Conditions: Irritability Associated With Autism Spectrum Disorder
Keywords: Autism Autism Spectrum Disorder ASD Irritability
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 95
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the long-term safety and tolerability of brexpiprazole in children and adolescent participants, aged 5 to 17, with irritability associated with autism spectrum disorder.

Detailed description:

Arms:
arm 1: Participants received brexpiprazole based on the body weight for 26 weeks in this study.

Participants with body weight \< 50 kilograms (kg), received brexpiprazole tablets orally, once daily (QD) at dose of 0.25 mg on Days 1 to 3 followed by 0.5 mg on Days 4 to 7 and 1 mg on Days 8 to 14. Based on the investigator's judgment, the dose was increased to 1 or 1.5 mg starting from Day 15 until week 26.

Participants with body weight ≥ 50 kg received brexpiprazole tablet orally, QD at dose of 0.5 mg on Days 1 to 3, followed by 1.5 mg on Days 4 to 7, and 2 mg on Days 8 to 14. Based on the investigator's judgment the dose was increased to 1.5, 2, or 3 mg starting from Day 15 until week 26.

Interventions: intervention 1: Brexpiprazole
Intervention descriptions: intervention 1: Oral tablet; taken once daily

Protocol document:
Prot_000.pdf: 
Table of Contents
Table of Contents.............................................................................................................
1
Study 331-201-00191 Protocol Amendment 5; 07 Jul 2022............................................
2
Study 331-201-00191 Protocol Addendum; 06 Jul 2020.................................................
96
Clinical Study Report 331-201-00191
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
1


Otsuka Pharmaceutical 
Development & Commercialization, Inc.
Investigational Medicinal Product
Brexpiprazole (OPC-34712)
REVISED CLINICAL PROTOCOL
Protocol 331-201-00191: A Phase 3, Multicenter, Open-label Trial to Evaluate the 
Long-term Safety and Tolerability of Brexpiprazole (OPC-34712) in the Treatment of 
Children and Adolescents with Irritability Associated with Autism Spectrum Disorder
Protocol No. 331-201-00191
IND No. 141257 
EudraCT No. 2018-004899-35 
CONFIDENTIAL – PROPRIETARY INFORMATION
Clinical Development Phase: 
3
Sponsor:
Otsuka Pharmaceutical Development &
Commercialization, Inc.
2440 Research Boulevard
Rockville, Maryland 20850, United States
Immediately Reportable Event 
QLS.OtsukaPKD@Quintiles.com
  
Issue Date:
02 May 2019 
Version No.:
6.0
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Trial Conduct for COVID-19
All procedures and assessments in this protocol are to be followed to the fullest 
extent possible. The sponsor, in coordination with the sites, investigators, and 
medical monitor, will continuously monitor and evaluate the benefits and risks to 
subject participation in the clinical trial as it relates to COVID-19. If any 
protocol-specified activities were not able to be performed, or cannot be performed 
due to COVID-19 considerations, refer to the COVID-19 Addendum for the 
appropriate measures to be followed. Appropriate measures may include replacing 
in-person visits with virtual visits as deemed necessary by the investigator to ensure 
subject safety and maintain protocol requirements.
Clinical Study Report 331-201-00191
16.1.1 Protocol and Protocol Amendments
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Protocol 331-201-00191
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Protocol Synopsis 
Name of Sponsor: Otsuka Pharmaceutical 
Development & Commercialization, Inc.
Name of Investigational Medicinal Product:  
Brexpiprazole (OPC-34712)
Protocol No.: 331-201-00191
IND No.: 141257 
EudraCT No.: 
2018-004899-35
Protocol Title:
Protocol 331-201-00191: A Phase 3, Multicenter, Open-label 
Trial to Evaluate the Long-term Safety and Tolerability of 
Brexpiprazole (OPC-34712) in the Treatment of Children and 
Adolescents with Irritability Associated with Autism Spectrum 
Disorder
Clinical Phase/Trial 
Type:
3/Safety extension
Treatment Indication: Irritability associated with autism spectrum disorder (ASD)
Objective(s): 
Primary: To assess the long-term safety and tolerability of 
brexpiprazole monotherapy in children and adolescents with 
irritability associated with ASD.
Secondary: To assess the long-term efficacy of brexpiprazole 
monotherapy in children and adolescents with irritability 
associated with ASD.
Trial Design:
This is a phase 3, multicenter, open-label trial designed to 
assess the long-term safety and tolerability of oral 
brexpiprazole as treatment in children and adolescents with 
irritability in ASD. The trial is planned to be conducted on an 
outpatient basis. Enrollment into the trial will be drawn from 
eligible subjects who completed the treatment period in the 
double-blind, phase 3 efficacy trial (331-201-00148 [8 weeks 
of treatment]) and, in the investigator’s judgment, could 
potentially benefit from continued investigational treatment 
with oral brexpiprazole. 
The trial will be conducted as follows:
Screening/Baseline: Subjects who completed the treatment 
period of the double-blind trial and were deemed compliant 
with the protocol will be screened for eligibility at the last visit 
of the double-blind trial (Week 8). A separate fully executed 
informed consent/assent will be obtained for 
Trial 331-201-00191 before any procedures specific to the 
open-label trial are performed. The assessments from the last 
visit of the double-blind trial will serve as the baseline 
measures for Trial 331-201-00191 for any assessment that is 
Clinical Study Report 331-201-00191
16.1.1 Protocol and Protocol Amendments
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Protocol 331-201-00191
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not unique to the open-label trial. Medical history will be 
updated, if necessary.
Open-label Treatment Phase: Eligible subjects from 
Trial 331-201-00148 will receive 26 weeks of daily treatment 
with open-label brexpiprazole. Visits will occur at the end of 
Weeks 1, 2, 3, 4, 8, 14, 18, 22, and 26. Visits at Week 2, 
Week 14, and Week 26 will occur at the clinic. All other visits 
may be conducted either virtually or in clinic. Where the 
investigator and caregiver make the decision to conduct a visit 
virtually, the visit will be conducted by means of 
telecommunications technology. The caregiver and the subject 
will remain in their own home and complete trial assessments 
and questionnaires via an online technology. The caregiver and 
subject will interact with trial personnel using online 
communication tools which incorporate telemedicine. During 
virtual interactions (and at any other time), the trial personnel 
will be able to assess the subject and determine if an additional 
in-office visit for a physical evaluation is required at the 
discretion of the investigator.
Subjects from Trial 331-201-00148 will follow the 
titration/dosing schedule in the table below. Dose titrations 
will be performed in conjunction with a trial visit and 
therefore, trial visit windows are allowed for the titration 
schedule. As in the parent trial, the titration/dosing schedule 
will be based on body weight. Body weight at the Week 8 
double-blind visit/baseline visit for Trial 331-201-00191 will 
be used to determine the starting dose. The body weight of the 
subject at this time will determine dose requirements 
throughout the trial. Those subjects with body weight < 50 kg 
will receive a target dose range of 1 to 1.5 mg, and those 
subjects with body weight ≥ 50 kg will receive a target dose 
range of 1.5 to 3 mg. 
Open-label Titration/Dosing Schedule for Subjects with 
Irritability Associated with ASD
Trial Day
Number of 
Days on IMP
Brexpiprazole Dose
(Body Weight)
< 50 kg
≥ 50 kg
Days 1 to 3
3
0.25 mg QD
0.5 mg QD
Days 4 to 7
4
0.5 mg QD
1.5 mg QD
Days 8 to 14 
7 
1 mg QD
2 mg QD
Starting at Day 
15 (earliest 
opportunity to 
increase to 
maximum dose 
Based on 
investigator 
discretion to 
change dose 
based on 
1 or 1.5 mg QD
1.5, 2, or 3 mg 
QD
Clinical Study Report 331-201-00191
16.1.1 Protocol and Protocol Amendments
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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within target 
dose range)
therapeutic 
effect or 
tolerability
IMP = investigational medicinal product; QD = once daily
Follow-up: Subjects will have follow-up contact 21 (± 2) days 
after the last dose of open-label brexpiprazole to assess 
adverse events (AEs).
This trial will be monitored by an independent Data 
Monitoring Committee (DMC). The DMC will monitor safety 
based on a predetermined schedule as outlined in the DMC 
charter.
Subject Population:
The trial population will include children and adolescent 
rollover subjects from the double-blind, phase 3 efficacy trial 
of brexpiprazole monotherapy: Trial 331-201-00148 
(irritability in ASD). 
Subjects with a Diagnostic and Statistical Manual of Mental 
Disorders, 5th edition (DSM-5) diagnosis of ASD who have 
completed Trial 331-201-00148 may be enrolled into this 
open-label trial. All subjects are required to meet enrollment 
criteria for Trial 331-201-00191 prior to entering the trial.
Inclusion/Exclusion 
Criteria: 
Key Inclusion Criteria:
•
Subjects who, in the opinion of the investigator, could 
potentially benefit from administration of oral 
brexpiprazole for the treatment of irritability associated 
with ASD and who completed Trial 331-201-00148.
Key Exclusion Criteria:
•
Subjects with a substantial protocol violation during the 
course of their participation in the double-blind phase 3 
trial (331-201-00148).  
Trial Site(s): 
The trial is expected to enroll subjects at approximately 
30 sites in the United States. All trial centers will have 
participated as sites in Trial 331-201-00148.
Investigational 
Medicinal Product(s), 
Dose, Dosage 
regimen, Treatment 
Brexpiprazole will be supplied to the investigators by the 
sponsor or designated agent and will consist of open-label 
tablets in child-resistant blister cards, each containing 
sufficient tablets for 7 (+ 2) days. All doses of brexpiprazole 
Clinical Study Report 331-201-00191
16.1.1 Protocol and Protocol Amendments
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period, Formulation, 
Mode of 
Administration:
will be taken orally once daily, preferably in the morning, and 
will be administered without regard to meals. Brexpiprazole 
should be taken at approximately the same time each day.
Trial Assessments:
Safety: adverse events (AEs) and concomitant medications, 
clinical laboratory tests, urinalysis, vital signs, 
electrocardiogram (ECG), physical examination, body weight, 
height, body mass index (BMI), waist circumference, 
extrapyramidal scales (Simpson-Angus Scale [SAS], 
Abnormal Involuntary Movement Scale [AIMS], and Barnes 
Akathisia Rating Scale [BARS]), and suicidality using the 
Columbia-Suicide Severity Rating Scale (C-SSRS).
Efficacy: Aberrant Behavior Checklist - Irritability (ABC-I) 
and subscales, Clinical Global Impression - Severity (CGI-S) 
scale for irritability, 
 
Criteria for 
Evaluation:
Primary Endpoint: Safety will be assessed by the following 
standard endpoints for clinical trials and trials of antipsychotic 
drugs:
•
The frequency and severity of AEs, serious AEs, and 
discontinuation from the trial due to AEs.
•
Change from baseline to postbaseline time points in 
1) vital sign measurements, 2) electrocardiogram 
parameters, 3) clinical laboratory tests (including prolactin) 
and urinalysis, and 4) physical examination findings.
•
Analysis of potential suicide events recorded on the 
C-SSRS. 
•
Changes from baseline to postbaseline time points in 
results from extrapyramidal symptom (EPS) scales (SAS, 
AIMS, and BARS).
•
Percentage of subjects with clinically significant changes 
in weight (gain or loss) from baseline to specified time 
points.
•
Time to discontinuation.
Secondary Endpoint(s): 
•
Change from baseline to Week 26 in the ABC-I subscale 
score.
•
Change from baseline to Week 26 in CGI-S scale score 
focusing on irritability.
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Statistical Methods:
The sample size is not based on statistical considerations, but 
rather on the number of subjects rolling over from the parent 
trial (Trial 331-201-00148). The trial population will be 
derived from eligible subjects who completed the parent trial. 
The sample size of this open-label trial will be limited by the 
number of subjects enrolled into the parent trial.  
Descriptive statistics will be provided for all efficacy and 
safety variables. No inferential statistical analyses are planned 
for this open-label trial.  
Trial Duration:
The duration of this trial from first subject enrolled to last 
subject completed is estimated to be approximately 36 months. 
Individual participation for rollover subjects who complete the 
trial without early withdrawal will be approximately 29 weeks, 
consisting of a 26-week open-label treatment period, and a 
21 (± 2)-day follow-up. 
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Table of Contents 
Trial Conduct for COVID-19.......................................................................2
Protocol Synopsis...........................................................................................3
Table of Contents ..........................................................................................8
List of In-text Tables...................................................................................13
List of In-text Figures .................................................................................14
List of Appendices .......................................................................................15
List of Abbreviations and Definitions of Terms .......................................16
1
Introduction........................................................................................18
1.1
Nonclinical Data................................................................................................19
1.2
Clinical Data......................................................................................................19
1.2.4
Autism Spectrum Disorder .............................................................................21
1.3
Known and Potential Risks and Benefits ..........................................................21
2
Trial Rationale and Objectives .........................................................23
2.1
Trial Rationale...................................................................................................23
2.2
Dosing Rationale...............................................................................................23
2.3
Trial Objectives.................................................................................................25
3
Trial Design.........................................................................................25
3.1
Type/Design of Trial .........................................................................................26
3.2
Trial Treatments ................................................................................................28
3.3
Trial Population.................................................................................................30
3.3.1
Description of Population...............................................................................30
3.3.2
Subject Selection and Numbering ..................................................................30
3.4
Eligibility Criteria .............................................................................................30
3.4.1
Informed Consent/Assent ...............................................................................30
3.4.2
Inclusion Criteria ............................................................................................32
3.4.3
Exclusion Criteria...........................................................................................32
3.5
Endpoints...........................................................................................................33
3.5.1
Primary Endpoint............................................................................................33
3.5.2
Secondary Endpoints ......................................................................................33
Clinical Study Report 331-201-00191
16.1.1 Protocol and Protocol Amendments
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3.6
Measures to Minimize/Avoid Bias....................................................................34
3.7
Trial Procedures ................................................................................................34
3.7.1
Schedule of Assessments................................................................................38
3.7.1.1
Screening and Baseline ...............................................................................38
3.7.1.2
Weeks 1, 2, 3, 4, 8, 14, 18, and 22..............................................................39
3.7.1.3
End of Treatment (Week 26 or Early Termination)....................................39
3.7.1.4
Follow-up....................................................................................................40
3.7.2
Efficacy Assessments .....................................................................................40
3.7.2.1
Aberrant Behavior Checklist.......................................................................40
3.7.2.2
Clinical Global Impression - Severity of Illness Scale ...............................40
3.7.3
Safety Assessments.........................................................................................42
3.7.3.1
Adverse Events ...........................................................................................42
3.7.3.2
Clinical Laboratory Assessments................................................................42
3.7.3.3
Physical Examination and Vital Signs........................................................44
3.7.3.3.1
Physical Examination ..............................................................................44
3.7.3.3.2
Vital Signs ...............................................................................................45
3.7.3.4
Electrocardiogram Assessments .................................................................46
3.7.3.5
Other Safety Assessments...........................................................................47
3.7.3.5.1
Simpson Angus Scale..............................................................................47
3.7.3.5.2
Abnormal Involuntary Movement Scale .................................................47
3.7.3.5.3
Barnes Akathisia Rating Scale ................................................................48
3.7.3.5.4
Columbia-Suicide Severity Rating Scale ................................................48
3.7.4
Prior and Concomitant Medications...............................................................49
3.7.5
Pharmacokinetic/Pharmacodynamic Assessments.........................................49
3.7.5.1
Pharmacokinetic Assessments ....................................................................49
3.7.6
End of Trial.....................................................................................................49
3.7.7
Independent Data Monitoring Committee......................................................49
3.8
Stopping Rules, Withdrawal Criteria, and Procedures......................................49
3.8.1
Entire Trial......................................................................................................49
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3.6
Measures to Minimize/Avoid Bias....................................................................34
3.7
Trial Procedures ................................................................................................34
3.7.1
Schedule of Assessments................................................................................38
3.7.1.1
Screening and Baseline ...............................................................................38
3.7.1.2
Weeks 1, 2, 3, 4, 8, 14, 18, and 22..............................................................39
3.7.1.3
End of Treatment (Week 26 or Early Termination)....................................39
3.7.1.4
Follow-up....................................................................................................40
3.7.2
Efficacy Assessments .....................................................................................40
3.7.2.1
Aberrant Behavior Checklist.......................................................................40
3.7.2.2
Clinical Global Impression - Severity of Illness Scale ...............................40
3.7.3
Safety Assessments.........................................................................................42
3.7.3.1
Adverse Events ...........................................................................................42
3.7.3.2
Clinical Laboratory Assessments................................................................42
3.7.3.3
Physical Examination and Vital Signs........................................................44
3.7.3.3.1
Physical Examination ..............................................................................44
3.7.3.3.2
Vital Signs ...............................................................................................45
3.7.3.4
Electrocardiogram Assessments .................................................................46
3.7.3.5
Other Safety Assessments...........................................................................47
3.7.3.5.1
Simpson Angus Scale..............................................................................47
3.7.3.5.2
Abnormal Involuntary Movement Scale .................................................47
3.7.3.5.3
Barnes Akathisia Rating Scale ................................................................48
3.7.3.5.4
Columbia-Suicide Severity Rating Scale ................................................48
3.7.4
Prior and Concomitant Medications...............................................................49
3.7.5
Pharmacokinetic/Pharmacodynamic Assessments.........................................49
3.7.5.1
Pharmacokinetic Assessments ....................................................................49
3.7.6
End of Trial.....................................................................................................49
3.7.7
Independent Data Monitoring Committee......................................................49
3.8
Stopping Rules, Withdrawal Criteria, and Procedures......................................49
3.8.1
Entire Trial......................................................................................................49
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3.8.2
Individual Site.................................................................................................49
3.8.3
Individual Subject Discontinuation ................................................................50
3.8.3.1
Treatment Interruption ................................................................................50
3.8.3.2
Treatment Discontinuation..........................................................................50
3.8.3.3
Documenting Reasons for Treatment Discontinuation...............................50
3.8.3.4
Withdrawal of Consent ...............................................................................51
3.8.3.5
Procedures to Encourage Continued Trial Participation.............................52
3.9
Screen Failures ..................................................................................................52
3.10
Definition of Completed Subjects.....................................................................53
3.11
Definition of Subjects Lost to Follow-up..........................................................53
3.12
Subject Compliance...........................................................................................53
3.13
Protocol Deviations...........................................................................................53
4
Restrictions .........................................................................................54
4.1
Prohibited Medications .....................................................................................54
4.2
Other Restrictions..............................................................................................56
5
Reporting of Adverse Events.............................................................57
5.1
Definitions.........................................................................................................57
5.2
Eliciting and Reporting Adverse Events ...........................................................59
5.3
Immediately Reportable Events ........................................................................60
5.4
Potential Serious Hepatotoxicity.......................................................................60
5.5
Pregnancy..........................................................................................................60
5.6
Procedure for Breaking the Blind......................................................................62
5.7
Follow-up of Adverse Events............................................................................62
5.7.1
Follow-up of Nonserious Adverse Events......................................................62
5.7.2
Follow-up of Serious Adverse Events............................................................62
5.7.3
Follow-up and Reporting of Serious Adverse Events Occurring after 
Last Scheduled Contact ..................................................................................63
6
Pharmacokinetic/Pharmacodynamic Analysis................................63
7
Statistical Analysis..............................................................................63
7.1
Sample Size.......................................................................................................63
7.2
Datasets for Analysis.........................................................................................63
Clinical Study Report 331-201-00191
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7.3
Handling of Missing Data .................................................................................64
7.4
Primary and Secondary Endpoint Analyses......................................................64
7.4.1
Primary Endpoint Analysis.............................................................................64
7.4.2
Secondary Endpoint Analysis.........................................................................64
7.4.4
Interim Analysis..............................................................................................65
7.5
Analysis of Demographic and Baseline Characteristics....................................65
7.6
Safety Analysis..................................................................................................65
7.6.1
Adverse Events...............................................................................................65
7.6.2
Clinical Laboratory Data ................................................................................65
7.6.3
Physical Examination and Vital Signs Data...................................................65
7.6.4
Electrocardiogram Data..................................................................................66
7.6.5
Other Safety Data ...........................................................................................66
7.6.5.1
Extrapyramidal Symptoms..........................................................................66
7.6.5.2
Suicidality ...................................................................................................66
8
Management of Investigational Medicinal Product........................66
8.1
Packaging and Labeling ....................................................................................66
8.2
Storage...............................................................................................................67
8.3
Accountability ...................................................................................................67
8.4
Returns and Destruction....................................................................................67
8.5
Reporting of Product Quality Complaints.........................................................67
8.5.1
Eliciting and Reporting Product Quality Complaints.....................................68
8.5.2
Information Required for Reporting Purposes ...............................................68
8.5.3
Return Process ................................................................................................68
8.5.4
Assessment/Evaluation...................................................................................69
9
Records Management ........................................................................69
9.1
Source Documents.............................................................................................69
9.2
Data Collection..................................................................................................69
9.3
File Management at the Trial Site.....................................................................70
9.4
Records Retention at the Trial Site....................................................................70
10
Quality Control and Quality Assurance...........................................71
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7.3
Handling of Missing Data .................................................................................64
7.4
Primary and Secondary Endpoint Analyses......................................................64
7.4.1
Primary Endpoint Analysis.............................................................................64
7.4.2
Secondary Endpoint Analysis.........................................................................64
7.4.4
Interim Analysis..............................................................................................65
7.5
Analysis of Demographic and Baseline Characteristics....................................65
7.6
Safety Analysis..................................................................................................65
7.6.1
Adverse Events...............................................................................................65
7.6.2
Clinical Laboratory Data ................................................................................65
7.6.3
Physical Examination and Vital Signs Data...................................................65
7.6.4
Electrocardiogram Data..................................................................................66
7.6.5
Other Safety Data ...........................................................................................66
7.6.5.1
Extrapyramidal Symptoms..........................................................................66
7.6.5.2
Suicidality ...................................................................................................66
8
Management of Investigational Medicinal Product........................66
8.1
Packaging and Labeling ....................................................................................66
8.2
Storage...............................................................................................................67
8.3
Accountability ...................................................................................................67
8.4
Returns and Destruction....................................................................................67
8.5
Reporting of Product Quality Complaints.........................................................67
8.5.1
Eliciting and Reporting Product Quality Complaints.....................................68
8.5.2
Information Required for Reporting Purposes ...............................................68
8.5.3
Return Process ................................................................................................68
8.5.4
Assessment/Evaluation...................................................................................69
9
Records Management ........................................................................69
9.1
Source Documents.............................................................................................69
9.2
Data Collection..................................................................................................69
9.3
File Management at the Trial Site.....................................................................70
9.4
Records Retention at the Trial Site....................................................................70
10
Quality Control and Quality Assurance...........................................71
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10.1
Monitoring.........................................................................................................71
10.2
Auditing.............................................................................................................71
11
Ethics and Responsibility...................................................................72
12
Confidentiality....................................................................................72
13
Amendment Policy .............................................................................72
14
Publication Authorship Requirements.............................................73
15
References ...........................................................................................75
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List of In-text Tables
Table 3.2-1
Open-label Titration/Dosing Schedule for Subjects with 
Irritability Associated with ASDa ..................................................28
Table 3.4.2-1
Inclusion Criteria ...........................................................................32
Table 3.4.3-1
Exclusion Criteria ..........................................................................32
Table 3.7-1
Schedule of Assessments - Rollover Subjects from 
Trial 331-201-00148......................................................................35
Table 3.7.3.2-1
Clinical Laboratory Assessments...................................................43
Table 4.1-1
List of Medications Prohibited During the Trial............................54
Table 4.1-2
Oral Benzodiazepine Rescue Therapy During the Trial................55
Table 4.1-3
Selected CYP2D6 Inhibitors and CYP3A4 Inhibitors and 
Inducers Prohibited During the Trial.............................................56
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List of In-text Figures
Figure 3.1-1
Trial Design Schematic..................................................................27
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List of Appendices
Appendix 1
Criteria for Identifying Vital Signs Outside of Normal Values 
and of Potential Clinical Relevancea..............................................77
Appendix 2
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance .........................................................................78
Appendix 3
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance .........................................................................80
Appendix 4
Protocol Amendment(s)/Administrative Change(s) ......................81
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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
AAD
Agitation associated with dementia of the Alzheimer’s type
ABC
Aberrant Behavior Checklist
ABC-I
Aberrant Behavior Checklist - Irritability
ACTH
Adrenocorticotropic hormone
ADHD
Attention-deficit hyperactivity disorder
AE
Adverse event
AIMS
Abnormal Involuntary Movement Scale
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
ASD
Autism spectrum disorder
AST
Aspartate aminotransferase
AUC0-24h
Area under the plasma concentration-time curve from time 0 hours to 
time 24 hours
AUCτ
Area under the plasma concentration-time curve to the last observable 
concentration
BARS
Barnes Akathisia Rating Scale
BMI
Body mass index
BUN
Blood urea nitrogen
CGI-S
Clinical Global Impression - Severity
CL/F
Apparent clearance of drug from plasma after extravascular 
administration
CNS
Central nervous system
CPK
Creatine phosphokinase
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
Cytochrome P450
DMC
Data Monitoring Committee
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
ECG
Electrocardiogram
EPS
Extrapyramidal symptoms
ET
Early termination
EudraCT
European Clinical Trial Data Base
FDA
(United States) Food and Drug Administration
FOCBP
Female(s) of child-bearing potential
GABA
Gamma-aminobutyric acid
GCP
Good Clinical Practice
GMR
Geometric mean ratio
HbA1c
Glycosylated hemoglobin
HDL
High density lipoprotein
IAF
Informed assent form
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
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ICMJE
International Committee of Medical Journal Editors
ID
Identification
IEC
Independent ethics committee
IMP
Investigational medicinal product
IND
Investigational New Drug application
INR
International normalized ratio
IRB
Institutional review board
IRE
Immediately reportable event
LDH
Lactic dehydrogenase
LDL
Low density lipoprotein
MCH
Mean corpuscular hemoglobin
MDD
Major depressive disorder
MTD
Maximum tolerated dose
OPC
Otsuka Pharmaceutical Co.
OTC
Over the counter 
PK
Pharmacokinetic(s)
PQC
Product Quality Complaint
PT
Prothrombin time
PTSD
Post-traumatic stress disorder
QD
Once daily
QTc
Corrected QT interval
QTcF
QT interval as corrected for heart rate by Fridericia’s formula
RDW
Red cell distribution width
SAE
Serious adverse event
SAS
Simpson Angus Scale
TEAE
Treatment-emergent adverse event
tmax
Time to maximum (peak) plasma concentration
ULN
Upper limit of normal
US 
United States 
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1
Introduction
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by 
Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria as 
deficits in reciprocal social communication and social interaction (verbal and 
nonverbal).1 The severity of ASD is defined by the degree of restricted, repetitive 
patterns of behavior, interests, and activities. Symptoms are present from early childhood 
and contribute to difficulties in developing, maintaining, and understanding relationships.
In addition to the core symptoms that characterize the disorder, children and adolescents 
with ASD often suffer from problem behaviors such as symptoms of irritability and 
aggression, which may manifest as tantrums, self-injury, and aggressive behaviors toward 
others.2 Approximately 20% of people with ASD exhibit irritability and aggression3 with 
> 50% exhibiting significant emotion dysregulation.4 Irritability and aggression often 
negatively affect the lives of people with ASD and their families. 
The prevalence of ASD in the pediatric population in the United States (US) has 
increased over the past decade from estimates of 1 in 150 (0.67%) in 2000 to 1 in 
68 (1.46%) in 2012, with increases occurring in all racial, ethnic, and socioeconomic 
groups (Autism and Developmental Disabilities Monitoring Network, 11 sites).5 In 2011, 
the total costs per year for children with ASD in the US were estimated at between 
$11.5 billion and $60.9 billion which could be attributed to medical care, special 
education, and lost parental productivity.6 
At present, the atypical antipsychotics risperidone and aripiprazole are the only 
medications approved by the US Food and Drug Administration (FDA) for the treatment 
of irritability associated with ASD.7 
With regard to the safety profile of atypical antipsychotics, available data across 
indications suggest that children and adolescents are at higher risk than adults for 
experiencing sedation, acute extrapyramidal symptoms (EPS), withdrawal dyskinesia, 
and significant weight gain during treatment.8,9 For patients with ASD, the common side 
effects of these medications10 are likely to further isolate children and adolescents from 
social interaction. Thus, there is a need to identify additional efficacious agents for 
children with psychiatric disorders, especially considering the safety and tolerability 
issues that may be associated with the use of selected antipsychotics in children and 
adolescents.11 
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Brexpiprazole (also referred to as OPC-34712 and Lu AF41156) is an atypical 
antipsychotic synthesized by Otsuka that is being codeveloped by Otsuka and Lundbeck. 
Brexpiprazole (OPC-34712) is currently approved in the US as monotherapy for the 
treatment of schizophrenia and for use as an adjunctive therapy to antidepressants for the 
treatment of major depressive disorder (MDD) in adults. 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. 
1.1
Nonclinical Data
A complete description of the available data from nonclinical studies, including 
pharmacokinetics (PK) and toxicology studies in different animal species, can be found 
in the Investigator’s Brochure (IB).12 
1.2
Clinical Data
Pharmacokinetic (PK) and pharmacodynamic (PD) data, as well as data from 
schizophrenia and MDD are summarized below. A complete description of the available 
data from clinical trials can be found in the IB.12 
1.2.1
Pharmacokinetics/Pharmacodynamics
The PK of single and multiple doses of brexpiprazole was studied in healthy subjects and 
in subjects with MDD, attention-deficit hyperactivity disorder (ADHD), and 
schizophrenia or schizoaffective disorder. Based on preclinical data and human clinical 
trials, brexpiprazole (OPC-34712) and one metabolite, DM-3411, were identified as the 
major analytes that are present in human plasma. In vitro, the activity of DM-3411 is 
17 times lower than that of brexpiprazole and thus is considered as an inactive 
metabolite. Both brexpiprazole and DM-3411 PK were linear following single oral doses 
of brexpiprazole 0.2 to 8 mg to healthy subjects. The terminal phase elimination half-life 
of brexpiprazole and DM-3411 was 48.3 to 80.8 hours and 48.6 to 77.5 hours, 
respectively. The median time to maximum (peak) plasma concentration (tmax) occurred 
at approximately 2 to 6 hours postdose for brexpiprazole and at approximately 10 to 
24 hours postdose for DM-3411. In healthy subjects, administration of single-dose 
brexpiprazole with a high-fat meal did not affect its rate and extent of absorption.
Steady state PK also appeared to be linear following multiple daily doses of 
brexpiprazole in the range of 0.5 to 2 mg to healthy subjects. The accumulation factor 
based on maximum (peak) plasma concentration and area under the concentration-time 
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curve calculated to the last observable concentration at time t was approximately 4 times. 
After multiple dose administration of brexpiprazole (1 to 12 mg/day) to subjects with 
schizophrenia or schizoaffective disorder, brexpiprazole and DM-3411 mean terminal 
elimination half-life at steady state was 95.4 and 89.3 hours, respectively; median tmax 
was 3.0 and 8.0 hours, respectively.
In drug interaction trials in healthy subjects, brexpiprazole was shown to be metabolized 
by cytochrome P450 (CYP) 3A4 and CYP2D6 isozymes and was not an inhibitor of 
CYP3A4, CYP2B6, CYP2D6, or P-glycoprotein. Co-administration of potent CYP3A4 
or CYP2D6 inhibitors with brexpiprazole resulted in about a 2-fold higher exposure and 
about a 1.5-fold increase in the terminal elimination half-life of brexpiprazole.
In a single-dose trial in healthy subjects, approximately 46.0% and 24.6% of 
administered radioactivity following an oral dose of 14C-brexpiprazole was excreted in 
feces and urine, respectively. In this same trial, brexpiprazole did not preferentially bind 
to red blood cells. Brexpiprazole showed high protein binding in human serum ( 99.8%) 
in vitro.
In Trial 331-201-00103, a phase 1 pediatric trial to assess PK and safety of oral 
brexpiprazole in children age 6 to < 13 years old with central nervous system (CNS) 
disorders, mean apparent clearance of drug from plasma after extravascular 
administration (CL/F) of brexpiprazole of 1.5 or 3 mg in children 10 to < 13 years old 
was comparable with that observed in adults following a single dose of brexpiprazole 
2 mg. Dose proportionality was observed within treatment cohorts (ie, within the same 
age range) and children in the younger age group (6 to < 10 years old) appeared to have 
slightly higher brexpiprazole and DM-3411 exposure and lower brexpiprazole CL/F as 
compared with children in the older group (10 to < 13 years old).
Trial 331-10-233 was a phase 1, multicenter, open-label dose escalation trial to assess the 
safety, tolerability, and PK of oral brexpiprazole in adolescents with schizophrenia or 
other related psychiatric disorders. In Trial 331-10-233, overall systemic exposure was 
measured by dose-normalized maximum concentration at steady state (Cmax,ss) and area 
under the plasma concentration-time curve to the last observable concentration (AUCτ), 
and was slightly higher (geometric mean ratio [GMR] adult/adolescent: 0.765 and 0.904, 
respectively), and CL/F was slightly lower (GMR adult/adolescent: 1.11) in adolescents 
compared to adults in the more important PK evaluable population. For the less important 
PK population, slightly lower dose-normalized AUCs from time 0 to 24 hours (AUC0-24h) 
(GMR adult/adolescent: 1.05), and slightly higher dose-normalized maximized 
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concentrations (Cmax) (GMR adult/adolescent: 0.904) were observed in adolescents when 
compared to adults. The difference in the results for the 2 populations may be due to 
potential noncompliance, especially in the lower dose groups (0.5 and 1.0 mg), when 
dosing was not under medical supervision.
1.2.2
Schizophrenia
The efficacy of brexpiprazole as monotherapy for the treatment of adults with 
schizophrenia has been studied in 2 completed placebo-controlled trials 
(Trials 331-10-230 and 331-10-231), a long-term maintenance trial (Trial 331-10-232), 
and a long-term safety trial (Trial 331-10-237), and was approved for the treatment of 
schizophrenia in adults (ages 18 to 65 years) by the US FDA on 10 Jul 2015. 
Brexpiprazole is currently being studied for the treatment of schizophrenia in adolescents 
13 to 17 years old in the double-blind Trial 331-10-234 and open-label Trial 331-10-236.
1.2.3
Major Depressive Disorder
The efficacy of brexpiprazole as adjunctive therapy for the treatment of MDD has been 
studied in 3 completed placebo-controlled trials (Trials 331-10-227, 331-10-228, and 
331-13-214) and a long-term, open-label safety trial (Trial 331-10-238). A double-blind, 
placebo-controlled trial to evaluate the safety, efficacy, and tolerability of brexpiprazole 
(Trial 331-201-00079) is currently ongoing. Brexpiprazole was approved in the US on 
10 Jul 2015 in adult patients for use as an adjunctive therapy to antidepressants for the 
treatment of MDD.
1.2.4
Autism Spectrum Disorder
There is 1 planned double-blind trial (Trial 331-201-00148) in pediatric subjects with 
ASD. 
1.3
Known and Potential Risks and Benefits
As of 17 Apr 2021, the brexpiprazole clinical development program consisted of a total 
of 97 clinical trials conducted in North America, Latin America, Europe, and Asia 
(77 completed and 20 ongoing). This total includes 77 trials conducted under US 
Investigational New Drug applications (INDs) (65 completed and 12 ongoing) for 
schizophrenia, adjunctive treatment of MDD, adjunctive treatment of ADHD, agitation 
associated with dementia of the Alzheimer’s type (AAD), post-traumatic stress disorder 
(PTSD), or bipolar disorder; and 20 non-US IND trials (12 completed and 8 ongoing in 
China, Japan, and Canada) conducted in healthy subjects, subjects with schizophrenia, 
subjects with MDD, and subjects with AAD.
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Safety data are available from the 76 completed clinical trials. The total number of 
subjects exposed to either single or multiple doses of brexpiprazole is composed of 
9831 subjects in trials conducted under US IND applications and 876 subjects 
(collectively) in non-US IND trials conducted in Japan, China, and South Korea.
Combined data from the completed phase 1 clinical trials indicate that the maximum 
tolerated dose (MTD) for healthy adult subjects was determined to be 6 mg after single-
dose administration and 2 mg after once-daily, multiple-dose (14 days) administration. 
The MTD of brexpiprazole in subjects with schizophrenia, MDD, AAD, ADHD, or 
bipolar disorder has not been established. Data from completed phase 1 clinical trials 
indicate that brexpiprazole is tolerated at multiple oral doses up to 12 mg/day in subjects 
with schizophrenia or schizoaffective disorder; up to 4 mg/day when coadministered with 
marketed antidepressant therapy in subjects with MDD; up to 3 mg/day in elderly 
subjects (70 - 85 years of age) with MDD; and up to 4 mg/day when coadministered with 
marketed stimulant therapy in subjects with ADHD. 
Overall, 69.6% of subjects who received brexpiprazole either alone or coadministered 
with another marketed medication reported at least 1 treatment-emergent adverse event 
(TEAE, with ≥ 2% incidence in total brexpiprazole and more than placebo). The most 
frequently reported TEAEs (incidence ≥ 5% of the total brexpiprazole group and more 
than total placebo) in all subjects who received brexpiprazole were increased weight 
(11.7%), headache (8.9%), insomnia (7.5%), akathisia (7.3%), somnolence (6.0%), and 
dizziness (5.2%). In the total placebo group, headache (8.4%) was the most frequently 
reported TEAE (incidence ≥ 5% of subjects). The majority of TEAEs reported in 61 
pooled completed brexpiprazole clinical trials under US INDs were mild or moderate in 
severity.
A total of 33 deaths have been reported in the brexpiprazole interventional clinical trials 
as of the cutoff date of 17 Apr 2021: 30 deaths in the US IND trials and 3 deaths in the 
non-US IND trials. Nine deaths occurred in schizophrenia trials, 12 deaths in MDD trials, 
9 deaths in the AAD trials, and 3 deaths in PTSD trials. One death, a completed suicide, 
was considered by the investigator to be related to investigational medicinal product 
(IMP).
Serious TEAEs have been reported for 415 subjects who received brexpiprazole (either 
alone or coadministered with another medication) in the 61 completed trials conducted 
under the US INDs, and in 58 subjects in the 12 completed non-US IND trials. 
Clinical Study Report 331-201-00191
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Overall, 9.3% of subjects who received brexpiprazole (either alone or coadministered 
with another medication) and 4.5% of subjects who received placebo (either alone or 
coadministered with another medication) discontinued from IMP due to TEAEs in 61 
pooled completed brexpiprazole trials conducted under the US INDs as of the cutoff date 
of 17 Apr 2021. Overall, 10.6% of subjects who received brexpiprazole discontinued 
from IMP due to TEAEs in completed non-US IND trials.    
In the phase 1, pediatric Trial 331-201-00103, brexpiprazole was safe and well tolerated 
at single oral doses of 0.75 to 1.5 mg in subjects 6 to < 10 years old and 1.5 to 3 mg in 
subjects 10 to < 13 years old with CNS disorders including, but not limited to, ADHD, 
autism-spectrum disorders, bipolar I disorder, conduct disorder, oppositional defiant 
disorder, or any psychotic disorder. The most frequently reported TEAE (> 1 subject) 
was nausea. Additionally, in Trial 331-10-233, multiple oral doses of 0.5 to 4 mg/day 
brexpiprazole in subjects 13 to 17 years old with schizophrenia or other related 
psychiatric disorders were safe and well tolerated. The observed IMP-related TEAEs 
were similar in both trials.
The recommended dose ranges are as follows: 2 to 4 mg/day for the treatment of 
schizophrenia in adults and 2 to 3 mg/day in adult subjects with MDD. The following 
dose ranges of brexpiprazole were selected for evaluation in additional clinical trials (by 
indication): 0.5 to 3 mg/day in adult subjects with AAD, 1 to 3 mg/day in adult subjects 
with PTSD, and 2 to 4 mg/day in adult subjects with bipolar disorder.
Please refer to the current IB for a detailed summary of available nonclinical and clinical 
safety data.12 
2
Trial Rationale and Objectives
2.1
Trial Rationale
Trial 331-201-00191 is being conducted to evaluate the long-term safety and tolerability 
of brexpiprazole in children and adolescent subjects with irritability in ASD 
(ages 5 - 17 years) who have completed the corresponding double-blind, phase 3 efficacy 
trial, Trial 331-201-00148. 
2.2
Dosing Rationale
Two clinical trials have been conducted to investigate the PK, safety, and tolerability of 
brexpiprazole in children and adolescent patients with schizophrenia or other CNS 
disorders: in Trial 331-10-233, subjects 13 to 17 years old received multiple daily doses 
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of brexpiprazole 0.5 to 4 mg; and in Trial 331-201-00103, subjects 6 to 13 years old 
received single doses of brexpiprazole 0.75, 1.5, or 3 mg.
In order to guide dose selection of brexpiprazole in adolescents 5 to 17 years of age with 
irritability associated with ASD, a population PK model was developed using PK data 
from the 2 PK trials in children and adolescents (Trial 331-10-233 and Trial 331-201-
00103) and 3 PK trials in healthy adults or adults with schizophrenia (Trials 
, 
 and 
) in healthy or schizophrenic subjects. In this model, 
clearance and volume of distribution were allometrically scaled by body weight (raised to 
the power of 0.75 for clearance, and 1 for volume of distribution); poor and ultra-rapid 
CYP2D6 metabolizers were excluded in the analysis data; when needed for simulation, 
the effect of CYP2D6 metabolic status on clearance can be imputed using the value 
reported in the adult population PK model previously submitted. The allometrically 
scaled PK model adequately described the PK data in adults, children, and adolescents. 
Pharmacokinetic simulations were performed using this model to predict systemic 
exposure of brexpiprazole in adults and adolescents given different doses of 
brexpiprazole. Target exposure used for the simulations of ASD in subjects 5 to 17 years 
of age was similar to that of the adult subjects with MDD (0.5 - 3 mg/day).
Brexpiprazole systemic exposure, represented AUCτ were simulated and the 5th, median, 
and 95th percentiles were compared between children or adolescents 5 to 17 years of age 
and adult subjects with MDD. Based on the simulation result and clinical considerations, 
a weight cutoff at 50 kg was suggested to make sure subjects receive appropriate dose; 
and the following was observed:
•
AUCτ following 0.25 mg in children and adolescents <50 kg and AUCτ following 
0.5 mg in children and adolescents ≥ 50 kg are comparable with that following 
0.5 mg in adult subjects.
•
AUCτ following 1.5 mg in children and adolescents <50 kg and AUCτ following 
3 mg in children and adolescents ≥ 50 kg are comparable with that following 3 mg in 
adult subjects.
Based on PK simulation, starting and maximum doses were determined. Pharmacokinetic 
profiles following the proposed titration/dosing schedule was also simulated and 
compared with the titration schedule in ongoing trials in adult subjects with bipolar I 
disorder. The dosing schedules for this trial, based on simulation results and clinical 
considerations are shown in Table 3.2-1. 
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
Table 3.2-1
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2.3
Trial Objectives
The primary objective is to assess the long-term safety and tolerability of brexpiprazole 
monotherapy in children and adolescents with irritability in ASD.
The secondary objective is to assess the long-term efficacy of brexpiprazole monotherapy 
in children and adolescents with irritability in ASD.
3
Trial Design
This is a multicenter, open-label trial designed to assess the long-term safety and 
tolerability of oral brexpiprazole as treatment in children and adolescents with irritability 
in ASD. The trial is planned to be conducted on an outpatient basis. Enrollment into the 
trial will be drawn from eligible subjects who completed the treatment period in the 
double-blind, phase 3 efficacy trial, Trial 331-201-00148 (8 weeks of treatment) and, in 
the investigator’s judgment, could potentially benefit from continued investigational 
treatment with oral brexpiprazole. 
The trial will be conducted as follows:
Screening/Baseline: Subjects who completed the treatment period of the double-blind 
trial and were deemed compliant with the protocol will be screened for eligibility at the 
last visit of the double-blind trial (Week 8). A separate fully executed informed 
consent/assent will be obtained for Trial 331-201-00191 before any procedures specific 
to the open-label trial are performed. The assessments from the last visit of the double-
blind trial will serve as the baseline measures for Trial 331-201-00191 for any assessment 
that is not unique to the open-label trial. Medical history will be updated, if necessary.
Open-label Treatment Phase: Eligible subjects from Trial 331-201-00148 will receive 
26 weeks of daily treatment with open-label brexpiprazole in Trial 331-201-00191, as 
described in Section 3.7. Visits will occur at the end of Weeks 1, 2, 3, 4, 8, 14, 18, 22, 
and 26. 
The baseline, Week 2, Week 14, and Week 26 visits will occur in the clinic. All other 
visits may be conducted either virtually or in clinic. Where the investigator and caregiver 
make the decision to conduct a visit virtually, the visit will be conducted by means of 
telecommunications technology. The caregiver and the subject will remain in their own 
home and complete trial assessments and questionnaires via an online technology. The 
caregiver and subject will interact with trial personnel using online communication tools 
which incorporate telemedicine. During virtual interactions (and at any other time), the 
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trial personnel will be able to assess the subject and determine if an additional in-office 
visit for a physical evaluation is required at the discretion of the investigator.
Follow-up: Subjects will have a follow-up contact 21 (± 2) days after the last dose of 
open-label brexpiprazole.
3.1
Type/Design of Trial
A schematic of the trial design is provided in Figure 3.1-1.
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Figure 3.1-1
Trial Design Schematic
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3.2
Trial Treatments
Brexpiprazole will be supplied by the sponsor or designated agent in child-resistant 
blister cards, each containing sufficient tablets for 7 (+ 2) days. All doses of open-label 
brexpiprazole are to be taken orally once daily and can be administered without regard to 
meals. Every effort should be made to administer the open-label brexpiprazole at the 
same time every day, preferably in the morning. 
The first dose of open-label brexpiprazole will be taken the following day after the last 
dose of double-blind IMP is taken in the parent trial so that treatment continues without 
interruption. Whenever possible, it is anticipated that the last dose of IMP in the double-
blind, phase 3 efficacy trial will be taken on the day of the baseline visit for the open-
label trial. Subjects should not be dosed using double-blind and open-label IMP on the 
same day.  
Titration/Dosing Instructions:
Subjects will follow the titration/dosing schedule in Table 3.2-1. As in the parent trial, the 
titration/dosing schedule will be based on body weight. Body weight at the Week 8 
double-blind visit/baseline visit for Trial 331-201-00191 will be used to determine the 
starting dose. The body weight of the subject at this time will determine titration/dose 
requirements throughout the trial. Those subjects with body weight < 50 kg will receive a 
target dose range of 1 to 1.5 mg, and those subjects with body weight ≥ 50 kg will receive 
a target dose range of 1.5 to 3 mg.
Table 3.2-1
Open-label Titration/Dosing Schedule for Subjects with 
Irritability Associated with ASDa
Trial Day
Number of Days on 
IMP
Brexpiprazole Dose
(Body Weight)
< 50 kg (QD)
≥ 50 kg (QD)
Days 1 to 3
3
0.25 mg 
0.5 mg 
Days 4 to 7
4
0.5 mg 
1.5 mg 
Days 8 to 14 
7 
1 mg 
2 mg 
Starting at Day 15 
(earliest opportunity to 
increase to maximum 
dose within target dose 
range)
Based on investigator 
discretion to change 
dose based on 
therapeutic effect or 
tolerability
1 or 1.5 mg 
1.5, 2, or 3 mg 
QD = once daily.
aDose titrations will be performed in conjunction with a trial visit and therefore, trial visit windows are 
allowed for the titration schedule. 
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Subjects with body weight < 50 kg will receive brexpiprazole at a dose of 0.25 mg for 
Days 1 to 3, 0.5 mg for Days 4 to 7, and 1.0 mg for Days 8 to 14. Day 15 is the earliest 
opportunity that the investigator can increase to the maximum dose of 1.5 mg within the 
target dose range. The decision to increase the dose to 1.5 mg and when to increase the 
dose will be based on investigator judgment in order to reach a desired therapeutic effect. 
Subjects with body weight ≥ 50 kg will receive brexpiprazole at a dose of 0.5 mg for 
Days 1 to 3, 1.5 mg for Days 4 to 7, and 2 mg for Days 8 to 14. Day 15 is the earliest 
opportunity that the investigator can increase to the maximum dose of 3 mg within the 
target dose range. The decision to increase the dose to 3 mg and when to increase the 
dose will be based on investigator judgment in order to reach a desired therapeutic effect. 
For all subjects, doses can be down-titrated due to tolerability based on investigator 
judgment. Subjects < 50 kg should receive a dose of 1.5 mg before decreasing the dose to 
1 mg. Subjects ≥ 50 kg should receive a dose of 2 mg before decreasing the dose to 
1.5 mg and 3 mg before decreasing to 2 mg. 
If a subject with body weight < 50 kg is unable to tolerate the 1 mg dose, the subject will 
be discontinued. If a subject with body weight ≥ 50 kg is unable to tolerate the 1.5 mg, 
the subject will be discontinued.
Dose titrations will be performed in conjunction with a trial visit and therefore, trial visit 
windows are allowed for the titration schedule. 
To accommodate maximum flexibility in dosing for the subjects with irritability 
associated with ASD, more than 1 dose decrease or increase will be allowed during the 
open-label period. Any increase or decrease, however, should happen in a stepwise 
fashion based on investigator discretion to change dose based on therapeutic effect or 
tolerability according to Table 3.2-1.  
Depending on the visit, IMP will be dispensed either at a clinic visit or delivery will be 
made to a subject’s home. The IMP for dose increases or decreases occurring between 
scheduled visits will be dispensed as an unscheduled visit and accommodations arranged 
to have IMP received by the subject/caregiver, either by home delivery or pickup at the 
site. Instructions will be supplied to the subject/caregiver by trial/team support staff 
regarding any dosing changes.  
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3.3
Trial Population
3.3.1
Description of Population
The trial population will include children and adolescent rollover subjects from the 
double-blind, phase 3 efficacy trial of brexpiprazole monotherapy: Trial 331-201-00148 
(irritability in ASD). 
Subjects with a DSM-5 diagnosis of ASD who have completed Trial 331-201-00148 may 
be enrolled into this open-label trial. All subjects are required to meet enrollment criteria 
for Trial 331-201-00191 prior to entering the trial.
3.3.2
Subject Selection and Numbering
Subjects will retain their subject identification (ID) numbers from the parent trial and are 
required to sign a new informed consent form (ICF) and assent form for this trial, as 
applicable.
3.4
Eligibility Criteria
3.4.1
Informed Consent/Assent
Informed consent/assent will be freely obtained from all subjects (or their guardian or 
legally acceptable representative, as applicable for local laws). Consent and assent will be 
documented on an electronic or written ICF and informed assent form (IAF). The 
ICF/IAF will be approved by the same institutional review board/independent ethics 
committee (IRB/IEC) that approves this protocol. Subjects who are too young to sign an 
ICF/IAF either via wet signature or electronic signature (e-signature) will provide 
informed assent per local law, and the subject must be able to understand that he or she 
can withdraw from the trial at any time and for any reason.
Each ICF/IAF will comply with the International Conference on Harmonisation (ICH) 
Good Clinical Practice (GCP) Guideline13 and local regulatory requirements. The 
investigator will ensure that the sponsor reviews and authorizes any site-specific ICF/IAF 
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/assent. However, informed consent/assent must be 
obtained and documented prior to initiation of any procedures that are performed solely 
for the purpose of determining eligibility for research, including withdrawal from current 
medication(s). 
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Potential subjects are free to refuse entry into the trial, or withdraw from the trial at any 
time, without justification, and there will be no consequences to their further care.
Once appropriate essential information has been provided and fully explained in 
layman’s language to the subject and/or his/her parent/legal guardian or legally 
acceptable representative, as applicable by the investigator (or a qualified designee), and 
it has been documented that the subject and his/her parent/legal guardian or legally 
acceptable representative has had the opportunity to ask questions, the IRB/IEC-approved 
written ICF/IAF will be signed and dated by the subject, the subject’s legally acceptable 
representative (eg, guardian), and the person obtaining consent/assent (investigator or 
designee), as well as by any other parties required by the IRB/IEC. The subject will 
receive a copy of the signed ICF/IAF; the original shall be kept on file by the 
investigator.
At sites where the electronic ICF/IAF application is used, prospective trial participants 
will be provided with controlled access to the application by trial site staff. When the trial 
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 ICF/IAF in 
the electronic ICF application and an electronic date and timestamp will be applied to the 
signature. The subject will be given a printed, signed copy of the ICF/IAF. Any other 
parties required by the IRB/IEC (trial site staff, witnesses, or legally authorized 
representative) are also required to sign electronically and these signatures will be stored 
with the electronic ICF/IAF in accordance with the ICH GCP Guideline and local 
regulatory requirements/guidelines. These signatures cannot be altered, removed, or 
copied. At sites where the electronic ICF/IAF application is not used, paper consent and 
assent forms will be signed after trial site staff and the participant agree that the 
participant has enough information to make an informed decision to participate. Any 
other parties required to provide signatures will also sign the paper forms, and the forms 
will be stored in accordance with the ICH GCP Guideline and local regulatory 
requirements/guidelines.
Subjects or their parent/legal guardian or legally acceptable representative, as applicable 
for local laws, may be asked to sign additional ICFs/IAFs if the protocol is amended and 
the changes to the protocol result in additional information that needs to be provided to 
the subjects, so that they can make a knowledgeable and voluntary decision on trial 
participation. 
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If a subject is legally emancipated, informed consent must be sought directly from the 
subject. Subjects who turn age 18 (or the age of adulthood as specified by local laws or 
regulations) during the trial must sign a new ICF at that time.
In addition to the English version of the ICF/IAF, the documents may also be translated 
into local languages for use in this trial. Translation with back-translation for 
confirmation will be utilized to ensure accuracy.
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, in the opinion of the investigator, could potentially benefit from administration of 
oral brexpiprazole for the treatment of irritability associated with ASD and who completed 
Trial 331-201-00148.
2.
Male and female subjects 5 to 17 years of age, inclusive, at the time of informed consent/assent. 
Subjects who turned 18 years old during Trial 331-201-00148 are permitted in this trial.
3.
Written informed consent/assent obtained from a legally acceptable representative (eg, guardian) or 
subject prior to the initiation of any protocol-required procedures. In addition, the subject must 
provide informed assent at screening and must be able to understand that he or she can withdraw 
from the trial at any time. All informed consent/assent procedures must be in accordance with the 
trial site’s IRB/IEC and local regulatory requirements.
4.
Ability, in the opinion of the principal investigator, of the subject or the subject’s legally acceptable 
representative (eg, guardian) or caregiver(s) to understand the nature of the trial and follow 
protocol requirements, including the prescribed dosage regimens, tablet ingestion, and 
discontinuation of prohibited concomitant medications, to read and understand the written word in 
order to complete subject-reported outcomes measures, and to be reliably rated on assessment 
scales.
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
1. 
Subjects with a substantial protocol violation during the course of their participation in the double-
blind phase 3 Trial 331-201-00148. Lesser violations such as occasional visits outside of the 
acceptable window or a missing blood draw will not exclude a subject from participation in 
Trial 331-201-00191; however, continual lack of compliance with the visit schedule, trial 
assessments, or treatment regimen in the prior double-blind trial would be considered a substantial 
violation that would result in exclusion from Trial 331-201-00191. The medical monitor should be 
contacted if the investigator is unsure of a subject’s eligibility.
2.
Sexually active males or FOCBP who do not agree to practice 2 different methods of birth control 
or remain abstinent during the trial and for 30 days after the last dose of IMP. If employing birth 
control, 2 of the following precautions must be used: vaginal diaphragm, intrauterine device, birth 
control pill, birth control implant, birth control depot injection, condom with spermicide, or sponge 
with spermicide. 
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Table 3.4.3-1
Exclusion Criteria
3.
Females who are breast-feeding and/or who have a positive pregnancy test result prior to receiving 
IMP.
4.
Subjects who, in the opinion of the investigator, medical monitor, or sponsor, should not participate 
in the trial.
5.
Subjects who are siblings, or are unrelated and live in the same household, cannot simultaneously 
participate in the trial.
FOCBP = females of child-bearing potential
Subjects must agree to restrictions to medications and lifestyle as described in Section 4.
3.5
Endpoints
3.5.1
Primary Endpoint
Safety will be assessed by the following standard endpoints for clinical trials and trials of 
antipsychotic drugs:
•
The frequency and severity of adverse events (AEs), serious AEs (SAEs), and 
discontinuation from the trial due to AEs.
•
Change from baseline to postbaseline time points in 1) vital sign measurements, 
2) electrocardiogram (ECG) parameters, 3) clinical laboratory tests (including 
prolactin) and urinalysis, and 4) physical examination findings.
•
Analysis of potential suicide events recorded on the Columbia-Suicide Severity 
Rating Scale (C-SSRS). 
•
Changes from baseline to postbaseline time points in results from EPS scales 
(Simpson Angus Scale [SAS], Abnormal Involuntary Movement Scale [AIMS], and 
Barnes Akathisia Rating Scale [BARS]).
•
Percentage of subjects with clinically significant changes in weight (gain or loss) 
from baseline to specified time points. 
•
Time to discontinuation.
3.5.2
Secondary Endpoints
•
Change from baseline to Week 26 in the Aberrant Behavior Checklist -– Irritability 
(ABC-I) subscale score.
•
Change from baseline to Week 26 in Clinical Global Impression - Severity (CGI-S) 
scale score targeted on irritability.
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3.6
Measures to Minimize/Avoid Bias
Not applicable; this is an open-label trial.
3.7
Trial Procedures
Trial assessment time points are summarized in Table 3.7-1.
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Table 3.7-1
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Table 3.7-1
Schedule of Assessments - Rollover Subjects from Trial 331-201-00148
26-week Open-label Treatment Period
EOT
Follow-
up
Assessment
Screening/ 
Baseline
Last visit 
from Trial 
331-201-
00148/
Baseline
for Trial
331-201-
00191
Week 
1
(Day 7 
± 2 
days)
Virtual 
or In 
office
Week 
2
(Day 
14 ± 2 
days)
In 
office
Week 
3
(Day 21 
± 2 
days)
Virtual 
or In 
office
Week 
4
(Day 28 
± 2 
days)
Virtual 
or In 
office
Week 
8
(Day 56 
± 2 
days)
Virtual 
or In 
office
Week 
14
(Day 
98 ± 
2 
days)
In 
office
Week 
18 
(Day 
126 ± 2 
days)
Virtual 
or In 
office
Week 22 
(Day 154 
± 2 days)
Virtual 
or In 
office
Week 
26/ ET
(Day 
182 ± 
2 
days)
In 
office
21 (± 2) 
days 
after 
last 
dose of 
IMP
By Tele
phone
Notes
Informed 
consent/assent, 
update medical 
history, as needed
X
Section 3.4.1
Prior medications
X
Section 3.7.4
Inclusion/exclusion 
criteria
X
CGI-S
X
X
X
X
X
X
X
X
X
X
Section 3.7.2.2
SAS, AIMS, & 
BARS
X
X
X
X
Section 3.7.3.5
C-SSRS
X
X
X
X
X
X
X
X
X
X
Section 3.7.3.5.4
ABC
X
X
X
X
X
X
X
X
X
X
Section 3.7.2.1
Physical 
examination
X
X
Section 3.7.3.3.1
Body weight and 
waist 
circumference
X
X
X
Section 3.7.3.3.1
Height
X
X
X
Section 3.7.3.3.1
Vital signs 
X
X
X
X
X
X
X
X
X
X
Section 3.7.3.3.2
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
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Table 3.7-1
Schedule of Assessments - Rollover Subjects from Trial 331-201-00148
26-week Open-label Treatment Period
EOT
Follow-
up
Assessment
Screening/ 
Baseline
Last visit 
from Trial 
331-201-
00148/ 
Baseline 
for Trial 
331-201-
00191
Week 
1
(Day 7 
± 2 
days)
Virtual 
or In 
office
Week 
2
(Day 
14 ± 2 
days)
In 
office
Week 
3
(Day 21 
± 2 
days)
Virtual 
or In 
office
Week 
4
(Day 28 
± 2 
days)
Virtual 
or In 
office
Week 
8
(Day 56 
± 2 
days)
Virtual 
or In 
office
Week 
14
(Day 
98 ± 
2 
days)
In 
office
Week 
18 
(Day 
126 ± 2 
days)
Virtual 
or In 
office
Week 22 
(Day 154 
± 2 days)
Virtual 
or In 
office
Week 
26/ ET
(Day 
182 ± 
2 
days)
In 
office
21 (± 2) 
days 
after 
last 
dose of 
IMP
By Tele
phone
Notes
ECG
X
X
X
Section 3.7.3.4
Clinical laboratory 
tests (hematology, 
serum chemistry, 
and urinalysis)
X
X
X
Section 3.7.3.2
HbA1c
X
X
X
Section 3.7.3.2
Prolactin 
X
X
X
Section 3.7.3.2
Urine pregnancy 
test
X
X
X
Section 3.7.3.2
ACTH
X
X
Section 3.7.3.2
Cortisol
X
X
Section 3.7.3.2
TSH with reflex to 
free T4 if abnormal
X
X
X
Section 3.7.3.2
Coagulation 
parameters
X
X
Section 3.7.3.2
Adverse events
X
X
X
X
X
X
X
X
X
X
X
Section 5
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
Section 3.7.4
Dispense IMP
X
X
X
X
X
X
X
X
X
IMP accountability
X
X
X
X
X
X
X
X
X
X
Clinical Study Report 331-201-00191
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ABC = Aberrant Behavior Checklist; ACTH = Adrenocorticotropic hormone; AIMS =Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia 
Rating Scale; BP = blood pressure; CGI-S = Clinical Global Impression - Severity of Illness scale; C-SSRS = Columbia-Suicide Severity Rating Scale; 
ECG = electrocardiogram; ET = early termination; 
; 
; SAS = Simpson-
Angus Scale; TSH = thyroid-stimulating hormone.
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3.7.1
Schedule of Assessments
3.7.1.1
Screening and Baseline
Rollover subjects who do not qualify for the open-label trial at the screening/baseline 
visit may not be rescreened at a later date. If results of clinical laboratory tests from the 
last visit of the prior double-blind trial are not available to assess eligibility, the 
assessment for the affected criteria should be based on the last available measurement 
during the double-blind trial. Results from the last visit of the double-blind trial should be 
reviewed when they become available and action should be taken if there are any 
clinically significant and/or exclusionary values. 
Screening for rollover subjects occurs simultaneously with baseline at the 
end-of-treatment (Week 8) of Trial 331-201-00148 (Table 3.7-1). Subjects and their 
parent/legal guardian must sign the ICF/IAF for the open-label trial before any 
procedures specific to Trial 331-201-00191 can be performed. Subjects will retain the 
same subject ID number assigned in the parent trial. 
Screening/baseline values will be derived from the last visit of the double-blind phase 3 
trial for the following assessments (as appropriate): CGI-S, SAS, AIMS, BARS, C-SSRS, 
PARS, PedsQL, ABC, physical examination, body weight, height, waist circumference, 
vital signs, ECG, clinical laboratory tests (including prolactin), urine drug screen, and 
urine pregnancy test. The only additional procedures to be performed for rollover 
subjects at screening/baseline of the open-label trial are as follows:
•
An assessment of all inclusion and exclusion criteria will be made to determine 
the subject’s eligibility for the trial.
•
Medical history from the parent trial will be retained, but will be updated if 
necessary.
•
Concomitant medications will be reviewed to assure that the subject is not 
receiving any prohibited medications.
•
AE recording will begin with the signing of the ICF/IAF for Trial 331-201-00191.
•
If the subject remains eligible for the trial after completion of the baseline 
evaluations, trial personnel will use eSource to obtain an IMP assignment. 
•
The IMP will be dispensed to the subject and the subject will be advised to begin 
dosing from this card the next day.
All subjects will be assessed at various scheduled clinic visits as described below. 
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3.7.1.2
Weeks 1, 2, 3, 4, 8, 14, 18, and 22
Evaluations will be performed at Weeks (± 2 days) 1, 2, 3, 4, 8, 14, 18, and 22 visits.
The baseline, Week 2, and Week 14 visits will occur in the clinic. All other visits may be 
conducted either virtually or in clinic. Where the investigator and caregiver make the 
decision to conduct a visit virtually, the visit will be conducted by means of 
telecommunications technology. For these virtual visits, the caregiver and subject will 
remain in their own home and complete trial assessments and questionnaires via an 
online technology. The caregiver and subject will interact with trial personnel using 
online communication tools which incorporate telemedicine. During virtual interactions 
(and at any other time), the trial personnel will be able to assess the subject and determine 
if an additional in-office visit for a physical evaluation is required at the discretion of the 
investigator. The telecommunication equipment is supplied to all caregivers and subject 
pairs. The equipment will be returned at the end of trial participation. 
Visits are to occur within ± 2 days of the target visit date. All required evaluations will be 
performed as described in the Schedule of Assessments (Table 3.7-1). The following 
should also be noted: 
•
Subjects will have their IMP dispensed at a clinic visit or delivered to the home 
for a virtual visit. Pickup of IMP at the trial site by the caregiver can also be 
accommodated.
•
IMP accountability will be performed
3.7.1.3
End of Treatment (Week 26 or Early Termination) 
The treatment period for the entire trial will conclude at the Week 26 visit. This in clinic 
visit is to occur within ± 2 days of the target visit date. If a subject discontinues early 
before Week 26, procedures noted for Week 26 must be completed at the early 
termination (ET) visit. All required evaluations will be performed as described in the 
Schedule of Assessments (Table 3.7-1). The following should also be noted: 
•
Trial personnel will register completion or discontinuation from the trial in 
eSource.
•
IMP accountability will be performed.
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3.7.1.4
Follow-up
All subjects will be followed up either by telephone or other acceptable means of contact 
21 (± 2) days after the last dose of IMP to assess any new or ongoing AEs and to record 
any concomitant medications. Depending upon the type of follow-up required, other 
evaluations or tests may be conducted or performed.
3.7.2
Efficacy Assessments
It is required that a qualified and experienced clinician administer the efficacy 
assessments. Raters will be trained on the administration of these scales. The number of 
raters within each trial site 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 (if 
applicable), and materials for rating will be provided.  
3.7.2.1
Aberrant Behavior Checklist 
The ABC-I is 1 of 5 subscales of the ABC, a standardized parent-reported rating scale 
originally designed to assess treatment effects on problem behavior in people with 
intellectual disabilities. The ABC measures emotional and behavioral symptoms of ASD, 
including aggression toward others, deliberate self-injuriousness, temper tantrums, and 
quickly changing moods. Since its use in the seminal studies with risperidone, the ABC 
has been accepted as a standard in medication trials for ASD. The irritability subscale is 
the main subscale of interest in this trial.14,15
3.7.2.2
Clinical Global Impression - Severity of Illness Scale 
The severity of illness for subjects with ASD will be rated using the CGI-S with a focus 
on symptoms of irritability.16 To perform this assessment, the rater or investigator will 
answer the following question: “Considering your total clinical experience with this 
particular population, how ill is the patient at this time with regard to symptoms of 
irritability?” Response choices include: 0 = not assessed; 1 = normal, not at all ill; 
2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 
7 = among the most extremely ill patients.  
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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
Table 3.7.3.2-1 presents the protocol-required clinical laboratory test for all subjects in 
this trial. 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 laboratory tests, 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. Urine will be collected, and blood will be drawn from each subject at 
screening and then at the scheduled visits designated in the Schedule of Assessments 
(Table 3.7-1). The results of these tests must be reviewed by the investigator prior to 
initiation of IMP. 
Urine drug screens and blood alcohol tests will be conducted at the discretion of the 
investigator.
Subjects should be fasting for a minimum of 8 hours prior to blood draws, if at all 
possible. If fasting blood samples are not feasible, nonfasting blood samples may be 
obtained. If a subject is not fasting at a visit, the blood draw should still be performed, 
and the status documented as nonfasting on the laboratory requisition sheet. 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:
Hematocrit
Hemoglobin
Mean corpuscular hemoglobin concentration 
Mean corpuscular volume 
Platelets
RBC count
WBC count with differential 
MCH
RDW
RBC morphology
Urinalysis:
Appearance
Color 
Blood
Glucose
Microscopic analysis, WBC/RBC counts per high 
powered field
pH
Protein
Specific gravity
Urine drug screen:
Amphetamines
Barbiturates
Opiates
Benzodiazepines
Cannabinoids
Cocaine
Marijuana
Methadone
Phencyclidine
Propoxyphene
Serum Chemistry:
Albumin
Alkaline phosphatase
ALT
AST
Bicarbonate 
Bilirubin, total 
BUN 
Calcium
Chloride
Cholesterol (total, LDL, HDL)
CPK
Creatinine
GGT
Glucose
Insulin
LDH
Potassium
Protein, total 
Sodium
Triglycerides
Uric acid
Additional Tests:
Blood alcohol test
Blood HbA1c
Urine or serum pregnancy for all FOCBP
Serum TSH, with reflex to free T4 if TSH is 
abnormal
ACTH 
Cortisol
Serum prolactin 
Coagulation Parameters:
PT
aPTT
INR
aPTT = activated partial thromboplastin time; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; CPK = creatine phosphokinase; INR = international 
normalized ratio; GGT = gamma glutamyl transferase; HbA1c = glycosylated hemoglobin; HDL = high 
density lipoprotein; LDH = lactic dehydrogenase; LDL = low density lipoprotein, MCH = mean 
corpuscular hemoglobin; PT = prothrombin time; RBC = red blood cell; RDW = red cell distribution width; 
WBC = white blood cell.
The total volume of blood to be collected during the trial will be documented in the 
ICF/IAF.
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A urine pregnancy test will be conducted in all females of child-bearing potential 
(FOCBP) prior to trial intervention; results must be available prior to the administration 
of the IMP. A confirmatory serum pregnancy test will be done for subjects with a positive 
urine test. Subjects with a positive pregnancy test result at screening will be excluded 
from the trial. The frequency of pregnancy tests may be modified based on local 
regulatory requirements and pregnancy tests can be performed at any point during trial if 
pregnancy is suspected.
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 1 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 on clinically significant abnormalities. Unscheduled laboratory tests may be 
repeated at any time at the discretion of the investigator for appropriate medical care.
In addition, subjects should be excluded if they have any other abnormal laboratory test 
result 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 laboratory result(s) considered to be clinically significant should 
be repeated as soon as possible to confirm the finding(s) before excluding the subject 
from the trial. Appendix 2 is included to assist investigators in their assessments of 
results that may be potentially medically significant, depending on the subject’s medical 
history and clinical presentation.
3.7.3.3
Physical Examination and Vital Signs
3.7.3.3.1
Physical Examination
The physical examination will consist of measurement of height and a review of the 
following body systems: head, ears, eyes, nose, and throat; thorax; abdomen; urogenital; 
extremities; neurological; and skin and mucosae. A complete physical examination is an 
integral part of trial safety assessments and includes a urogenital assessment. A 
urogenital assessment should be performed on all trial subjects according to local medical 
standards as applied to other body systems. For the purposes of this trial, at a minimum, 
the urogenital examination should be performed within the year prior to the date of the 
ICF being signed or during the screening period for Trial 331-201-00148. The urogenital 
examination may be performed by the subject’s primary care provider or pediatrician as 
long as the source records are obtained, and the findings documented. At baseline and 
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post-baseline for Trial 331-201-00191, medically relevant questions about the urogenital 
body system must be asked of the subject at all protocol-required physical exams, with 
answers documented accordingly in the source. The extent and scope of any part of the 
physical examination is to be left to the discretion of the investigator as deemed 
appropriate for each subject. 
Height will be measured with a stadiometer, measuring stick or tape at specified visits. 
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 Delegation of Authority Log. Whenever possible, the same individual 
should perform all physical examinations. Any condition present at the post-treatment 
physical examination that was not present at the baseline examination should be 
documented as an AE and followed to a satisfactory conclusion.
The following procedures will aid in the standardization of waist circumference 
measurements:
•
The subject should be minimally clothed (ie, lightweight clothing; no heavy 
overgarments).
•
Waist circumference should be recorded before a subject’s meal and at approximately 
the same time at each visit.
•
Measurement will be accomplished by locating the upper hip bone and the top of the 
right iliac crest and placing a weighted measuring tape in a horizontal plane around 
the abdomen at the level of the crest. Before reading the tape measure, the assessor 
should assure that the tape is snug, but does not compress the skin, and is parallel to 
the floor. The measurement is to be made at the end of a normal exhalation.18 
3.7.3.3.2
Vital Signs
Vital sign measurements will include body weight (measured at baseline, Week 14, and 
Week 26), 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.
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•
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. At the in-clinic visits, 
equipment at the site will be used for the measurements. For the virtual visits, equipment 
will be provided to the caregiver with instructions for home use. The results of these tests 
must be reviewed by the investigator in order to determine if any results are considered to 
be clinically significant.
Subjects should be excluded if they have any 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 may be repeated once to confirm 
the finding(s) before excluding the subject from the trial. Appendix 1 is included to assist 
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 ECGs may be obtained at the investigator’s discretion and 
should always be obtained in the event of an ET. A central ECG service will be utilized 
for reading all ECGs in order to standardize interpretations for the safety analysis. In 
addition, ECG results will be evaluated at the investigational site to monitor safety during 
the trial. The principal investigator or qualified designee will review, sign, and date each 
ECG reading, noting whether or not any abnormal results are of clinical significance. The 
ECG will be repeated if any results are considered to be clinically significant.
If, according to the investigator's judgment, any abnormal ECG finding is deemed 
medically significant (impacting the safety of the subject and/or the interpretation of the 
trial results) or meets an exclusion criterion, the subject should be excluded from the trial. 
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 
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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. 
A screening ECG finding of QT interval as corrected for heart rate by Fridericia’s 
formula (QTcF) ≥ 450 msec for males and ≥ 470 msec for females based on the results 
from the central reader is exclusionary. However, any ECG with abnormal result(s) 
considered to be clinically significant should be repeated as soon as possible to confirm 
the finding(s) before excluding the subject from the trial. Appendix 3 is provided as a 
guide for determining potentially clinically relevant ECG abnormalities. 
3.7.3.5
Other Safety Assessments
It is required that a trained and experienced clinician administer the safety assessments, 
including the EPS scales (SAS, AIMS, and BARS), and C-SSRS. The number of raters 
within each trial site should be kept to a minimum. All efforts will be made to ensure that 
the same clinician administers the scales for a given subject. Training and materials for 
rating will be provided by Otsuka or designee.
3.7.3.5.1
Simpson Angus Scale 
The SAS19 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 8 hours of 
scale administration (see Section 4). Investigators are encouraged to delay scale 
administration until 8 hours have elapsed, if at all possible. However, if delaying 
administration of the scale is not feasible, the SAS should still be administered and the 
use of the medication documented, including a notation of the drug name, dose, and time 
of administration on the eSource.
3.7.3.5.2
Abnormal Involuntary Movement Scale 
The AIMS16 assessment consists of 10 items describing symptoms of dyskinesia. Facial 
and oral movements (items 1 through 4), extremity movements (items 5 and 6), and trunk 
movements (item 7) will be observed unobtrusively while the subject is at rest (eg, in the 
waiting room), and the investigator will also make global judgments on the subject’s 
dyskinesias (items 8 through 10). Each item will be rated on a 5-point scale, with a score 
of zero representing absence of symptoms (for item 10, no awareness), and a score of 4 
indicating a severe condition (for item 10, awareness, severe distress). For this scale, the 
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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 8 hours of 
scale administration (see Section 4). Investigators are encouraged to delay scale 
administration until 8 hours have elapsed, if at all possible. However, if delaying 
administration of the scale is not feasible, the AIMS should still be administered and the 
use of the medication documented, including a notation of the drug name, dose, and time 
of administration on the eSource.
The AIMS Movement Rating Score is defined as the sum of items 1 through 7 (ie, items 
1 through 4, facial and oral movements; items 5 and 6, extremity movements; and item 7, 
trunk movements).
3.7.3.5.3
Barnes Akathisia Rating Scale 
The BARS20 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 activity on the ward) 
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 8 hours of scale administration (see Section 4). Investigators are 
encouraged to delay scale administration until 8 hours have elapsed, if at all possible. 
However, if delaying administration of the scale is not feasible, the BARS should still be 
administered and the use of the medication documented, including a notation of the drug 
name, dose, and time of administration on the eSource. The BARS Global Score is 
defined as the global clinical assessment of akathisia.
3.7.3.5.4
Columbia-Suicide Severity Rating Scale
Suicidality will be monitored during the trial using the C-SSRS. The “since last visit” 
C-SSRS will be completed for all subjects at all visits. The pediatric version will be used 
and may be completed with caregiver assistance if required (eg, if the subject is unwilling 
or unable to participate as the primary respondent). Whether the caregiver is required to 
assist will be left to investigator judgment.
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3.7.4
Prior and Concomitant Medications
The investigator will record all medications and therapies taken by the subject at the time 
of signing the informed consent/assent of Trial 331-201-00191 through the end of the 
evaluation period (defined as the time period during which subjects are evaluated for 
primary and/or secondary objectives) in the eSource. The investigator will record all 
medications and therapies taken by the subject for treatment of an AE or which caused an 
AE until the end of the trial (defined as the last date of contact or date of final contact 
attempt) in the eSource.
3.7.5
Pharmacokinetic/Pharmacodynamic Assessments
3.7.5.1
Pharmacokinetic Assessments 
There are no PK assessments in this trial.
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 page for the last subject completing or 
withdrawing from the trial.
3.7.7
Independent Data Monitoring Committee
This trial will be monitored by an independent Data Monitoring Committee (DMC). The 
DMC will monitor safety based on a predetermined schedule as outlined in the DMC 
charter. The DMC meetings will occur as outlined in the DMC charter, but can be 
convened at any time at the discretion of the DMC chair or the trial medical officer. The 
details of the DMC structure and its roles and responsibilities will be documented in a 
DMC charter.
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.
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. A particular trial site may 
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be terminated from the trial at the discretion of the investigator, sponsor, or IRB/IEC, eg, 
for non-enrollment of subjects or noncompliance with GCP or with the protocol. 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
All attempts should be made to avoid treatment interruption during the trial. For subjects 
who have an interruption of treatment, the investigator or designee will contact the 
medical monitor as soon as possible. The investigator and medical monitor 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 medical monitor. The 
treatment interruption will be recorded in the eSource and also recorded as a protocol 
deviation (Section 3.13).
3.8.3.2
Treatment Discontinuation
After starting open-label IMP, 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 3.8.3.3.
If a subject discontinues from the trial prematurely, the reason must be fully evaluated 
and recorded appropriately in source documents and in eSource. If the subject is being 
withdrawn because of an AE, that AE should be indicated as the reason for withdrawal. 
All subjects have the right to withdraw at any point during treatment without prejudice. 
The investigator can discontinue a subject’s participation in the trial at any time if 
medically necessary.  
3.8.3.3
Documenting Reasons for Treatment Discontinuation
A subject may 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)
•
Serious adverse event (SAE) 
•
Clinical worsening, suicidality, and unusual changes in behavior, and the risk 
of increased suicidality
•
Death
•
Reasons unrelated to medical condition (provide detail and review AE history with 
subject)
•
Withdrawal of informed consent/assent (complete written withdrawal of ICF/IAF)
•
Lost to follow-up
•
Pregnancy (see Section 5.5)
•
Termination of all or part of the trial by the sponsor
If the subject 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 5.7 should be followed.
3.8.3.4
Withdrawal of Consent
All subjects have the right to withdraw their consent/assent from further participation in 
the trial at any time without prejudice. Subjects cannot withdraw consent/assent 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 (or their legal guardian) provides their written 
withdrawal of consent/assent or there is other written documentation by the investigator 
confirming the subject’s verbal intent to completely withdraw from the trial, subjects 
should be followed for all protocol-specified evaluations and assessments, if possible.
Complete withdrawal of consent/assent 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.
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•
Contact of alternative person(s) who have been designated in source records as being 
available to discuss the subject’s medical condition, even if only by telephone, mail, 
or e-mail (eg, family, spouse, partner, legal representative, friend, neighbor, or 
physician).
•
Access to medical information from alternative sources (eg, hospital/clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, social media sources). 
Withdrawal of consent/assent 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/assent. 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 (or their legal guardian) may initially express their desire 
to discontinue IMP administration, which is not equivalent to a complete withdrawal of 
consent/assent for further participation (see 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 (or their legal guardians) who withdraw their permission for all of the 
above degrees of follow-up are considered to have completely withdrawn their 
consent/assent to participate in the trial.
3.8.3.5
Procedures to Encourage Continued Trial Participation
In all cases of impending IMP discontinuation or consent/assent 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/assent.  
3.9
Screen Failures
A screen failure subject is one from whom informed consent/assent is obtained and is 
documented in writing (ie, subject signs an ICF), but who is not started on open-label 
treatment. Rollover subjects who do not qualify for Trial 331-201-00191 at the last visit 
of Trial 331-201-00148 may not be rescreened.
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3.10
Definition of Completed Subjects
The treatment period is defined as the time period during which subjects are evaluated for 
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 26 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 26 visit during the treatment 
period, who do not have a known reason for discontinuation (eg, withdrew consent/assent 
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 (open-label brexpiprazole) to subjects. 
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), discontinuation of the subject from the trial should be 
considered.
3.13
Protocol Deviations
This trial is intended to be conducted as described in this protocol. In the event of a 
significant deviation from the protocol due to an emergency, accident, or mistake (eg, 
violation of informed consent/assent 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 
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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 abstain from prohibited medications during the trial 
(Table 4.1-1). Other therapies prohibited prior to enrollment and during the trial are 
presented in Section 4.2.
Table 4.1-1
List of Medications Prohibited During the Trial
1.
All psychotropic agents including, but not limited to, the following:
a) Antipsychotics, including IR IM and depot or long-acting injectable formulations
b) Symbyax
c)   Antidepressants (including monoamine oxidase inhibitors)
d) Mood stabilizers (ie, lithium or anticonvulsants)
e) Benzodiazepines, except specific benzodiazepines when used as rescue therapya
f)
Stimulants, except when being used for treatment of ADHD.b
g) Other psychotropics 
2.
Ramelteon and other non-benzodiazepine sleep aids, except for limited use of specific medications 
for the treatment of insomniac
3.
Antihistamines (except for loratadine and cetirizine)
4.
Varenicline
5.
Other nutritional supplements and nonprescription herbal preparations with central nervous system 
effects (eg, St. John’s Wort, omega-3 fatty acids, kava extracts, GABA supplements) unless 
approved in advance by the medical monitor.
6.
CYP2D6 inhibitors and CYP3A4 inhibitors and inducers. 
7.
Investigational agents
GABA = gamma-aminobutyric acid; IM = intramuscular; IR = immediate-release.
aUse of intramuscular benzodiazepines and continual use of oral benzodiazepines are prohibited 
throughout the trial. However, limited use of specific oral benzodiazepines is allowed for the control 
of agitation or insomnia.
bMust be on a stable dose for ≥ 30 days. Stimulant dose at entry must not be changed during trial 
participation.
cNon-benzodiazepine sleep aids (ie, clonidine, melatonin, zolpidem, zaleplon, zopiclone, and 
eszopiclone only) are permitted in the trial for the treatment of insomnia, but not on the same day as 
administration of a benzodiazepine, regardless of indication. For the non-benzodiazepine sleep aids, 
sites should only utilize one 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 (exceptions: clonidine, which is 
commonly prescribed off label as a sleep aid, and melatonin, which is available over the counter 
[OTC]). Non-benzodiazepine sleep aids must not be administered within 8 hours prior to scheduled 
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efficacy and EPS scales. Investigators are encouraged to delay scale administration until 8 hours have 
elapsed, if at all possible. However, if delaying administration of efficacy and EPS 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.
During the course of the trial, oral benzodiazepine rescue medication can be used for 
symptomatic relief based on the investigator’s judgment with the exceptions and 
restrictions outlined in Table 4.1-2. All concomitant medications should be prescribed 
according to the respective drug labels. Subjects who are started on therapy should be 
observed closely for clinical worsening, suicidality, and unusual changes in behavior, and 
the risk of increased suicidality must be balanced with the clinical need.
Table 4.1-2
Oral Benzodiazepine Rescue Therapy During the Trial
Oral Benzodiazepine
Maximum Allowable Dose (mg/day)c
Lorazepama
3
Oxazepama
45
Diazepama,b
15
Clonazepama,b
1.5
Alprazolama,b
1.0
aBenzodiazepines must not be administered within 8 hours prior to scheduled efficacy and EPS scales. 
Investigators are encouraged to delay scale administration until 8 hours have elapsed, if at all 
possible. However, if delaying administration of efficacy and EPS scales is not feasible, the scales 
should still be administered and the use of benzodiazepine documented, including a notation of the 
drug name, dose, and time of administration on the eSource.
bIn countries or institutions where no short-acting benzodiazepines are commercially available, use of 
oral diazepam, alprazolam, or clonazepam may be acceptable if prior authorization is obtained from 
the medical monitor.
cBody weight of the subject should be considered when dosing decisions are made by the investigator.
Daily doses should not exceed the maximum.
Table 4.1-3 below provides a select list of CYP2D6 inhibitors and CYP3A4 inhibitors 
and inducers which are prohibited during the duration of the trial. 
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Table 4.1-3
Selected CYP2D6 Inhibitors and CYP3A4 Inhibitors and 
Inducers Prohibited During the Trial
Selected CYP2D6 Inhibitors
Celecoxib
Hydroxyzine
Chloroquine
Methadone
Chlorpheniramine
Moclobemide
Clemastine
Paroxetine
Clomipramine
Pyrilamine
Diphenhydramine
Quinidine
Fluoxetine
Terbinafine
Halofantrine
Tripelennamine
Selected CYP3A4 Inhibitors
Amiodarone
Fluvoxamine
Amprenavir
Indinavir
Aprepitant
Itraconazole
Chloramphenicol
Ketoconazole
Cimetidine
Nefazodone
Clarithromycin
Nelfinavir
Clotrimazole (if used orally)
Quinupristin/Dalfopristin 
Delavirdine
Ritonavir
Diltiazem
Saquinavir
Erythromycin
Troleandomycin
Fluconazole
Verapamil
Selected CYP3A4 Inducers
Carbamazepine
Phenytoin
Dexamethasone
Primidone
Efavirenz
Rifampin
Nevirapine
St. John’s Wort
Oxcarbazepine
Troglitazone
Phenobarbital
4.2
Other Restrictions 
Any history of electroconvulsive therapy is exclusionary.
Anticholinergics are permitted for the treatment of EPS up to a maximum of 4 mg/day 
benztropine or its equivalent and propranolol is permitted as needed (PRN), but subject 
age and body weight should be considered for dose selection. Subjects receiving a stable 
dose of propranolol for other conditions at entry into Trial 331-201-00191 may remain on 
propranolol. Trial sites should only utilize medications that are approved for these 
indications in their respective countries.
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 
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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. 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.
4.2.1
Non-therapy Precautions and Restrictions
4.2.1.1
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.
4.2.1.2
Restrictions
With the exception of group therapy and outpatient group therapy, new-onset 
psychotherapy is prohibited during the trial. In other words, except for inpatient and 
outpatient group therapies, subjects may continue to receive psychotherapy (eg, 
individual, group, or family therapy) if this has been ongoing throughout the double-blind 
trial period directly preceding trial entry, and if psychotherapy participation and 
frequency are maintained during the course of the trial, 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. Adverse events would not include information recorded 
as medical history at screening for pre-planned procedures for which the underlying 
condition was known and no worsening occurred. An adverse reaction is any untoward 
and unintended response to an IMP related to any dose administered.
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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
•
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 serious hepatotoxicity 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 page of the 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 
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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 
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 in 
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. Serious AE 
collection is to begin after a subject has signed the ICF.  
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. A reported AE 
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that undergoes a change in severity, seriousness, or toxicity should be reported as a new 
AE on the eSource.
Note: Normal pregnancy is not an AE and should not be recorded on the eSource; 
guidelines outlined in Section 5.5 should be followed for pregnancy reporting.
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.
5.3
Immediately Reportable Events 
The investigator must immediately report after either the investigator or site personnel 
become aware of any SAE, potential serious hepatotoxicity, 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 page of the 
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 Serious Hepatotoxicity
For a subject who experiences an elevation in aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) that is  2 times the upper limit of normal (ULN), a total 
bilirubin level should also be evaluated. If the total bilirubin is  1.6 times the ULN, 
complete an IRE form with all values listed and also report as an AE in the eSource.
5.5
Pregnancy
Females of child-bearing potential (FOCBP) 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 FOCBP 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 
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dose of IMP. If employing birth control, 2 of the following precautions must be used: 
vaginal diaphragm, intrauterine device, birth control pill, birth control implant, birth 
control depot injection, condom with spermicide, or sponge with spermicide. The 
contraceptive methods will be documented at each trial visit.
Before enrolling FOCBP in this clinical trial, investigators must review the below 
guidelines about trial participation with all FOCBP. The topics should generally include:
•
General information
•
Informed consent/assent 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, FOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy. The subject and the subject’s legally acceptable representative (eg, guardian) 
must sign an ICF/IAF stating that the above-mentioned risk factors and the consequences 
were discussed with them. 
A urine pregnancy test for human chorionic gonadotropin will be performed at screening 
on all FOCBP and female subjects ≥ 12 years of age and all female subjects < 12 years of 
age, if menstruation has started. If a urine test is performed and is positive, the 
investigator will follow up with a confirmatory serum test.
During the trial, all FOCBP should be instructed to contact the investigator immediately 
if they suspect they might be pregnant (eg, missed or late menstrual cycle).
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 
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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. 
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 
Not applicable; this is an open-label trial.
5.7
Follow-up of Adverse Events 
For this trial, information on AEs will be followed for up to 21 (± 2) days after the last 
dose of IMP has been administered.
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 page in the 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 in 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).
5.7.2
Follow-up of Serious Adverse Events
This trial requires that subjects be actively monitored for SAEs up to 21 (± 2) days after 
the last dose of IMP is administered.
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Serious AEs that are identified or ongoing at the last scheduled contact must be 
recorded on the AE page in the eSource 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.
5.7.3
Follow-up and Reporting of Serious Adverse Events Occurring 
after Last Scheduled Contact
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 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.
6
Pharmacokinetic/Pharmacodynamic Analysis
Not applicable; there is no PK analysis in this trial.
7
Statistical Analysis
7.1
Sample Size
The sample size is not based on statistical considerations, but rather on the number of 
subjects rolling over from the parent trial (Trial 331-201-00148). The trial population will 
be derived from eligible subjects who completed the parent trial. The sample size of this 
open-label trial will be limited by the number of subjects enrolled into the parent trial.
7.2
Datasets for Analysis
The following analysis samples are defined for this trial:
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Enrolled Sample: All subjects who sign an ICF/IAF for the trial and are enrolled into the 
trial.Safety Sample: All subjects who receive at least 1 dose of brexpiprazole.
Efficacy Sample: All subjects in the Safety Sample who have a baseline assessment and 
at least one post-baseline assessment of the ABC-I subscale score.   
7.3
Handling of Missing Data
Not applicable.
7.4
Primary and Secondary Endpoint Analyses
7.4.1
Primary Endpoint Analysis
The primary objective of this trial is to evaluate safety and tolerability. The primary 
endpoints are the frequency and severity of AEs, serious TEAEs (clinical and laboratory), 
and discontinuation from trial due to AEs. As there is no primary efficacy objective, there 
is no defined primary efficacy endpoint. Descriptive statistics will be provided for all 
efficacy and safety variables. No inferential statistical analyses are planned for this 
open-label trial.
7.4.2
Secondary Endpoint Analysis
Descriptive statistics will be provided for mean change from baseline in ABC-I subscale 
score and CGI-S score. The analysis will be carried out on the Efficacy Sample. 
Descriptive statistics will be summarized at each trial visit using the observed cases (OC) 
data set and at the last visit using the last observation carried forward (LOCF) data set. 
Kaplan Meier curves will be used for time-to-event (eg, time to loss of effect analyses).
Further details will be provided in the statistical analysis plan (SAP).
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7.4.4
Interim Analysis
Not applicable.
7.5
Analysis of Demographic and Baseline Characteristics
Baseline demographic characteristics including age, race, ethnicity, gender, weight, 
height, and body mass index (BMI) will be summarized by descriptive statistics 
(frequency, mean, median, standard deviation, maximum, minimum, and percentage 
when applicable). 
7.6
Safety Analysis
7.6.1
Adverse Events
All AEs will be coded by system organ class and Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term. The incidence of the following events in 
Trial 331-201-00191 will be summarized by parent trial or previous treatment group:
•
Treatment-emergent AEs (TEAEs)
•
TEAEs by severity
•
TEAEs potentially causally related to the IMP
•
TEAEs with an outcome of death
•
Serious TEAEs
•
TEAEs leading to discontinuation of the IMP 
The above summaries will also be prepared for TEAEs potentially causally related to the 
IMP.
7.6.2
Clinical Laboratory Data
The incidence of potentially clinically significant values for routine laboratory tests and 
of prolactin concentrations above the upper limit of normal will be calculated for the 
Safety Sample.
In addition to the evaluation of potentially clinically significant values, mean change 
from baseline in clinical laboratory values will be calculated. Results will be summarized 
by visit.
7.6.3
Physical Examination and Vital Signs Data
The incidence of potentially clinically significant vital sign abnormalities will be 
calculated. Body weight changes will be evaluated by calculating the mean change from 
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baseline and by tabulating the incidence of clinically significant changes in body weight, 
defined as ≥ 7% increase or decrease from baseline. Mean changes in BMI, waist 
circumference and z-scores for height and body weight from baseline will also be 
summarized by visit. Physical examination findings will be listed by subject.
7.6.4
Electrocardiogram Data 
Mean change from baseline and the incidence of clinically significant changes will be 
calculated for ECG parameters for the Safety Sample.
For the analysis of QT and corrected QT interval (QTc), data from 3 consecutive 
complexes (representing 3 consecutive heart beats) will be measured to determine 
average values. The following QT corrections will be used for reporting purposes in the 
clinical study report:
1) QTcF is the length of the QT interval corrected for heart rate by the Fridericia 
formula: QTcF = QT/(RR)0.33
2) 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.
7.6.5
Other Safety Data
7.6.5.1
Extrapyramidal Symptoms
Descriptive statistics will be provided for the mean change from baseline to end of period 
in SAS, AIMS, and BARS scores for the Safety Sample. Results will be summarized by 
specified post-baseline time-points.
7.6.5.2
Suicidality
The incidence of suicidality, suicidal behavior, and suicidal ideation will be calculated 
from the potential suicide events recorded on the C-SSRS. Results will be summarized by 
visit and presented for all subjects in the Safety Sample.
8
Management of Investigational Medicinal Product
For full details on IMP management, please refer to the brexpiprazole (OPC-34712) IB.12
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 (open-label 
brexpiprazole) will be supplied in child resistant blister cards. Each blister card used in 
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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, 
appropriate precautionary statements, and other information required by local regulatory 
authorities.  
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 blister packs should be stored and maintained according to the storage conditions 
indicated on the IMP label. The clinical site staff or designees will maintain a 
temperature log in the IMP storage area recording the temperature at least once each 
working day. When applicable, containers for shipping to subjects will include 
appropriate temperature monitoring.
8.3
Accountability
The investigator or designee must maintain an inventory record of IMP received, 
dispensed, administered, and returned.
8.4
Returns and Destruction
The IMP will be destroyed by the clinical trial site. The IMP may only be destroyed by 
the trial site(s), if approved by the sponsor and if the IMP destruction meets all local 
regulations. The IMP accountability must be completed and verified by the assigned trial 
monitor prior to destruction. The trial site(s) may utilize qualified third party vendors for 
IMP destruction.
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
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•
Packaging issues (eg, damaged, dirty, crushed, missing product)
•
Blister defects (eg, missing, empty blisters)
•
Bottle defects (eg, under/over-fill, no safety seal)
•
Vial defects
•
Product defect (eg, odor, chipped, broken, embossing illegible)
•
Loss or theft of product
8.5.1
Eliciting and Reporting Product Quality Complaints
The investigator 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 OAPI 
EQCProductComplaints@Otsuka-us.com.
•
Telephone - Rocky Mountain Call Center at 1-800-438-6055.
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 (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.
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It must be documented in the site accountability record that a complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation.
8.5.4
Assessment/Evaluation
Assessment and evaluation of PQCs will be handled by the sponsor.
9
Records Management
9.1
Source Documents
Source documents are defined as the results of original observations and activities of a 
clinical investigation. Source documents will include but are not limited to 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.
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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 
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 
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
Regulatory requirements for the archival of records for this trial necessitate that 
participating investigators maintain detailed clinical data for the longest of the following 
3 periods:
•
A period of at least 2 years after the date on which approval to market the drug is 
obtained (or if IMP development is discontinued, the date regulatory authorities were 
notified of discontinuation); OR
•
A period of at least 3 years after the sponsor notifies the investigator that the final 
report has been filed with regulatory authorities.
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•
Longer, region-specific storage requirements, if applicable.  
The investigator must not dispose of any records relevant to this trial without either 
(1) written permission from the sponsor or (2) provision of an opportunity for sponsor to 
collect such records. The investigator will be responsible to maintain adequate and 
accurate electronic or hard copy source documents of all observations and data generated 
during this trial including any data clarification forms received from the sponsor. Such 
documentation is subject to inspection by the sponsor and relevant regulatory authorities. 
If the investigator withdraws from the trial (eg, due to relocation or retirement), all trial-
related records should be transferred to a mutually agreed-upon designee within a 
sponsor-specified timeframe. Notice of such transfer will be given to the sponsor in 
writing.
10
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/assent process, and comparison of eSource 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.
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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 (CIOMS) guidelines, and 
applicable local laws and regulations. Each trial site will seek approval/favorable opinion 
by an IRB or IEC according to regional requirements, and the investigator will provide 
that documentation to the sponsor. The IRB/IEC will evaluate the ethical, scientific and 
medical appropriateness of the trial. Further, in preparing and handling eSource, the 
investigator, sub-investigator and their staff will take measures to ensure adequate care in 
protecting 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 eSource. 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/assent and subsequent approval/favorable opinion by the IRB/IEC. Any 
permanent change to the protocol, whether an overall change or a change for specific trial 
site(s), must be handled as a protocol amendment. Any amendment will be written by the 
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sponsor. Each amendment will be submitted to the IRB/IEC, as required by local 
regulations. Except for “administrative” or “non-substantial” amendments, investigators 
will wait for IRB/IEC approval/favorable opinion of the amended protocol before 
implementing the change(s). Administrative amendments are defined as having no effect 
on the safety of subjects, conduct or management of the trial, trial design, or the quality 
or safety of IMP(s) used in the trial. A protocol change intended to eliminate an apparent 
immediate hazard to subjects should be implemented immediately after agreement by the 
sponsor and investigator, followed by IRB/IEC notification within local applicable 
timelines. The sponsor will submit protocol amendments to the applicable regulatory 
agencies within local applicable timelines.
When the IRB/IEC, investigators, and/or the sponsor conclude that the protocol 
amendment substantially alters the trial design and/or increases the potential risk to the 
subject, the currently approved written ICF will require similar modification. In such 
cases, after approval/favorable opinion of the new ICF by the IRB/IEC, repeat written 
informed consent/assent 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.
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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/assent to such acknowledgement in 
any publications resulting from its conduct.
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15
References
1
American Psychiatric Association: Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition. Washington, DC: American Psychiatric Association, 2013.
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Christensen DL, Baio J, Braun KVN, Bilder, D, Charles J, Constantino JN, et al. 
Prevalence and characteristics of autism spectrum disorder among children aged 8 
years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United 
States, 2012. MMWR Surveill Summ. 2016;65(No. SS-3):1-23.
3
Lecavalier L. Behavioral and emotional problems in young people with pervasive 
developmental disorders: relative prevalence, effects of subject characteristics, and 
empirical classification. J Autism Dev Disord. 2006;36(8):1101–1114.
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Samson AC, Phillips JM, Parker KJ, Shah S, Gross JJ, Hardan AY. Emotion 
dysregulation and the core features of autism spectrum disorder. J Autism Dev 
Disord. 2014;44(7):1766–1772.
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Autism and Developmental Disabilities Monitoring Network Surveillance Year 2000 
Principal Investigators; Centers for Disease Control and Prevention. Prevalence of 
autism spectrum disorders—Autism and Developmental Disabilities Monitoring 
Network, six sites, United States, 2000. MMWR Surveill Summ. 2007;56(1):1–11.
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Lavelle TA, Weinstein MC, Newhouse JP, Munir K, Kuhlthau KA, Prosser LA. 
Economic burden of childhood autism spectrum disorders. Pediatrics. 
2014;133(3):e520-e529.
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Elbe D, Lalani Z. Review of the Pharmacotherapy of Irritability of Autism. J Can 
Acad Child Adolesc Psychiatry. 2012;21(2):130-146.
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Correll CU, Carlson HE. Endocrine and metabolic adverse effects of psychotropic 
medications in children and adolescents. J Am Acad Child Adolesc Psychiatry. 
2006;45(7):771-791.
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Varley CK, McClellan J. Implications of marked weight gain associated with atypical 
antipsychotic medications in children and adolescents. JAMA. 2009;302:1811-1812.
10 Fung LK, Mahajan R, Nozzolillo A, Bernal P, Krasner A, Jo B, et al. Pharmacologic 
treatment of severe irritability and problem behaviors in autism: a systematic review 
and meta-analysis. Pediatrics. 2016;137(s2):S124-S135.
11 Correll CU, Manu P, Olshanskiy V, Napolitano B, Kane JM, Malhotra AK. 
Cardiometabolic risk of second-generation antipsychotic medications during first-
time use in children and adolescents. JAMA. 2009;302(16):1765-1773.
12 Otsuka Pharmaceutical Development & Commercialisation, Inc. Brexpiprazole 
(OPC-34712) Investigator’s Brochure, Edition 17. Otsuka Report, issued 27 Sep 
2021.
13 International Conference for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. Guideline For Good Clinical 
Clinical Study Report 331-201-00191
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Practice: E6(R1). Geneva, Switzerland: International Conference on Harmonisation; 
1996.
14 Aman MG, Singh NN. Aberrant Behavior Checklist-Community. East Aurora, NY: 
Slosson; 1994.
15 Kaat AJ, Lecavalier L, Aman MG. Validity of the aberrant behavior checklist in 
children with autism spectrum disorder. Journal of Autism and Developmental 
Disorders. 2014;44:1103-1116.
16 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.
 
18 The Practical Guide: Identification, evaluation, and treatment of overweight and 
obesity in adults. Developed by National Institutes of Health National Heart, Lung 
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Publication Number 00-4084, October 2000.
19 Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta 
Psychiatr Scand Suppl. 1970;212(Suppl 44):S11-19.
20 Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672-
676.
21 Hughes HK, Kahl LK. The Johns Hopkins Hospital: The Harriet Lane Handbook. 
21st edition. 2015.
22 Flynn JT, Kaelber DC, Baker-Smith CM, Blowey D, Carroll AE, Daniels SR, et al. 
Clinical practice guideline for screening and management of high blood pressure in 
children and adolescents. Pediatrics. 2017;140(3).
23 Soghier L, Pham K, Rooney S. Reference range values for pediatric care. The 
American Academy of Pediatrics. 2014.
24 Covance. Central laboratory services manual; Protocol 331-201-00191. Created 
11 Dec 2019.
25 American Diabetes Association. 2. Classification and Diagnosis of Diabetes: 
Standards of Medical Care in Diabetes-2019. Diabetes Care. 
2019;42(Suppl 1):S13-S28.
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Appendix 1
Criteria for Identifying Vital Signs Outside of Normal Values 
and of Potential Clinical Relevancea
Variable
Criterion Value
Change Relative to Baseline
Heart Rate at Rest21
<60 bpm or >110 bpm
Increase or decrease of ≥ 15 bpm
Systolic Blood Pressure22
     Preschooler (5 y)
<80 mmHg or >115 mmHg
Increase or decrease of ≥ 20 mmHg
     School-age (6-9 y)
<85 mmHg or >115 mmHg
Increase or decrease of ≥ 20 mmHg
     Preadolescent (10-12 y)
<90 mmHg or >120 mmHg
Increase or decrease of ≥ 15 mmHg
     Adolescent (13-17 y)
<90 mmHg or >120 mmHg
Increase or decrease of ≥ 15 mmHg
Diastolic Blood Pressure22
     Preschooler (5 y)
<45 mmHg or >80 mmHg
Increase or decrease of ≥ 15 mmHg
     School-age (6-9 y)
<50 mmHg or >80 mmHg
Increase or decrease of ≥ 15 mmHg
     Preadolescent (10-12 y)
<60 mmHg or >80 mmHg
Increase or decrease of ≥ 15 mmHg
     Adolescent ≥ 13 y
<60 mmHg or >85 mmHg
Increase or decrease of ≥ 15 mmHg
aThe criterion value and change relative to baseline represented in this table are intended to identify 
on-treatment values outside of normal changes and that could potentially be clinically relevant.  In 
order to be identified as potentially clinically relevant, the 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. When evaluating these values the 
emotional state of the subject must be taken into consideration (eg, crying, screaming) and 
documented as applicable.
Adapted information.21,22
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Appendix 2
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance21,23,24,25
Laboratory Tests
Criteria (Normal Ranges) for Subjects 5 to 17 Years of 
Age
Chemistry
AST 
≥ 2 × ULN
ALT 
≥ 2 × ULN
ALP
≥ 2 × ULN
Bicarbonate
  
< 6 y
< 17.0 or > 26.0 mEq/L (17.0–26.0 mEq/L)
6 y to 12 y
< 19.0 or > 27.0 mEq/L (19.0–27.0 mEq/L)
≥ 12 y
< 19.3 or > 29.3 mEq/L (19.3–29.3 mEq/L)
BUN
≥ 24 mg/dL (≤ 4 mg/dL or ≥ 24 mg/dL)
Creatinine
              ≤ 12 y
≥ 0.7 mg/dL (≤ 0.2 mg/dL or ≥ 0.7 mg/dL)
              ≥13 y
≥ 1.1 mg/dL (≤ 0.3 mg/dL or ≥ 1.1 mg/dL)
Uric Acid
≤ 12 y
≥ 6.7 mg/dL (≤ 1.6 mg/dL or ≥ 6.7 mg/dL)
≥ 13 y
≥ 8.2 mg/dL (≤ 2.2 mg/dL or ≥ 8.2 mg/dL)
Bilirubin (total)
≥ 1.6 mg/dL (≤ 0.2 mg/dL or ≥ 1.6 mg/dL)
CPK
≥ 2 × ULN
Prolactin
                ≤ 12 y
≥ 21.00 ng/dL (≤ 2.63 ng/dL or ≥ 21.00 ng/dL)
                ≥ 13 y
≥ 39.00 ng/dL (≤ 2.52 ng/dL or ≥ 39.00 ng/dL)
Hematology
Hematocrit
≤ 12 y
≤ 33 % (≤ 33 % or ≥ 44%)
        ≥ 13 y
≤ 34 % (≤ 34 % or ≥ 54%)
Hemoglobin
≤ 12 y
≤11.2 g/dL (≤ 11.2 g/dL or ≥ 15.5 g/dL)
≥ 13 y
≤ 11.6 g/dL (≤ 11.6 g/dL or ≥ 18.1 g/dL)
White blood count
≤ 4.35 × 103/uL (≤ 4.35 × 103/uL or ≥ 13.65 × 103/uL) 
Eosinophils
               ≤ 12 y
≥ 4.8%
               ≥ 13 y
≥ 4.1%
Neutrophils
≤ 40.5% (≤ 40.5% or ≥ 75.0 %)
Absolute neutrophil count
                ≤ 12 y
≤ 1.00 × 103/uL or ≥ 9.00 × 103/uL
                ≥ 13 y
≤ 1.35 × 103/uL or ≥ 8.15 × 103/uL
Platelet count
               ≤ 12 y
       ≤ 130 × 103/uL (≤ 130 × 103/uL or ≥ 570 × 103/uL)
               ≥ 13 y
         ≤ 140 × 103/uL (≤ 140 × 103/uL or ≥ 400 × 103/uL)
Urinalysis
Protein
Change from baseline
Glucose
Presence
Additional Criteria
Chloride
≤ 94 mEq/L or ≥ 112 mEq/L
HbA1c
≥ 5.7%
ACTH
< 7.2 pg/mL - > 63.3 pg/mL
Cortisol
AM: 6.7 ug/dL - 22.60 ug/dL
PM: < 10 ug/dL
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Laboratory Tests
Criteria (Normal Ranges) for Subjects 5 to 17 Years of 
Age
Potassium
≤ 3.3 mEq/L or ≥ 5.2 mEq/L
Sodium
≤ 132 mEq/L or ≥ 148 mEq/L
Calcium
≤ 8.3 mg/dL or ≥ 10.9 mg/dL
Glucose
Fasting
≥ 100 mg/dL (≥70 mg/dL and ≤ 100 mg/dL)
Non-Fasting
≥ 139 mg/dL (≥ 70 mg/dL and ≤ 139 mg/dL)
Total Cholesterol, Fasting
                  ≤ 12 y
≥ 217 mg/dL (≤ 97 mg/dL or ≥ 217 mg/dL)
                  ≥ 13 y
≥ 217 mg/dL (≤ 124 mg/dL or ≥ 217 mg/dL)
LDL Cholesterol, Fasting
≥ 130 mg/dL 
HDL Cholesterol, Fasting
  ≤ 12 y
≤ 34 mg/dL (≤ 34 mg/dL or ≥ 75 mg/dL)
   ≥ 13 y
≤ 30 mg/dL (≤ 30 mg/dL or ≥ 74 mg/dL)
Triglycerides, Fasting
                  ≤ 12 y
≥ 131 mg/dL (≤ 30 mg/dL or ≥ 131 mg/dL)
                  ≥ 13 y
≥ 148 mg/dL (≤ 32 mg/dL or ≥ 148 mg/dL)
       TSH
                  ≤ 12 y
≤ 0.34 mIU/mL or ≥ 5.40 mIU/mL
                  ≥ 13 y
≤ 0.34 mIU/mL or ≥ 5.60 mIU/mL
       Free T4
                  ≤ 12 y
≤ 9 pmol/L or ≥ 30 pmol/L
                  ≥ 13 y
≤ 10 pmol/L or ≥ 24 pmol/L
       PT
≥ 12.3 sec (≤ 9.7 sec or ≥ 12.3 sec)
       aPTT
≥ 29.4 sec (≤ 21.9 sec or ≥ 29.4 sec)
       INR
                  Not taking anticoagulants
                  Taking anticoagulants
≥ 1.2 (≤ 0.8 or ≥ 1.2)
≥ 3.0 (≤ 2.0 or ≥ 3.0)
The recommended criteria represented in this table are intended to identify on-treatment outside of normal 
values that could potentially be clinically relevant. Variations based on local laboratory ranges may need to 
be considered.
Adapted information.21,23,24,25
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Appendix 3
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance
Variable
Criterion Valuea
Change Relative to Baselinea
Rhythm
Sinus tachycardiab
≥ 110 bpm
increase of ≥ 15 bpm
Sinus bradycardiac
≤ 60 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 for 
males, ≥ 470 msec 
for females
increase of 60 msec from 
baseline
 a The criterion value and change relative to baseline represented in this table are intended to identify on-
treatment values outside of normal changes and that could potentially be clinically relevant. In order 
to be identified as potentially clinically relevant, the 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. When evaluating these values the emotional state of the 
subject must be taken into consideration (eg, crying, screaming) and documented as applicable.
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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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, brexpiprazole (OPC-34712), the 
concurrent medications, the efficacy and safety parameters and the conduct of the trial in general. 
I am aware that this protocol must be approved by the Institutional Review Board (IRB) or receive 
a favorable opinion by the Independent Ethics Committee (IEC) responsible for such matters in 
the clinical trial facility where brexpiprazole 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/assent 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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T hi s p a g e i s a m a nif e st ati o n of a n el e ctr o ni c all y c a pt ur e d si g n at ur e
SI G N A T U R E P A G E
D o c u m e nt N a m e: Pr ot o c ol 3 3 1- 2 0 1- 0 0 1 9 1 A m e n d m e nt 5
D o c u m e nt N u m b er: 
D o c u m e nt V er si o n: 8. 0
Si g n e d b y
M e a ni n g of Si g n at ur e
S er v er D at e
( d d- M M M-
y y y y h h: mi n) -
U T C ti m e z o n e
Cli ni c al A p pr o v al
0 7- J ul- 2 0 2 2
1 7: 5 1: 1 3
Bi o st ati sti c s A p pr o v al
0 7- J ul- 2 0 2 2
2 2: 0 5: 3 1
Cli ni c al A p pr o v al
0 7- J ul- 2 0 2 2
1 8: 1 5: 5 1
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 9 1
1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
U ntil t he i nf or m ati o n herei n is rele ase d b y Ots u k a t o t he p u blic d o m ai n, t he c o nte nts of t his d oc u me nt are Ots u k a
c o nfi de nti al i nf or m ati o n a n d s h o ul d n ot be d u plic ate d or re- distri b ute d wit h o ut pri or writte n c o nse nt of Ots u k a.
9 5
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Otsuka Pharmaceutical Development & Commercialization, Inc
Investigational Medicinal Product
Brexpiprazole (OPC-34712)
ADDENDUM FOR CLINICAL PROTOCOL FOR TRIAL 331-201-00191
Protocol 331-201-00191: A Phase 3, Multicenter, Open-label Trial to Evaluate the 
Long-term Safety and Tolerability of Brexpiprazole (OPC-34712) in the Treatment of 
Children and Adolescents with Irritability Associated with Autism Spectrum Disorder
Protocol No. 331-201-00191
IND No. 141257
EudraCT No. 2018-004899-35
CONFIDENTIAL – PROPRIETARY INFORMATION
Clinical Development Phase:
3
Sponsor:
Otsuka Pharmaceutical Development & 
Commercialization, Inc
2440 Research Boulevard
Rockville, Maryland 20850
Immediately Reportable Event 
QLS.OtsukaPKD@Quintiles.com
Issue Date:
06 Jul 2020
Version No.:
1.0
Clinical Study Report 331-201-00191
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Trial Conduct for COVID-19
All procedures and assessments in the protocol are to be followed to the fullest 
extent possible. The sponsor, in coordination with the sites, investigators, and 
medical monitor, will continuously monitor and evaluate the benefits and risks to 
subject participation in the clinical trial as it relates to COVID-19. If any protocol-
specified activities were not able to be performed, or cannot be performed due to 
COVID-19 considerations, the appropriate measures to be followed will be provided 
in this document.
Clinical Study Report 331-201-00191
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Table of Contents
Trial Conduct for COVID-19.......................................................................2
Table of Contents...........................................................................................3
List of In-text Tables .....................................................................................4
List of In-text Figures....................................................................................5
List of Abbreviations and Definitions of Terms .........................................6
1
Trial 331-201-00191 COVID-19 Protocol Summary.........................7
1.1
Trial Design Schematic .......................................................................................7
1.2
Schedules of Assessments...................................................................................9
2
General Considerations......................................................................15
2.1
Telemedicine Virtual Visits...............................................................................15
2.2
Reconsent ..........................................................................................................15
2.3
Protocol Deviations...........................................................................................15
2.4
Guidance to Record Adverse Events and Discontinuations Due to 
COVID-19.........................................................................................................15
2.5
Statistical Analyses............................................................................................16
2.6
Clinical Outcomes.............................................................................................16
3
Trial Population..................................................................................17
3.1
Inclusion Criteria...............................................................................................17
3.2
Exclusion Criteria..............................................................................................17
4
Trial Procedures .................................................................................18
4.1
Safety Assessments ...........................................................................................18
4.1.1
Weight and Waist Circumference...................................................................18
4.1.2
Pregnancy .......................................................................................................19
4.1.3
Extrapyramidal Symptom Scales....................................................................19
4.2
Efficacy Assessments........................................................................................20
4.2.1
Pediatric Quality of Life .................................................................................20
5
Investigational Medicinal Product....................................................20
6
Prohibited Medications (Delayed Rollover Subjects From 
Trial 331-201-00148)...........................................................................20
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List of In-text Tables
Table 1.2-1
COVID-19 Impact Schedule of Assessments - Subjects Who 
Rollover Directly From Trial 331-201-00148 ................................ 9
Table 1.2-2
COVID-19 Impact Schedule of Assessments - Delayed 
Rollover Subjects From Trial 331-201-00148.............................. 12
Table 3.2-1
Exclusion Criteria for Delayed Rollover Subjects From 
Trial 331-201-00148..................................................................... 17
Table 6-1
List of Washout of Prohibited Medications for Delayed 
Rollover Subjects From Trial 331-201-00148.............................. 21
Clinical Study Report 331-201-00191
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List of In-text Figures
Figure 1.1-1
COVID-19 Impact Trial Design Schematic - Subjects Who 
Rollover Directly From Trial 331-201-00148 ................................ 7
Figure 1.1-2
Trial Design Schematic - Delayed Rollover Subjects From 
Trial 331-201-00148....................................................................... 8
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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
ABC
Aberrant Behavior checklist
ACTH
Adrenocorticotropic hormone
ADHD
Attention-deficit/hyperactivity disorder
AE
Adverse event
AIMS
Abnormal Involuntary Movement Scale
BARS
Barnes Akathisia Rating Scale
BP
Blood pressure
CGI-S
Clinical Global Impression - Severity
CPK
Creatine phosphokinase
CRO
Clinical research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
Cytochrome P450
ECG
Electrocardiogram
eCRF
Electronic case report form
EOT
End of treatment
EPS
Extrapyramidal symptoms
ET
Early termination
FOCBP
Females of child bearing potential
HbA1c
Glycosylated hemoglobin
IMP
Investigational medicinal product
QTcB
QT interval corrected for heart rate by Bazett's formula
QTcF
QT interval corrected for heart rate by Fridericia's formula
SAE
Serious adverse event
SAS
Simpson Angus Scale
TSH
Thyroid-stimulating hormone
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1
Trial 331-201-00191 COVID-19 Protocol Summary
1.1
Trial Design Schematic
Figure 1.1-1
COVID-19 Impact Trial Design Schematic - Subjects Who Rollover Directly From Trial 331-201-00148
Note: In order to be eligible for this trial, the baseline visit must be in office per the protocol. Eligible subjects are those subjects who complete 
Trial 331-201-00148. Subjects who were not able to rollover directly into this trial (Trial 331-201-00191) or are terminated early from Trial 331-201-00148 
due to the COVID-19 pandemic will have an opportunity to enter this trial upon completion of in office screening and baseline visits as detailed in 
Figure 1.1-2.
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Figure 1.1-2
Trial Design Schematic - Delayed Rollover Subjects From Trial 331-201-00148
Note: In order to eligible for this trial, the screening and baseline visits must be in office.
Treatment Period (26 weeks)
Follow-up
Follow-up
21 (± 2 days)
after last
dose
of
brexpiprazole
Screening
(Day −28 to −1)
End of
treatment/
Week 26
visit
Visits at Weeks 1, 2, 3, 4, 8, 14, 18, and 22
Open-label brexpiprazole 0.25 to 3 mg/day
Subjects who were not able to 
rollover directly or are 
terminated early from 
Trial 331-201-00148 due to the 
COVID-19 pandemic and who 
could potentially benefit from 
treatment with brexpiprazole per 
the investigator
Day 1
(Baseline)
Entry into 
treatment 
period
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1.2
Schedules of Assessments
Table 1.2-1
COVID-19 Impact Schedule of Assessments - Subjects Who Rollover Directly From Trial 331-201-00148
Assessment
Screening/ 
Baseline
Last visit 
from Trial 
331-201-
00148/ 
Baseline 
for Trial 
331-201-
00191
In officea
26-week Open-label Treatment Period
EOT
Follow-
up
Week 
1
(Day 7 
± 2 
days)
Virtual
Week 
2
(Day 14 
± 2 
days)
Virtual
Week 
3
(Day 21 
± 2 
days)
Virtual
Week 
4
(Day 28 
± 2 
days)
Virtual
Week 
8
(Day 56 
± 2 
days)
Virtual
Week 
14
(Day 98 
± 2 
days)
Virtual
Week 
18 
(Day 
126 ± 2 
days)
Virtual
Week 
22 
(Day 
154 ± 
2 
days)
Virtual
Week 
26/ 
ET
(Day 
182 ± 
2 
days)
In 
office
21 (± 2) 
days 
after 
last 
dose of 
IMP
By Tele-
phone
Notes
Informed 
consent/assent, 
update medical 
history, as needed
X
Prior medications
X
Inclusion/exclusion 
criteria
X
CGI-S
X
X
X
X
X
X
X
X
X
X
SAS, AIMS, & 
BARS
X
X
(AIMS 
and 
BARS)
X
(AIMS 
and 
BARS)
X
Section 4.1.3
C-SSRS 
X
X
X
X
X
X
X
X
X
X
ABC
X
X
X
X
X
X
X
X
X
X
Physical 
examination
X
X
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Section 4.1.3
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Table 1.2-1
COVID-19 Impact Schedule of Assessments - Subjects Who Rollover Directly From Trial 331-201-00148
Assessment
Screening/ 
Baseline
Last visit 
from Trial 
331-201-
00148/ 
Baseline 
for Trial 
331-201-
00191
In officea
26-week Open-label Treatment Period
EOT
Follow-
up
Week 
1
(Day 7 
± 2 
days)
Virtual
Week 
2
(Day 14 
± 2 
days)
Virtual
Week 
3
(Day 21 
± 2 
days)
Virtual
Week 
4
(Day 28 
± 2 
days)
Virtual
Week 
8
(Day 56 
± 2 
days)
Virtual
Week 
14
(Day 98 
± 2 
days)
Virtual
Week 
18 
(Day 
126 ± 2 
days)
Virtual
Week 
22 
(Day 
154 ± 
2 
days)
Virtual
Week 
26/ 
ET
(Day 
182 ± 
2 
days)
In 
office
21 (± 2) 
days 
after 
last 
dose of 
IMP
By Tele-
phone
Notes
Body weight and 
waist 
circumference
X
X
X
Section 4.1.1
Height
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
ECG
X
X
Clinical laboratory 
tests (hematology, 
serum chemistry, 
and urinalysis)
X
X
HbA1c
X
X
Prolactin 
X
X
Urine pregnancy 
test
X
X
X
Section 4.1.2
ACTH
X
X
Cortisol
X
X
TSH with reflex to 
free T4 if abnormal
X
X
Coagulation 
parameters
X
X
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Table 1.2-1
COVID-19 Impact Schedule of Assessments - Subjects Who Rollover Directly From Trial 331-201-00148
Assessment
Screening/ 
Baseline
Last visit 
from Trial 
331-201-
00148/ 
Baseline 
for Trial 
331-201-
00191
In officea
26-week Open-label Treatment Period
EOT
Follow-
up
Week 
1
(Day 7 
± 2 
days)
Virtual
Week 
2
(Day 14 
± 2 
days)
Virtual
Week 
3
(Day 21 
± 2 
days)
Virtual
Week 
4
(Day 28 
± 2 
days)
Virtual
Week 
8
(Day 56 
± 2 
days)
Virtual
Week 
14
(Day 98 
± 2 
days)
Virtual
Week 
18 
(Day 
126 ± 2 
days)
Virtual
Week 
22 
(Day 
154 ± 
2 
days)
Virtual
Week 
26/ 
ET
(Day 
182 ± 
2 
days)
In 
office
21 (± 2) 
days 
after 
last 
dose of 
IMP
By Tele-
phone
Notes
Adverse events
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
Dispense IMP
X
X
X
X
X
X
X
X
X
IMP accountability
X
X
X
X
X
X
X
X
X
X
ABC = Aberrant Behavior Checklist; ACTH = Adrenocorticotropic hormone; AIMS =Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia 
Rating Scale; BP = blood pressure; CGI-S = Clinical Global Impression - Severity of Illness scale; C-SSRS = Columbia-Suicide Severity Rating Scale; 
ECG = electrocardiogram; EOT = end of treatment; ET = early termination; HbA1c = glycosylated hemoglobin; IMP = investigational medicinal product; 
; 
; SAS = Simpson-Angus Scale; TSH = thyroid-stimulating hormone.
Note: If efficacy or safety assessments cannot be obtained at consecutive virtual visits, the investigator should discuss possible discontinuation of the subject 
with the medical monitor. 
aIn order to eligible for this trial, the baseline visit must be in office per the protocol. Eligible subjects are those subjects who complete Trial 331-201-00148. 
Subjects who were not able to rollover directly into this trial (Trial 331-201-00191) or are terminated early from Trial 331-201-00148 due to the COVID-19 
pandemic will have an opportunity to enter this trial upon completion of in office screening and baseline visits as detailed in Table 1.2-2.
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Table 1.2-2
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Table 1.2-2
COVID-19 Impact Schedule of Assessments - Delayed Rollover Subjects From Trial 331-201-00148
Assessment
Screening
(Day −28 
to −1)
In
officea
26-week Open-label Treatment Period
EOT
Follow-
up
Base
line
(Day 1)
In 
office
Week 
1
(Day 7 
± 2 
days)
Virtual
Week 
2
(Day 
14 ± 2 
days)
Virtual
Week 
3
(Day 
21 ± 2 
days)
Virtual
Week 
4
(Day 
28 ± 2 
days)
Virtual
Week 
8
(Day 
56 ± 2 
days)
Virtual
Week 
14
(Day 
98 ± 2 
days)
Virtual
Week 
18 
(Day 
126 ± 
2 
days)
Virtual
Week 
22 
(Day 
154 ± 
2 
days)
Virtual
Week 
26/ 
ET
(Day
182 ± 
2 
days)
In 
office
21 (± 2) 
days 
after 
last 
dose of 
IMP
By Tele-
phone
Notes
Informed 
consent/assent
X
Inclusion/exclusion 
criteria
X
X
Medical history
X
Psychiatric history
X
Verification of 
stability of 
comorbid 
conditionsb
X
Prior medications 
and washout, if 
applicable
X
CGI-S
X
X
X
X
X
X
X
X
X
X
X
SAS, AIMS, & 
BARS
X
X
(AIMS 
and 
BARS)
X
(AIMS 
and 
BARS)
X
C-SSRS 
X
X
X
X
X
X
X
X
X
X
X
ABC
X
X
X
X
X
X
X
X
X
X
X
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FRQILGHQWLDOLQIRUPDWLRQDQGVKRXOGQRWEHGXSOLFDWHGRUUHGLVWULEXWHGZLWKRXWSULRUZULWWHQFRQVHQWRI2WVXND

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Table 1.2-2
COVID-19 Impact Schedule of Assessments - Delayed Rollover Subjects From Trial 331-201-00148
Assessment
Screening
(Day −28 
to −1)
In
officea
26-week Open-label Treatment Period
EOT
Follow-
up
Base
line
(Day 1)
In 
office
Week 
1
(Day 7 
± 2 
days)
Virtual
Week 
2
(Day 
14 ± 2 
days)
Virtual
Week 
3
(Day 
21 ± 2 
days)
Virtual
Week 
4
(Day 
28 ± 2 
days)
Virtual
Week 
8
(Day 
56 ± 2 
days)
Virtual
Week 
14
(Day 
98 ± 2 
days)
Virtual
Week 
18 
(Day 
126 ± 
2 
days)
Virtual
Week 
22 
(Day 
154 ± 
2 
days)
Virtual
Week 
26/ 
ET
(Day
182 ± 
2 
days)
In 
office
21 (± 2) 
days 
after 
last 
dose of 
IMP
By Tele-
phone
Notes
Physical 
examination
X
X
Body weight and 
waist 
circumference
X
X
X
X
Height
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
ECG
Xc
Xd
X
Clinical laboratory 
tests (hematology, 
serum chemistry, 
and urinalysis)
Xc
Xd
X
HbA1c
X
X
Prolactin 
X
X
Urine drug screen
X
Blood alcohol test
X
Urine pregnancy 
test
X
X
X
ACTH
X
X
Cortisol
X
X
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FRQILGHQWLDOLQIRUPDWLRQDQGVKRXOGQRWEHGXSOLFDWHGRUUHGLVWULEXWHGZLWKRXWSULRUZULWWHQFRQVHQWRI2WVXND

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Table 1.2-2
COVID-19 Impact Schedule of Assessments - Delayed Rollover Subjects From Trial 331-201-00148
Assessment
Screening
(Day −28 
to −1)
In
officea
26-week Open-label Treatment Period
EOT
Follow-
up
Base
line
(Day 1)
In 
office
Week 
1
(Day 7 
± 2 
days)
Virtual
Week 
2
(Day 
14 ± 2 
days)
Virtual
Week 
3
(Day 
21 ± 2 
days)
Virtual
Week 
4
(Day 
28 ± 2 
days)
Virtual
Week 
8
(Day 
56 ± 2 
days)
Virtual
Week 
14
(Day 
98 ± 2 
days)
Virtual
Week 
18 
(Day 
126 ± 
2 
days)
Virtual
Week 
22 
(Day 
154 ± 
2 
days)
Virtual
Week 
26/ 
ET
(Day
182 ± 
2 
days)
In 
office
21 (± 2) 
days 
after 
last 
dose of 
IMP
By Tele-
phone
Notes
TSH with reflex to 
free T4 if abnormal
X
X
Coagulation 
parameters
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
Dispense IMP
X
X
X
X
X
X
X
X
X
IMP accountability
X
X
X
X
X
X
X
X
X
Note: If efficacy or safety assessments cannot be obtained at consecutive virtual visits, the investigator should discuss possible discontinuation of the subject 
with the medical monitor.
In order to eligible for this trial, the screening and baseline visits must be in office. All other visits of the open-label treatment period after the baseline visit
can be virtual or performed per the protocol.
aDelayed rollover subjects must agree to discontinue all prohibited medications during the screening period as summarized in Table 6-1.
bThe investigator should verifiy the stability of comorbid conditions and that there is no potential new diagnosis since the screening vist in 
Trial 331-201-00148.
cThe screening period may be extended in order to repeat clinical laboratory tests and ECGs; if an extension is required, the site should contact the medical 
monitor.
dBaseline clinical laboratory tests (hematology, serum chemistry, and urinalysis) and ECGs are not collected if screening clinical laboratory tests/ECGs were obtained 
within 28 days prior to the baseline visit and within normal ranges.
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2
General Considerations
2.1
Telemedicine Virtual Visits
Telemedicine virtual visits will be completed using the existing trial equipment and 
systems for virtual visits.
2.2
Reconsent
If there is an immediate need to reconsent subjects during the period of COVID-19 
restrictions, a paper reconsent process will be followed and sites are encouraged to 
contact the clinical research organization (CRO) and sponsor with questions.
2.3
Protocol Deviations
Protocol deviations that occur as a direct result of the COVID-19 pandemic must be 
recorded in eSource separately from other protocol deviations as soon as they are 
identified and will be recorded as “Major” in eSource for data capture purposes. 
Examples of the types of COVID-19 related deviations to be reported may include: 
missed visits, missed assessments, assessments performed remotely (completed outside 
of protocol procedure), missed investigational medicinal product (IMP) dose, IMP 
dispensed/returned via courier, IMP not returned to site/site unable to verify medication 
compliance, out of window visits, changes in rater, and prohibited concomitant 
medication. A “direct result” is defined as being due to actual illness, or as a result of 
quarantine, social distancing, or site closures. All other deviations will follow the normal 
deviation process described in the protocol and should not be entered proactively by sites.
2.4
Guidance to Record Adverse Events and Discontinuations Due to 
COVID-19
If a subject tests positive OR is presumed positive with COVID-19, the subject may 
continue in the trial with virtual visits only at the discretion of the investigator as long as 
they remain asymptomatic for COVID-19, but an adverse event (AE) of “Coronavirus 
Infection” OR “Coronavirus Positive Test Result” must be recorded on the AE page of 
the electronic case report form (eCRF). All subjects who have mild symptoms of 
COVID-19 must be reviewed with the medical monitor and approval must be received 
for the subject to continue in the trial. A positive test result or a presumed positive subject 
is not automatically a serious adverse event (SAE), unless an SAE criterion is met 
(eg, hospitalization). If the event meets the criterion for an SAE, then the subject will be 
discontinued from the trial.
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If a subject discontinues due to COVID-19 either because the subject tests positive OR is
presumed positive with COVID-19, then the primary reason for discontinuation should be 
reported as “Adverse Event” and indicate the AE number in the “Specify the reason for 
discontinuation” space that corresponds with the AE of “Coronavirus Infection” OR
“Coronavirus Positive Test Result.” Be sure to remember to enter an AE in the AE form 
for the “Coronavirus Infection” OR “Coronavirus Positive Test Result.”
If a subject discontinues due to COVID-19 other than the subject testing positive OR 
being presumed positive with COVID-19, then the primary reason for discontinuation 
should be reported as “Other.” Be sure to specify the reason as “COVID-19” followed by
the reason ensuring that the prefix of the description includes “COVID-19.” Do note that 
the reason “Other” should be selected even if the subject decides to withdraw consent or 
if the investigator decides to withdraw the subject due to COVID-19 concerns.
In case of a caregiver that is COVID-19 positive and another caregiver is available to 
continue the trial, the situation should be discussed with the medical monitor to determine 
continuation in the trial on a case-by-case basis. If there is no other caregiver, the subject
needs to be early terminated from the trial.
2.5
Statistical Analyses
Any impact of COVID-19 on the planned statistical analyses for the trial will be 
described in the final statistical analysis plan.
2.6
Clinical Outcomes
The administration of scales at virtual visits should be performed as described in the 
protocol, 
To decrease variability, sites should attempt to standardize the method of administration 
for a scale for an individual subject and across all subjects in the trial. Assessments 
should be administered by the same qualified/trained rater who rated the subject 
previously; if this is not possible due to staff availability and/or technological limitations, 
discuss relevant information with previous raters to obtain clinical context (note that per 
protocol raters must be trained/qualified to conduct assessments in all cases). Raters 
should conduct all assessments for that visit during the same remote session, where 
possible.
Please refer to Study Operations Manual for modification of administration methods for 
virtual visits.
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
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3
Trial Population
3.1
Inclusion Criteria
There are no changes to the inclusion criteria due to COVID-19 for purposes of this 
addendum. For delayed rollover subjects, inclusion criteria can be found in Section 3.4.2 
of the protocol.
3.2
Exclusion Criteria
There are no changes to exclusion criteria for subjects who rollover directly from 
Trial 331-201-00148.
Delayed rollover subjects (ie, those who were unable to directly rollover from 
Trial 331-201-00148 due to the COVID 19 pandemic or who were terminated early due 
to the COVID-19 pandemic) will be excluded if they meet any of the exclusion criteria 
presented in Table 3.2-1.
Table 3.2-1
Exclusion Criteria for Delayed Rollover Subjects From 
Trial 331-201-00148
1.
Sexually active males or FOCBP who do not agree to practice 2 different methods of birth 
control or remain abstinent during the trial and for 30 days after the last dose of IMP. If 
employing birth control, 2 of the following precautions must be used: vaginal diaphragm, 
intrauterine device, birth control pill, birth control implant, birth control depot injection, condom 
with spermicide, or sponge with spermicide. 
2.
Females who are breast-feeding and/or who have a positive pregnancy test result prior to 
receiving IMP.
3.
Subjects who have a significant risk of committing violent acts, serious self-harm, or suicide 
based on history or routine psychiatric status examination, or those who are homicidal or 
considered to be a high risk to others, or subjects with an answer of “yes” on C-SSRS Suicidal 
Ideation Item 4 (Active Suicidal Ideation with Some Intent to Act, Without Specific Plan) at 
entry or within the past three months, OR Subjects with a response of “yes” on the C-SSRS 
Suicidal Ideation Item 5 (Active Suicidal Ideation with Specific Plan and Intent) at entry or 
within the past three months, OR Subjects with a response of “yes” on any of the 5 C-SSRS 
Suicidal Behavior Items(actual attempt, interrupted attempt, aborted attempt, preparatory acts, or 
behavior) at entry or within the past year.
4.
Non-pharmacological therapy (eg, psychotherapy, behavior modification) is not stable for 
30 days prior to screening and is not likely to be consistent throughout the trial.
5.
Subjects with Type I or Type II diabetes are excluded if all of the following criteria are not met:

HbA1c ≤ 6.5%,

Screening fasting glucose is ≥70 mg/dL and ≤ 100 mg/dL or nonfasting glucose is 
≥70 mg/dL and ≤ 139 mg/dL. If the nonfasting glucose is ≥139 mg/dL, subjects must be 
retested in the fasting state. At retest, fasting glucose must be ≤ 100 mg/dL

Subject has been maintained on a stable regimen of non-insulin 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,

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.
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Table 3.2-1
Exclusion Criteria for Delayed Rollover Subjects From 
Trial 331-201-00148
6.
Subjects with uncontrolled hypertension or symptomatic hypotension, or orthostatic hypotension 
which is defined as a decrease of ≥15 mmHg in SBP or a decrease of ≥15 mmHg in DBP after 
at least 3 minutes standing compared to the previous supine blood pressure, OR development of 
symptoms.
7.
Subjects ≥ 13 years of age that engage in social activities with peers without adult supervision 
who test positive for drugs of abuse or with a positive blood alcohol test at screening are 
excluded. A positive test for amphetamines, barbiturates, opiates, benzodiazepines may not result 
in exclusion of the subjects if the investigator determines that the positive test is a result of 
prescription medicine(s). When a subject tests positive for cannabinoids (tetrahydrocannabinol) 
at screening, the investigator is required to evaluate the subject's ability to abstain from using this 
substance during the trial and to discuss his/her evaluation with the Medical Monitor prior to 
randomization.
8.
The following laboratory test and ECG results are exclusionary:
1)
Platelets ≤ 130 × 103/uL for ≤ 12 years of age, ≤ 140 × 103/uL for ≥ 13 years of age
2)
Hemoglobin ≤ 11.2 g/dL for ≤ 12 years of age, ≤ 11.6 g/dL for ≥ 13 years of age
3)
Neutrophils, absolute ≤ 1.00 × 103/uL for ≤ 12 years of age, ≤ 1.35 × 103/uL for ≥ 13 years 
of age
4)
AST ≥2 × upper limit of normal
5)
ALT ≥2 × upper limit of normal
6)
Creatinine ≥ 0.7 mg/dL for ≤ 12 years of age, ≥ 1.1 mg/dL for ≥ 13 years of age
7)
HbA1c ≥6.5%
8)
CPK ≥2 × upper limit of normal
9)
QTcF ≥450 msec for males and ≥470 msec for females using the QTcF correction
9.
The subject weighs < 15 kg.
10.
Subjects who would be likely to require prohibited concomitant therapy during the trial.
11.
Any subject who, in the opinion of the investigator, should not participate in the trial.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
C-SSRS  = Columbia-Suicide Severity Rating Scale; FOCBP = females of childbearing potential; 
HbA1C = Glycosylated hemoglobin; QTcB = QT interval corrected for heart rate by Bazett's formula; 
QTcF = QT interval corrected for heart rate by Fridericia's formula.
4
Trial Procedures
4.1
Safety Assessments
Safety assessments at virtual visits will be performed as described in the protocol. 
Assessments which are not currently described for virtual visits will be completed as 
described below.
4.1.1
Weight and Waist Circumference
Weight and waist circumference will be measured as described in the protocol at the 
virtual visits defined in this COVID-19 Addendum Schedules of Assessments 
(Table 1.2-1 and Table 1.2-2) with the following changes: 
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
Caregivers will be asked to use any weight collection device they currently own
regardless of calibration or validation, for weight measurements. (If there is no home 
weight collection device, the site will provide or reimburse for equipment.);

Weight and waist circumference measurement does not need to be videotaped. The 
caregiver will be instructed to provide the weight and waist circumference
measurement result to site staff on the visit day. Subjects will be instructed to be as 
consistent as possible regarding the time of day the measurements are taken, and to 
notify the site staff of the measurement results via telephone, or other means, on the 
appropriate visits.

Site staff will be instructed to record the weight and waist circumference 
measurements in eSource, and if there are believed to be any errors, inconsistencies, 
or safety concerns with the reported home measurement, the medical monitor should 
be notified.
4.1.2
Pregnancy
Pregnancy tests will be performed as described in the protocol at the virtual visits defined 
in this COVID-19 Addendum Schedules of Assessments (Table 1.2-1 and Table 1.2-2) 
with the following changes: 

For planned visits that require a pregnancy test for females of childbearing potential
(FOCBP), the site will provide the necessary tests and instructions so the test may be 
performed at home;

Applicable subjects will perform a pregnancy test prior to dosing with IMP, ensuring 
a date and time-stamped picture or video of the result is taken. The caregiver is to 
provide/show the result during the virtual visit.

If negative, site to inform the subject to proceed with dosing.

If positive, the site must instruct the subject to immediately stop taking IMP, and 
the site will refer to the Pregnancy section of the protocol for appropriate 
immediately reportable event reporting.
4.1.3
Extrapyramidal Symptom Scales
The Abnormal Involuntary Movement Scale (AIMS) and Barnes Akathisia Rating Scale
(BARS) will be assessed at the virtual visits defined in this COVID-19 Addendum 
Schedules of Assessments (Table 1.2-1 and Table 1.2-2) by providing the subject and 
caregiver verbal instructions and observing their movements over video. The Simpson 
Angus Scale (SAS) will not be assessed remotely.
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4.2
Efficacy Assessments
Efficacy assessments at virtual visits will be performed as described in the protocol. 
.
5
Investigational Medicinal Product
Investigational medicinal product will be shipped directly to caregivers and subjects as 
per existing procedures for this trial.
6
Prohibited Medications (Delayed Rollover Subjects From 
Trial 331-201-00148)
Delayed rollover subjects must agree to discontinue all prohibited medications during the 
screening period, after signing the informed consent form/informed assent form, in order 
to meet the protocol-specified washout periods. Table 6-1 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.
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Table 6-1
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Table 6-1
List of Washout of Prohibited Medications for Delayed 
Rollover Subjects From Trial 331-201-00148
Medication
Required Washout Prior to 
Dosing
Antipsychotics
Oral aripiprazole
Oral antipsychotics (other than cariprazine and clozapine) 
Depot or long-acting injectable antipsychotics or clozapine
14 days
7 days
EXCLUDED
Antidepressants
Fluoxetine or Symbyax
Monoamine oxidase inhibitors
Citalopram and escitalopram
Venlafaxine and desvenlafaxine
All other antidepressants
28 days
14 days
14 days
14 days
14 days
Other psychotropics
Atomoxetine
For subjects without ADHD 
diagnosis - 7 days 
Stimulants
Minimum 5× half- life for subjects 
without diagnosis of ADHD 
Mood stabilizers (ie, lithium or anticonvulsants)
7 days
Varenicline
5 days
Oral benzodiazepines used as rescue therapy during washouta
Lorazepam, oxazepam, diazepam, or clonazepam
Other benzodiazepines
8 hours before scalesb
14 days
CYP2D6 inhibitors and CYP3A4 inhibitors and inducers 
(see Table 4.1-3 of the protocol).
14 days
ADHD = attention-deficit/hyperactivity disorder; CYP = cytochrome P450.
aUse of intramuscular benzodiazepines and continual use of oral benzodiazepines are prohibited 
throughout the trial. However, limited use of specific oral benzodiazepines is permitted during 
screening to treat agitation or insomnia as shown in Table 4.1-2 of the protocol.
bBenzodiazepines must not be administered within 8 hours prior to scheduled efficacy assessments, and
EPS scales. Investigators are encouraged to delay scale administration until 8 hours have elapsed, if at 
all possible. However, if delaying administration of efficacy and EPS scales is not feasible, the scales 
should still be administered and the use of benzodiazepine documented, including a notation of the 
drug name, dose, and time of administration in eSource.
Clinical Study Report 331-201-00191
16.1.1 Protocol and Protocol Amendments
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116


T hi s p a g e i s a m a nif e st ati o n of a n el e ctr o ni c all y c a pt ur e d si g n at ur e
SI G N A T U R E P A G E
D o c u m e nt N a m e: Pr ot o c ol 3 3 1- 2 0 1- 0 0 1 9 1 A d d e n d u m
D o c u m e nt N u m b er: 
D o c u m e nt V er si o n: 2. 0
Si g n e d b y
M e a ni n g of Si g n at ur e
S er v er D at e
( d d- M M M-
y y y y h h: mi n) -
U T C ti m e z o n e
Bi o st ati sti c s A p pr o v al
0 7- J ul- 2 0 2 0
2 1: 1 5: 1 8
A p pr o v e d f or Cli ni c al
P h ar m a c ol o g y
a n d N o n cli ni c al
0 7- J ul- 2 0 2 0
1 6: 3 2: 0 8
Cli ni c al A p pr o v al
0 7- J ul- 2 0 2 0
1 5: 5 5: 1 1
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 9 1
1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
U ntil t he i nf or m ati o n herei n is rele ase d b y Ots u k a t o t he p u blic d o m ai n, t he c o nte nts of t his d oc u me nt are Ots u k a
c o nfi de nti al i nf or m ati o n a n d s h o ul d n ot be d u plic ate d or re- distri b ute d wit h o ut pri or writte n c o nse nt of Ots u k a.
1 1 7
C CI
P P D
P P D
P P D

SAP_001.pdf: 
Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigational New Drug
Brexpiprazole (OPC-34712)
Protocol 331-201-00191: A Phase 3, Multicenter, Open-label Trial to Evaluate the 
Long-term Safety and Tolerability of Brexpiprazole (OPC-34712) in the Treatment of 
Children and Adolescents with Irritability Associated with Autism Spectrum Disorder
Protocol No. 331-201-00191
IND No. 141257
EudraCT No. 2018-004899-35
Statistical Analysis Plan
Version: Final 3.0
Date: 08 May 2023
CONFIDENTIAL - PROPRIETARY INFORMATION
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Otsuka Pharmaceutical Development & Commercialization, Inc.
Clinical Study Report 331-201-00191
16.1.9 Documentation of Statistical Methods
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Table of Contents
Table of Contents ..........................................................................................2
List of In-text Tables.....................................................................................4
List of In-text Figures ...................................................................................5
List of Appendices .........................................................................................6
List of Abbreviations and Definitions of Terms .........................................7
1
Introduction..........................................................................................9
2
Study Objectives...................................................................................9
3
Trial Details ..........................................................................................9
3.1
Study Design .......................................................................................................9
3.2
Trial Treatments ................................................................................................12
4
Sample Size and Power Justification................................................12
5
Data Sets for Analysis and Missing Data .........................................12
5.1
Data Sets for Analysis.......................................................................................12
5.2
Handling of Missing Data .................................................................................13
6
Study Conduct ....................................................................................14
6.1
Subject Disposition, Completion Rate and Reasons for Discontinuation.........14
6.2
Treatment Compliance ......................................................................................14
6.3
Protocol Deviation.............................................................................................14
7
Baseline Characteristics.....................................................................14
7.1
Baseline Definition............................................................................................14
7.2
Demographic Characteristics ............................................................................15
7.3
Baseline Psychiatric Evaluations.......................................................................15
7.4
Medical and Psychiatric History .......................................................................15
8
Safety Analysis....................................................................................15
8.1
Adverse Events (AEs) .......................................................................................16
8.2
Clinical Laboratory Tests..................................................................................17
8.3
Vital Signs.........................................................................................................18
8.4
Electrocardiogram Data.....................................................................................18
8.5
Physical Examinations ......................................................................................19
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8.5.1
Body Weight, Waist Circumference and BMI ...............................................19
8.5.2
Z-score............................................................................................................20
8.5.2.1
Calculation of Z-scores for Body Weight, Height, and BMI......................20
8.6
Extrapyramidal Symptoms Rating Scales (SAS, AIMS and BARS)................21
8.7
Columbia Suicide Severity Scale (C-SSRS) .....................................................21
8.8
Concomitant Medications .................................................................................22
8.9
Extent of Exposure............................................................................................22
9
Efficacy Analysis ................................................................................23
9.1
The Secondary Endpoints..................................................................................23
9.3
Interim Analysis ................................................................................................24
9.4
Multiplicity Adjustment ....................................................................................24
10
Conventions.........................................................................................24
10.1
Software for Statistical Analysis and Reporting ...............................................24
10.2
Study Day..........................................................................................................24
10.3
Visit Window and the Derived Analysis Visit..................................................24
10.4
Descriptive Statistics for Continuous and Categorical Variables .....................25
10.5
Display of Statistical Outputs............................................................................26
11
Scales: Rules for Scoring and Handling of Missing Data...............26
11.1
ABC Subscales..................................................................................................26
11.2
Clinical Global Impressions - Severity (CGI-S) ...............................................27
11.5
Simpson Angus Scale (SAS).............................................................................29
11.6
Abnormal Involuntary Movement Scale (AIMS) .............................................29
11.7
Barnes Akathisia Rating Scale (BARS)............................................................29
11.8
Columbia-Suicide Severity Rating Scale (C-SSRS) .........................................30
12
Proposed List of Summary Tables....................................................31
13
References ...........................................................................................37
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8.5.1
Body Weight, Waist Circumference and BMI ...............................................19
8.5.2
Z-score............................................................................................................20
8.5.2.1
Calculation of Z-scores for Body Weight, Height, and BMI......................20
8.6
Extrapyramidal Symptoms Rating Scales (SAS, AIMS and BARS)................21
8.7
Columbia Suicide Severity Scale (C-SSRS) .....................................................21
8.8
Concomitant Medications .................................................................................22
8.9
Extent of Exposure............................................................................................22
9
Efficacy Analysis ................................................................................23
9.1
The Secondary Endpoints..................................................................................23
9.3
Interim Analysis ................................................................................................24
9.4
Multiplicity Adjustment ....................................................................................24
10
Conventions.........................................................................................24
10.1
Software for Statistical Analysis and Reporting ...............................................24
10.2
Study Day..........................................................................................................24
10.3
Visit Window and the Derived Analysis Visit..................................................24
10.4
Descriptive Statistics for Continuous and Categorical Variables .....................25
10.5
Display of Statistical Outputs............................................................................26
11
Scales: Rules for Scoring and Handling of Missing Data...............26
11.1
ABC Subscales..................................................................................................26
11.2
Clinical Global Impressions - Severity (CGI-S) ...............................................27
11.5
Simpson Angus Scale (SAS).............................................................................29
11.6
Abnormal Involuntary Movement Scale (AIMS) .............................................29
11.7
Barnes Akathisia Rating Scale (BARS)............................................................29
11.8
Columbia-Suicide Severity Rating Scale (C-SSRS) .........................................30
12
Proposed List of Summary Tables....................................................31
13
References ...........................................................................................37
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List of In-text Tables
Table 8.4-1
Categorical Change Criteria in QT/QTc Parameters.....................19
Table 10.3-1
Mapping of the Analysis Visit for the Open-label Treatment 
Period.............................................................................................25
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List of In-text Figures
Figure 3.1-1
Trial Design Schematic..................................................................11
Clinical Study Report 331-201-00191
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List of Appendices
Appendix 1
Criteria for Identifying Vital Signs Outside of Normal Values 
and of Potential Clinical Relevance...............................................40
Appendix 2
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance.........................................................................41
Appendix 3
Criteria for Identifying ECG Measurement of Potential 
Clinical Relevance.........................................................................43
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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
ABC
Aberrant Behavior Checklist
ABC-I
Aberrant Behavior Checklist - Irritability
AE
Adverse event
AIMS
Abnormal Involuntary Movement Scale
ALT
Alanine aminotransferase
ASD
Autism Spectrum Disorder
AST
Aspartate aminotransferase
BARS
Barnes Akathisia Rating Scale
BMI
Body mass index
CDC
Center for Disease Control and Prevention
CGI-S
Clinical Global Impressions - Severity
CRF
Case Report Form
C-SSRS
Columbia-Suicide Severity Rating Scale
DBP
Diastolic blood pressure
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
ECG
Electrocardiogram
EPS
Extrapyramidal symptoms
ET
Early termination
FDA
(United States) Food and Drug Administration
HbA1c
Glycosylated hemoglobin
HDL
High density lipoprotein
IAF
Informed assent form
ICF
Informed consent form
IMP
Investigational medicinal product
IRE
Immediately reportable event
LDL
Low density lipoprotein
LOCF
Last Observation Carried Forward
MedDRA
Medical Dictionary for Regulatory Activities
OC
Observed Case
OPDC
Otsuka Pharmaceutical Development and Commercialization, Inc.
PE
Physical examination
PT
Preferred Term
QTc
Corrected QT interval
QTcF
QT interval as corrected for heart rate by Fridericia’s formula
QTcN
QT interval as corrected for heart rate by the FDA Neuropharm Division
SAE
Serious adverse event
SAS
Simpson Angus Scale
SAS®
Statistical Analysis System®
SAP
Statistical Analysis Plan
SBP
Systolic blood pressure
SOC
System Organ Class
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Abbreviation
Definition
TEAE
Treatment-emergent adverse event
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
WHO
World Health Organization
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1
Introduction
This statistical analysis plan (SAP) expands the statistical section of the protocol 
331-201-00191 (version 6.0) and documents in detail the statistical methodologies and 
data analysis algorithms and conventions to be applied to the analysis and reporting of the 
safety and tolerability data collected in the study. All amendments to the protocol have 
been taken into consideration in developing this SAP.
2
Study Objectives
Primary: To assess the long-term safety and tolerability of brexpiprazole monotherapy in 
children and adolescents of 5 to 17 years old with irritability associated with autism 
spectrum disorder (ASD).
Secondary: To assess the long-term efficacy of brexpiprazole monotherapy in the same 
patient population.
3
Trial Details
3.1
Study Design
This is a phase 3, multicenter, single-arm, open-label extension trial designed to assess 
the long-term safety and tolerability of oral brexpiprazole monotherapy in children and 
adolescents with irritability associated with ASD. Enrollment into the trial will be drawn 
from eligible subjects who complete the double-blind treatment period of the phase 3 
ASD trial (Trial 331-201-001481), and in the investigator’s judgment, could potentially 
benefit from continued investigational treatment with oral brexpiprazole. 
The trial is planned to be conducted on an outpatient basis. Individual subjects’ 
participation into the trial will be up to 29 weeks, including 26 weeks of open-label 
treatment, and 3 weeks of follow-up period. See Figure 3.1-1 for the design schematic of 
the trial. The trial will be organized as follows.
Screening Phase: Subjects who completed the double-blind treatment period of Trial 
331-201-00148 (also referred to as the parent trial) and are deemed compliant with the 
protocol will be screened for eligibility at the last assessment visit of the double-blind 
treatment period. A separate fully executed informed consent/assent will be obtained for 
this open-label extension trial (Trial 331-201-001912) before any procedures specific to 
this trial are performed. Unless specified otherwise, the assessments at the last visit in the 
double-blind treatment period of the parent trial will serve as the baseline measures for 
this open-label extension trial. Medical history will be updated for this trial, if necessary.
Clinical Study Report 331-201-00191
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Open-label Treatment Phase: Eligible subjects will receive 26 weeks of daily treatment 
with brexpiprazole in Trial 331-201-00191. Subject will start the open-label dosing of 
brexpiprazole - the investigational medicinal product (IMP) on the very next day of the 
last assessment visit of the double-blind treatment period in the parent trial. Subjects will 
be evaluated at baseline and all the scheduled visits which will occur at the end of 
Weeks 1, 2, 3, 4, 8, 14, 18, 22 and 26 during the treatment period. Visits are to occur 
within ± 2 days of the target visit date. All required evaluations as described in the 
Schedule of Assessments (see Table 3.7-1of the Protocol for Trial 331-201-00191) will 
be performed. If a subject discontinues from the trial before the end-of-trial visit at 
Week 26, assessments or procedures noted for the Week 26 visit must be completed at an 
early termination (ET) visit. Attempts should be made to complete all evaluations prior to 
the administration of any new medications or treatment. Of note, the baseline, Week 2, 
Week 14, and Week 26 visits will occur in the clinic. All other visits will be virtual or in 
clinic. Where the investigator and caregiver make the decision to conduct a visit virtually, 
the visit will be conducted by means of telecommunications technology.
Follow-up Phase: Subjects will have a follow-up contact 21 (± 2) days after the last dose 
of the IMP to assess any new or ongoing AEs and to record any concomitant medications. 
The follow-up contact also applies to the subjects who are prematurely withdrawn from 
the trial.
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Figure 3.1-1
Trial Design Schematic 
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3.2
Trial Treatments
The first dose of open-label brexpiprazole will be taken the following day after the last 
dose of double-blind IMP is taken in the parent trial so that treatment continues without 
interruption. Whenever possible, it is anticipated that the last dose of IMP in the double 
blind, phase 3 efficacy trial will be taken on the day of the baseline visit for the open-
label trial. Subjects should not be dosed using double-blind and open-label IMP on the 
same day. Throughout 26 weeks of treatment in this open-label extension trial, enrolled 
subjects will follow a titration/dosing schedule depending upon subject’s body weight at 
the baseline visit. Subjects will receive a target dose range of 1 to 1.5 mg/day if body 
weight < 50 kg, and 1.5 to 3 mg/day if ≥ 50 kg. Refer to Table 3.2-1 of the Protocol for 
Trial 331-201-00191, which shows the titration/dosing schedule per subject’s body 
weight stratum at baseline.
4
Sample Size and Power Justification
The sample size planned for this open-label extension trial is not based on considerations 
of statistical power.
Participants in this trial will be the subjects who completed the double-blind treatment 
period of the parent trial (Trial 331-201-00148) and who would likely benefit from a 
longer term of treatment with brexpiprazole in the judgement of the investigator. The 
sample size for this rollover trial will not exceed that of the parent trial (ie,
119 randomized subjects).
5
Data Sets for Analysis and Missing Data 
5.1
Data Sets for Analysis
To adequately describe the statistical analyses and reporting, three analysis populations 
are defined as follows.
•
Enrolled Sample: Consists of subjects who completed the double-blind treatment 
period of the parent trial and who gave consent/assent for participation into this 
open-label trial and who also met all the eligibility criteria for this trial.
•
Safety Sample: Consists of all Enrolled subjects who took at least one dose of the 
IMP as indicated on the dosing records of this open-label extension trial. A 
subject will be excluded from this population only if there is documented 
evidence that the subject has not taken the IMP (ie, number of tablets/capsules 
dispensed = number of tablets/capsules returned, or no IMP dispensed). If a 
subject is dispensed trial medications but subsequently lost to follow-up, the 
subject will be considered exposed to the IMP.
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•
Efficacy Sample: All subjects in the Safety Sample who have a baseline 
assessment and at least one post-baseline assessment of the Aberrant Behavior 
Checklist - Irritability (ABC-I) subscale score.
Summary statistics of demographics, baseline characteristics and subject disposition 
variables will be computed on the Enrolled Sample. Summary statistics of adverse events 
and all other safety parameters will be computed on the Safety Sample, and summary 
statistics of all efficacy parameters will be computed on the Efficacy Sample.
5.2
Handling of Missing Data
For scoring via the aggregation of component items of the efficacy and safety scales, and 
how to handle the items with unrecorded (missing) ratings for the scoring, refer to 
Section 11 for details.
The Observed Case (OC) dataset for the parameters (eg, efficacy or safety variables) of 
interest will consist of all the actual observations or assessments of the parameters 
recorded at the visits during the open-label treatment period and the follow-up period. 
Note that if observations or assessments are unrecorded, thus missing, at a visit, the 
missing values will not be imputed. Subjects discontinued from treatment before 
Week 26 will have an ET visit where all assessments originally scheduled for the 
Week 26 visit will be made. Such data collected at the ET visit (or any other unscheduled 
visits, if any) will be mapped to a specific visit per the visit window algorithm given in 
Section 10.3. In the instances where a subject discontinues the treatment early but 
somehow does not subsequently attend the ET visit, all scheduled assessments after the 
timepoint of his or her treatment discontinuation will remain missing. All by-visit 
analysis (including summary) will be based on the OC dataset.
The Last-Observation-Carried-Forward (LOCF) dataset include all OC data and in 
addition the imputed data per a commonly used imputation rule (the LOCF rule) as 
follows: If no observation or assessment is recorded at a scheduled visit, the missing 
value for that visit will be imputed by carrying forward the last available (ie, the 
immediately preceding) observation or assessment (inclusive of the value at an ET visit, 
if any). Note that baseline data cannot be carried forward to impute post-baseline values.
Of particular interest is the timepoint of the end-of-trial visit at Week 26. Serving as a 
kind of supplementary evidence for the results, the analysis will be repeated on the 
Week 26 LOCF data for each analysis performed on the Week 26 OC data.
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6
Study Conduct
6.1
Subject Disposition, Completion Rate and Reasons for 
Discontinuation
Subject disposition will be summarized on the Enrolled Sample by clinical center as well 
as by prior treatment group. Subject completion rate and reasons for discontinuation will 
be summarized on the Enrolled Sample by prior treatment group. Subjects who are 
evaluated at the last scheduled visit of the open-label treatment period will be defined as 
trial completers. For purposes of this trial, subjects who complete the Week 26 visit will 
be defined as trial completers. 
6.2
Treatment Compliance
Based on the IMP panel of the Case Report Form (CRF), an individual subject’s overall 
compliance score with respect to his/her taking IMP will be calculated by dividing the 
number of tablets/capsules (actually) taken by the total number of tablets/capsules 
scheduled to be taken for the observed treatment period, then multiply by 100. For the 
subject who is prematurely discontinued from treatment or lost to follow-up, the last dose 
date recorded on the subject will be used as the endpoint of the observed treatment 
period. The denominator (ie, number of tablets/capsules scheduled to be taken) will be 
downwardly adjusted for early treatment discontinuation. 
6.3
Protocol Deviation
Protocol deviations including the types of deviations (eg, deviations in entry criteria, 
dosing, concomitant medications, procedurals, etc) will be summarized on the Enrolled 
Sample by trial center and prior treatment group. A listing of protocol deviations will also 
be provided. 
A flagging variable taking values of “yes” or “no” will be created to indicate whether the 
deviation or violation was related to the COVID-19 pandemic.
7
Baseline Characteristics
7.1
Baseline Definition 
An individual subject’s baseline value is defined as the observation or assessment taken 
on the subject at the last visit of the double-blind treatment period in the parent trial. If a 
subject has separate screening visit(s) after end of the parent trial, then the last 
observation or assessment prior to the first dose of the open-label IMP will be considered 
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as baseline. For baseline values, there will be no imputation for missing or unknown 
values.
7.2
Demographic Characteristics
Demographic and baseline characteristics include age, sex, race, ethnicity, height, body 
weight, waist circumference, and body mass index (BMI). Demographic characteristics 
will be summarized on the Enrolled Sample by prior treatment group and for the overall 
analysis sample as well. Age, height, body weight, waist circumference and BMI will be 
treated as continuous variables, while sex, race and ethnicity will be treated as categorical 
variables. Refer to Section 10.4 for the conventions on using descriptive statistics for 
continuous and categorical variables.
7.3
Baseline Psychiatric Evaluations
Baseline psychiatric evaluations for this open-label extension trial are the ones taken at 
the last assessment visit of the parent trial. The baseline values in the following 
parameters will be summarized on the Enrolled Sample on the OC data using descriptive 
statistics: the ABC-I subscale score; all other ABC subscale scores; the CGI-S score; 
Refer to Section 11 for the scales and the scoring via the aggregation of component items 
of the scales.
7.4
Medical and Psychiatric History 
Medical history and psychiatric history data will be summarized on the Enrolled Sample 
by prior treatment group using descriptive statistics.
8
Safety Analysis
All safety analyses specified in this section will be performed on the Safety Sample. The 
baseline of a safety variable is defined as the last observation or assessment in the 
variable prior to the first dose of the open-label IMP.
Safety is the primary objective for this study. Safety will be assessed by the following 
standard endpoints for clinical trials and trials of antipsychotic drugs:
•
The frequency and severity of treatment-emergent adverse events (TEAEs), 
serious TEAEs, and discontinuation from trial due to AEs.
•
Change from baseline to post-baseline time points in: a) vital sign measurements; 
b) electrocardiogram (ECG) parameters; c) clinical laboratory tests (including 
prolactin) and urinalysis; and d) physical examination findings.
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•
Analysis of potential suicide events recorded on the Columbia-Suicide Severity 
Rating Scale (C-SSRS).
•
Changes from baseline to post-baseline time points in results from extrapyramidal 
symptoms (EPS) scales (Simpson Angus Scale [SAS], Abnormal Involuntary 
Movement Scale [AIMS], and Barnes Akathisia Rating Scale [BARS]).
•
Percentage of subjects with clinically significant changes in weight (gain or loss) 
from baseline to specified time points.
•
Time to discontinuation.
8.1
Adverse Events (AEs)
All AEs will be coded by System Organ Class (SOC) and Preferred Term (PT) according 
to the latest version (Version 25.0 or newer) of Medical Dictionary for Regulatory 
Activities (MedDRA). A TEAE is defined as an AE that starts after the first dose of the 
open-label IMP or an AE that is present at baseline and increases in intensity or becomes 
serious or trial drug-related or results in death, discontinuation, interruption or reduction 
of the IMP. AEs occurring up to 30 days after the last dose of IMP in the open-label 
treatment period will be included in the AE summary tables. AEs having occurred 
30 days after the last dose of IMP, if collected, will be listed only.
The incidence of the following AEs in Trial 331-201-00191 will be tabulated by prior 
treatment group and for the overall:
a) TEAEs 
b) TEAEs by severity
c) TEAEs potentially causally related to the IMP
d) TEAEs with an outcome of death
e) Serious TEAEs
f)
TEAEs leading to discontinuations of the IMP
g) EPS-related TEAEs
The above summaries (b), (e) and (f) will also be prepared for TEAEs potentially 
causally related to the IMP.
In addition, TEAE incidence with rate ≥ 2% at any SOC and PT levels in any of the two 
prior treatment groups will be provided. Incidence of TEAEs by SOC and PT will also be 
summarized for subgroups defined by sex, race, age, and body weight category at 
enrollment. Of note, AEs that are sex-specific, eg, ovarian cancer, will have the incidence 
rate evaluated for the specific sex.
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8.2
Clinical Laboratory Tests
During the open-label treatment period, clinical laboratory assessments, including 
hematology, serum chemistry, urinalysis, serum bicarbonate, glycosylated hemoglobin 
(HbA1c), serum prolactin concentrations, thyroid stimulating hormone (TSH), and free 
T4 (if the TSH is abnormal) will be made in office at the Week 14 and 26 visits. 
Coagulation parameters will be assessed only at the end timepoint (the Week 26 visit) of 
the open-label treatment period. Of note, metabolic parameters (ie, total cholesterol, low 
density lipoprotein (LDL), high density lipoprotein (HDL) and triglycerides) and serum 
glucose will be separately summarized for fasting and non-fasting tests, and serum 
prolactin concentrations will be separately summarized for male and female subjects.
The assessment value and the change from baseline value at each of the specified visits 
above in each of the above-mentioned clinical laboratory parameters will be summarized 
on the OC data by using the descriptive statistics for continuous variables. Likewise, the 
summary statistics will also be computed on the LOCF data for the last assessment visit.
Potentially clinically relevant laboratory measurement test results during the open-label 
treatment period will be identified and the number and percentage of subjects who had 
such a laboratory value will be tabulated by laboratory parameter and prior treatment 
group based on the observation from the scheduled and the unscheduled (if any) post-
baseline visits. Criteria for Identifying Laboratory Values of Potential Clinical Relevance 
for the children and adolescent subjects enrolled into this study are provided in Appendix 
2.
Potential serious hepatotoxicity is an immediately reportable adverse event of interest. 
The case of potential serious hepatotoxicity at a post-baseline visit is defined as having 
(1) aspartate aminotransferase (AST) or alanine aminotransferase (ALT) that is ≥ 2 times 
the upper limit of normal (ULN), and (2) the total Bilirubin ≥ 1.6 times the ULN. The 
incidence of potential serious hepatotoxicity (ie, the number and percentage of subjects 
who had a case of potential serious hepatotoxicity) will be tubulated by prior treatment 
group based on the observation from the scheduled and the unscheduled (if any) post-
baseline visits.
All potentially clinically significant laboratory abnormalities will be listed by prior 
treatment group, patient ID, baseline value, age, sex, body weight, visit, and dose at onset 
of the event if applicable.
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8.3
Vital Signs
Vital signs measurements will include body temperature, systolic blood pressure (SBP), 
diastolic blood pressure (DBP), and heart rate. Blood pressure (ie, SBP, DBP) and heart 
rate will be measured in the supine and standing positions. Measurements at different 
positions will be treated as different parameters for purposes of data analysis. Thus, there 
will be 7 parameters for the vital signs.
The assessment value and the change from baseline value in each of the 7 vital signs 
parameters during the open-label treatment period will be summarized by visit on the OC 
data by using descriptive statistics for continuous variables. Likewise, the summary 
statistics will be computed for the last assessment visit based on the LOCF data.
Potentially clinically relevant vital signs abnormalities during the open-label treatment 
period will be identified, and the number and percentage of subjects who had such an 
abnormality in each of the vital signs will be tabulated by prior treatment group based on 
the observation from the scheduled and the unscheduled (if any) post-baseline visits.
All potentially clinically significant vital signs abnormalities will be listed by prior 
treatment group, patient ID, baseline value, age, sex, body weight, visit week, type of 
visit (virtual or in office), and dose at onset of the event if applicable.
Criteria for Identifying Vital Signs of Potential Clinical Relevance for subjects 5 to 
17 years of age are provided in Appendix 1.
8.4
Electrocardiogram Data
Electrocardiogram (ECG) measurements will be made in office at 2 specified visits 
(Weeks 14 and 26 visits) during the open-label treatment period. The standard 12-lead 
measurements include QTc, heart rate, PR interval, and QRS complex. For the analysis of 
QT and QTc, data from three consecutive complexes (representing three consecutive 
heart beats) will be measured to determine average values. The following QT corrections 
will be used for reporting purposes:
1) QTcF is the length of the QT interval corrected for heart rate by the Fridericia 
formula: QTcF = QT/(RR)0.33
2) QTcN is the length of the QT interval corrected for heart rate by the FDA 
Neuropharm Division formula: QTcN = QT/(RR)0.37.
For each of the quantitative ECG parameters, assessment value and change from baseline 
value will be summarized on the OC data for each of the specified visits above, as well as 
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on the LOCF data for the last assessment visit, by using descriptive statistics for 
continuous variables.
Criteria for identifying potentially clinically relevant ECG abnormality for subjects of 
5 to 17 years of age are provided in Appendix 3. All potentially clinically relevant ECG 
abnormalities during the open-label treatment period will be listed by prior treatment 
group, patient number, sex, age, body weight, baseline value, visit, description of the 
findings, and dose at onset of the event if applicable. In addition, the number and 
percentage of patients who had a potentially clinically relevant ECG abnormality will be 
tabulated by prior treatment group based on the observation at the scheduled and the 
unscheduled (if any) post-baseline visits.
Categorical Change in ECG parameters during the open-label treatment period will be 
summarized based on the following criteria:
Table 8.4-1
Categorical Change Criteria in QT/QTc Parameters
Classification
Category
Criteria 
QT
New onset (≥ 450 msec for men 
or ≥ 470 msec for women)
New onset in QT means a subject who attains a cut 
off value during treatment period but not at baseline.
QTca
New onset (≥ 450 msec for men 
or ≥ 470 msec for women)
New onset in QTc means a subject who attains a cut-
off value during treatment period but not at baseline.
New onset (≥ 450 msec for men 
or ≥ 470 msec for women) and 
> 10% increase
New onset and > 10% increase in QTc means a 
subject who attains a cut off value and > 10% 
increase during treatment period but not at baseline
New onset (> 500 msec)
New onset (> 500 msec) in QTc means a subject who 
attains a value > 500 msec during treatment period 
but not at baseline.
Increase 30 - 60 msec
Increase from baseline value > 30 and ≤ 60 msec in 
QTc.
Increase > 60 msec
Increase from baseline value > 60 msec in QTc.
aQTc categorical change criteria apply to QTcF and QTcN.
8.5
Physical Examinations
By-subject listings will be provided for physical examinations (PE), which is scheduled 
at the end (ie, the Week 26 visit) of the open-label treatment period, following the 
screening/baseline visit.
8.5.1
Body Weight, Waist Circumference and BMI
Measurements on body weight, waist circumference and height will be collected at two 
specified visits (ie, Weeks 14 and 26) in office at clinical site during the open-label 
treatment period. For each visit, BMI will be derived as: weight in kilograms divided by 
the square of height in meters.
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Measurement value and change from baseline value at each of the two specified visits 
above during the open-label treatment period in each of the above-mentioned four 
parameters will be summarized on the OC data by using descriptive statistics for 
continuous variables. Likewise, the summary statistics will also be computed on the 
LOCF data for the last visit.
Number and percentage of subjects having had significant weight gain (≥ 7% increase in 
body weight relative to baseline) and significant weight loss (≥ 7% decrease in body 
weight relative to baseline) during the open-label treatment period will be respectively 
tabulated by visit and for the overall treatment period as well.
8.5.2
Z-score
Z-score is a variable of interest to be derived due to the natural growth of children and 
adolescent subjects. Weight z-score describes how similar a subject is to his/her age and 
gender peers by determining the number of standard deviations from the expected weight. 
For each scheduled visit, weight z-score is calculated as the deviation of the subject’s 
weight from the mean weight of the reference population divided by the standard 
deviation for the reference population. Weight z-score and change from baseline in 
weight z-scores will be summarized on the OC data by specified visit (ie, Weeks 14 
and 26) and the last visit by using descriptive statistics for continuous variables.
Height z-score and BMI z-score will be similarly calculated and similarly summarized as 
that for weight, based on the OC data and last visit. Refer to Section 8.5.2.1 for the 
calculation of z-score for body weight, height, and BMI. Furthermore, the number and 
percentage of subjects with the magnitude of change being ≥ 0.5 or ≤ −0.5 in BMI z-
score (relative to baseline) will be tabulated on the OC data by specified visit (ie, 
Weeks 14 and 26) and the last visit.
8.5.2.1
Calculation of Z-scores for Body Weight, Height, and BMI
Age and gender adjusted z-scores for body weight, height and BMI will be calculated 
using the approach of the Center for Disease Control and Prevention (CDC), USA. The 
CDC provides a reference dataset (CDCref_d.sas7bdat in sas data format or 
CDCref_d.csv in csv data format) and a SAS program (cdc-source-code.sas) along with 
detailed instructions for the calculations3.
Z-scores are calculated as Z = [ ((value / M) ** L) − 1] / (S * L), in which “value” is the 
child’s BMI, weight, height, etc. The L, M, and S values are in the reference dataset and 
vary according to the child’s sex and age. The following rules will be observed:
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1) Age (in months) at the day of assessment, which is an input for the calculations, 
will be calculated as: (assessment date − birth date + 1)/(365.25/12).
2) In principle, BMI and its z-score will be calculated only if weight and height are 
both taken on the same day.
3) The above calculations are applicable in children and adolescents older than 
24 months but younger than 20 years of age.
It is not anticipated that CDC’s information (including the reference dataset or the SAS 
program or the instructions for the calculations) will be updated in the short run. 
Nevertheless, the information at the CDC website will be re-checked for any updates 
within a month prior to the final database lock, and updated information will be used if 
any.
8.6
Extrapyramidal Symptoms Rating Scales (SAS, AIMS and BARS)
Extrapyramidal symptoms scales (SAS, AIMS and BARS) will be assessed in office at 
clinical site at three specified visits (Weeks 2, 14 and 26) during the open-label treatment 
period. The SAS total score, the AIMS total score, and the BARS global clinical 
assessment score (see Section 11.5, Section 11.6, and Section 11.7 for the construction of 
these scores) and the change from baseline in these scores will be respectively 
summarized on the OC data by visit above and on the LOCF for last visit by using 
descriptive statistics for continuous variables. For the AIMS individual item score on 
Item 8, 9 and 10, summary statistics will be computed analogously to the above.
In addition, incidence of BARS global clinical assessment during the open-label 
treatment period by severity category will be provided using summary statistics on OC 
data and last visit.
8.7
Columbia Suicide Severity Scale (C-SSRS)
Suicidality will be monitored during the trial (excluding the 21-day follow-up period) 
using the C-SSRS (Child Version). Suicidality data will be collected at all the visits 
including the scheduled visits and the ET visit.
Variables pertaining to suicidality assessments are categorical in nature. For each of the 
suicidality categories of interest, the number and percentage of subjects with the presence 
of suicidality will be tabulated (or say, summarized) by visit and for the overall treatment 
period. Note that, the presence of suicidality is defined as reporting of at least one 
occurrence of any types of suicidal ideation or behavior. Also note that, for the tabulation 
for the overall treatment period, a subject will be counted only once if he or she had 
multiple occurrences of suicidal ideation or behavior during the treatment period.
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And the following four categories of treatment emergent suicidality will be analogously 
summarized: (1) Emergence of suicidal ideation, which is defined as reporting of any 
types of suicidal ideation during the treatment period while there was no suicidal ideation 
at baseline; (2) Emergence of serious suicidal ideation, which is defined as having 
observation of suicidal ideation severity rating of 4 or 5 during the treatment period while 
there was no suicidal ideation at baseline; (3) Worsening of suicidal ideation, which is 
defined as having a suicidal ideation severity rating that is more severe compared to 
baseline; (4) Emergence of suicidal behavior, which is defined as reporting of any types 
of suicidal behavior during the treatment period while there was no suicidal behavior at 
baseline. Specifically, for each of the above categories of treatment emergent suicidality, 
descriptive statistics in the form of count and percentage of the subjects who experienced 
such an event will be calculated on the OC data by visit and for the overall treatment 
period.
There are 4 specific types of suicidal behavior and 5 specific types of suicidal ideation. 
The number and percentage of subjects who experienced any of those types of behavior 
or ideation will be tabulated on the OC data by visit and for the overall treatment period.
Wherever applicable, assessments on all individual questionnaires pertaining to suicidal 
behavior or ideation will be summarized by visit by using the descriptive statistics for 
categorical variables.
8.8
Concomitant Medications
Concomitant medications will be coded using the latest version of the World Health 
Organization (WHO) drug dictionary. The number and percentage of subjects taking 
concomitant medications prior to the open-label treatment period, during the open-label 
treatment period, and during the follow-up period will be respectively tabulated by drug 
classification, based on the Safety Sample.
8.9
Extent of Exposure
An individual subject’s Total Days of Exposure to IMP is calculated as: last dose 
date − first dose date + 1, regardless of any gaps in treatment (such as dose interruption 
or omission) during the 26-week open-label treatment period. The variable Total Days of 
Exposure will be summarized on the Safety Sample by using descriptive statistics for a 
continuous variable.
The number and percentage of subjects who received the IMP during the open-label 
treatment will be calculated by dosing week. The dosing week will be based on the actual 
week since the start of the open-label dosing (ie, Days 1 to 7 as Week 1, Days 8 to 14 as 
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Week 2, etc). An individual subject’s Average Daily Dosage will be derived for each 
dosing week by dividing the subject’s total doses taken during the week by the number of 
his/her exposure days in that week. Note that the number of exposure days in a dosing 
week is not always equal to 7. It can be less than 7 for the week in which early treatment 
discontinuation occurs. Note that the number of exposure days in a week will not be 
adjusted for any gaps in treatment during the week. The variable Average Daily Dosage 
will be summarized by dosing week by using descriptive statistics.
9
Efficacy Analysis
All efficacy analysis will be performed on the Efficacy Sample.
9.1
The Secondary Endpoints
The secondary endpoints for this trial pertain to a few efficacy variables constructed from 
the rating scales (see Section 11). Two key efficacy variables are the ABC-I subscale 
score and the CGI-S score. Each of these variables and the change from baseline in each 
of them will be summarized on the OC data by visit and additionally on the LOCF data 
for the last visit at Week 26, by using descriptive statistics for continuous variables.
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9.3
Interim Analysis
No interim analysis is planned.
9.4
Multiplicity Adjustment
Not applicable.
10
Conventions
10.1
Software for Statistical Analysis and Reporting
The Statistical Analysis System® (SAS®, version 9.3 or newer) will be used for all 
statistical analysis and reporting.
10.2
Study Day
The open-label IMP dosing will start on the very next day after the last assessment visit 
of the double-blind period of the parent trial (Trial 331-201-00148).
For this trial, study day is derived as follows: (1) study day = observation date − IMP 
dosing start date + 1, for observation date ≥ IMP dosing start date; (2) study 
day = observation date − IMP dosing start date, for observation date < IMP dosing start 
date. The open-label IMP dosing start date is referred to as Day 1.
10.3
Visit Window and the Derived Analysis Visit
The analysis visit variable will be needed for the by-visit analysis (including summary). 
For efficacy parameters and selected safety parameters (including all ABC subscales, 
CGI-S, 
 SAS, AIMS and BARS), the analysis visit will be derived per 
Table 10.3-1 below. Observations or assessments at the ET visit or any other unscheduled 
visit will be programmatically mapped to an analysis visit per Table 10.3-1 below. If an 
observation date is ≤ (the last dose date + 7), then the mapping algorithm in Table 10.3-1
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Table 10.3-1
Table 10.3-1
Table 10.3-1
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below applies; else if an observation date > (the last dose date + 7), then the observation 
will be excluded from data analysis.
For all other parameters, the protocol-specified scheduled visit per se (as recorded on the 
eCRF) will be taken as the analysis visit.
Table 10.3-1
Mapping of the Analysis Visit for the Open-label Treatment 
Period
Analysis Visit
Target Study Daya per Protocol
Study Daya Interval (end points inclusive)
Day 1
1
1 
Week 1
7 
2 to 10
Week 2
14 
11 to 17
Week 3
21 
18 to 24
Week 4
28 
25 to 42
Week 8
56 
43 to 77
Week 14
98
78 to 112
Week 18
126
113 to 140
Week 22
154
141 to 168
Week 26
182
169 to 196
a See Study Day definition in Section 10.2.
The preceding algorithm ensures that all observations collected at the ET visit or any 
other unscheduled visit will be mapped to an analysis visit. In the instances where 
multiple observations (of same parameter on the same subject) fall into one study day 
interval, all values of the multiple observations in the study interval will be included for 
listings, but only the last observation (in the study day interval) will be used for the by-
visit analysis.
10.4
Descriptive Statistics for Continuous and Categorical Variables
For continuous variables, descriptive statistics include N (which is number of subjects 
with non-missing value), mean, standard deviation, median, quartile, minimum and 
maximum. For categorical (eg, nominal or dichotomous) variables, descriptive statistics 
refer to frequency distribution (eg, count and percentage). Unless stated otherwise, 
ordinal variables such as assessment scores on all the scales used for this trial will be 
treated as continuous. Wherever possible, inferential statistics will be accompanied by 
descriptive statistics for presentation. Descriptive statistics can be used alone for data 
summary purpose, for example, for summarizing baseline demographic characteristics, 
medical history, etc. Unless specified otherwise, the denominator used for calculating 
percentage will be the number of unique subjects in the analysis sample (or its 
subgroups). And whenever applicable, a row of “Missing/Unknown” will be presented 
along with rows of recorded outcomes for the tabulation of the categorical variables.
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10.5
Display of Statistical Outputs 
Unless stated otherwise, data analysis and summary will be performed for the overall 
analysis sample (or the subgroups of interest) and separately for the two prior treatment 
groups. Thus, a statistical table output generated via SAS® programming will display the 
following three columns: (1) prior brexpiprazole; (2) prior placebo; and (3) all.
Wherever applicable statistical listings should be sorted by prior treatment group, subject 
ID, date of assessment, visit, etc. And in general, the listing should present the sorting 
variables, prior treatment, baseline demographics and all the variables of interest.
11
Scales: Rules for Scoring and Handling of Missing Data
11.1
ABC Subscales
The ABC scale has 58 items, which divide into 5 subscales as follows: (1) Irritability, 
Agitation; (2) Lethargy, Social Withdrawal; (3) Stereotypic Behavior; (4) Hyperactivity, 
Noncompliance; and (5) Inappropriate Speech. Each of the 58 ABC items is rated on a 
4-point scale (0 = not at all a problem; 1 = the behavior is a problem, but slight in degree; 
2 = the problem is moderately serious; 3 = the problem is severe in degree).
The Irritability subscale (ABC-I) subscale score is the sum of the ratings over 15 ABC 
items as follows. Item 2: injuries self on purpose; Item 4: verbally or physically 
aggressive to other children or adults; Item 8: scream inappropriately; Item 10: temper 
tantrums or outbursts; Item 14: irritable and whiny; Item 19: yells at inappropriate times; 
Item 25: depressed mood; Item 29: demands must be met immediately; Item 34: cries 
over minor annoyances and hurts; Item 36: mood changes quickly; Item 41: cries and 
screams inappropriately; Item 47: stamps feet or bangs objects or slam doors; Item 50: 
deliberately hurts himself/herself; Item 52: does physical violence to self; Item 57: has 
temper outbursts or tantrums when he/she does not get own way. Thus, ABC-I subscale 
score ranges from 0 to 45. For a visit, a subject’s ABC-I subscale score will be 
unevaluable and set to missing if less than 12 of the 15 items are recorded for the visit. If 
12, 13 or 14 of the 15 items are recorded, the ABC-I subscale score will be the mean of 
the recorded items multiplied by 15 and then rounded to the first decimal place. To state 
equivalently, if more than 20% of the component items have missing ratings (or say, not 
recorded), the ABC-I subscale score will be set to missing; otherwise, the total score will 
be the mean of the recorded items multiplied by 15.
The ABC subscale score on Social Withdrawal, Stereotypic Behavior, 
Hyperactivity/Noncompliance, and Inappropriate Speech is respectively the sum of 
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ratings over 16, 7, 16 and 4 individual ABC items. For each of these 4 subscales, if more 
than 20% of the component items have missing ratings (of note, at the subject-visit level), 
the subscale score will be set to missing; otherwise, the subscale score will be the mean 
of the recorded items multiplied by the total number of component items for the subscale.
11.2
Clinical Global Impressions - Severity (CGI-S)
The severity of illness for subjects with ASD will be rated using the CGI-S with a focus 
on symptoms of irritability. To perform this assessment, the rater or investigator will 
answer the following question: “Considering your total clinical experience with this 
particular population, how ill is the patient at this time with regard to symptoms of 
irritability?” Response choices include: 0 = not assessed; 1 = normal, not at all ill; 
2 = borderline; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 
7 = among the most extremely ill patients. The response choice 0 (= not assessed) will be 
set to missing. The CGI-S is thus a 7-point scale from 1 to 7, and the CGI-S score ranges 
from 1 to 7.
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11.5
Simpson Angus Scale (SAS)
The SAS will be used to evaluate extrapyramidal symptoms (EPS). It consists of a list of 
10 symptoms of Parkinsonism (gait, arm dropping, shoulder shaking, elbow rigidity, 
wrist rigidity, head rotation, glabella tap, tremor, salivation, and akathisia). Each item 
will be rated on a 5-point Likert scale, with 0 representing absence of symptoms and 4 
representing a severe condition. The SAS total score is the sum of ratings over all 
10 items, with possible total score ranging from 0 to 40. The SAS total score will be 
un-evaluable if less than 8 of the 10 items are recorded. If 8 or 9 of the 10 items are 
recorded, the total score will be the mean of the recorded items multiplied by 10 and then 
rounded to the first decimal place.
11.6
Abnormal Involuntary Movement Scale (AIMS)
The AIMS is a 12-item scale. The first 10 items are rated on a Likert 5-point scale from 
0 to 4 (0 = best, 4 = worst). An item score of 0, depending on specific item, means either 
“no abnormal Involuntary movement (AIM)” or “no incapacitation due to AIM” or “no 
awareness of AIM”. An item score of 4 means either “severe AIM” or “severe 
incapacitation due to AIM” or “being aware of, and severe distress caused by AIM”. 
Items 11 and 12 are related to dental status, taking dichotomous response: 0 = no and 
1 = yes. The AIMS total score is the sum of the ratings over the first 7 items, with 
possible total score ranging from 0 to 28. The AIMS total Score will be un-evaluable if 
less than 6 of the first 7 items are recorded. If 6 of the items are recorded, then the total 
score will be the mean of the recorded items multiplied by 7 and then rounded to the first 
decimal place.
11.7
Barnes Akathisia Rating Scale (BARS)
The BARS consists of 4 items related to akathisia as follows. Item 1: objective 
observation of akathisia by the investigator; Item 2: subjective feelings of restlessness by 
the subject; Item 3: subjective distress due to akathisia; and Item 4: global clinical 
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assessment of akathisia. The first 3 items will be rated on a 4-point Likert scale from 
0 to 3, with 0 representing absence of symptoms and 3 representing a severe condition. 
The BARS global clinical assessment score refers to the ratings from the fourth item 
Global Clinical Assessment of akathisia, which is a 6-point Likert scale from 0 to 5, with 
0 representing absence of symptoms and 5 representing severe akathisia. Thus, the BARS 
global clinical assessment score ranges 0 to 5.
11.8
Columbia-Suicide Severity Rating Scale (C-SSRS)
Suicidality will be monitored at all visits during the trial (excluding the 21-day follow-up 
period) using the C-SSRS (Child Version). The “Since Last Visit” of the scale will be 
completed for all subjects at all visits. For subjects in this trial, the pediatric version will 
be used and may be completed with caregiver assistance if required.
Suicidal ideation has 5 types of ideations with increasing severity from Type 1 to Type 5. 
A subject can report or can be rated with multiple types of ideations at the visit level. The 
most severe type of ideation on the subject at the visit level will be used for data 
summary purpose. The variable Intensity of Suicidal Ideation also has 4 other 
dimensions, which are the frequency of ideation, duration of ideation, controllability, and 
deterrents, each of which is rated on a scale of 0 to 5 or 1 to 5, with higher integers 
representing more worse clinical outcomes. 
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12
Proposed List of Summary Tables
CT-1.1.1   Subject Disposition (Enrolled Sample)
CT-1.1.2   Subject Disposition by Clinical Trial Center (Enrolled Sample)
CT-1.1.3.1   Subject Disposition by Gender (Enrolled Sample)
CT-1.1.3.2   Subject Disposition by Race (Enrolled Sample)
CT-1.1.3.3   Subject Disposition by Age Group (Enrolled Sample)
CT-1.1.3.4   Subject Disposition by Body Weight Group (Enrolled Sample)
CT-1.2   Subject Completion Rate by Week (Enrolled Sample)
CT-2.1.1   Reasons for Discontinuation (Enrolled Sample)
CT-2.1.2   Reasons for Discontinuation Due to COVID-19 (Enrolled Sample)
CT-2.1.3.1   Reasons for Discontinuation by Gender (Enrolled Sample)
CT-2.1.3.2   Reasons for Discontinuation by Race (Enrolled Sample)
CT-2.1.3.3   Reasons for Discontinuation by Age Group (Enrolled Sample)
CT-2.1.3.4   Reasons for Discontinuation by Body Weight Group (Enrolled Sample)
CT-3.1.1   Demographic Characteristics (Enrolled Sample)
CT-3.1.2.1   Demographic Characteristics by Gender (Enrolled Sample)
CT-3.1.2.2   Demographic Characteristics by Race (Enrolled Sample)
CT-3.1.2.3   Demographic Characteristics by Age Group (Enrolled Sample)
CT-3.1.2.4   Demographic Characteristics by Body Weight Group (Enrolled Sample)
CT-3.2   Medical History (Enrolled Sample)
CT-3.3   Psychiatric History (Enrolled Sample)
CT-3.4.1   Baseline Psychiatric Scale Evaluation (Enrolled Sample)
CT-3.4.2.1   Baseline Psychiatric Scale Evaluation by Gender (Enrolled Sample)
CT-3.4.2.2   Baseline Psychiatric Scale Evaluation by Race (Enrolled Sample)
CT-3.4.2.3   Baseline Psychiatric Scale Evaluation by Age Group (Enrolled Sample)
CT-3.4.2.4   Baseline Psychiatric Scale Evaluation by Body Weight Group (Enrolled 
Sample)
CT-4.1.1   Concomitant Medications: Medications Taken prior to the Start of the Open-
Label Treatment (Safety Sample)
CT-4.1.2   Concomitant Medications: Medications Taken during the Open-Label 
Treatment Period (Safety Sample)
CT-4.1.3   Concomitant Medications: Medications Taken Post Open-Label Treatment 
Period (Safety Sample)
CT-5.1   Summary of Change from Baseline in ABC-I Subscale Score during the Open-
Label Treatment Period by Visit (Efficacy Sample)
CT-5.2   Summary of Change from Baseline in Clinical Global Impression - Severity 
(CGI-S) Score during the Open-Label Treatment Period by Visit (Efficacy 
Sample)
CT-5.3   Summary of Proportion of Responders Defined as Subjects having had at least 
25% Reduction in ABC-Irritability Subscale Total Score and at Least 1 Point 
Reduction in CGI-S Score during the Open-Label Treatment Period (Efficacy 
Sample)
CT-5.4   Summary of Treatment Discontinuation Due to Lack of Efficacy (Efficacy 
Sample)
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CT-5.7.1   Summary of Change from Baseline in ABC- Social Withdrawal Subscale 
Score during the Open-Label Treatment Period by Visit (Efficacy Sample)
CT-5.7.2   Summary of Change from Baseline in ABC- Stereotypic Behavior Subscale 
Score during the Open-Label Treatment Period by Visit (Efficacy Sample)
CT-5.7.3   Summary of Change from Baseline in ABC- Hyperactivity/Noncompliance 
Subscale Score during the Open-Label Treatment Period by Visit (Efficacy 
Sample)
CT-5.7.4   Summary of Change from Baseline in ABC- Inappropriate Speech Subscale 
Score during the Open-Label Treatment Period by Visit (Efficacy Sample)
CT-6.1   Summary of Change from Baseline in Simpson-Angus Scale (SAS) Total Score 
during the Open-Label Treatment Period (Safety Sample)
CT-6.2   Summary of Change from Baseline in Abnormal Involuntary Movement Scale 
(AIMS) Total Score and Item Score on Item 8, 9 and 10 during the Open-Label 
Treatment Period (Safety Sample)
CT-6.3.1   Summary of Change from Baseline in Barnes Akathisia Rating Scale (BARS) 
Global Clinical Assessment Score during the Open-Label Treatment Period 
(Safety Sample)
CT-6.3.2   Incidence of Barnes Akathisia Rating Scale (BARS) Global Clinical 
Assessment of Akathisia during the Open-Label Treatment Period (Safety 
Sample)
CT-6.4.1   Summary of Mean Change from Baseline in Body Weight by Visit for the 
Open-label Treatment Period (Safety Sample)
CT-6.4.2.1   Summary of Mean Change from Baseline in Body Weight by Visit for the 
Open-label Treatment Period - in Male Subjects (Safety Sample)
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CT-6.4.2.2   Summary of Mean Change from Baseline in Body Weight by Visit for the 
Open-label Treatment Period - in Female Subjects (Safety Sample)
CT-6.4.3   Incidence of Potentially Clinically Relevant Weight Gain or Loss for the 
Open-label Treatment Period (Safety Sample) 
CT-6.4.4   Incidence of Potentially Clinically Relevant Weight Gain or Loss by Baseline 
BMI for the Open-Label Treatment Period (Safety Sample)
CT-6.4.5   Summary of Mean Change from Baseline in Age-and-Gender-Adjusted Body 
Weight Z-score by Visit for the Open-label Treatment Period (Safety Sample)
CT-6.4.6.1   Summary of Mean Change from Baseline in Age-and-Gender-Adjusted 
Body Weight Z-score by Visit for the Open-label Treatment Period - in Male 
Subjects (Safety Sample)
CT-6.4.6.2   Summary of Mean Change from Baseline in Age-and-Gender-Adjusted 
Body Weight Z-score by Visit for the Open-label Treatment Period - in Female 
Subjects (Safety Sample)
CT-6.4.7   Incidence of Change-from-Baseline Body Weight Z-score Exceeding 0.5 
during the Open-label Treatment Period (Safety Sample)
CT-6.5   Summary of Mean Change from Baseline in Waist Circumference by Visit for 
the Open-label Treatment Period (Safety Sample)
CT-6.6   Summary of Mean Change from Baseline in Age-and-Gender-Adjusted Height 
Z-score by Visit for the Open-label Treatment Period (Safety Sample)
CT-6.7.1   Summary of Mean Change from Baseline in Body Mass Index (BMI) by Visit 
for the Open-label Treatment Period (Safety Sample)
CT-6.7.2   Summary of Mean Change from Baseline in Age-and-Gender-Adjusted BMI 
Z-Score by Visit for the Open-label Treatment Period (Safety Sample)
CT-6.7.3   Number and Percentage of Subjects with Significant Change in BMI Z-score 
by Visit for the Open-label Treatment Period (Safety Sample)
CT-7.1   Extent of Exposure to Study Medication during the Open-Label Treatment 
Period (Safety Sample)
CT-8.1   Adverse Events (All Causalities) (Safety Sample)
CT-8.2.1   Incidence of TEAEs by System Organ Class (Safety Sample)
CT-8.2.2   Incidence of TEAEs by System Organ Class and MedDRA Preferred Term 
(Safety Sample)
CT-8.2.3   Incidence of TEAEs by System Organ Class, MedDRA Preferred Term and 
Severity (Safety Sample)
CT-8.2.4   Incidence of TEAEs by System Organ Class and MedDRA Preferred Term, by 
Sex (Safety Sample)
CT-8.2.5   Incidence of TEAEs by System Organ Class and MedDRA Preferred Term, by 
Race (Safety Sample)
CT-8.2.6   Incidence of TEAEs by System Organ Class and MedDRA Preferred Term, by 
Age Group (Safety Sample)
CT-8.2.7   Incidence of TEAEs by System Organ Class and MedDRA Preferred Term, by 
Body Weight Group (Safety Sample)
CT-8.2.8   Incidence of TEAE with Rate at Least 2% in Brexpiprazole Group by System 
Organ class and MedDRA Preferred Term (Safety Sample)
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CT-8.2.9   Incidence of Potentially Drug-Related TEAE with Rate at Least 2% in 
Brexpiprazole  by System Organ class and MedDRA Preferred Term (Safety Sample)
CT-8.2.10   Incidence of Potentially Serious TEAE with Rate at Least 2% in 
Brexpiprazole Group by System Organ class and MedDRA Preferred Term (Safety 
Sample)
CT-8.2.11   Incidence of TEAE Resulting in Discontinuation of Study Medication with 
Rate at Least 2% in Brexpiprazole Group by System Organ class and MedDRA 
Preferred Term (Safety Sample)
CT-8.2.12    Incidence of Deaths Due to TEAE with Rate at Least 2% in Brexpiprazole 
by System Organ class and MedDRA Preferred Term (Safety Sample)
CT-8.3.1   Incidence of Potentially Drug-Related TEAEs by System Organ Class and 
MedDRA Preferred Term (Safety Sample)
CT-8.3.2   Incidence of Potentially Drug-Related TEAEs by System Organ Class, 
MedDRA Preferred Term and Severity (Safety Sample)
CT-8.4   Incidence of Deaths Due to TEAEs by System Organ Class and MedDRA 
Preferred Term (Safety Sample)
CT-8.5.1   Incidence of Serious TEAEs by System Organ Class and MedDRA Preferred 
Term (Safety Sample)
CT-8.5.2   Incidence of Serious TEAEs by System Organ Class, MedDRA Preferred 
Term and Severity (Safety Sample)
CT-8.6.1   Incidence of TEAEs Resulting in Discontinuation from the Study Medication 
by System Organ Class and MedDRA Preferred Term (Safety Sample)
CT-8.6.2   Incidence of TEAEs Resulting in Discontinuation from the Study Medication 
by System Organ Class, MedDRA Preferred Term and Severity (Safety Sample)
CT-8.7   Incidence of TE EPS-related AEs by EPS Category and MedDRA Preferred 
Term (Safety Sample)
CT-8.8   Incidence of Onset of Akathisia Adverse Event by Visit (Safety Sample)
CT-8.9.1   Listing of TEAEs that Are Related or Probably Related to COVID-19 (Safety 
Sample)
CT-8.9.2   Listing of Serious TEAEs or Deaths that Are Related or Probably Related to 
COVID-19 (Safety Sample)
CT-9.1   Listing of Deaths (Safety Sample)
CT-9.2   Listing of Serious Adverse Events (Safety Sample)
CT-9.3   Listing of Discontinuations from Study Medication Due to Adverse Events 
(Safety Sample)
CT-10.1   Criteria for Laboratory Test Values with Potentially Clinical Relevance
CT-10.2.1   Listing of Laboratory Test Values with Potentially Clinical Relevance by 
Subject (Safety Sample)
CT-10.2.2   Listing of Laboratory Test Values with Potentially Clinical Relevance by 
Test (Safety Sample)
CT-10.2.3   Incidence of Laboratory Test Values with Potentially Clinical Relevance 
(Safety Sample)
CT-10.3.1   Summary of Change from Baseline in Clinical Laboratory Test Results - 
Serum Chemistry (Safety Sample)
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CT-10.3.2   Summary of Change from Baseline in Clinical Laboratory Test Results - 
Hematology (Safety Sample)
CT-10.3.3   Summary of Change from Baseline in Clinical Laboratory Test Results - 
Urinalysis (Safety Sample)
CT-10.3.4   Summary of Change from in Clinical Laboratory Test Results - Prolactin, by 
Sex (Safety Sample)
CT-10.3.5   Summary of Change from in Clinical Laboratory Test Results - Other Tests 
(Safety Sample)
CT-10.4.1   Shift Tables of Clinical Laboratory Test Results - Serum Chemistry (Safety 
Sample)
CT-10.4.2   Shift Tables of Clinical Laboratory Test Results - Hematology (Safety 
Sample)
CT-10.4.3   Shift Tables of Clinical Laboratory Test Results - Urinalysis (Safety Sample)
CT-10.4.4   Shift Tables of Clinical Laboratory Test Results - Prolactin (Safety Sample)
CT-10.5.1   Incidence of Potential Serious Hepatotoxicity (Safety Sample)
CT-10.5.2   Listing of Potential Serious Hepatotoxicity (Safety Sample)
CT-10.6.1   Incidence of Laboratory Test Values with Potential Clinical Relevance - 
Serum Prolactin (Safety Sample)
CT-10.6.2   Listing of Laboratory Test Values with Potential Clinical Relevance - Serum 
Prolactin (Safety Sample)
CT-11.1   Criteria for Potentially Clinically Relevant Abnormalities in Vital Signs
CT-11.2.1   Listing of Potentially Clinically Relevant Abnormalities in Vital Signs 
(Safety Sample)
CT-11.2.2   Incidence of Potentially Clinically Relevant Abnormalities in Vital Signs 
(Safety Sample)
CT-11.2.3   Summary of Change from Baseline in Vital Signs by Visit (Safety Sample)
CT-12.1.1   Criteria for Potentially Clinically Relevant Abnormalities in ECG 
Evaluations
CT-12.1.2   ECG Diagnosis Mapping for Potentially Clinically Relevant 
Electrocardiogram Abnormalities (Safety Sample)
CT-12.2.1   Listing of Potentially Clinically Relevant Abnormalities in ECG Evaluations 
(Safety Sample)
CT-12.2.2   Incidence of Potentially Clinically Relevant Changes in ECG Evaluations 
(Safety Sample)
CT-12.2.3   Summary of Change from Baseline in Electrocardiogram Results by Visit 
(Safety Sample)
CT-12.3.1   Listing of Categorical Changes in QT/QTc (Safety Sample)
CT-12.3.2   Incidence of Categorical Changes in QT/QTc (Safety Sample)
CT-13.1.1   Columbia-Suicide Severity Rating Scale(C-SSRS), Suicidality (Safety 
Sample)
CT-13.1.2   Columbia-Suicide Severity Rating Scale(C-SSRS), Suicidal Ideation by Type 
(Safety Sample)
CT-13.1.3   Columbia-Suicide Severity Rating Scale(C-SSRS), Suicidal Behavior by 
Type (Safety Sample)
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CT-13.1.4   Columbia-Suicide Severity Rating Scale(C-SSRS), Treatment Emergent 
Suicidal Ideation and Behavior (Safety Sample) 
CT-13.1.5   Columbia-Suicide Severity Rating Scale (C-SSRS) - Listing of Treatment 
Emergent Suicidal Ideation (Safety Sample)
CT-13.1.6   Columbia-Suicide Severity Rating Scale (C-SSRS) - Listing of Treatment 
Emergent Suicidal Behavior (Safety Sample)
CT-13.1.7   Columbia-Suicide Severity Rating Scale (C-SSRS) - Listing of Treatment 
Emergent Serious Suicidal Ideation (Safety Sample)
CT-13.1.8   Columbia-Suicide Severity Rating Scale (C-SSRS) - Listing of Worsening 
Suicidal Ideation (Safety Sample)
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13
References
1
Otsuka Pharmaceutical Development & Commercialization, Inc. A phase 3, 
multicenter, randomized, double-blind, placebo-controlled trial of brexpiprazole in 
treatment of children and adolescents with irritability associated with autism spectrum 
disorder. Protocol 331-201-00148, issued 26 Apr 2019, amended 14 Aug 2019, 22 
Nov 2019, 12 Feb 2020, 06 Jul 2020, and 07 Jul 2022.
2
Otsuka Pharmaceutical Development & Commercialization, Inc. A phase 3, 
multicenter, open-label trial to evaluate the long-term safety and tolerability of 
brexpiprazole (OPC-34712) in the treatment of children and adolescents with 
irritability associated with autism spectrum disorder. Protocol 331-201-00191, issued 
02 May 2019, amended 09 Sep 2019, 06 Nov 2019, 12 Feb 2020, 06 Jul 2020, and 07 
Jul 2022.
3
Centers for Disease Control and Prevention. Division of Nutrition, Physical Activity, 
and Obesity. SAS Program for the 2022 CDC Growth Charts that Includes the 
Extended BMI calculation. Available from: 
https://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm. Updated Dec 
15, 2022. Accessed Dec 19 2022 
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Appendix 1
Criteria for Identifying Vital Signs Outside of Normal Values 
and of Potential Clinical Relevance
Variable
Criterion Value
Change Relative to Baseline
Heart Rate at Rest
< 60 bpm or > 110 bpm
Increase or decrease of ≥ 15 bpm
Systolic Blood Pressure
     Preschooler (5 y)
< 80 mmHg or > 115 mmHg
Increase or decrease of ≥ 20 mmHg
     School-age (6-9 y)
< 85 mmHg or > 115 mmHg
Increase or decrease of ≥ 20 mmHg
     Preadolescent (10-12 y)
< 90 mmHg or > 120 mmHg
Increase or decrease of ≥ 15 mmHg
     Adolescent (13-17 y)
< 90 mmHg or > 120 mmHg
Increase or decrease of ≥ 15 mmHg
Diastolic Blood Pressure
     Preschooler (5 y)
< 45 mmHg or > 80 mmHg
Increase or decrease of ≥ 15 mmHg
     School-age (6-9 y)
< 50 mmHg or > 80 mmHg
Increase or decrease of ≥ 15 mmHg
     Preadolescent (10-12 y)
< 60 mmHg or > 80 mmHg
Increase or decrease of ≥ 15 mmHg
     Adolescent ≥ 13 y
< 60 mmHg or > 85 mmHg
Increase or decrease of ≥ 15 mmHg
The criterion value and change relative to baseline represented in this table are intended to identify on-
treatment values outside of normal changes and that could potentially be clinically relevant. In order 
to be identified as potentially clinically relevant, the 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. When evaluating these values, the emotional state of 
the subject must be taken into consideration (eg, crying, screaming) and documented as applicable.
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Appendix 2
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance
Laboratory Tests
Criteria (Normal Ranges) for Subjects 5 to 17 Years of Age
Chemistry
AST
≥ 2 × ULN
ALT
≥ 2 × ULN
ALP
≥ 2 × ULN
Bicarbonate
  
        < 6 y
< 17.0 or > 26.0 mEq/L (17.0-26.0 mEq/L)
        6 y to 12 y
< 19.0 or > 27.0 mEq/L (19.0-27.0 mEq/L)
        ≥ 12 y
< 19.3 or > 29.3 mEq/L (19.3-29.3 mEq/L)
BUN
≥ 24 mg/dL (≤ 4 mg/dL or ≥ 24 mg/dL)
Creatinine
         ≤ 12 y
≥ 0.7 mg/dL (≤ 0.2 mg/dL or ≥ 0.7 mg/dL)
         ≥ 13 y
≥ 1.1 mg/dL (≤ 0.3 mg/dL or ≥ 1.1 mg/dL)
Uric Acid
         ≤ 12 y
≥ 6.7 mg/dL (≤ 1.6 mg/dL or ≥ 6.7 mg/dL)
         ≥ 13 y
≥ 8.2 mg/dL (≤ 2.2 mg/dL or ≥ 8.2 mg/dL)
Bilirubin (total)
≥ 1.6 mg/dL (≤ 0.2 mg/dL or ≥ 1.6 mg/dL)
CPK
≥ 2 × ULN
Prolactin
         ≤ 12 y
≥ 21.00 ng/dL (≤ 2.63 ng/dL or ≥ 21.00 ng/dL)
         ≥ 13 y
≥ 39.00 ng/dL (≤ 2.52 ng/dL or ≥ 39.00 ng/dL)
Hematology
Hematocrit
         ≤ 12 y
≤ 33% (≤ 33% or ≥ 44%)
         ≥ 13 y
≤ 34% (≤ 34% or ≥ 54%)
Hemoglobin
         ≤ 12 y
≤ 11.2 g/dL (≤ 11.2 g/dL or ≥ 15.5 g/dL)
         ≥ 13 y
≤ 11.6 g/dL (≤ 11.6 g/dL or ≥ 18.1 g/dL)
White blood count
≤ 4.35 × 103/uL (≤ 4.35 × 103/uL or ≥ 13.65 × 103/uL) 
Eosinophils
         ≤ 12 y
≥ 4.8%
         ≥ 13 y
≥ 4.1%
Neutrophils
≤ 40.5% (≤ 40.5% or ≥ 75.0%)
Absolute neutrophil count
         ≤ 12 y
≤ 1.00 × 103/uL or ≥ 9.00 × 103/uL
         ≥ 13 y
≤ 1.35 × 103/uL or ≥ 8.15 × 103/uL
Platelet count
         ≤ 12 y
≤ 130 × 103/uL (≤ 130 × 103/uL or ≥ 570 × 103/uL)
         ≥ 13 y
≤ 140 × 103/uL (≤ 140 × 103/uL or ≥ 400 × 103/uL)
Urinalysis
Protein
Change from baseline
Glucose
Presence
Additional Criteria
Chloride
≤ 94 mEq/L or ≥ 112 mEq/L
HbA1c
≥ 5.7%
ACTH
< 7.2 pg/mL - > 63.3 pg/mL
Cortisol
AM: 6.7 ug/dL - 22.60 ug/dL
PM: < 10 ug/dL
Potassium
≤ 3.3 mEq/L or ≥ 5.2 mEq/L
Sodium
≤ 132 mEq/L or ≥ 148 mEq/L
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Laboratory Tests
Criteria (Normal Ranges) for Subjects 5 to 17 Years of Age
Calcium
≤ 8.3 mg/dL or ≥ 10.9 mg/dL
Glucose
         Fasting
≥ 100 mg/dL (≥ 70 mg/dL and ≤ 100 mg/dL)
         Non-Fasting
≥ 139 mg/dL (≥ 70 mg/dL and ≤ 139 mg/dL)
Total Cholesterol, Fasting
         ≤ 12 y
≥ 217 mg/dL (≤ 97 mg/dL or ≥ 217 mg/dL)
         ≥ 13 y
≥ 217 mg/dL (≤ 124 mg/dL or ≥ 217 mg/dL)
LDL Cholesterol, Fasting
≥ 130 mg/dL
HDL Cholesterol, Fasting
         ≤ 12 y
≤ 34 mg/dL (≤ 34 mg/dL or ≥ 75 mg/dL)
         ≥ 13 y
≤ 30 mg/dL (≤ 30 mg/dL or ≥ 74 mg/dL)
Triglycerides, Fasting
         ≤ 12 y
≥ 131 mg/dL (≤ 30 mg/dL or ≥ 131 mg/dL)
         ≥ 13 y
≥ 148 mg/dL (≤ 32 mg/dL or ≥ 148 mg/dL)
TSH
         ≤ 12 y
≤ 0.34 mIU/mL or ≥ 5.40 mIU/mL
         ≥ 13 y
≤ 0.34 mIU/mL or ≥ 5.60 mIU/mL
Free T4
         ≤ 12 y
≤ 9 pmol/L or ≥ 30 pmol/L
         ≥ 13 y
≤ 10 pmol/L or ≥ 24 pmol/L
PT
≥ 12.3 sec (≤ 9.7 sec or ≥ 12.3 sec)
aPTT
≥ 29.4 sec (≤ 21.9 sec or ≥ 29.4 sec)
INR
         Not taking anticoagulants
         Taking anticoagulants
≥ 1.2 (≤ 0.8 or ≥ 1.2)
≥ 3.0 (≤ 2.0 or ≥ 3.0)
The recommended criteria represented in this table are intended to identify on-treatment outside of 
normal values that could potentially be clinically relevant. Variations based on local laboratory ranges 
may need to be considered.
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Appendix 3
Criteria for Identifying ECG Measurement of Potential 
Clinical Relevance
Variable
Criterion Valuea
Change Relative to Baselinea
Rhythm
Sinus tachycardiab
≥ 110 bpm
increase of ≥ 15 bpm
Sinus bradycardiac
≤ 60 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 for 
males, ≥ 470 msec for 
females
increase of 60 msec from 
baseline
aThe criterion value and change relative to baseline represented in this table are intended to identify on-
treatment values outside of normal changes and that could potentially be clinically relevant. In order 
to be identified as potentially clinically relevant, the 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. When evaluating these values, the emotional state of 
the subject must be taken into consideration (eg, crying, screaming) and documented as applicable.
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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43


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