
Disulfiram
[not consecutive]
bNon-benzodiazepine sleep aids (ie, zolpidem, zaleplon, zopiclone, suvorexant, and eszopiclone only) 
are permitted for the treatment of 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 are encouraged to delay scale administration until 12 hours have elapsed, if 
at all possible.  However, if delaying administration of efficacy and safety scales is not feasible, the 
scales should still be administered and the use of the sleep aid documented, including a notation of 
the drug name, dose, and time of administration on the eSource
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New Text: Table 4.1-2 List of Medications Prohibited/Restricted During the Trial
Table 4.1-2
List of Medications Prohibited/Restricted During the Trial
All psychotropic agents including, but not limited to, the following:
a) Antipsychotics, including depot or long-acting injectable formulations
b) Anticonvulsants
c) Antidepressants 
d) Mood stabilizers (ie, lithium)
e) Benzodiazepines, except when used to manage TEAEs such as agitation and anxietya
f)
Hypnotics, including ramelteon and other non-benzodiazepine sleep aids, except for specific 
medications when used to manage TEAEs related to insomniab
g) Stimulants and atomoxetine – allowed if currently being taken for an appropriate indication at a stable 
dose for at least 14 days prior to Baseline (Day 0) Visit.  Should be continued throughout trial 
participation
h) Opioid analgesics, unless approval is obtained from the medical monitor.  Approval for opioid use may 
be considered for a documented and clinically appropriate indication (eg, episodic pain condition, tooth 
extraction) if prescribed at a medically appropriate dose and frequency.
i)
Nutritional supplements and non-prescription herbal preparations with central nervous system effects 
(eg, St. John’s Wort, omega-3 fatty acids, kava extracts, gamma-aminobutyric acid supplements, etc)
j) Disulfiram
k) Prazosin - allowed if currently being taken for an appropriate indication at a stable dose for at 
least 14 days prior to Baseline (Day 0) Visit.  Should be continued throughout trial participation
[not consecutive]
bNon-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 are encouraged to delay scale administration 
until 12 hours have elapsed, if at all possible.  However, if delaying administration of efficacy and 
safety scales is not feasible, the scales should still be administered and the use of the sleep aid 
documented, including a notation of the drug name, dose, and time of administration on the eSource.
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Section 4.2.1 
Restricted 
Therapies and 
Precautions
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 total during the 
treatment period, 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 and the 
prescribing information is to be used to 
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 total during the 
treatment period, 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 and the 
prescribing information is to be used to 
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Location
Old Text
Updated Text
determine the maximum allowable daily 
dose for the treatment of insomnia.
determine the maximum allowable daily 
dose for the treatment of insomnia.
Section 5.3 
Immediately 
Reportable 
Events
The investigator must immediately report 
after either the investigator or site 
personnel become aware of any SAE, DILI, 
or confirmed pregnancy, by telephone, fax, 
or e-mail to the sponsor using the contact 
information on the cover page of this 
protocol.  An IRE form must be completed 
and sent by e-mail, fax, or overnight courier 
to the sponsor.  (Please note that the IRE 
form is NOT the AE eSource.) 
The investigator must immediately report 
after either the investigator or site 
personnel become aware of any SAE, AE 
related to occupational exposure, DILI, 
or confirmed pregnancy, by telephone, fax, 
or e-mail to the sponsor using the contact 
information on the cover page of this 
protocol.  An IRE form must be completed 
and sent by e-mail, fax, or overnight courier 
to the sponsor.  (Please note that the IRE 
form is NOT the AE eSource.) 
Section 5.5 
Pregnancy
Women of childbearing potential 
(WOCBP) are defined as female subjects 
for whom menstruation has started and who 
are not documented as sterile (ie, have had 
a bilateral oophorectomy and/or 
hysterectomy or who have been 
postmenopausal for at least 12 months).
For WOCBP and for men who are sexually 
active, there must be a documented 
agreement that the subject and/or their 
partner will take effective measures (ie, 
double barrier method) to prevent 
pregnancy during the course of the trial and 
for 30 days after the last dose of IMP.  
Unless the subject is sterile (ie, women who 
have had a bilateral oophorectomy and/or 
hysterectomy or who have been 
postmenopausal for at least 12 consecutive 
months; or men who have had a bilateral 
orchidectomy) or remains abstinent, 2 of 
the following precautions must be used:  
vasectomy, tubal ligation, vaginal 
diaphragm, intrauterine device, birth 
control pills, birth control depot injection, 
birth control implant, condom with 
spermicide, or sponge with spermicide.  
Any single method of birth control, 
including vasectomy and tubal ligation, 
may fail, leading to pregnancy.  The 
contraceptive method will be documented 
at each trial visit.
Women of childbearing potential 
(WOCBP) are defined as female subjects 
for whom menstruation has started and who 
are not documented as sterile (ie, have had 
a bilateral oophorectomy and/or 
hysterectomy or who have been 
postmenopausal for at least 12 months with 
no menses without an alternative medical 
cause).
For WOCBP and for men who are sexually 
active, there must be a documented 
agreement that the subject and/or their 
partner will take effective measures (ie, 
double barrier method) to prevent 
pregnancy during the course of the trial and 
for 30 days after the last dose of IMP.  
Unless the subject is sterile (ie, women who 
have had a bilateral oophorectomy and/or 
hysterectomy or who have been 
postmenopausal for at least 12 consecutive 
months with no menses without an 
alternative medical cause; or men who 
have had a bilateral orchidectomy) or 
remains abstinent, 2 of the following 
precautions must be used:  vasectomy, tubal 
ligation, vaginal diaphragm, intrauterine 
device, birth control pills, birth control 
depot injection, birth control implant, 
condom with spermicide, or sponge with 
spermicide.  Any single method of birth 
control, including vasectomy and tubal 
ligation, may fail, leading to pregnancy.  
The contraceptive method will be 
documented at each trial visit.
Section 5.7 
Follow-up of 
Adverse 
Events
Delete:
For this trial, information on AEs will be followed for up to 14 (+ 2) days after the last 
dose of IMP has been administered.
Section 5.7.1 
Follow-up of 
Nonserious AEs that are identified at any 
time during the trial must be recorded on 
Nonserious AEs that are identified at any 
time during the trial must be recorded on 
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Nonserious 
Adverse 
Events
the AE eSource with the current status 
noted.  If a subject has an AE or has not 
recovered from an AE at the last scheduled 
contact, follow-up contacts will be 
scheduled at least every 4 weeks until 
resolution of the AE is confirmed or the 
condition is considered clinically stable.  
All nonserious events that are ongoing at 
the last scheduled contact will be recorded 
as ongoing on the eSource.  For any AE 
having been identified throughout the trial, 
during analysis, additional relevant medical 
history information may be requested to 
further ascertain causality (including, but 
not limited to, information such as risk-
related behavior, family history and 
occupation).
the AE eSource with the current status 
(ongoing or resolved/recovered) noted.  
All nonserious events (that are not IREs)
that are ongoing at the last scheduled 
contact will be recorded as ongoing on the 
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).
Section 5.7.2 
Follow-up of Serious Adverse Events
This trial requires that subjects be actively 
monitored for SAEs up to 14 (+ 2) days 
after the last dose of IMP is administered.
Serious AEs that are identified or 
ongoing at the last scheduled contact
must be recorded on the AE eSource page 
and reported to the sponsor according to the 
reporting procedures outlined in Section 
5.3.  This may include unresolved 
previously reported SAEs, or new SAEs.  
The investigator will follow SAEs until the 
events are resolved, stabilized, or the 
subject is lost to follow-up.  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 been resolved, 
stabilized, or the subject is lost to follow-
up. 
Follow-up of Serious Adverse Events and 
Immediately Reportable Events
This trial requires that subjects be actively 
monitored for SAEs and IREs up to 
14 (+ 2) days after the last dose of IMP is 
administered.
Serious AEs and nonserious IREs that are 
identified or ongoing at the last scheduled 
contact must be recorded as such on the 
AE eSource page.  If updated information 
(eg, resolved status) on SAE or IRE 
status becomes available after a subject’s 
last scheduled contact (up to last in-clinic 
visit for the entire trial), this must be 
reported to the sponsor and recorded on 
the AE eSource page according to the 
appropriate reporting procedures.  The 
investigator will follow SAEs until the 
events are resolved, stabilized, or 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 been 
resolved, stabilized, or the subject is lost to 
follow-up or has died. 
Section 5.7.3 
Follow-up 
and Reporting 
of Serious 
Adverse 
Any new SAEs reported by the subject to 
the investigator that 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 
Any new SAEs or 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 
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Events 
Occurring 
after Last 
Scheduled 
Contact
to the sponsor.  This may include SAEs that 
are captured on follow-up telephone contact 
or at any other time point after the defined 
trial period (ie, up to last scheduled 
contact).  The investigator should follow 
SAEs identified after the last scheduled 
contact until the events are resolved, 
stabilized, or the subject is lost to follow-
up.  The investigator should continue to 
report any significant follow-up 
information to the sponsor up to the point 
the event has been resolved or stabilized.
to the sponsor.  This may include SAEs or 
IREs that are captured on follow-up 
telephone contact or at any other time point 
after the defined trial period.  The 
investigator should follow SAEs or IREs
identified after the defined trial period 
and continue to report any significant 
follow-up information to the sponsor until
the events are resolved or stabilized, or the 
subject is lost to follow-up or has died.
Section 15 
References
15:  Weathers FW, Blake DD, Schnurr PP, 
Kaloupek DG, Marx BP, Keane TM. The 
Life Events Checklist for DSM-5 (LEC-5). 
White River Junction, VT: National Center 
for PTSD; 2013.
15:  Weathers FW, Blake DD, Schnurr PP, 
Kaloupek DG, Marx BP, Keane TM. The 
Life Events Checklist for DSM-5 (LEC-5) -
extended. National Center for PTSD; 2013.
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
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Agreement
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator's Brochure) and agree that it contains all the ethical, legal and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor's (or designee's) Clinical Trial Agreement.
I will provide copies of the protocol to all physicians, nurses, and other professional personnel to 
whom I delegate trial responsibilities. I will discuss the protocol with them to ensure that they are 
sufficiently informed regarding the investigational new drug, OPC-34712, the concurrent 
medications, the efficacy and safety parameters and the conduct of the trial in general. I am 
aware that this protocol must be approved by the Institutional Review Board (IRB) or receive a 
favorable opinion by the Independent Ethics Committee (IEC) responsible for such matters in the 
clinical trial facility where OPC-34712 will be tested prior to commencement of this trial. I agree to 
adhere strictly to the attached protocol (unless amended in the manner set forth in the sponsor's 
Clinical Trial Agreement, at which time I agree to adhere strictly to the protocol as amended).
I understand that this IRB- or IEC-approved protocol will be submitted to the appropriate 
regulatory authority/ies by the sponsor. I agree that clinical data entered on case report forms by 
me and my staff will be utilized by the sponsor in various ways, such as for submission to 
governmental regulatory authorities and/or in combination with clinical data gathered from other 
research sites, whenever applicable. I agree to allow sponsor and designee monitors and 
auditors full access to all medical records at the research facility for subjects screened or enrolled 
in the trial.
I agree to await IRB/IEC approval before implementation of any substantial amendments to this 
protocol. If, however, there is an immediate hazard to subjects, I will implement the amendment 
immediately, and provide the information to the IRB/IEC within the required local applicable 
timelines. Administrative changes to the protocol will be transmitted to the IRB/IEC for 
informational purposes only, if required by local regulations.
I agree to provide all subjects with informed consent forms, as required by the applicable 
regulations and by ICH guidelines. I agree to report to the sponsor any adverse experiences in 
accordance with the terms of the sponsor's Clinical Trial Agreement and the relevant regional 
regulation(s) and guideline(s). I further agree to provide all required information regarding 
financial certification or disclosure to the sponsor for all investigators and sub-investigators in 
accordance with the terms of the relevant regional regulation(s). I understand that participation in 
the protocol involves a commitment to publish the data from this trial in a cooperative publication 
before publication of efficacy and safety results on an individual basis may occur, and I consent to 
be acknowledged in any such cooperative publications that result.
____________________________
_____________________________
___________
Principal Investigator Print Name
Signature
Date
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Otsuka Pharmaceutical Development & Commercialization, Inc.
This page is a manifestation of an electronically captured signature
                                                                                                                                
SIGNATURE PAGE
Document Name:
Document Number:
Document Version:
Signed by
Meaning of Signature
Server Date
(dd-MMM-yyyy HH:mm ‘GMT’Z)
OPC-34712
331-201-00061 Protocol Amendment 1
0001243258
4.0
Biostatistics Approval
07-Jun-2017 20:44 GMT+00
Clinical Pharmacology
08-Jun-2017 00:17 GMT+00
Clinical Approval
08-Jun-2017 00:40 GMT+00
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Otsuka Pharmaceutical
Development & Commercialization, Inc.
Investigational Medicinal Product
Brexpiprazole (OPC-34712)
Revised CLINICAL PROTOCOL ADDENDUM 
for TRIAL 331-201-00061
A Phase 2, Multicenter, Randomized, Double-blind, Placebo- and Active-controlled Trial 
of Brexpiprazole (1 - 3 mg/day) as Monotherapy or as Combination Therapy in the 
Treatment of Adults with Post-traumatic Stress Disorder
Protocol No. 331-201-00061
IND No. 117,549
CONFIDENTIAL – PROPRIETARY INFORMATION
Drug Development Phase: 
2
Sponsor:
Otsuka Pharmaceutical Development & 
Commercialization, Inc.
2440 Research Boulevard
Rockville, Maryland  20850, United States
Immediately Reportable Event 
INC Research Pharmacovigilance & Drug 
Safety
Fax:  
Issue Date:
29 Sep 2016
Date of Amendment 1
8 Jun 2017
Version No.:
2.0
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BLINDING & CONFIDENTIALITY
This addendum is a separate entity from the associated clinical protocol 
for Trial 331-201-00061 and provides the details of procedures and 
statistical methods that are blinded in the protocol, namely, the 
UNBLINDED randomization timing and description of certain aspects of 
the trial design.  This document is intended for use only by Otsuka 
personnel or their designated agents or for review only by Institutional 
Review Boards, Independent Ethics Committees, regulatory authorities, or 
any other entity considered suitable by Otsuka.  The information contained 
herein is unblinded and confidential; therefore, it must NOT be shared 
with or communicated to any individual at an investigational site without 
written authorization from Otsuka Pharmaceutical Development & 
Commercialization, Inc.
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Table of Contents 
BLINDING & CONFIDENTIALITY .........................................................2
Table of Contents...........................................................................................3
List of In-text Tables .....................................................................................5
List of In-text Figures....................................................................................6
List of Appendices..........................................................................................7
List of Abbreviations and Definitions of Terms .........................................8
1
Background...........................................................................................9
2
Objectives ..............................................................................................9
3
Trial Design...........................................................................................9
3.1
Blinded Design of Trial.......................................................................................9
3.1.1
Screening ........................................................................................................11
11
3.1.3
Blinded Phase B - Treatment Phase................................................................11
3.1.4
End of Week 12/Early Termination................................................................11
3.1.5
Post-treatment Follow-up Period....................................................................11
3.2
Trial Treatments ................................................................................................11
3.2.1
Trial Treatment Administration......................................................................11
3.2.2
Brexpiprazole Administration ........................................................................11
3.2.3
Combination of Brexpiprazole plus Zoloft (Sertraline)..................................12
3.2.4
Zoloft (Sertraline) Administration..................................................................13
3.2.5
Placebo Administration ..................................................................................14
4
Statistical Analysis..............................................................................14
4.1
Sample Size.......................................................................................................14
4.2
Datasets for Analysis.........................................................................................14
4.3
Handling of Missing Data .................................................................................15
4.4
Primary and Secondary Endpoint Analyses ......................................................15
4.4.1
Primary Endpoint Analysis.............................................................................15
4.4.2
Other Efficacy Endpoint Analysis..................................................................16
4.5
Analysis of Demographic and Baseline Characteristics....................................17
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4.6
Safety Analysis..................................................................................................17
4.6.1
Adverse Events ...............................................................................................17
4.6.2
Clinical Laboratory Data ................................................................................18
4.6.3
Physical Examination and Vital Signs Data ...................................................18
4.6.4
Electrocardiogram Data..................................................................................18
4.6.5
Other Safety Data ...........................................................................................19
5
References............................................................................................19
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List of In-text Tables
Table 3.2.2-1
Dosing Schedule for Brexpiprazole.............................................. 12
Table 3.2.3-1
Dosing Schedule for Brexpiprazole plus Zoloft (Sertraline)........ 12
Table 3.2.4-1
Dosing Schedule for Zoloft (Sertraline) ....................................... 13
Table 3.2.5-1
Dosing Schedule for Placebo........................................................ 14
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List of In-text Figures
Figure 3.1-1
Unblinded Trial Design Schematic............................................... 10
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List of Appendices
Appendix 1
Protocol Amendment(s)/Administrative Change(s) ..................... 20
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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
AE
Adverse event
AIMS
Abnormal Involuntary Movement Scale
BARS
Barnes Akathisia Rating Scale
CAPS-5
Clinician-Administered PTSD Scale for DSM-5
C-SSRS
Columbia-Suicide Severity Rating Scale
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
ECG
Electrocardiogram
IMP
Investigational medicinal product
MMRM
Mixed-effect model repeated measure
OC
Observed-case
PTSD
Post-traumatic stress disorder
QTcF
QT interval as corrected by Fridericia’s formula
SAP
Statistical analysis plan
SAS
Simpson-Angus Scale
SD
Standard deviation
TEAE
Treatment-emergent adverse event
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1
Background
 
 
 
  This protocol addendum describes the blinded aspects of Trial 331-201-00061, 
including a detailed description of each trial phase.
This addendum does not repeat the details of the trial design found in the protocol and 
should be read in conjunction with the protocol.
2
Objectives
The objective of the addendum is to present the blinded procedures from the main 
protocol, namely, the unblinded trial phase descriptions, timing of randomization, and the 
timing of the final efficacy assessments.  
3
Trial Design
3.1
Blinded Design of Trial
This is a phase 2, randomized, double-blind, placebo- and active-controlled, 4-arm trial to 
evaluate the efficacy, safety, and tolerability of brexpiprazole (1 - 3 mg/day) as 
monotherapy or as combination therapy with Zoloft (sertraline) in adult subjects with 
post-traumatic stress disorder (PTSD).  See Figure 3.1-1 for a schematic of the trial 
design.
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Figure 3.1-1
Unblinded Trial Design Schematic
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3.1.1
Screening
This phase is not blinded and is discussed in the full protocol.
 
.
3.1.3
Blinded Phase B - Treatment Phase
At Week 1, subjects will be randomly assigned in a 1:1:1:1 ratio to one of the 
double-blind treatment regimens.
3.1.4
End of Week 12/Early Termination
This visit is not blinded and is discussed in the full protocol.
3.1.5
Post-treatment Follow-up Period
This period is not blinded and is discussed in the full protocol.
3.2
Trial Treatments
All subjects receive daily: one tablet (active or placebo-matched brexpiprazole) and two 
Zoloft (sertraline) capsules (active or placebo-matched).
3.2.1
Trial Treatment Administration
Treatment administration information is not blinded and is discussed in the full protocol.
3.2.2
Brexpiprazole Administration
 
 
 
 
 
 Dose decreases can occur at scheduled or unscheduled visits, 
but dose increases can occur only at scheduled visits.  No dose decreases are allowed 
after the Week 6 visit and no dose increases are allowed after the Week 4 visit.
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3.2.3
Combination of Brexpiprazole plus Zoloft (Sertraline)
 
 
 
 
 
 
 
 
 
 
Dose decreases can occur at scheduled or unscheduled visits, but dose increases can 
occur only at scheduled visits.  No dose decreases are allowed after the Week 6 visit and 
no dose increases are allowed after the Week 4 visit.
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3.2.4
Zoloft (Sertraline) Administration
 
 
 
 
 
 Dose decreases 
can occur at scheduled or unscheduled visits, but dose increases can occur only at 
scheduled visits.  No dose decreases are allowed after the Week 6 visit and no dose 
increases are allowed after the Week 4 visit.
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3.2.5
Placebo Administration
As shown in Table 3.2.5-1, subjects assigned to placebo for both treatments (sertraline 
and brexpiprazole).
4
Statistical Analysis
4.1
Sample Size
The primary efficacy endpoint is defined as change from baseline (Week 1 visit) 
 
 in the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total 
score. 
Sixty-eight subjects per arm will provide at least 80% power at a 2-sided alpha level of 
0.05 to detect the treatment difference of −6.5 points in primary efficacy endpoint for 
active arm vs placebo with a standard deviation (SD) of 13. Adjusting for 10% 
non-evaluable subjects, the total number of subjects to be randomized is 75 per treatment 
arm.
Further adjusting for 10% dropout between Baseline (Day 0) Visit and randomization, 
approximately 332 subjects are expected to be enrolled in the trial. 
4.2
Datasets for Analysis
The following samples are defined for this trial:

Enrolled Sample - all subjects enrolled in Placebo Lead-In Phase

Randomized Sample - all subjects randomized into this trial

Safety Sample - all subjects in the randomized sample who were administered at least 
one dose of double-blind investigational medicinal product (IMP)
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
Intent to Treat Sample - all subjects in the Randomized Sample who took at least one 
dose of double-blind IMP and have a baseline and at least one post baseline 
evaluation for the CAPS-5 total score
In general, baseline of an efficacy endpoint is defined as the last available measurement 
before the first dose of double-blind IMP.
4.3
Handling of Missing Data
In general, missing data will be handled by analysis of mixed-effect model repeated 
measures (MMRM) methodology based on observed-case (OC) data from protocol-
specified visits under the assumption of missing at random.
The OC dataset consists of actual observations recorded at each visit during the 
double-blind treatment period and no missing data will be imputed.
4.4
Primary and Secondary Endpoint Analyses
4.4.1
Primary Endpoint Analysis
The change from baseline in CAPS-5 total score will be analyzed using an MMRM 
methodology with unstructured variance covariance matrix.  The model will include fixed 
class-effect terms for treatment, trial site, type of trauma, visit week, and an interaction 
term of treatment by visit week and include the interaction term of baseline values of 
CAPS-5 total score by visit week as a covariate.  All scheduled visits during double-blind 
treatment will be included in the model but primary comparison will be performed 
 
.
In case the prespecified primary efficacy model does not converge, the algorithm to deal 
with convergence issues will be prespecified in the Statistical Analysis Plan (SAP).
The following 3 comparisons 
 after randomization will be estimated 
as the difference between Least Squares means utilizing the computing software SAS 
procedure PROC MIXED.
1) Brexpiprazole plus Sertraline vs Placebo
2) Brexpiprazole vs Placebo
3) Brexpiprazole plus Sertraline vs Sertraline
To protect the experiment-wise 2-sided alpha level at 0.05 when making 3 comparisons 
specified above, the statistical testing will be carried out using a hierarchical testing 
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procedure in the order of 1) comparison of brexpiprazole + sertraline vs placebo; 2) 
comparison of brexpiprazole vs placebo; and 3) comparison of brexpiprazole + sertraline
vs sertraline.  Additional test(s) might be added, and the order of the tests are subject to 
change.  The final order of the hierarchical statistical testing procedure will be specified 
in the SAP.
4.4.2
Other Efficacy Endpoint Analysis
The following additional subgroup analysis for the change from baseline in CAPS-5 total 
score will also be performed:

The Placebo non-responders subgroup analysis based on the response observed 
during placebo lead-in period (defined as at least 20%, 25%, and 30% change 
from baseline)

The subgroup analysis based on the type of trauma (combat related Yes/No)

The subgroup analysis by presence of psychosocial support at baseline

The subgroup analysis by previous pharmacological treatment intervention for 
PTSD
Other efficacy variables are as follows:

Change from baseline in PTSD behavior cluster sub scores of CAPS-5:1

re-experiencing cluster sub score 

avoidance cluster sub score

negative cognitions and mood cluster sub score

arousal cluster sub score 

Change from baseline in Clinical Global Impression - Severity score

Response at each visit as defined by:

decrease from baseline ≥30% in CAPS-5 total score

decrease from baseline by > 11 points in CAPS-5 total score

Shift in CAPS-5 PTSD severity category (moderate, severe or extreme at baseline to 
asymptomatic, mild, moderate, severe or extreme at each visit)

Change from baseline in Symptoms of Trauma Scale score

Change from baseline in Hospital Anxiety and Depression Scale score

Sleep related endpoints
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The continuous efficacy endpoints will be analyzed using MMRM model similar to that 
of prespecified for change from baseline in CAPS-5 total score, correcting for the 
relevant values at randomization.
The response in variables will be analyzed at each visit using a logistic regression model 
including treatment as a fixed factor and baseline of the analyzed variable at 
randomization as covariate. Missing values will be imputed with last-observation-
carried-forward approach.
Further details for each of the additional efficacy analysis and sleep endpoints will be 
prespecified in the SAP.
4.5
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.
4.6
Safety Analysis
Standard safety variables to be analyzed include adverse events (AEs), clinical laboratory 
tests, vital signs, 12-lead electrocardiograms (ECGs), and physical examinations. In 
addition, data from the following safety scales will be evaluated: assessments of 
suicidality (Columbia-Suicide Severity Rating Scale [C-SSRS]) and extrapyramidal 
symptoms (eg, the Simpson-Angus Scale [SAS], Abnormal Involuntary Movement Scale
[AIMS], and Barnes Akathisia Scale [BARS]). Safety analysis will be conducted based 
on the Safety Sample defined in Section 4.2. In general, baseline of a safety variable is 
defined as the last observation of the variable before taking the first dose of double-blind 
IMP, unless specified otherwise. Prospectively defined criteria will be used to identify 
potentially clinically relevant abnormal values for clinical laboratory tests, vital signs, 
ECGs, and body weight. Details of safety analyses will be provided in the SAP.
4.6.1
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:

Treatment-emergent AEs (TEAEs)

TEAEs by severity

TEAEs potentially causally related to the IMP
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
TEAEs with an outcome of death

Serious TEAEs

TEAEs leading to discontinuation of the IMP
The above summaries will also be prepared for TEAEs potentially causally related to the 
IMP.
4.6.2
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.
4.6.3
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.
4.6.4
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 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) 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
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Results will be summarized by visit.
4.6.5
Other Safety Data
Change from baseline in scores for the extrapyramidal symptoms (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.
5
References
1
Friedman MJ, Resick PA, Bryant RA, Brewin CR. Considering PTSD for DSM-5. 
Depress Anxiety. 2011;28:750-69.
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Appendix 1
Protocol Amendment(s)/Administrative Change(s)
Amendment Number:
1
Issue Date:
8 Jun 2017
PURPOSE:
The sponsor has determined the need for a formal amendment to the protocol addendum 
approved on 29 Sep 2016 to better clarify the statistical procedures of the study in 
Section 4.4.1, Section 4.2, and Section 4.6.
BACKGROUND:
This amendment to the protocol addendum was introduced to:

Change on the analyses population:  to specify that the Safety Sample is a subset 
of the Randomized Sample, and clarify the start dose of IMP used in the 
definition of the Safety Sample and the Intent to treat Sample in Section 4.2.

Change in primary efficacy analyses:  to allow flexibility to change the order or 
add tests to the testing sequence in Section 4.4.1.

Change in safety analyses:  to clarify the start dose of IMP in baseline definition
in Section 4.6.
MODIFICATION TO PROTOCOL:
Sectional Revision:
Location
Old Text
Updated Text
Section 4.2 
Datasets for 
Analysis
The following samples are defined for this 
trial:

Enrolled Sample - all subjects enrolled 
in Placebo Lead-In Phase

Randomized Sample - all subjects 
randomized into this trial

Safety Sample - all subjects who were 
administered at least one dose of 
investigational medicinal product 
(IMP)

Intent to Treat Sample - all subjects in 
the Randomized Sample who took at 
least one dose of IMP and have a 
baseline and at least one post baseline 
evaluation for the CAPS-5 total score
In general, baseline of an efficacy endpoint 
is defined as the last available measurement 
The following samples are defined for this 
trial:

Enrolled Sample - all subjects enrolled 
in Placebo Lead-In Phase

Randomized Sample - all subjects 
randomized into this trial

Safety Sample - all subjects in the 
randomized sample who were 
administered at least one dose of 
double-blind investigational medicinal 
product (IMP)

Intent to Treat Sample - all subjects in 
the Randomized Sample who took at 
least one dose of double-blind IMP 
and have a baseline and at least one 
post baseline evaluation for the CAPS-
5 total score
In general, baseline of an efficacy endpoint 
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Location
Old Text
Updated Text
before the first dose of double-blind IMP.
is defined as the last available measurement 
before the first dose of double-blind IMP.
Section 4.4.1 
Primary 
Endpoint 
Analysis
The change from baseline in CAPS-5 total 
score will be analyzed using an MMRM 
methodology with unstructured variance 
covariance matrix.  The model will include 
fixed class-effect terms for treatment, trial 
site, type of trauma, visit week, and an 
interaction term of treatment by visit week 
and include the interaction term of baseline 
values of CAPS-5 total score by visit week 
as a covariate.  All scheduled visits during 
double-blind treatment will be included in 
the model but primary comparison will be 
performed 
. 
In case the prespecified primary efficacy 
model does not converge, the algorithm to 
deal with convergence issues will be 
prespecified in the Statistical Analysis Plan 
(SAP).
The following 3 comparisons 
 
 after randomization will be 
estimated as the difference between Least 
Squares means utilizing the computing 
software SAS procedure PROC MIXED.
1)
Brexpiprazole plus Sertraline vs 
Placebo
2)
Brexpiprazole vs Placebo
3)
Brexpiprazole plus Sertraline vs 
Sertraline
To protect the experiment-wise 2-sided 
alpha level at 0.05 when making 3 
comparisons specified above, the statistical 
testing will be carried out using a 
hierarchical testing procedure in the order 
of 1) comparison of brexpiprazole + 
sertraline vs placebo; 2) comparison of 
brexpiprazole vs placebo; and 3) 
comparison of brexpiprazole + sertraline 
vs sertraline.  
The change from baseline in CAPS-5 total 
score will be analyzed using an MMRM 
methodology with unstructured variance 
covariance matrix.  The model will include 
fixed class-effect terms for treatment, trial 
site, type of trauma, visit week, and an 
interaction term of treatment by visit week 
and include the interaction term of baseline 
values of CAPS-5 total score by visit week 
as a covariate.  All scheduled visits during 
double-blind treatment will be included in 
the model but primary comparison will be 
performed 
. 
In case the prespecified primary efficacy 
model does not converge, the algorithm to 
deal with convergence issues will be 
prespecified in the Statistical Analysis Plan 
(SAP).
The following 3 comparisons 
 
after randomization will be 
estimated as the difference between Least 
Squares means utilizing the computing 
software SAS procedure PROC MIXED.
1)
Brexpiprazole plus Sertraline vs 
Placebo
2)
Brexpiprazole vs Placebo
3)
Brexpiprazole plus Sertraline vs 
Sertraline
To protect the experiment-wise 2-sided 
alpha level at 0.05 when making 3 
comparisons specified above, the statistical 
testing will be carried out using a 
hierarchical testing procedure in the order 
of 1) comparison of brexpiprazole + 
sertraline vs placebo; 2) comparison of 
brexpiprazole vs placebo; and 3) 
comparison of brexpiprazole + sertraline 
vs sertraline.  Additional test(s) might be 
added, and the order of the tests are 
subject to change.  The final order of the 
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Location
Old Text
Updated Text
hierarchical statistical testing procedure 
will be specified in the SAP.
Section 4.6 
Safety 
Analysis
Standard safety variables to be analyzed 
include adverse events (AEs), clinical 
laboratory tests, vital signs, 12-lead 
electrocardiograms (ECGs), and physical 
examinations.  In addition, data from the 
following safety scales will be evaluated:  
assessments of suicidality (Columbia-
Suicide Severity Rating Scale [C-SSRS]) 
and extrapyramidal symptoms (eg, the 
Simpson-Angus Scale [SAS], Abnormal 
Involuntary Movement Scale [AIMS], and 
Barnes Akathisia Scale [BARS]).  Safety 
analysis will be conducted based on the 
Safety Sample defined in Section 4.2.  In 
general, baseline of a safety variable is 
defined as the last observation of the 
variable before taking the first dose of IMP, 
unless specified otherwise.  Prospectively 
defined criteria will be used to identify 
potentially clinically relevant abnormal 
values for clinical laboratory tests, vital 
signs, ECGs, and body weight.  Details of 
safety analyses will be provided in the 
SAP.
Standard safety variables to be analyzed 
include adverse events (AEs), clinical 
laboratory tests, vital signs, 12-lead 
electrocardiograms (ECGs), and physical 
examinations.  In addition, data from the 
following safety scales will be evaluated:  
assessments of suicidality (Columbia-
Suicide Severity Rating Scale [C-SSRS]) 
and extrapyramidal symptoms (eg, the 
Simpson-Angus Scale [SAS], Abnormal 
Involuntary Movement Scale [AIMS], and 
Barnes Akathisia Scale [BARS]).  Safety 
analysis will be conducted based on the 
Safety Sample defined in Section 4.2.  In 
general, baseline of a safety variable is 
defined as the last observation of the 
variable before taking the first dose of 
double-blind IMP, unless specified 
otherwise.  Prospectively defined criteria 
will be used to identify potentially 
clinically relevant abnormal values for 
clinical laboratory tests, vital signs, ECGs, 
and body weight.  Details of safety analyses 
will be provided in the SAP.
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
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OPC-34712
331-201-00061 Protocol Addendum
0001245682
6.0
Clinical Approval
08-Jun-2017 12:31 GMT+00
Clinical Pharmacology
08-Jun-2017 14:50 GMT+00
Biostatistics Approval
08-Jun-2017 15:00 GMT+00
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