Conditions: Irritability Associated With Autism Spectrum Disorder (ASD)
Keywords: Autism Irritability Autism Spectrum Disorder ASD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 119
Healthy volunteers: no

Brief summary:
The purpose of this study is to find out about the potential benefits and safety 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 flexible doses of brexpiprazole 0.25 to 3 milligram per day (mg/day), orally, once daily (QD) up to Week 8. For participants with body weight \< 50 kilograms (kg) the dose was titrated up from 0.25 mg/day on Days 1 to 3, followed by 0.5 mg on Days 4 to 7, and to 1 mg on Days 8 to 14. Based on the investigator's judgment the dose was increased to 1.5 mg/day after Day 15. The dose was fixed after Week 6 and administration continued for another 2 weeks until Week 8.

For participants with body weight ≥ 50 kg the dose was titrated up from 0.5 mg/day on Days 1 to 3, followed by 1.5 mg on Days 4 to 7, and to 2 mg on Days 8 to 14. Based on the investigator's judgment the dose was increased to 3 mg/day after Day 15. The dose was fixed after Week 6 and administration continued for another 2 weeks until Week 8. arm 2: Participants received brexpiprazole matching placebo orally, QD, in the same way as brexpiprazole up to Week 8.

Interventions: intervention 1: Brexpiprazole intervention 2: Placebo
Intervention descriptions: intervention 1: Oral tablet; take once daily intervention 2: Administered orally daily for up to Week 8.

Protocol document:
Prot_002.pdf: 
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Table of Contents.............................................................................................................
1
Study 331-201-00148 Protocol Amendment 5; 07 July 2022..........................................
2
112
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CCI


Otsuka Pharmaceutical 
Development & Commercialization, Inc.
Investigational Medicinal Product
Brexpiprazole (OPC-34712)
REVISED CLINICAL PROTOCOL
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 No. 331-201-00148
IND No. 141257
EudraCT No. 2019-000723-40
CONFIDENTIAL – PROPRIETARY INFORMATION
Clinical Development Phase: 3
Sponsor:
Otsuka Pharmaceutical Development &
Commercialization, Inc.
2440 Research Boulevard
Rockville, Maryland 20850, United States 
Immediately Reportable Event 
Issue Date:
26 Apr 2019
Date of Amendment 1:
14 Aug 2019
Date of Amendment 2
22 Nov 2019
Date of Amendment 3:
12 Feb 2020
Date of Amendment 4:
06 Jul 2020
Date of Amendment 5: 
07 Jul 2022
Version No.:
6.0
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Protocol 331-201-00148
Confidential - Proprietary Information
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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 trial 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 331-201-00148
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 331-201-00148
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Protocol Synopsis 
Name of Sponsor: Otsuka Pharmaceutical 
Development & Commercialization, Inc.
Name of Investigational Medicinal Product: 
Brexpiprazole (OPC-34712)
Protocol No.: 331-201-00148
IND No.: 141257
EudraCT No.: 2019-000723-
40
Protocol Title:
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
Clinical Phase/Trial 
Type:
3/Therapeutic Use
Treatment Indication: Irritability Associated with Autism spectrum disorder (ASD)
Objective(s): 
Primary: To evaluate the efficacy, safety, and tolerability of 
brexpiprazole in reducing irritability in children and 
adolescents ages 5 to 17 years with a diagnosis of ASD.
Trial Design:
This is a phase 3, multicenter, randomized, double-blind, 
placebo-controlled, 8-week trial designed to evaluate the 
effects of flexibly-dosed brexpiprazole (0.25 - 3 mg/day, 
weight based) compared with placebo on irritability in children 
and adolescent subjects, ages 5 to 17 years, with a diagnosis of 
ASD. The trial will consist of a 1 to 28 day screening period, 
followed by an 8-week double-blind treatment period, and a 
21-day post-treatment safety follow-up period. 
Subjects who continue to meet entrance criteria at the baseline 
visit (Day 1) will be randomized 1:1 to receive brexpiprazole, 
or placebo daily. 
On Day 1 of the treatment period, subjects will begin titration 
to a target minimum dose of investigational medicinal product 
(IMP). 
The target dose range of IMP will be determined for each 
individual subject based on body weight. 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. Body weight at the 
time of randomization will determine dose/titration 
requirements throughout the trial. 
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, 
Clinical Study Report 331-201-00148
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and 1 mg for Days 8 to 14. Day 15 is the earliest opportunity 
that the investigator has to 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 must be on their final dose at 
Week 6. Subjects that require a change in dose between 
Week 6 and Week 8 will be discontinued.
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 has to 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. Subjects must be on their final dose at Week 6. Subjects 
that require a change in dose between Week 6 and Week 8 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.
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 a dose of 3 mg before 
decreasing to 2 mg.
Dosing Schedule During the Treatment Period
Trial Day
No. Days on 
IMP
Brexpiprazole Dose
Placebo
< 50 kg
≥ 50 kg
Days 1 to 3
3
0.25 mg QD
0.50 mg QD
placebo 
tablets QD
Days 4 to 7
4
0.50 mg QD
1.5 mg QD
placebo 
tablets QD
Days 8 to 14
7
1 mg QD
2 mg QD
placebo 
tablets QD
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 mg, or 
1.5 mg QD
1.5 mg, 
2 mg, or 
3 mg QD
placebo 
tablets QD
Clinical Study Report 331-201-00148
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If a subject < 50 kg is unable to tolerate the 1 mg dose, the 
subject will be discontinued. If a subject > 50 kg is unable to 
tolerate the 1.5 mg dose, the subject will be discontinued.
During the double-blind treatment phase, evaluations are 
planned on Day 1 (baseline) and at Weeks 1, 2, 3, 4, 6, and 8. 
Visits at baseline, Week 2, and Week 8 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. 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.
Eligible subjects who complete the 8-week double-blind phase 
may have the option to enroll into an open-label safety trial of 
brexpiprazole. Subjects who do not enroll in the open-label 
safety trial (Trial 331-201-00191) will have a follow-up 
contact 21 ± 2 days after the last dose of IMP 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 male and female subjects 
between 5 and 17 years of age, inclusive, at the time of 
informed consent/assent with a Diagnostic and Statistical 
Manual of Mental Disorders, 5th edition (DSM-5) diagnosis of 
ASD. Subjects will have irritability associated with ASD as 
defined by a score of ≥ 18 on the Aberrant Behavior checklist - 
Irritability (ABC-I) subscale and score ≥ 4 on the Clinical 
Global Impressions - Severity (CGI-S) scale for irritability. 
Clinical Study Report 331-201-00148
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Inclusion/Exclusion 
Criteria: 
Subjects must meet the inclusion criteria at both baseline and 
screening. 
Key inclusion criteria include the following:
•
Male and female subjects 5 to 17 years of age, with a 
current primary DSM-5 diagnosis of ASD, as determined 
by the investigator and supported by the Autism Diagnostic 
Interview - Revised (ADI-R).
•
Subjects with an ABC-I subscale score ≥ 18 and with a 
CGI-S scale score ≥ 4 pertaining to irritability at screening 
and at baseline (Day 1). 
•
Subjects must have a mental age of ≥ 2 years, as 
determined by the investigator based on school 
participation, social history, or medical records.
Key exclusion criteria include the following:
•
Subjects with a current primary DSM-5 diagnosis of 
bipolar disorder, including any DSM-5 current diagnosis of 
bipolar II disorder, schizophrenia, schizoaffective disorder, 
major depressive episode as determined by clinical 
instrument (Kiddie-Schedule for Affective Disorders and 
Schizophrenia - Present and Lifetime version [K-SADS-
PL]), or post-traumatic stress disorder (PTSD). Subjects 
with comorbid attention deficit/hyperactivity disorder 
(ADHD) are permitted to enroll in the trial, provided that 
ADHD is not the primary disorder, the subject is 
adequately treated, and based on the investigator judgment 
the disorder is clinically stable.
Trial Site(s): 
The trial is expected to enroll subjects at approximately 
30 sites in the United States.
Clinical Study Report 331-201-00148
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Secondary Endpoint(s): 
Efficacy: The key secondary endpoint of this trial will be the 
mean change from baseline to Week 8 in CGI-S score.
Safety: Safety will be assessed by the following standard 
endpoints for clinical trials and trials of antipsychotic drugs:
•
Frequency and severity of AEs, serious AEs (clinical and 
laboratory), and discontinuation from the trial due to AEs
•
Weight, height, body mass index (BMI), and waist 
circumference
•
Clinical laboratory tests (chemistry, hematology, and 
urinalysis) 
•
Vital signs and ECG parameters
•
EPS scale scores: AIMS, BARS, and SAS
•
Potential suicide events recorded on suicidality scale 
scores
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Statistical Methods:
A sample size of 51 subjects per arm will provide at least 85% 
power at a nominal 2-sided alpha level of 0.05 to detect a 
6.0-point reduction in change from baseline in ABC-I subscale 
score for brexpiprazole versus placebo, assuming a standard 
deviation (SD) = 10.
The primary efficacy endpoint is the change from baseline to 
Week 8 in the ABC-I subscale score. The primary statistical 
comparison of interest is the difference between brexpiprazole 
and placebo at Week 8, analyzed using a mixed-model 
repeated measures analysis with an unstructured 
variance-covariance matrix for within-subject variation. The 
model will include fixed-class effect terms of treatment, trial 
center, visit week, and an interaction term of treatment-by-visit 
week, and includes the interaction term of baseline values of 
ABC-I subscale score by visit week as a covariate. The 
primary comparison between brexpiprazole and the placebo 
arm at Week 8 will be estimated as the difference between 
least squares means. 
To ensure that trial is adequately powered, the estimate of the 
trial variability will be obtained in a blinded fashion upon 
approximately 75% of the subjects having completed or 
discontinued from the trial. The variability will be estimated 
based on a blinded and pooled analysis of all treatment arms 
and sample size could be further increased. For full details 
please refer to the Statistical Analysis Plan.
Trial Duration:
The duration of this trial from first subject enrolled to last 
subject completed is estimated to be approximately 28 months, 
of which 24 months are allotted for recruitment of subjects. 
Individual participation for subjects who complete the trial 
without early withdrawal will range from 11 to 15 weeks, 
consisting of a 1 to 28-day screening period, 8-week double-
blind treatment, and a 21 (± 2 day) safety follow-up period. 
Clinical Study Report 331-201-00148
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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
AAD
Agitation associated with dementia of the Alzheimer’s type
ABC-I
Aberrant Behavior checklist – Irritability
ACTH
Adrenocorticotropic hormone
ADHD
Attention-deficit/hyperactivity disorder
ADI-R
Autism Diagnostic Interview – Revised
ADOS
Autism Diagnostic Observation Schedule
AE
Adverse event
AIMS
Abnormal Involuntary Movement Scale
ALT
Alanine aminotransferase
APO
Apomorphine
aPTT
Activated partial thromboplastin time
ARH1
Heterogeneous autoregressive of order 1
ASD
Autism Spectrum Disorder
AST
Aspartate aminotransferase
AUC0-24h
Area under the plasma concentration-time curve from time 0 hours to 
time 24 hours
AUCtau
Area under the concentration curve at steady state during a 24-hour 
dosing interval
BARS
Barnes Akathisia Rating Scale
BMI
Body mass index
BUN
Blood urea nitrogen
CGI-S
Clinical Global Impressions - Severity
CL/F
Apparent clearance of drug from plasma after extravascular 
administration
CNS
Central nervous system
CPK
Creatine phosphokinase
CRO
Clinical Research Organization
CSH
Heterogeneous compound symmetry
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
Cytochrome P450
D2
Dopamine D2
D2L
Dopamine D2L
DBP
Diastolic blood pressure
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
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
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FOCBP
Female of childbearing potential
GABA
Gamma-aminobutyric acid
GCP
Good Clinical Practice
GGT
Gamma glutamyl transferase
GMR
Geometric means ratio
HbA1c
Glycosylated hemoglobin
HDL
High density lipoprotein
IAF
Informed assent form
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
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
IR
Immediate-release
IRB
Institutional review board
IRE
Immediately reportable event
IRT
Interactive research technology
K-SADS-PL
Kiddie-Schedule for Affective Disorders and Schizophrenia - Present 
and Lifetime version
LDH
Lactic dehydrogenase
LDL
Low density lipoprotein
MAR
Missing at random
MCH
Mean corpuscular hemoglobin
MDD
Major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple imputation
MMRM
Mixed model repeated measures
MNAR
Missing not at random
MTD
Maximum tolerated dose
OC
Observed cases
OPC
Otsuka Pharmaceutical Co.
OTC
Over the counter
QD
Once daily
QTcF
QT interval as corrected for heart rate by Fridericia’s formula
PD
Pharmacodynamic
PE
Physical examination
PGx
Pharmacogenomic
PK
Pharmacokinetic
PQC
Product quality complaint
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PT
Prothrombin time
PTSD
Post-traumatic stress disorder
PWR
Pediatric Written Request
RBC
Red blood cell
RDW
Red cell distribution width
SAE
Serious adverse event
SAS
Simpson Angus Scale
SD
Standard deviation
TEAE
Treatment-emergent adverse event
TOEPH
Heterogeneous toeplitz
tmax
Time to maximum (peak) plasma concentration
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
UN
Unstructured
US or USA
United States or United States of America
WBC
White blood cell
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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 mean terminal phase elimination 
half-life of brexpiprazole and DM-3411 was 79.3 hours and 73.6 hours, respectively. The 
median time to maximum (peak) plasma concentration (tmax) occurred at approximately 4 
hours post dose for brexpiprazole and at approximately 12 hours post dose 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 
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 91.4 and 85.7 hours, respectively; median tmax 
was 3.0 and 5.0 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 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 
Clinical Study Report 331-201-00148
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exposure and lower brexpiprazole CL/F as compared with children in the older group 
(10 to < 13 years old).
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) by the US Food and Drug Administration (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.
In Trial 331-10-233, overall systemic exposure was measured by dose-normalized 
maximum concentration at steady state and area under the plasma concentration-time 
curve to the last observable concentration, 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 AUC0-24h (GMR adult/adolescent: 1.05), and slightly higher dose-normalized 
Cmax (GMR adult/adolescent: 0.904) were observed in adolescents when compared to 
adults. The difference in the results for the two 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.
1.2.3
Major Depressive Disorder
The efficacy of brexpiprazole as adjunctive therapy for the treatment of MDD has been 
studied in 4 completed placebo-controlled trials (Trials 331-10-227, 331-10-228, 
331-13-214, and 331-12-282) 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
Other Indications
Brexpiprazole was investigated in a proof-of-concept trial in adult ADHD 
(Trial 331-08-213). This was a multicenter, randomized, double-blind, placebo-
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controlled, flexible dose trial in which adults with ADHD who had an incomplete/partial 
response to stimulant therapy in a prospective treatment phase were randomized to 
double-blind treatment with either brexpiprazole-plus-stimulant or placebo-plus-
stimulant. This trial showed no statistically significant improvement with brexpiprazole 
compared to placebo. Brexpiprazole is also currently being investigated in 2 ongoing 
double-blind trials (Trials 331-201-00080 and 331-201-00081) and 1 ongoing open-label 
trial (Trial 331-201-00083) in adult subjects with bipolar disorder.
1.3
Known and Potential Risks and Benefits
As of 17 Apr 2021 (ie, the current IB cutoff date), 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.
There are currently 2 ongoing phase 3 clinical trials in adolescent subjects with 
schizophrenia as of the cutoff date (Trials 331-10-234 and 331-10-236). Trial 331-10-234 
will evaluate the efficacy and safety of brexpiprazole monotherapy over a 6-week 
controlled treatment period in adolescents with schizophrenia, while Trial 331-10-236 is 
an open-label trial to evaluate the long-term (24 months) safety and tolerability of 
brexpiprazole.
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 
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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. 
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 
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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 or assent 
form 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 and 
assent form. 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. 
Subjects who are not started on treatment after the ICF/IAF is signed are permitted to be 
rescreened under the conditions specified in Section 3.9 (Screen Failures). In the event 
that the subject is rescreened for trial participation, a new ICF/IAF must be signed and a 
new ID number obtained.
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Table 3.4.3-1
Exclusion Criteria
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 with a current primary DSM-5 diagnosis of bipolar I disorder, including any DSM-5 
current diagnosis of bipolar II disorder, schizophrenia, schizoaffective disorder, major depressive 
episode as determined by clinical instrument (K-SADS-PL), or PTSD. Subjects with comorbid 
ADHD are permitted to enroll in the trial, provided that ADHD is not the primary disorder, the 
subject is adequately treated and based on the investigator judgment the disorder is clinically 
stable.
4.
The subject has a current or historical diagnosis of Fragile-X Syndrome or Rett’s Disorder.
5.
The subject has a history of neuroleptic malignant syndrome.
6.
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.
7.
Subjects who have epilepsy, a history of seizures (except for a single childhood febrile seizure or 
post-traumatic seizure), or a history of severe head trauma or stroke, or have a history or current 
evidence of other unstable medical conditions that would expose them to undue risk of a 
significant adverse event or interfere with assessments of safety or efficacy during the course of 
the trial, including but not limited to hepatic, renal, respiratory, cardiovascular, endocrine, 
neurologic, hematologic, or immunologic disease as determined by the clinical judgment of the 
investigator (eg, history of myocardial infarction or ischemic heart disease, arrhythmia, 
congestive heart failure, or cancer); subjects with a comorbid serious systemic illness that 
requires pharmacotherapy; subjects with a history of electroconvulsive therapy.
8.
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.
9.
Subjects with current hypothyroidism or hyperthyroidism (unless the condition has been 
stabilized with medications for at least the past 90 days). Eligibility of subjects that have an 
abnormal free T4 result that is considered not clinically significant can be discussed with the 
medical monitor prior to randomization.
10.
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 3.4.3-1
Exclusion Criteria
11.
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.
12.
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.
13.
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
14.
The subject weighs < 15 kg.
15.
Subjects who would be likely to require prohibited concomitant therapy during the trial.
16.
Subjects who have been exposed to brexpiprazole (eg, prior clinical trial or prescription).
17.
Subjects with a history of true allergic response (ie, not intolerance) to more than one class of 
medications.
18.
Inability to tolerate oral medication or swallow tablets.
19.
Subjects who participated in any clinical trial within the last 30 days prior to screening.
20.
Any subject who, in the opinion of the investigator, should not participate in the trial.
21.
Subjects who are siblings, or are unrelated and live in the same household, cannot simultaneously 
participate in the trial.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
C-SSRS = Columbia-Suicide Severity Rating Scale; CYP = cytochrome P450; DBP = diastolic blood 
pressure; ECG = Electrocardiogram; FOCBP = females of childbearing potential; 
HbA1c = glycosylated hemoglobin; IM = intramuscular; K-SADS-PL = Kiddie Schedule for 
Affective Disorders and Schizophrenia - Present and Lifetime version; PTSD = post-traumatic stress 
disorder; QTcF = QT interval as corrected for heart rate by Fridericia’s formula; SBP = systolic blood 
pressure; T4 = thyroxine; WBC = white blood cell.
Subjects must agree to restrictions to medications as described in Section 4.
Subjects excluded for positive drug/alcohol screen are not eligible to be rescreened for 
participation in the trial. However, subjects excluded for any other reasons may be 
rescreened at any time if the exclusion characteristic has changed. In the event that the 
subject is rescreened, a new ICF/IAF must be signed and a new ID number assigned.
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3.5
Endpoints
3.5.1
Primary Endpoint
3.5.1.1
Efficacy Endpoint
The primary efficacy endpoint of this trial will be the mean change from baseline to 
Week 8 in the ABC-I subscale score.
The estimand of the primary efficacy endpoint is described in Section 7.4.1. 
3.5.2
Secondary Endpoints
3.5.2.1
Efficacy Endpoint
The key secondary endpoint of this trial will be the mean change from baseline to Week 8 
in CGI-S score for irritability.
3.5.3
Safety Endpoints
Safety will be assessed by the following standard endpoints for clinical trials and trials of 
antipsychotic drugs:
•
Frequency and severity of AEs, serious AEs (clinical and laboratory), and 
discontinuation from the trial due to AEs
•
Weight, height, body mass index (BMI), and waist circumference
•
Clinical laboratory tests (chemistry, hematology, and urinalysis) 
•
Vital signs and electrocardiogram (ECG) parameters
•
EPS scale scores: Abnormal Involuntary Movement Scale (AIMS), Barnes 
Akathisia Rating Scale (BARS), and Simpson Angus Scale (SAS)
•
Potential suicide events recorded on suicidality scale scores
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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 initially. 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. If 
fasting or nonfasting blood and clinical laboratory tests (chemistry, hematology, and 
urinalysis) were obtained at screening with results within normal ranges and collected 
less than 28 days before baseline, blood and urine samples do not need to be repeated at 
the baseline visit. 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, HDL, LDL)
CPK
Creatinine
GGT
Glucose
Insulin
LDH
Potassium
Protein, total 
Sodium
Triglycerides
Uric acid
Additional Tests:
Blood alcohol test 
Urine or serum pregnancy for all FOCBP
Serum TSH, with reflex to free T4 if TSH is 
abnormal
ACTH
Cortisol
HbA1c
Serum prolactin (blinded)
Coagulation Parameters:
PT
aPTT
INR
ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; GGT = gamma glutamyl transferase; HDL = high density 
lipoprotein; INR = international normalized ratio; 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.
A urine pregnancy test will be conducted in all females of childbearing potential 
(FOCBP) prior to trial intervention; results must be available prior to the administration 
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of the IMP. A confirmatory serum pregnancy test will be done for subjects with a positive 
urine test. Subjects with a positive serum 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.
A urine drug screen and blood alcohol test will occur in children ≥ 13 years of age that 
engage in social activities with peers without adult supervision.
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.
The following laboratory test 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) Aspartate aminotransferase (AST) ≥ 2 × the upper limit of normal (ULN)
5) Alanine aminotransferase (ALT) ≥ 2 × the ULN
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 × ULN
9) QTcF  450 msec for males and  470 msec for females
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 
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results that may be potentially medically significant, depending on the subject’s medical 
history and clinical presentation.
Clinical laboratory samples at Week 8 should be taken as part of the predose PK blood 
draw.
3.7.3.3
Physical Examination and Vital Signs
3.7.3.3.1
Physical Examination
The physical examination (PE) will consist of measurement of weight, 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 PE 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, a 
screening urogenital exam is required, which could have been performed up to one 
calendar year prior to the date of the ICF being signed, or can be performed during the 
screening period. 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. Post-baseline, 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. The following guidelines will aid in the standardization of body weight 
measurements:
•
The same scale should be used to weigh a given subject each time, if possible.
•
Scales should be calibrated and reliable; scales should be at zero just prior to each 
subject’s weigh-in session.
•
A subject should void prior to being weighed and be minimally clothed (ie, no shoes 
or heavy overgarments).
•
Weight should be recorded before a subject’s meal and at approximately the same 
time at each visit (screening, baseline/Day 1, and Week 8).
Height will be measured with a stadiometer, measuring stick or tape. 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 
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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. Every attempt should be made for the subject to remain supine for 
5 minutes to obtain the ECG reading. If the subject experiences changes in behavior (eg, 
restlessness, crying) due to the procedure these should be noted in the chart next to the 
ECG reading and will not be considered a protocol deviation. Additional ECGs may be 
obtained at the investigator’s discretion and should always be obtained in the event of an 
ET. Electrocardiogram results will be evaluated at the investigational site to determine 
the subject’s eligibility and to monitor safety during the trial. The principal investigator 
or qualified designee will review, sign, and date each ECG reading, noting whether or not 
any abnormal results are of clinical significance. The ECGs 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 
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 QTcF ≥ 450 msec for males and ≥ 470 msec for females 
based on the results from the central reader is exclusionary. In addition, subjects should 
be excluded if they have any other abnormal ECG finding 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 screening 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. 
If ECG was conducted at screening with results within normal range and obtained less 
than 28 days prior to baseline, then ECG does not need to be repeated at the baseline 
visit. However, if the ECG results repeated at baseline indicate a QTcF ≥ 450 msec for 
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reliably according to investigator judgment). Investigators should use their discretion as 
to whether caregiver assistance is needed.
3.7.3.6
Other Assessments
3.7.3.6.1
Autism Diagnostic Interview - Revised
The ADI-R is a semi-structured caregiver interview used for diagnosis of autism, 
planning treatment, and distinguishing autism from other developmental disorders. The 
interview focuses on behaviors in three domains: language/communication, reciprocal 
social interactions, and restricted/repetitive/stereotyped behaviors and interests. It is 
suitable for individuals with a mental age of 2 years or older. The ADI-R must be 
administered by a qualified clinician trained in the use of the assessment. 
An ADI-R assessment completed within the past 3 years is considered acceptable for use 
by the investigator in making a current diagnosis. Assessment with the Autism 
Diagnostic Observation Schedule (ADOS) can also serve as documentation in place of 
the ADI-R, provided that it was completed within the last 3 years. Subjects with a well-
established and ADI-R/ADOS supported DSM-IV-TR diagnosis of autistic disorder, 
Asperger’s disorder, or pervasive developmental disorder not otherwise specified should 
be given a DSM-5 diagnosis of ASD.
3.7.3.6.2
Kiddie Schedule for Affective Disorders and Schizophrenia - 
Present and Lifetime version
The Kiddie Schedule for Affective Disorders and Schizophrenia - Present and Lifetime 
version (K-SADS-PL) is a semi-structured interview aimed at early diagnosis of affective 
disorders such as depression, bipolar disorder, and anxiety disorder. The majority of 
items in the K-SADS-PL are scored using a 0 to 3 point rating scale. Scores of 0 indicate 
no information is available; scores of 1 suggest the symptom is not present; scores of 
2 indicate sub-threshold presentation and scores of 3 indicate threshold presentation of 
symptoms. The K-SADS-PL ratings are made based on clinician summary of available 
sources of information, including interview with child and parent, if available.
If a subject is rescreened for participation in the trial, the K-SADS-PL does not need to 
be repeated at the screening visit.
3.7.4
Prior and Concomitant Medications
The investigator will record all medications and therapies taken by the subject from 
30 days prior to signing of informed consent/assent through the end of the evaluation 
period (defined as the time period during which subjects are evaluated for primary and/or 
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3.7.7
End of Trial
The end of trial date is defined as the last date of contact or the date of final contact 
attempt from the post-treatment follow-up eSource for the last subject completing or 
withdrawing from the trial.
3.7.8
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 monitor. The 
details of the DMC structure and its role and responsibilities will be documented in the 
DMC charter.
3.8
Stopping Rules, Withdrawal Criteria, and Procedures
3.8.1
Entire Trial or Treatment Arm(s)
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 
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.
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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 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 randomization, a subject may stop treatment permanently for a variety of reasons. 
Treatment discontinuations may be initiated by a subject who is not satisfied with 
treatment or may become medically necessary due to AEs, required treatment with a 
disallowed medication or therapy, or other issues, as determined by the investigator. 
However, each investigator must comprehensively review the circumstances and offer the 
subject options for continued treatment to the degree possible as described in 
Section 3.8.3.5.
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
•
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) 
•
Other potentially IMP-related safety concerns or AEs
•
Death
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•
Reasons unrelated to medical condition (provide detail and review AE history with 
subject)
•
Withdrawal of informed consent/assent (complete written withdrawal of 
consent/assent form)
•
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 must be followed.
3.8.3.4
Withdrawal of Consent/Assent
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/IAF):
•
Participation in all follow-up procedures specified in the protocol (whether in-clinic, 
by telephone, or by an in-home visit).
•
Participation in a subset of protocol specified follow-up procedures (by a frequency 
schedule and method, as agreed by subject and staff).
•
Contact of the subject by trial personnel, even if only by telephone, to assess current 
medical condition, and obtain necessary medical or laboratory reports relevant to the 
trial’s objectives.
•
Contact of alternative person(s) who have been designated in source records as being 
available to discuss the subject’s medical condition, even if only by telephone, mail, 
or e-mail (eg, family, spouse, partner, legal representative, friend, neighbor, or 
physician).
•
Access to medical information from alternative sources (eg, hospital/clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, social media sources). 
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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 guardian) 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 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/IAF), but who is not started on treatment, 
whether through randomization or open assignment.
Screen failures may be rescreened at any time if the exclusion characteristic has changed. 
Subjects who sign an ICF/IAF but who are not started on treatment are permitted to be 
rescreened. In the event that the subject is rescreened for trial participation, a new 
ICF/IAF must be signed and new ID assigned.
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 
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Table 4.1-4
Selected CYP2D6 Inhibitors and CYP3A4 Inhibitors and 
Inducers Prohibited During the Trial
Selected CYP2D6 Inhibitors
Fluconazole
Verapamil
Selected CYP3A4 Inducers
Carbamazepine
Phenytoin
Dexamethasone
Primidone
Efavirenz
Rifampin
Nevirapine
St. John’s Wort
Oxcarbazepine
Troglitazone
Phenobarbital
4.1.1
Restricted Therapies and Precautions
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, 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 
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
Other Restrictions
Any history of electroconvulsive therapy is exclusionary.
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 
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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, new-onset psychotherapy is prohibited during the 
trial. In other words, except for outpatient group therapies, subjects may only receive 
psychotherapy (eg, individual, group, or family therapy) if they have been participating in 
the therapy regularly (ie, weekly) for 30 days prior to screening/baseline and commit to 
maintain their participation during the course of the trial at the current frequency or 
unless permission is obtained from the medical monitor.
Consumption of grapefruit, grapefruit products, Seville oranges, or Seville orange 
products within 72 hours prior to dosing and during the trial is prohibited. Subjects will 
be instructed to refrain from drinking alcoholic beverages or using illicit drugs during 
participation in the trial. The investigator may request a blood or urine drug screen at any 
time during the trial if there is a suspicion of illicit drug use in children ≥ 13 years of age 
that engage in social activities with peers without adult supervision.
5
Reporting of Adverse Events
5.1
Definitions
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. AEs would not include information recorded as medical 
history at screening for pre planned procedures for which the underlying condition was 
known and no worsening occurred. An adverse reaction is any untoward and unintended 
response to an IMP related to any dose administered.
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE. For the purpose of Investigational New Drug (IND) safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal relationship between 
the IMP and the AE. Suspected adverse reaction implies a lesser degree of certainty about 
causality.
An SAE includes any event that results in any of the following outcomes:
•
Death
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•
Life-threatening; ie, the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred. It does not include an event 
that, had it occurred in a more severe form, might have caused death.
•
Persistent or significant incapacity/disability or substantial disruption of the 
ability to conduct normal life functions.
•
Requires in-patient hospitalization or prolongs hospitalization.

Hospitalization itself should not be reported as an SAE; whenever possible the 
reason for the hospitalization should be reported.

Hospitalizations or prolonged hospitalizations for social admissions (ie, those 
required for reasons of convenience or other non-medical need) are not 
considered SAEs.
•
Congenital anomaly/birth defect.
•
Other medically significant events that, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above; eg, allergic 
bronchospasm requiring intensive treatment in an emergency room or home, 
blood dyscrasias or convulsions that do not result in hospitalization, or the 
development of drug dependency or drug abuse.
Nonserious adverse events are all AEs that do not meet the criteria for a "serious" AE.
Immediately Reportable Event: 
•
Any SAE.
•
Any AE related to occupational exposure.
•
Potential serious hepatotoxicity case (see Section 5.4). 
•
Pregnancies are also defined as immediately reportable events (IREs). Although 
normal pregnancy is not an AE, it will mandate IMP discontinuation and must be 
reported on an IRE form to the sponsor. Pregnancy will only be documented on 
the AE eSource if there is an abnormality or complication.
Clinical Laboratory Test Value Changes: It is the investigator’s responsibility to review 
the results of all laboratory tests as they become available. This review will be 
documented by the investigator’s dated signature on the laboratory report. For each 
abnormal laboratory test result, the investigator needs to ascertain if this is an abnormal 
(ie, clinically significant) change from baseline for that individual subject. This 
determination, however, does not necessarily need to be made the first time an abnormal 
value is observed. The investigator may repeat the laboratory test or request additional 
tests to verify the results of the original laboratory tests. If this laboratory value is 
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considered medically relevant by the investigator (subject is symptomatic, requiring 
corrective treatment or further evaluation), or if the laboratory value leads to 
discontinuation, and/or fulfills a seriousness criterion, this is considered an AE. 
Severity: Adverse events will be graded on a 3-point scale and reported as indicated on 
the eSource. The intensity of an AE is defined as follows:
1 = Mild:
Discomfort noticed, but no disruption to daily activity.
2 = Moderate:
Discomfort sufficient to reduce or affect normal daily activity.
3 = Severe:
Inability to work or perform normal daily activity.
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. Collection of 
AEs is to begin after a subject has signed the ICF/IAF.
Use medical terminology in AE reporting. Adverse events should be reported as a single 
unifying diagnosis whenever possible or, in the absence of a unifying diagnosis, as 
individual signs or symptoms. Exacerbation or disease progression should be reported as 
an AE only if there are unusual or severe clinical features that were not present, or 
experienced earlier, or not expected based on the course of the condition.
In addition, the sponsor must be notified immediately by telephone, fax, or e-mail of any 
IREs according to the procedure outlined below, in Section 5.3. Special attention should 
be paid to recording hospitalization and concomitant medications.
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5.3
Immediately Reportable Events 
The investigator must immediately report after either the investigator or site personnel 
become aware of any SAE, 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 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 on the eSource.
5.5
Pregnancy
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 
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 method 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
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•
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 
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), 
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follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome. Infants will be followed for a minimum of 6 months from the date of 
birth. 
5.6
Procedure for Breaking the Blind
The investigator is encouraged to contact the sponsor/ clinical research organization 
(CRO) medical monitor to discuss their rationale for unblinding. However, to prevent 
delays to the investigator or medical personnel responding to a potentially emergent 
situation, unblinding of IMP will not be dependent upon the investigator receiving 
approval from the sponsor/CRO medical monitor (ie, the investigator will be able to 
obtain the code break information independent of the sponsor/CRO medical monitor). 
The investigator must contact the sponsor/CRO medical monitor by telephone or e-mail 
with an explanation of the need for opening the treatment assignment code within 24 
hours of opening the code. If the blind is broken, the Clinical Safety and 
Pharmacovigilance department must be notified immediately (see the cover page of this 
protocol for contact information). Documentation of breaking the blind should be 
recorded in the subject’s medical record with the date and time the blind was broken and 
the names of the personnel involved. Once the blind is broken for a subject, that subject 
may not reinitiate treatment with the IMP.
5.7
Follow-up of Adverse Events 
5.7.1
Follow-up of Nonserious Adverse Events
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE eSource with the current status noted. If a subject has an AE or has not recovered 
from an AE at the last scheduled contact, follow-up contacts will be scheduled at least 
every 4 weeks until resolution of the AE is confirmed, or the condition is considered 
clinically stable. All nonserious events that are ongoing at the last scheduled contact will 
be recorded as ongoing on the eSource. For any AE having been identified throughout the 
trial, during analysis, additional relevant medical history information may be requested to 
further ascertain causality (including, but not limited to, information such as risk-related 
behavior, family history and occupation).
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 eSource page and reported to the sponsor according to the reporting 
procedures outlined in Section 5.3. This may include unresolved previously reported 
SAEs, or new SAEs. The investigator will follow SAEs until the events are resolved, 
stabilized, or the subject is lost to follow-up. Resolution means that the subject has 
returned to the baseline state of health and stabilized means that the investigator does not 
expect any further improvement or worsening of the subject’s condition. The investigator 
will continue to report any significant follow-up information to the sponsor up to the 
point the event has been resolved.
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 Analysis
Pharmacokinetic data collected in this trial will be examined in a population PK analysis 
which will be reported separately from the clinical study report. Pharmacogenomics data 
collected will be used to determine each subject’s CYP2D6 metabolizer status which will 
be utilized in the population PK analysis.
7
Statistical Analysis
7.1
Sample Size
Approximately 102 subjects will be randomized (51 per treatment arm). A sample size of 
51 subjects per arm will provide at least 85% power at a nominal 2-sided alpha level of 
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The primary estimand defining the treatment effect of interest in the protocol uses the 
hypothetical strategy specified in the International Council for Harmonisation (ICH) E9 
Addendum. The objective of the primary analysis is to compare the efficacy of 
brexpiprazole versus placebo in reducing irritability in children and adolescents ages 5 to 
17 years with a diagnosis of ASD. The estimand, or target of estimation, following the 
hypothetical strategy is the treatment effect seen, assuming no withdrawals occurred. 
Subjects who withdraw from IMP treatment either could have lost their treatment effect, 
had the subjects not taken any other treatment after withdrawal, or could have their 
treatment effect been masked, had the subjects taken other treatment after withdrawal. 
This means that any observations made after subjects stop IMP will most likely not 
contribute relevant information about the treatment effect of the drug. Due to this 
strategy, the last efficacy assessment after premature trial discontinuation will be done 
only once at the ET Visit. Every effort will be made to complete all of the ET evaluations 
prior to administering any additional medications for the treatment of ASD or other 
prohibited medications. In the case of terminal or lost to follow-up events, no ET 
evaluations would be expected, and only scheduled assessments would be performed 
before such an event occurred.  
The primary estimand for this trial is defined by the following components: 
•
Target Population: Children and adolescent subjects 5 to 17 years of age with 
irritability associated with ASD who met the protocol-defined inclusion/exclusion 
criteria and were qualified for the Efficacy Sample
•
Endpoint: Change from Baseline to Week 8 in the ABC-I subscale score 
•
Intercurrent Events: Intercurrent events refer to premature treatment discontinuation 
(ie, early dropout) prior to Week 8 attributable to adverse events, lack of efficacy, 
withdrawal of consent/assent, or any other causes  
•
Measure of Intervention Effect: Difference in endpoint means between the 
brexpiprazole arm and the placebo arm. 
In this hypothetical strategy, the event of withdrawing IMP is considered MAR, and the 
primary endpoint of the trial could be considered to be a combination of the responses of 
on treatment completers at Week 8 and the imputation of the endpoint to Week 8 
following the trend in each treatment group, using the MMRM method to impute missing 
data for subjects who withdraw IMP during the trial. All data collected during the trial 
treatment period will be used for statistical analysis. For the primary efficacy analysis, 
the treatment effect will be estimated using the MMRM method described below. Under 
the MAR assumption, MMRM provides an unbiased estimate of treatment effect for the 
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treatment period. Analyses with missing values imputed by multiple imputation (MI) 
under MNAR and other methods will be performed as sensitivity analyses.  
The primary statistical comparison of interest is the difference between brexpiprazole and 
placebo at Week 8, analyzed using a MMRM analysis with an unstructured (UN) 
variance-covariance matrix for within-subject variation, and with the change from 
baseline in ABC-I subscale score during the double-blind treatment period as the 
dependent variable based on the Efficacy Sample OC dataset. The model will include 
fixed-class effect terms of treatment, trial center, visit week, and an interaction term of 
treatment-by-visit week, and includes the interaction term of baseline values of ABC-I 
subscale score by visit week as a covariate. The primary comparison between 
brexpiprazole and the placebo arm at Week 8 will be estimated as the difference between 
least squares means. The comparison will be tested at a significance level of 0.05 
(2-sided). 
If there is a convergence problem with the MMRM model based on the UN variance 
covariance matrix, the following structures other than the UN will be used in order of: 1) 
heterogeneous toeplitz (TOEPH), 2) heterogeneous autoregressive of order 1 (ARH1), 
and 3) heterogeneous compound symmetry (CSH), and the first (co)variance structure 
converging to the best fit will be used as the primary analysis. If a structured covariance 
has to be used, the empirical “sandwich” estimator of the standard error of the fixed 
effects parameters will be used in order to deal with possible model misspecification of 
the covariance matrix. 
Small centers will be defined as centers that do not have at least one evaluable subject 
(evaluable with respect to the primary efficacy variable) in each treatment arm in the 
double-blind treatment period. All small centers will be pooled to form “pseudo centers” 
for the purpose of analysis according to the following algorithm. Small centers will be 
ordered from the largest to the smallest based on the number of evaluable subjects 
(ie, subjects who have baseline and at least one post-baseline value for the primary 
endpoint in the double-blind treatment period). The process will start by pooling the 
largest of the small centers with the smallest of the small centers until a non-small center 
is formed. This process will be repeated using the centers left out of the previous pass. In 
case of ties in center size, the center with the smallest center code will be selected. If any 
centers are left out at the end of this process, they will be pooled with the smallest pseudo 
centers, or if no pseudo centers exist, they will be pooled with the smallest non-small 
center. 
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7.4.2
Secondary Endpoint Analysis
The key secondary efficacy endpoint is change from baseline to Week 8 in CGI-S score. 
This secondary endpoint will be analyzed using the same MMRM model as described in 
the primary endpoint analysis. Additionally, by-treatment descriptive statistics for CGI-S 
score will be provided for each trial visit. 
Further details will be provided in the statistical analysis plan (SAP).
7.4.4
Interim Analysis
To ensure that trial is adequately powered, the estimate of the trial variability will be 
obtained in a blinded fashion upon approximately 75% of the subjects having completed 
or discontinued from the trial. The variability will be estimated based on a blinded and 
pooled analysis of all treatment arms and sample size could be further increased. For full 
details please refer to the SAP.
7.5
Analysis of Demographic and Baseline Characteristics
Baseline demographic characteristics including age, race, ethnicity, gender, weight, 
height, and BMI will be summarized by descriptive statistics (frequency, mean, median, 
standard deviation, maximum, minimum, and percentage when applicable).
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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 according to the storage conditions indicated on the 
IMP label. The clinical site staff 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 (including 
investigational, active control, or placebo) 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
•
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
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•
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
•
Phone - 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.
It must be documented in the site accountability record that a complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation.
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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/IAF. In all cases, subject confidentiality must be 
maintained in accordance with local regulatory requirements.
9.2
Data Collection
Source document and source data will be captured electronically in this trial, and will 
meet the same fundamental elements of data quality (eg, attributable, legible, 
contemporaneous, original, and accurate) as paper records. These data will be collected 
into a system that is fully validated. Changes to the data will be captured by an automatic 
audit trail.
The trial site will be given a tablet to directly record subject data and clinical 
observations on electronic forms. Designated trial site staff will not be given access to the 
system until they have been appropriately trained. Information to be originally captured 
and reviewed electronically shall include details of the subject visit and the 
protocol-required assessments performed as a part of these visits, medical history, AEs, 
and concomitant medications. Because this trial is using an electronic source record as 
the original point of data capture, there is no additional data entry step for the site for data 
collected directly into the application - rather, the electronic source record directly 
populates the trial database.
Some data may be captured via paper and then entered into the eSource system. These 
and any other data treated in this manner will be source data verified by the trial clinical 
research associate, and the location of the source data (ie, eSource, paper, or a local 
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electronic system) will be documented before the trial start. Any changes to information 
in paper source documents will be initialed and dated on the day the change is made by a 
trial site staff member authorized to make the change. Changes will be made by striking a 
single line through erroneous data (so as not to obliterate the original data), and clearly 
entering the correct data (eg, right data). If the reason for the change is not apparent, a 
brief explanation for the change will be written in the source documentation by the 
clinician.
Another exception will be safety laboratory data, where the official source documentation 
will be considered the report issued by the analyzing laboratory.
Remote monitoring of the original electronic source record will take place, however 
on-site monitoring inspections will continue to take place in order to review data entry 
source documentation directly captured on paper and transcribed into the system, to 
ensure protocol adherence, to assess site operational capabilities and to perform other 
monitoring activities that cannot be performed remotely. 
At the end of the trial, the investigator must certify that the data entered into the eSource 
application are complete and accurate. After database lock, the investigator will receive 
an electronic copy of the subject data. 
9.3
File Management at the Trial Site
The investigator will ensure that the trial site file is maintained in accordance with 
Section 8 of the ICH GCP Guideline E6 and as required by applicable local regulations. 
The investigator/institution will take measures to prevent accidental or premature 
destruction of these documents.
9.4
Records Retention at the Trial Site
Regulatory requirements for the archival of records for this trial necessitate that 
participating investigators maintain detailed clinical data for the longest of the following 
3 periods:
•
A period of at least 2 years after the date on which approval to market the drug is 
obtained (or if IMP development is discontinued, the date regulatory authorities were 
notified of discontinuation); OR
•
A period of at least 3 years after the sponsor notifies the investigator that the final 
report has been filed with regulatory authorities.
•
Longer, region-specific storage requirements, if applicable. 
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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 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 identification 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 
identification 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/IAF will require similar modification. In such 
cases, after approval/favorable opinion of the new ICF/IAF 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.
2
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.
4
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.
5
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.
6
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.
7
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.
8
Varley CK, McClellan J. Implications of marked weight gain associated with atypical 
antipsychotic medications in children and adolescents. JAMA. 2009;302:1811-1812.
9
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.
10 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.
11 Otsuka Pharmaceutical Development & Commercialisation, Inc. Brexpiprazole 
(OPC-34712) Investigator’s Brochure, Edition 17. Otsuka Report, issued 27 Sep 
2021.
12 Autism and Developmental Disabilities Monitoring Network Surveillance Year 2000 
Principal Investigators. Prevalence of autism spectrum disorders—Autism and 
Developmental Disabilities Monitoring Network, six sites, United States, 2000. 
MMWR Surveill Summ. 2007;56(No. SS-1):1–11.
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28 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 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
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. 
Clinical Study Report 331-201-00148
16.1.1 Protocol and Protocol Amendments
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Protocol 331-201-00148
Confidential - Proprietary Information
109
Version 6.0, 07 Jul 2022
Agreement
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator's Brochure) and agree that it contains all the ethical, legal and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor's (or designee's) Clinical Trial Agreement.
I will provide copies of the protocol to all physicians, nurses, and other professional personnel to 
whom I delegate trial responsibilities. I will discuss the protocol with them to ensure that they are 
sufficiently informed regarding the investigational new drug, brexpiprazole (OPC-34712), the 
concurrent medications, the efficacy and safety parameters and the conduct of the trial in general. 
I am aware that this protocol must be approved by the Institutional Review Board (IRB) or receive 
a favorable opinion by the Independent Ethics Committee (IEC) responsible for such matters in 
the clinical trial facility where brexpiprazole (OPC-34712) will be tested prior to commencement of 
this trial. I agree to adhere strictly to the attached protocol (unless amended in the manner set 
forth in the sponsor's Clinical Trial Agreement, at which time I agree to adhere strictly to the 
protocol as amended).
I understand that this IRB- 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
Clinical Study Report 331-201-00148
16.1.1 Protocol and Protocol Amendments
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110


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 4 8 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: 1 0. 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 0: 5 5
Cli ni c al A p pr o v al
0 7- J ul- 2 0 2 2
1 8: 1 6: 0 8
Bi o st ati sti c s A p pr o v al
0 7- J ul- 2 0 2 2
2 2: 0 8: 3 8
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
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 1
P P D
P P D
P P D
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1
Confidential - Proprietary Information
Version 1.0, 06 Jul 2020
Otsuka Pharmaceutical Development & Commercialization, Inc
Investigational Medicinal Product
Brexpiprazole (OPC-34712)
ADDENDUM FOR CLINICAL PROTOCOL FOR TRIAL 331-201-00148
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 No. 331-201-00148
IND No. 141257
EudraCT No. 2019-000723-40
CONFIDENTIAL – PROPRIETARY INFORMATION
Clinical Development Phase:
3
Sponsor:
Otsuka Pharmaceutical Development &
Commercialization, Inc
2440 Research Boulevard
Rockville, Maryland 20850, United States
Immediately Reportable Event 
Issue Date:
06 Jul 2020
Version No.:
1.0
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Protocol 331-201-00148
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Confidential - Proprietary Information
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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 331-201-00148
16.1.1 Protocol and Protocol Amendments
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Protocol 331-201-00148
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Confidential - Proprietary Information
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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 331-201-00148 COVID-19 Protocol Summary.........................7
1.1
Trial Design Schematic .......................................................................................7
1.2
Schedule of Assessments.....................................................................................8
2
General Considerations......................................................................12
2.1
Telemedicine Virtual Visits...............................................................................12
2.2
Reconsent ..........................................................................................................12
2.3
Protocol Deviations...........................................................................................12
2.4
Guidance to Record Adverse Events and Discontinuations Due to 
COVID-19.........................................................................................................12
2.5
Statistical Analyses............................................................................................13
2.6
Clinical Outcomes.............................................................................................13
3
Trial Population..................................................................................14
3.1
Inclusion Criteria...............................................................................................14
3.2
Exclusion Criteria..............................................................................................14
4
Trial Procedures .................................................................................14
4.1
Safety Assessments ...........................................................................................14
4.1.1
Weight and Waist Circumference...................................................................14
4.1.2
Pregnancy .......................................................................................................15
4.1.3
Extrapyramidal Symptom Scales....................................................................15
4.2
Efficacy Assessments........................................................................................15
4.2.1
Pediatric Quality of Life .................................................................................15
5
Investigational Medicinal Product....................................................16
Clinical Study Report 331-201-00148
16.1.1 Protocol and Protocol Amendments
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Protocol 331-201-00148
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List of In-text Tables
Table 1.2-1
COVID-19 Impact Schedule of Assessments................................. 8
Clinical Study Report 331-201-00148
16.1.1 Protocol and Protocol Amendments
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List of In-text Figures
Figure 1.1-1
COVID-19 Impact Trial Design Schematic.................................... 7
Clinical Study Report 331-201-00148
16.1.1 Protocol and Protocol Amendments
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8
Confidential - Proprietary Information
Version 1.0, 06 Jul 2020
1.2
Schedule of Assessments
Table 1.2-1
COVID-19 Impact Schedule of Assessments
Screening
Double-blind Treatment
Follow-
up
Assessment
Day -28 
to -1
In office
Baseline 
(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 6
(Day 42 
± 2 days)
Virtual
Week 
8/ET
(Day 56 
± 2 days)
Virtuala
21 ± 
2 days) 
after last 
dose of 
IMP
By Tele-
phone
Notes
Trial Entrance and History
Informed consent/assent
X
Inclusion/exclusion criteria
X
X
Demography
X
Medical history
X
Psychiatric history
X
ADI-Rb
X
Prior medications and 
washout, if applicable
X
K-SADS-PLc
X
Randomization
X
Efficacy Assessments
ABC
X
X
X
X
X
X
X
X
CGI-S
X
X
X
X
X
X
X
X
Safety Assessments
Physical examination
X
Vital signs
X
X
X
X
X
X
X
X
Height
X
X
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Protocol 331-201-00148
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cIf a subject is rescreened for participation in the trial, the K-SADS-PL does not need to be repeated at the screening visit.
dThe 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.
eBaseline 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.
fOne PK sample will be collected 1 to 4 hours postdose on Day 1. Two PK samples will be collected at the Week 8 visit (predose and 1-4 hours postdose). The 
actual time of the PK sample will be recorded as well as the dosing time prior to the PK sample collection. The longest time possible within the 1 to 4 hour range is 
preferred but should be no less than 1 hour.
gPharmacogenomic 
 (if done), are to be taken with the postdose PK draw to avoid additional blood draws.
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Protocol 331-201-00148
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Confidential - Proprietary Information
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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 contract 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 of the subject or 
caregiver, 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.
Clinical Study Report 331-201-00148
16.1.1 Protocol and Protocol Amendments
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Protocol 331-201-00148
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5
Investigational Medicinal Product
Investigational medicinal product will be shipped directly to caregivers and subjects as 
per existing procedures for this trial.
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SAP_003.pdf: 
Ots u k a P h ar m ace utic al De vel o p me nt & C o m merci aliz ati o n, I nc.
I n vesti gati o nal Ne w Dr u g
Bre x pi praz ole ( O P C- 3 4 7 1 2)
A P hase 3, M ultice nter, Ra n d o mize d, D o u ble- bli n d, Place b o-c o ntr olle d Trial of 
Bre x pi praz ole i n Treat me nt of c hil dre n a n d A d olesce nts wit h Irrita bilit y Ass ociate d wit h 
A utis m S pectr u m Dis or der
Pr ot oc ol N o. 3 3 1- 2 0 1- 0 0 1 4 8
I N D N o. 1 4 1 2 5 7
E u dra C T N o. 2 0 1 9- 0 0 0 7 2 3- 4 0
St atistic al A n al ysis Pl a n
Versi o n: Fi n al 4. 0
D ate:  2 8 Se p 2 0 2 2
C O N FI D E N TI A L - P R O P RI E T A R Y I N F O R M A TI O N
C o nfi de ntial
Ma y n ot be use d, di v ul ge d, p u blis he d or ot her wise discl ose d
wit h o ut t he c o nse nt of Ots u ka P har mace utical De vel o p me nt & C o m mercializati o n, I nc.
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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














S A P 3 3 1- 2 0 1- 0 0 1 4 8
C o nfi de ntial - Pr o prietar y I nf or mati o n
8
2 8 Se p 2 0 2 2
Li st of A b br e vi ati o n s a n d D efi niti o n s of T er m s
A b bre vi ati o n
Defi niti o n
A B C
A berra nt Be ha vi or C hec klist
A B C-I
A berra nt Be ha vi or C hec klist - Irrita bilit y
A DI- R
A utis m Dia g n ostic I nter vie w - Re vise d
A E
A d verse e ve nt
AI M S
A b n or mal I n v ol u ntar y M o ve me nt Scale
A L T
Ala ni ne a mi n otra nsferase
A N C O V A
A nal ysis of C o varia nce
A S D
A utis m S pectr u m Dis or der
A S T
As partate a mi n otra nsferase
B A R S
Bar nes A kat hisia Rati n g Scale
B MI
B o d y mass i n de x
C D C
Ce nter f or Disease C o ntr ol a n d Pre ve nti o n
C GI- S
Cli nical Gl o bal I m pressi o ns - Se verit y
C M H
C oc hra n- Ma ntel- Hae nszel
C R F
Case Re p ort F or m
C- S S R S
C ol u m bia- S uici de Se verit y Rati n g Scale
D B P
Diast olic bl o o d press ure
D S M- 5
Di a g n ostic a n d St atistic al M a n u al of Me nt al Dis or ders, 5t h e diti o n
E C G
Electr ocar di o gra m
E P S
E xtra p yra mi dal s y m pt o ms
E T
Earl y ter mi nati o n
F D A
( U nite d States) F o o d a n d Dr u g A d mi nistrati o n
G E E
Ge neralize d Esti mati n g E q uati o ns
H b A 1c
Gl yc os ylate d he m o gl o bi n
H D L
Hi g h de nsit y li p o pr otei n
I A F
I nf or me d asse nt f or m
I C F
I nf or me d c o nse nt f or m
I D
I de ntificati o n
I M P
I n vesti gati o nal me dici nal pr o d uct
I R E
I m me diatel y re p orta ble e ve nt
I R T
I nteracti ve researc h tec h n ol o g y
K- S A D S- P L
Ki d die- Sc he d ule f or Affecti ve Dis or ders a n d Sc hiz o p hre nia - Prese nt 
a n d Lifeti me versi o n
L D L
L o w de nsit y li p o pr otei n
L O C F
Last O bser vati o n Carrie d F or war d
L O E
Lac k of Efficac y
M A R
Missi n g at Ra n d o m
M C M C
M o nte Carl o Mar k o v C hai n
Me d D R A
MI
Me dical Dicti o nar y f or Re g ulat or y Acti vities
M ulti ple I m p utati o n
M M R M
Mi xe d-effect M o del Re peate d Meas ures
M N A R
Missi n g N ot at Ra n d o m
O C
O bser ve d Case
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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.
8


S A P 3 3 1- 2 0 1- 0 0 1 4 8
C o nfi de ntial - Pr o prietar y I nf or mati o n
9
2 8 Se p 2 0 2 2
O P D C
Ots u ka P har mace utical De vel o p me nt a n d C o m mercializati o n, I nc.
P A R S
Pe diatric A n xiet y Rati n g Scale
P E
P h ysical e xa mi nati o n
Pe ds Q L
Pe diatric Q ualit y of Life I n ve nt or y
P D
P har mac o d y na mic
P K
P har mac o ki netic
P W R
Pe diatric Writte n Re q uest
Q D
O nce Dail y
Q Tc F
Q T i nter val as c orrecte d f or heart rate b y Fri dericia’s f or m ula
Q Tc N
Q T i nter val as c orrecte d f or heart rate b y t he F D A Ne ur o p har m Di visi o n
R E M L
Restricte d Ma xi m u m Li keli h o o d
S A E
Seri o us a d verse e ve nt
S A P
Statistical A nal ysis Pla n
S A S
Si m ps o n A n g us Scale
S A S ®
Statistical A nal ysis S yste m ®
S B P
S yst olic bl o o d press ure
S D
Sta n dar d de viati o n
S O C
S yste m Or ga n Class
T E A E
Treat me nt-e mer ge nt a d verse e ve nt
T S H
T h yr oi d sti m ulati n g h or m o ne
U L N
U p per li mit of n or mal
W H O
W orl d Healt h Or ga nizati o n
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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






S A P 3 3 1- 2 0 1- 0 0 1 4 8
C o nfi de ntial - Pr o prietar y I nf or mati o n
1 2
2 8 Se p 2 0 2 2
Fi g ure 3. 1- 1 
Tri al Desi g n Sc he m atic 
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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 2






















S A P 3 3 1- 2 0 1- 0 0 1 4 8
C o nfi de ntial - Pr o prietar y I nf or mati o n
2 3
2 8 Se p 2 0 2 2
2)
A n M M R M a nal ysis usi n g t he n o n- C O VI D data set base d o n Efficac y Sa m ple. 
T he n o n- C O VI D data set c o nsists of t he O C data d uri n g t he n o n- C O VI D 
treat me nt peri o d. F or eac h s u bject, t he n o n- C O VI D treat me nt peri o d starts fr o m 
ra n d o mizati o n a n d e n ds o n t he Wee k 8/ E T date or t he date bef ore t he first 
C O VI D- 1 9 relate d pr ot oc ol de viati o n, w hic he ver occ urs earlier. T he n o n- C O VI D 
treat me nt peri o d re prese nts t he ti me peri o d w he n s u bjects di d n ot ha ve a n y 
C O VI D- 1 9 relate d pr ot oc ol de viati o ns d uri n g t he d o u ble- bli n d treat me nt peri o d.
3)
A n M M R M a nal ysis base d o n t he n o n- C O VI D Sa m ple. T he n o n- C O VI D Sa m ple 
c o m prises t h ose s u bjects i n Efficac y Sa m ple w h o di d n ot ha ve a n y C O VI D- 1 9 
relate d pr ot oc ol de viati o ns.
4)
T o e x pl ore t he i m pact of assess me nts bef ore vers us after t he C O VI D brea k o ut, a 
s u b gr o u p a nal ysis f or s u bjects w h o c o m plete d or disc o nti n ue d fr o m t he st u d y 
bef ore Marc h 1 3, 2 0 2 0 a n d s u bjects w h o c o m plete d or disc o nti n ue d fr o m t he 
st u d y o n or after Marc h 1 3, 2 0 2 0 will be perf or me d. A n M M R M a nal ysis base d 
o n t he Efficac y Sa m ple will be perf or me d t o t he e xte nt w here data all o ws or t he 
s u m mar y statistics will be pr o vi de d.
8. 1. 4 
S u b gr o u p A n al y s e s
F or t his st u d y, s u b gr o u p a nal yses will ser ve as e x pl orat or y or h y p ot hesis- ge nerati n g 
p ur p ose, gi ve n t he s maller s u b gr o u p sa m ple size. S u b gr o u p a nal yses f or t he pri mar y 
efficac y e n d p oi nt will be perf or me d o n t he O C data f or t he f oll o wi n g s u b gr o u ps: 
•
A ge ( A ges 5 t o 1 2 a n d A ges 1 3 t o 1 7)
•
B o d y wei g ht ( < 5 0 k g a n d ≥ 5 0 k g)
•
Se x ( Male a n d Fe male, base d o n bi ol o gical stat us)
•
Race ( W hite a n d All Ot her Races)
All s u b gr o u p a nal yses will be c o n d ucte d usi n g t he sa me M M R M m o del as t hat f or t he 
pri mar y efficac y a nal ysis e xce pt t hat t he fi xe d effect ter m f or trial ce nter a n d baseli ne 
b o d y wei g ht strat u m will be e xcl u de d fr o m t he m o del. A d di n g a B Y state me nt i nt o t he 
s y nta x of S A S P R O C MI X E D will e na ble se parate a nal yses of o bser vati o ns i n s u b gr o u ps 
t hat are defi ne d b y a s u b gr o u pi n g varia ble.  
I nteracti o n effects of treat me nt- b y-s u b gr o u p will be assesse d at Wee k 8 f or t he s u b gr o u ps 
i de ntifie d i n t he pre vi o us para gra p h. T he sa me M M R M m o del will be use d as f or t he 
pri mar y efficac y a nal ysis wit h t he a d diti o n of ter ms f or s u b gr o u p- b y- wee k a n d treat me nt-
b y-s u b gr o u p- b y- wee k. T hese treat me nt- b y-s u b gr o u p i nteracti o n a nal yses will be 
prese nte d i n statistical d oc u me ntati o n.
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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.
2 3








S A P 3 3 1- 2 0 1- 0 0 1 4 8
C o nfi de ntial - Pr o prietar y I nf or mati o n
2 7
2 8 Se p 2 0 2 2
I n J ul y 2 0 2 2, a bli n de d i nteri m a nal ysis was c o n d ucte d w he n a b o ut 8 1 % of s u bjects 
ha vi n g c o m plete d t he Wee k 8 visit or pre mat urel y disc o nti n ue d fr o m t he trial. T he res ults 
s h o we d t hat t he c urre nt sa m ple size (ie, 1 0 2 ra n d o mize d s u bjects) will a de q uatel y 
mai ntai n 8 5 % st u d y p o wer. As a res ult, n o sa m ple size i ncrease is nee de d.
9 
S af et y A n al y si s
All safet y a nal yses will be perf or me d o n t he Safet y Sa m ple. Sta n dar d safet y varia bles t o 
be a nal yze d i ncl u de A d verse E ve nts ( A Es), r o uti ne cli nical la b orat or y tests ( he mat ol o g y, 
ser u m c he mistr y, a n d uri nal ysis), H b A 1c, vital si g ns, b o d y wei g ht, waist circ u mfere nce, 
b o d y mass i n de x ( B MI), 1 2-lea d E C Gs, p h ysical e xa mi nati o ns, c oa g ulati o ns, pr olacti n 
c o nce ntrati o ns, T S H, a n d free T 4. I n a d diti o n, data fr o m t he f oll o wi n g safet y scales will 
be e val uate d: A b n or mal I n v ol u ntar y M o ve me nt Scale ( AI M S), Si m ps o n- A n g us Scale 
( S A S), Bar nes A kat hisia Rati n g Scale ( B A R S) a n d C ol u m bia- S uici de Se verit y Rati n g 
Scale ( C- S S R S). 
A s u bject’s baseli ne val ue i n a safet y varia ble is defi ne d as t he last o bser vati o n or 
assess me nt of t he varia ble o n t he s u bject pri or t o his/ her t he first d ose of I M P. I n fact, t he 
baseli ne defi niti o n f or t his trial is t he sa me f or all a nal yses ( de m o gra p hics, efficac y a n d 
safet y). 
Pr os pecti vel y defi ne d criteria will be use d t o i de ntif y p ote ntiall y cli nicall y rele va nt 
a b n or mal val ues f or cli nical la b orat or y tests, vital si g ns a n d E C Gs. 
9. 1  
A d v er s e E v e nt s ( A E s)
All a d verse e ve nts will be c o de d b y S yste m Or ga n Class ( S O C) a n d Preferre d Ter m ( P T) 
acc or di n g t o t he latest versi o n ( Versi o n 2 2. 0 or ne wer) of Me dical Dicti o nar y f or 
Re g ulat or y Acti vities ( Me d D R A). A Es t hat are se x-s pecific, e g, o varia n ca ncer, will ha ve 
t he i nci de nce rates e val uate d f or t he s pecific se x. Treat me nt-e mer ge nt A Es ( T E A Es) are 
defi ne d as A Es wit h a n o nset date o n or after t he start of d o u ble- bli n d treat me nt peri o d. 
I n m ore detail, T E A Es are all a d verse e ve nts w hic h starte d after start of t he d o u ble- bli n d 
I M P; or if t he e ve nt was c o nti n u o us fr o m baseli ne a n d was w orse ni n g, seri o us, st u d y 
dr u g relate d, or res ulte d i n deat h, disc o nti n uati o n, i nterr u pti o n or re d ucti o n of st u d y 
t hera p y. A d verse e ve nts occ urri n g u p t o 3 0 da ys after t he last d ose of I M P will be 
i ncl u de d i n t he s u m mar y ta bles. A Es ha vi n g occ urre d 3 0 da ys after t he last d ose of I M P, 
if c ollecte d, will be liste d o nl y.  
T he i nci de nce of t he f oll o wi n g e ve nts i n t he d o u ble- bli n d treat me nt peri o d will be 
ta b ulate d b y treat me nt gr o u p a n d o verall:  
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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.
2 7


S A P 3 3 1- 2 0 1- 0 0 1 4 8
C o nfi de ntial - Pr o prietar y I nf or mati o n
2 8
2 8 Se p 2 0 2 2
a)
T E A Es 
b)
T E A Es b y se verit y
c)
T E A Es p ote ntiall y ca usall y relate d t o t he I M P
d)
T E A Es wit h a n o utc o me of deat h
e)
Seri o us T E A Es
f)
T E A Es lea di n g t o disc o nti n uati o ns of t he I M P
T he a b o ve s u m maries ( b), (e), a n d (f) will als o be pre pare d f or T E A Es p ote ntiall y 
ca usall y relate d t o t he I M P.  
I n a d diti o n, T E A E i nci de nce wit h rate ≥ 5 % i n t he bre x pi praz ole ar m a n d greater t ha n 
t hat of t he place b o ar m at a n y S O C a n d P T le vels will be pr o vi de d. I nci de nce of T E A Es 
b y S O C a n d P T will als o be s u m marize d f or s u b gr o u ps defi ne d b y se x, race, a ge a n d 
b o d y wei g ht strat u m at ra n d o mizati o n.  
9. 2  
Cli ni c al L a b or at or y T e st s
C ha n ge fr o m baseli ne at t he Wee k 8 visit i n t he r o uti ne cli nical la b orat or y para meters 
(ie,  he mat ol o g y, ser u m c he mistr y, a n d uri nal ysis), gl yc os ylate d he m o gl o bi n ( H b A 1c), 
ser u m pr olacti n c o nce ntrati o ns, c oa g ulati o n para meters, t h yr oi d sti m ulati n g h or m o ne 
( T S H), a n d free T 4 (if t he T S H is a b n or mal) will be s u m marize d o n t he O C data a n d last 
visit b y usi n g descri pti ve statistics f or c o nti n u o us varia bles. Of n ote, meta b olic 
para meters (ie, t otal c h olester ol, l o w de nsit y li p o pr otei n ( L D L), hi g h de nsit y li p o pr otei n 
( H D L) a n d tri gl yceri des) a n d ser u m gl uc ose will be se paratel y s u m marize d f or fasti n g 
a n d n o n-fasti n g tests, a n d ser u m pr olacti n c o nce ntrati o ns will be se paratel y s u m marize d 
f or male a n d fe male s u bjects.   
P ote ntiall y cli nicall y rele va nt la b orat or y test res ults i n t he d o u ble- bli n d treat me nt peri o d 
will be i de ntifie d, a n d t he n u m ber a n d perce nta ge of s u bjects w h o ha d s uc h a res ult will 
be ta b ulate d b y la b orat or y para meter a n d treat me nt gr o u p base d o n t he o bser vati o n fr o m 
t he sc he d ule d (ie, Wee k 8) a n d t he u nsc he d ule d (if a n y) p ost- baseli ne visits.  
P ote ntial seri o us he pat ot o xicit y is a n i m me diatel y re p orta ble a d verse e ve nt of i nterest. 
T he case of p ote ntial seri o us he pat ot o xicit y at a p ost- baseli ne visit is defi ne d as ha vi n g 
( 1) as partate a mi n otra nsferase ( A S T) or ala ni ne a mi n otra nsferase ( A L T) t hat is ≥ 2 ti mes 
t he u p per li mit of n or mal ( U L N), a n d ( 2) t he t otal Bilir u bi n ≥ 1. 6 ti mes t he U L N. T he 
i nci de nce of p ote ntial seri o us he pat ot o xicit y will be ta b ulate d b y treat me nt gr o u p base d 
o n t he o bser vati o n fr o m t he sc he d ule d (ie, Wee k 8) a n d t he u nsc he d ule d (if a n y) p ost-
baseli ne visits.   
All p ote ntiall y cli nicall y rele va nt la b orat or y a b n or malities will be liste d b y treat me nt 
gr o u p, patie nt I D, baseli ne val ue, a ge, se x, b o d y wei g ht, visit, a n d d ose at o nset of t he 
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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.
2 8










S A P 3 3 1- 2 0 1- 0 0 1 4 8
C o nfi de ntial - Pr o prietar y I nf or mati o n
3 3
2 8 Se p 2 0 2 2
T he n u m ber a n d perce nta ge of s u bjects wit h t he prese nce of s uici dalit y d uri n g t he e ntire 
st u d y will be ta b ulate d. N ote t hat, t he prese nce of s uici dalit y is defi ne d as re p orti n g of at 
least o ne occ urre nce of a n y t y pes of s uici dal i deati o n or be ha vi or at a n y visits d uri n g t he 
st u d y (i ncl u di n g t he f oll o w- u p peri o d). N ote t hat a s u bject will be c o u nte d o nl y o nce if 
he/s he ha d m ulti ple occ urre nces of s uici dal i deati o n or be ha vi or d uri n g t he st u d y.
A n d t he f oll o wi n g f o ur cate g ories of treat me nt e mer ge nt s uici dalit y will be a nal o g o usl y 
s u m marize d: ( 1) E mer ge nce of s uici dal i deati o n, w hic h is defi ne d as re p orti n g of a n y 
t y pes of s uici dal i deati o n d uri n g t he treat me nt a n d t he f oll o w- u p peri o d w hile t here was 
n o  s uici dal i deati o n at baseli ne; ( 2) E mer ge nce of seri o us s uici dal i deati o n, w hic h is 
defi ne d as ha vi n g o bser vati o n of s uici dal i deati o n se verit y rati n g of 4 or 5 d uri n g t he 
treat me nt a n d t he f oll o w- u p peri o d w hile t here was n o s uici dal i deati o n at baseli ne; ( 3) 
W orse ni n g of s uici dal i deati o n, w hic h is defi ne d as ha vi n g a s uici dal i deati o n se verit y 
rati n g t hat is m ore se vere c o m pare d t o baseli ne; ( 4) E mer ge nce of s uici dal be ha vi or, 
w hic h is defi ne d as re p orti n g of a n y t y pes of s uici dal be ha vi or d uri n g t he treat me nt a n d 
f oll o w- u p peri o d w hile t here was n o s uici dal be ha vi or at baseli ne. S pecificall y, f or eac h 
of t he a b o ve cate g ories of treat me nt e mer ge nt s uici dalit y, descri pti ve statistics i n t he 
f or m of c o u nt a n d perce nta ge of t he s u bjects w h o e x perie nce d s uc h a treat me nt e mer ge nt 
e ve nt at a n y visits d uri n g t he st u d y will be pr o vi de d b y treat me nt gr o u p.   
T here are 4 s pecific t y pes of s uici dal be ha vi or a n d 5 s pecific t y pes of s uici dal i deati o n. 
T he n u m ber a n d perce nta ge of s u bjects w h o e x perie nce d a n y of t h ose t y pes of be ha vi or 
or i deati o n will be ta b ulate d b y treat me nt gr o u p. 
W here ver a p plica ble, assess me nts o n all i n di vi d ual q uesti o n naires pertai ni n g t o s uici dal 
be ha vi or or i deati o n will be s u m marize d b y visit b y usi n g t he descri pti ve statistics f or 
cate g orical varia bles.   
9. 8  
C o n c o mit a nt M e di c ati o n s
T he n u m ber a n d perce nta ge of patie nts ta ki n g c o nc o mita nt me dicati o ns pri or t o t he 
d o u ble- bli n d treat me nt peri o d, d uri n g t he d o u ble- bli n d treat me nt peri o d, a n d d uri n g t he 
f oll o w- u p peri o d will be res pecti vel y ta b ulate d b y dr u g classificati o n usi n g t he latest 
versi o n of t he W orl d Healt h Or ga nizati o n ( W H O) dr u g dicti o nar y. 
9. 9 
E xt e nt of E x p o s ur e
A n i n di vi d ual s u bject’s T otal Da ys of E x p os ure t o I M P is calc ulate d as: last d ose date - 
first d ose date + 1, re gar dless of a n y ga ps i n treat me nt (s uc h as d ose i nterr u pti o n or 
o missi o n). T he varia ble T otal Da ys of E x p os ure will be s u m marize d o n t he Safet y 
Sa m ple b y descri pti ve statistics f or a c o nti n u o us varia ble.  
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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.
3 3




S A P 3 3 1- 2 0 1- 0 0 1 4 8
C o nfi de ntial - Pr o prietar y I nf or mati o n
3 5
2 8 Se p 2 0 2 2
I n t he i nsta nces w here m ulti ple o bser vati o ns fall wit hi n o ne visit wi n d o w ( or sa y, st u d y 
da y i nter val), t he last o bser vati o n wit hi n t he wi n d o w will be selecte d f or a nal ysis use a n d 
will be ma p pe d t o a n a nal ysis visit. H o we ver, t he o bser vati o ns t hat are n ot selecte d will 
be liste d or d oc u me nte d. E val uati o ns or assess me nts t hat ta ke place m ore t ha n 7 da ys 
after t he last d ose of I M P will n ot be ma p pe d i nt o a n a nal ysis visit a n d will be e xcl u de d 
fr o m data a nal ysis.   
F or t he listi n g prese ntati o n of data, t he deri ve d varia bles St u d y Da y a n d A nal ysis Visit 
will be liste d al o n g wit h t he ori gi nal C R F visit (ie, t he visit as rec or de d o n t he C R F). 
N ote t hat t he ori gi nal C R F visit will be use d f or data s u m mar y a n d a nal ysis f or t he 
para meters s uc h as A Es, C o nc o mita nt Me dicati o n, a n d C- S S R S.
( N ote t hat, if a n y pri mar y assess me nts are ma de m ore t ha n 7 da ys after treat me nt   
disc o nti n uati o n or after t he E T visit, t he assess me nts will n ot be use d i n t he pri mar y 
a nal ysis b ut will be re p orte d i n listi n g.)  
1 0. 3 
P o oli n g of s m all c e nt er s
A s mall ce nter is defi ne d as a ce nter t hat d oes n ot ha ve at least o ne e val ua ble s u bject 
( wit h res pect t o t he efficac y varia ble of i nterest) i n eac h treat me nt ar m i n t he d o u ble-
bli n d treat me nt peri o d. N ote t hat a n e val ua ble s u bject is defi ne d as a n efficac y s u bject 
(ie, s u bjects i n t he Efficac y Sa m ple) w h o has baseli ne assess me nt a n d at least o ne 
p ost- baseli ne assess me nt of t he efficac y varia ble of i nterest d uri n g t he d o u ble- bli n d 
treat me nt p hase. F or t he pri mar y efficac y a nal ysis f or t he A B C-I s u bscale sc ore, t he set 
of e val ua ble s u bjects is si m pl y t he Efficac y Sa m ple. F or t he sec o n dar y efficac y a nal ysis 
f or t he C GI- S, t he set of e val ua ble s u bjects c o ul d be a pr o per s u bset of t he Efficac y 
Sa m ple if t here is a n y efficac y s u bject w h o has a n A B C assess me nt b ut d oes n ot ha ve a n y 
p ost- baseli ne C GI- S assess me nt d uri n g t he d o u ble- bli n d treat me nt p hase.   
Beca use of stratifie d ra n d o mizati o n b y trial ce nter, t he pr o ble m of s mall ce nter is u nli kel y 
t o occ ur. If it d oes occ ur, s mall ce nters will be p o ole d t o f or m pse u d o-ce nters f or p ur p ose 
of a nal ysis acc or di n g t o t he al g orit h m as f oll o ws. S mall ce nters will be or dere d fr o m t he 
lar gest t o t he s mallest base d o n t he n u m ber of e val ua ble s u bjects. T he pr ocess will start 
b y p o oli n g t he lar gest of t he s mall ce nters wit h t he s mallest of t he s mall ce nters u ntil a 
n o n-s mall ce nter is f or me d. T his pr ocess will be re peate d usi n g t he ce nters left o ut of t he 
pre vi o us pass. I n case of ties i n ce nter size, t he ce nter wit h t he s mallest ce nter c o de will 
be selecte d. If a n y ce nters are left o ut at t he e n d of t his pr ocess, t he y will be p o ole d wit h 
t he s mallest pse u d o- ce nters, or if n o pse u d o-ce nter e xists, t he y will be p o ole d wit h t he 
s mallest n o n-s mall ce nter.  
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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.
3 5


S A P 3 3 1- 2 0 1- 0 0 1 4 8
C o nfi de ntial - Pr o prietar y I nf or mati o n
3 6
2 8 Se p 2 0 2 2
T he pse u d o-ce nter will be use d f or all efficac y a nal yses w here t he m o del is a dj uste d f or 
st u d y ce nter.  
1 0. 4  
D e s cri pti v e St ati sti c s f or C o nti n u o u s a n d C at e g ori c al V ari a bl e s 
F or c o nti n u o us varia bles, descri pti ve statistics refer t o N (ie, n u m ber of s u bjects wit h 
n o n- missi n g val ue), mea n, sta n dar d de viati o n, me dia n, q uartile, mi ni m u m a n d 
ma xi m u m. F or cate g orical (e g, n o mi nal or dic h ot o m o us) varia bles, descri pti ve statistics 
refer t o fre q ue nc y distri b uti o n (e g, c o u nt a n d perce nta ge). U nless state d ot her wise, 
or di nal varia bles s uc h as assess me nt sc ores o n all t he scales use d f or t his trial will be 
treate d as c o nti n u o us. W here ver p ossi ble, ( m o del- base d) i nfere ntial statistics s h o ul d be 
acc o m pa nie d b y descri pti ve statistics f or prese ntati o n. Descri pti ve statistics ca n be use d 
al o ne f or data s u m mar y p ur p ose, f or e xa m ple, f or s u m marizi n g baseli ne de m o gra p hic 
c haracteristics, me dical hist or y, etc. F or t his st u d y, descri pti ve statistics will be pr o vi de d 
b y treat me nt (ie, se paratel y f or eac h treat me nt gr o u p). U nless s pecifie d ot her wise, t he 
de n o mi nat or use d f or calc ulati n g perce nta ge will be t he n u m ber of u ni q ue s u bjects i n t he 
a nal ysis sa m ple. A n d w he ne ver a p plica ble, a r o w of “ Missi n g/ U n k n o w n” will be 
prese nte d al o n g wit h r o ws of rec or de d o utc o mes f or t he ta b ulati o n of cate g orical 
varia bles.   
1 1
S c al e s: R ul e s f or S c ori n g a n d H a n dli n g of Mi s si n g D at a
1 1. 1  
A b err a nt B e h a vi or C h e c kli st ( A B C) S u b s c al e s
T he A B C scale has 5 8 ite ms, w hic h di vi de i nt o 5 s u bscales as f oll o ws: ( 1) Irrita bilit y, 
A gitati o n; ( 2) Let har g y, S ocial Wit h dra wal; ( 3) Stere ot y pic Be ha vi or; ( 4) H y peracti vit y, 
N o nc o m plia nce; a n d ( 5) I na p pr o priate S peec h. Eac h of t he 5 8 A B C ite ms is rate d o n a 4- 
p oi nt scale ( 0 = n ot at all a pr o ble m; 1 = t he be ha vi or is a pr o ble m, b ut sli g ht i n de gree; 
2 = t he pr o ble m is m o deratel y seri o us; 3 = t he pr o ble m is se vere i n de gree).
T he Irrita bilit y s u bscale ( A B C-I) t otal sc ore is t he s u m of t he rati n gs o ver 1 5 A B C ite ms 
as f oll o ws. Ite m 2: i nj uries self o n p ur p ose; Ite m 4: ver ball y or p h ysicall y a g gressi ve t o 
ot her c hil dre n or a d ults; Ite m 8: screa m i na p pr o priatel y; Ite m 1 0: te m per ta ntr u ms or 
o ut b ursts; Ite m 1 4: irrita ble a n d w hi n y; Ite m 1 9: yells at i na p pr o priate ti mes; Ite m 2 5: 
de presse d m o o d; Ite m 2 9: de ma n ds m ust be met i m me diatel y; Ite m 3 4: cries o ver mi n or 
a n n o ya nces a n d h urts; Ite m 3 6: m o o d c ha n ges q uic kl y; Ite m 4 1: cries a n d screa ms 
i na p pr o priatel y; Ite m 4 7: sta m ps  feet or ba n gs o bjects or sla m d o ors; Ite m 5 0: 
deli beratel y h urts hi mself/ herself; Ite m 5 2: d oes  p h ysical vi ole nce t o self; Ite m 5 7: has 
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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.
3 6


S A P 3 3 1- 2 0 1- 0 0 1 4 8
C o nfi de ntial - Pr o prietar y I nf or mati o n
3 7
2 8 Se p 2 0 2 2
te m per o ut b ursts or ta ntr u ms w he n he/s he d oes n ot get  o w n wa y. T h us, A B C-I t otal 
sc ore ra n ges fr o m 0 t o 4 5. F or a visit, a s u bject’s A B C-I t otal sc ore will be u ne val ua ble 
a n d set t o missi n g if less t ha n 1 2 of t he 1 5 ite ms are rec or de d f or t he visit. If 1 2, 1 3 or 1 4 
of t he 1 5 ite ms are rec or de d, t he A B C-I t otal sc ore will be t he mea n of t he rec or de d ite ms 
m ulti plie d b y 1 5 a n d t he n r o u n de d t o t he first deci mal place. T o state e q ui vale ntl y, if 
m ore t ha n 2 0 % of t he c o m p o ne nt ite ms ha ve missi n g rati n gs ( or sa y, n ot rec or de d), t he 
A B C-I t otal sc ore will be set t o missi n g; ot her wise t he t otal sc ore will be t he mea n of t he 
rec or de d ite ms m ulti plie d b y 1 5.    
T he A B C s u bscale sc ore o n S ocial Wit h dra wal, Stere ot y pic Be ha vi or, 
H y peracti vit y/ N o nc o m plia nce, a n d I na p pr o priate S peec h is res pecti vel y t he s u m of 
rati n gs o ver 1 6, 7, 1 6 a n d 4 i n di vi d ual A B C ite ms. F or eac h of t hese 4 s u bscales, if m ore 
t ha n 2 0 % of t he c o m p o ne nt ite ms ha ve missi n g rati n gs ( of n ote, at t he s u bject- visit le vel), 
t he s u bscale sc ore will be set t o missi n g; ot her wise t he s u bscale sc ore will be t he mea n of 
t he rec or de d ite ms m ulti plie d b y t he t otal n u m ber of c o m p o ne nt ite ms f or t he s u bscale.    
1 1. 2  
Cli ni c al Gl o b al I m pr e s si o n s - S e v erit y ( C GI- S)
T he se verit y of ill ness f or s u bjects wit h A S D will be rate d usi n g t he C GI- S wit h a f oc us 
o n s y m pt o ms of irrita bilit y. T o perf or m t his assess me nt, t he rater or i n vesti gat or will 
a ns wer t he f oll o wi n g q uesti o n: “ C o nsi deri n g y o ur t otal cli nical e x perie nce wit h t his 
partic ular p o p ulati o n, h o w ill is t he patie nt at t his ti me wit h re gar d t o s y m pt o ms of 
irrita bilit y?” Res p o nse c h oices i ncl u de: 0 = n ot assesse d; 1 = n or mal, n ot at all ill; 
2 = b or derli ne; 3 = mil dl y ill; 4 = m o deratel y ill; 5 = mar ke dl y ill; 6 = se verel y ill; a n d 
7 = a m o n g t he m ost e xtre mel y ill patie nts. T he res p o nse c h oice 0 ( = n ot assesse d) will be 
set t o missi n g. T he C GI- S is t h us a 7- p oi nt scale fr o m 1 t o 7, a n d t he C GI- S sc ore ra n ges 
fr o m 1 t o 7.  
1 1. 3 
P e di atri c Q u alit y of Lif e I n v e nt or y ( P e d s Q L)
Q ualit y of life will be assesse d f or s u bjects via pare nt pr o x y re p ort usi n g t he Pe ds Q L ™ 
Ge neric C ore Scales Versi o n 4. 0 f or t he c orres p o n di n g a ge gr o u p ( Tee ns a ge d 1 3 t o 1 8, 
C hil dre n a ge d 8 t o 1 2, Y o u n g C hil dre n a ge d 5 t o 7). T he “ac ute” versi o n meas uri n g t he 
past se ve n da ys will be use d. T he 2 3-ite m Pe ds Q L Ge neric C ore Scale meas ures healt h-
relate d q ualit y of life acr oss 4 di me nsi o ns, c o nsisti n g of a n 8-ite m P h ysical F u ncti o n, a 
5-ite m E m oti o nal F u ncti o n, a 5-ite m S ocial F u ncti o n, a n d a 5-ite m Sc h o ol F u ncti o n. F or 
c hil dre n a n d a d olesce nts a ge d ≥ 8, eac h ite m will be rate d o n a 5- p oi nt Li kert scale fr o m 
0 t o 4, wit h a sc ore of 0 re prese nti n g “ Ne ver” a n d 4 re prese nti n g “ Al m ost Al wa ys”. F or 
y o u n g c hil dre n a ge d 5 t o 7, t o facilitate t heir c o m pre he nsi o n, eac h ite m will be rate d o n a 
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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.
3 7


S A P 3 3 1- 2 0 1- 0 0 1 4 8
C o nfi de ntial - Pr o prietar y I nf or mati o n
3 8
2 8 Se p 2 0 2 2
3- p oi nt Li kert scale, wit h a sc ore of 0 re prese nti n g “ N ot at all”, 2 re prese nti n g 
“ S o meti mes”, a n d 4 re prese nti n g “ A l ot”. Ite ms m ust be re verse d sc ore d a n d li nearl y 
tra nsf or me d t o a 0 t o 1 0 0 scale as f oll o ws: 0 = 1 0 0, 1 = 7 5, 2 = 5 0, 3 = 2 5 a n d 4 = 0. T he 
tra nsf or me d scale will be use d f or t he sc ori n g of t he f oll o wi n g varia bles of i nterest.   
1)
T he Pe ds Q L Ge neric C ore Scale A vera ge Sc ore is t he a vera ge of t he tra nsf or me d 
sc ore o ver 2 3 ite ms acr oss t he 4 di me nsi o ns as af ore me nti o ne d. 
2)
T he Pe ds Q L Ps yc h os ocial Healt h A vera ge Sc ore is t he a vera ge of t he tra nsf or me d 
sc ore o ver 1 5 ite ms acr oss 3 di me nsi o ns ( E m oti o nal F u ncti o n, S ocial F u ncti o n 
a n d Sc h o ol F u ncti o n). 
3)
T he Pe ds Q L P h ysical Healt h A vera ge Sc ore is t he a vera ge of t he tra nsf or me d 
sc ore o ver t he 8 ite ms fr o m t he P h ysical F u ncti o n di me nsi o n. 
4)
T he Pe ds Q L E m oti o nal F u ncti o n A vera ge Sc ore is t he a vera ge of t he tra nsf or me d 
sc ore o ver t he 5 ite ms fr o m t he E m oti o nal F u ncti o n di me nsi o n. 
5)
T he Pe ds Q L S ocial F u ncti o n A vera ge Sc ore is t he a vera ge of t he tra nsf or me d 
sc ore o ver t he 5 ite ms fr o m t he S ocial F u ncti o n di me nsi o n. 
6)
T he Pe ds Q L Sc h o ol F u ncti o n A vera ge Sc ore is t he a vera ge of t he tra nsf or me d 
sc ore o ver t he 5 ite ms fr o m t he Sc h o ol F u ncti o n di me nsi o n. 
Q ualit y of life f u ncti o n f or t he s u bject’s fa mil y will be assesse d via pare nt re p ort usi n g 
t he Pe ds Q L 2. 0 Fa mil y I m pact M o d ule meas uri n g t he 8 di me nsi o ns ( d o mai ns) as 
f oll o ws:  P h ysical F u ncti o ni n g ( 6 ite ms), E m oti o nal F u ncti o ni n g ( 5 ite ms), S ocial 
F u ncti o ni n g ( 4 ite ms), C o g niti ve F u ncti o ni n g ( 5 ite ms), C o m m u nicati o n ( 3 ite ms), W orr y 
( 5 ite ms), Dail y Acti vities ( 3 ite ms), a n d Fa mil y Relati o ns hi ps ( 5 ite ms) t hat are i m pacte d 
b y t he c hil d’s disease. T he “ac ute” versi o n meas uri n g t he past se ve n da ys will be use d. 
Eac h ite m will be rate d o n a 5- p oi nt Li kert scale, wit h a sc ore of 0 re prese nti n g “ Ne ver” 
a n d 4 re prese nti n g “ Al m ost Al wa ys”. Ite ms m ust be re verse d sc ore d a n d li nearl y 
tra nsf or me d t o a 0 t o 1 0 0 scale as f oll o ws: 0 = 1 0 0, 1 = 7 5, 2 = 5 0, 3 = 2 5 a n d 4 = 0. T he 
tra nsf or me d scale will be use d f or t he sc ori n g of t he f oll o wi n g varia bles of i nterest.   
7)
Fa mil y I m pact M o d ule A vera ge Sc ore is t he a vera ge of t he tra nsf or me d sc ore 
o ver 3 6 ite ms acr oss t he 8 di me nsi o ns as af ore me nti o ne d. 
8)
Pare nt H R Q L A vera ge Sc ore is t he a vera ge of t he tra nsf or me d sc ore o ver 
2 0 ite ms acr oss t he 4 di me nsi o ns ( P h ysical, E m oti o nal, S ocial a n d C o g niti ve 
f u ncti o ni n g). 
9)
Fa mil y F u ncti o ni n g A vera ge Sc ore is t he a vera ge of t he tra nsf or me d sc ore o ver 
8 ite ms acr oss t he 2 di me nsi o ns ( Dail y Acti vities a n d Fa mil y Relati o ns hi p).
All t he a b o ve c o nstr ucte d varia bles ta ke val ues (a vera ge sc ores) fr o m 0 t o 1 0 0. Hi g her 
sc ores i n dicate better healt h-relate d q ualit y of life. N ote t hat, if m ore t ha n 5 0 % of t he 
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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.
3 8


S A P 3 3 1- 2 0 1- 0 0 1 4 8
C o nfi de ntial - Pr o prietar y I nf or mati o n
3 9
2 8 Se p 2 0 2 2
c o m p o ne nt ite ms i n t he sc ori n g (ie, c o nstr ucti n g t he a vera ge sc ore of i nterest as descri be d 
a b o ve) are n ot rate d, t he a vera ge sc ore will be set t o missi n g.    
1 1. 4 
P e di atri c A n xi et y R ati n g S c al e ( P A R S)
T he P A R S is a cli nicia n-rate d i nstr u me nt f or assessi n g t he se verit y of a n xiet y s y m pt o ms 
ass ociate d wit h c o m m o n D S M- 5  a n xiet y dis or ders i n c hil dre n. T he P A R S c o ntai ns t w o 
c o m p o ne nts: a s y m pt o m c hec klist a n d se verit y ite ms. T he c hec klist has 5 0 ite ms of 
s y m pt o ms, eac h ite m will be rate d b y t he rater (i nter vie wi n g cli nicia n) as prese nt or 
a bse nt ( yes/ n o). T he P A R S has 7 se verit y ite ms as f oll o ws: 1) O verall n u m ber of a n xiet y 
s y m pt o ms; 2) O verall fre q ue nc y of a n xiet y s y m pt o ms; 3) O verall se verit y of a n xiet y 
feeli n gs; 4) O verall se verit y of p h ysical s y m pt o ms of a n xiet y; 5) O verall a v oi da nce of 
a n xiet y- pr o v o ki n g sit uati o ns; 6) I nterfere nce wit h fa mil y relati o ns hi p a n d/ or perf or ma nce 
at h o me; 7) I nterfere nce wit h peer a n d a d ult relati o ns hi p a n d/ or perf or ma nce o utsi de of 
h o me. F or eac h of t he 7 se verit y ite ms, se verit y is rate d wit h a 6- p oi nt Li kert scale fr o m 
0 t o 5 ( 0 f or n o ne, a n d 1 t o 5 f or mi ni mal t o e xtre me). T he P A R S t otal sc ore is calc ulate d 
as s u m mi n g 5 (s pecificall y, Ite m 2, 3, 5, 6 a n d 7) of t he 7 se verit y ite ms, a n d t h us t he 
t otal sc ore ra n ges fr o m 0 t o 2 5. If 3 or m ore o ut of t he 5 s u m ma n ds ha ve missi n g val ues, 
t he P A R S t otal sc ore will be set t o missi n g; ot her wise t he P A R S t otal sc ore will be t he 
mea n of t he rate d ite ms m ulti plie d b y 5.     
1 1. 5 
Si m p s o n A n g u s S c al e ( S A S)
T he S A S will be use d t o e val uate e xtra p yra mi dal s y m pt o ms ( E P S). It c o nsists of a list of 
1 0 s y m pt o ms of Par ki ns o nis m ( gait, ar m dr o p pi n g, s h o ul der s ha ki n g, el b o w ri gi dit y, 
wrist ri gi dit y, hea d r otati o n, gla bella ta p, tre m or, sali vati o n, a n d a kat hisia). Eac h ite m 
will be rate d o n a 5- p oi nt Li kert scale, wit h 0 re prese nti n g a bse nce of s y m pt o ms a n d 
4 re prese nti n g a se vere c o n diti o n. T he S A S t otal sc ore is t he s u m of rati n gs o ver all 
1 0 ite ms, wit h p ossi ble t otal sc ores ra n gi n g fr o m 0 t o 4 0. T he S A S t otal sc ore will be 
u n-e val ua ble if less t ha n 8 of t he 1 0 ite ms are rec or de d. If 8 or 9 of t he 1 0 ite ms are 
rec or de d, t he t otal sc ore will be t he mea n of t he rec or de d ite ms m ulti plie d b y 1 0 a n d t he n 
r o u n de d t o t he first deci mal place.
1 1. 6  
A b n or m al I n v ol u nt ar y M o v e m e nt S c al e ( AI M S)
T he AI M S is a 1 2-ite m scale. T he first 1 0 ite ms are rate d o n a Li kert 5- p oi nt scale fr o m 
0 t o 4 ( 0 = best, 4 = w orst). A n ite m sc ore of 0, de pe n di n g o n s pecific ite m, mea ns eit her 
“ n o a b n or mal I n v ol u ntar y m o ve me nt ( AI M)” or “ n o i nca pacitati o n d ue t o AI M” or “ n o 
a ware ness of AI M”. A n ite m sc ore of 4 mea ns eit her “se vere AI M” or “se vere 
i nca pacitati o n d ue t o AI M” or “ bei n g a ware of, a n d se vere distress ca use d b y AI M”. 
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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.
3 9


S A P 3 3 1- 2 0 1- 0 0 1 4 8
C o nfi de ntial - Pr o prietar y I nf or mati o n
4 0
2 8 Se p 2 0 2 2
Ite ms 1 1 a n d 1 2 are relate d t o de ntal stat us, ta ki n g dic h ot o m o us res p o nse: 0 = n o a n d 
1 = yes. T he AI M S t otal sc ore is t he s u m of t he rati n gs o ver t he first 7 ite ms, wit h 
p ossi ble t otal sc ore ra n gi n g fr o m 0 t o 2 8. T he AI M S t otal Sc ore will be u n-e val ua ble if 
less t ha n 6 of t he first 7 ite ms are rec or de d. If 6 of t he ite ms are rec or de d, t he n t he t otal 
sc ore will be t he mea n of t he rec or de d ite ms m ulti plie d b y 7 a n d t he n r o u n de d t o t he first 
deci mal place.
1 1. 7  
B ar n e s A k at hi si a R ati n g S c al e ( B A R S)
T he B A R S c o nsists of 4 ite ms relate d t o a kat hisia as f oll o ws. Ite m 1: o bjecti ve 
o bser vati o n of a kat hisia b y t he i n vesti gat or; Ite m 2: s u bjecti ve feeli n gs of restless ness b y 
t he s u bject; Ite m 3: s u bjecti ve distress d ue t o a kat hisia; a n d Ite m 4: gl o bal cli nical 
assess me nt of a kat hisia. T he first 3 ite ms will be rate d o n a 4- p oi nt Li kert scale fr o m 0 t o 
3, wit h 0 re prese nti n g a bse nce of s y m pt o ms a n d 3 re prese nti n g a se vere c o n diti o n. T he 
B A R S gl o bal cli nical assess me nt sc ore refers t o t he rati n gs fr o m t he f o urt h ite m Gl o bal 
Cli nical Assess me nt of a kat hisia, w hic h is a 6- p oi nt Li kert scale fr o m 0 t o 5, wit h 
0 re prese nti n g a bse nce of s y m pt o ms a n d 5 re prese nti n g se vere a kat hisia. T h us, t he B A R S 
gl o bal cli nical assess me nt sc ore ra n ges 0 t o 5.  
1 1. 8  
C ol u m bi a- S ui ci d e S e v erit y R ati n g S c al e ( C- S S R S)
S uici dalit y will be m o nit ore d d uri n g t he trial usi n g t he C- S S R S ( C hil d Versi o n). 
S uici dalit y data will be c ollecte d at all t he visits (i ncl u di n g all t he sc he d ule d visits, t he 
E T visit, a n d t he f oll o w- u p visit). T his trial will use t he “ baseli ne/scree ni n g” a n d “ Si nce 
Last Visit” versi o ns of t he scale. T he “ baseli ne/scree ni n g” versi o n, w hic h assesses t he 
lifeti me e x perie nce of t he s u bject wit h s uici de e ve nts a n d s uici dal i deati o n a n d t he 
occ urre nce of s uici de e ve nts a n d/ or i deati o n wit hi n a s pecifie d peri o d pri or t o e ntr y i nt o 
t he trial, will be c o m plete d f or all s u bjects at scree ni n g t o deter mi ne eli gi bilit y. A n y 
s u bject wit h acti ve s uici dal i deati o n wit hi n t he last 3 m o nt hs, s uici dal be ha vi ors wit hi n 
t he last year, or w h o i n t he cli nical j u d g me nt of t he i n vesti gat or prese nts a seri o us ris k of 
s uici de s h o ul d be e xcl u de d fr o m t he trial. T he “ Si nce Last Visit” C- S S R S f or m will be 
c o m plete d at all ot her visits.  
S uici dal i deati o n has 5 t y pes of i deati o n wit h i ncreasi n g se verit y fr o m T y pe 1 t o T y pe 5. 
A s u bject ca n re p ort or ca n be rate d wit h m ulti ple t y pes of i deati o n at t he visit le vel. T he 
m ost se vere t y pe of i deati o n o n t he s u bject at t he visit le vel will be use d f or data 
s u m mar y p ur p ose. T he varia ble I nte nsit y of S uici dal I deati o n als o has 4 ot her 
di me nsi o ns, w hic h are t he fre q ue nc y of i deati o n, d urati o n of i deati o n, c o ntr olla bilit y a n d 
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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.
4 0


S A P 3 3 1- 2 0 1- 0 0 1 4 8
C o nfi de ntial - Pr o prietar y I nf or mati o n
4 1
2 8 Se p 2 0 2 2
deterre nts, eac h of w hic h is rate d o n a scale of 0 t o 5 or 1 t o 5, wit h hi g her i nte gers 
re prese nti n g m ore w orse cli nical o utc o mes. 
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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.
4 1


S A P 3 3 1- 2 0 1- 0 0 1 4 8
C o nfi de ntial - Pr o prietar y I nf or mati o n
4 2
2 8 Se p 2 0 2 2
1 2
R ef er e n c e s
1       Cli nical Pr ot oc ol, O P D C Pr ot oc ol N o: 3 3 1- 2 0 1- 0 0 1 4 8, Versi o n 6. 0. A P hase 3, 
M ultice nter, Ra n d o mize d, D o u ble- Bli n d, Place b o-c o ntr olle d Trial of Bre x pi praz ole i n 
Treat me nt of C hil dre n a n d A d olesce nts wit h Irrita bilit y Ass ociate d wit h A utis m 
S pectr u m Dis or der. 0 7 J ul 2 0 2 2.
2     I C H E 9 ( R 1), Esti ma n ds a n d Se nsiti vit y A nal ysis i n Cli nical Trials, Ste p 2 Draft 
G ui deli ne, 2 0 1 7.
3
Si d di q ui O, H u n g J H M, O' Neill R. M M R M vs. L O C F:  A c o m pre he nsi ve c o m paris o n 
base d o n si m ulati o n st u d y a n d 2 5 N D A datasets. J Bi o p har mace utical Stats. 2 0 0 9; 
1 9( 2): 2 2 7- 4 6.
4       Little RJ A. M o deli n g t he dr o p- o ut mec ha nis m i n re peate d meas ures st u dies. J A m 
Stat Ass oc. 1 9 9 5; 9 0: 1 1 1 2- 2 1.
5
Di g gle P, Ke n war d M G. I nf or mati ve dr o p- o ut i n l o n git u di nal data a nal ysis. A p plie d 
Statistics. 1 9 9 4; 4 3: 4 9- 9 3.
6
Little RJ A. Patter n- mi xt ure m o dels f or m ulti variate i nc o m plete data. J A m Stat 
Ass oc. 1 9 9 3; 8 8: 1 2 5- 3 4.
7
He de ker D, Gi b b o ns R D. A p plicati o n of ra n d o m effects patter n- mi xt ure m o dels f or 
missi n g data i n l o n git u di nal st u dies. Ps yc h ol o gical Met h o ds. 1 9 9 7; 2: 6 4- 7 8.
8
Ali M W, Si d di q ui O. M ulti ple i m p utati o n c o m pare d wit h s o me i nf or mati o n dr o p o ut 
pr oce d ures i n t he esti mati o n a n d c o m paris o n of rates of c ha n ge i n l o n git u di nal 
cli nical trials wit h dr o p o uts. J Bi o p har mace utical Stats. 2 0 0 0; 1 0( 2): 1 6 5- 8 1.
9
W u M C, Baile y K R. Esti mati o n a n d c o m paris o n of c ha n ges i n t he prese nce of 
i nf or mati ve ri g ht ce ns ori n g:  C o n diti o nal li near m o del. Bi o metrics. 1 9 8 9; 4 5: 9 3 9- 5 5.
1 0
Va n Eltere n, P H. O n t he c o m bi nati o n of i n de pe n de nt t w o sa m ple tests of Wilc o x o n. 
B ull I nt Stat I nst. 1 9 6 0; 3 7: 3 5 1- 6 1.
1 1
Me hr otra D, Li X, Li u J, L u K. A nal ysis of L o n git u di nal Cli nical Trials wit h Missi n g 
Data Usi n g M ulti ple I m p utati o n i n C o nj u ncti o n wit h R o b ust Re gressi o n. Bi o metrics 
2 0 1 2; 6 8: 1 2 5 0- 1 2 5 9. 
1 2
C orti na, J. M., & N o uri, H. ( 2 0 0 0). Effect Size f or A N O V A Desi g ns . T h o usa n d Oa ks, 
Calif.: Sa ge P u blicati o ns. 
1 3   G o ul d, A. L., & S hi h, W.J. Sa m ple- Size Re-esti mati o n wit h o ut U n bli n di n g f or 
N or mall y Distri b ute d Data wit h U n k n o w n Varia nce. C o m m u nicati o n i n Statistics -
T he or y a n d Met h o ds. 1 9 9 2; 2 1( 1 0): 2 8 3 3- 2 8 5 3.   
1 4
H u g hes H K, Ka hl L K. T he J o h ns H o p ki ns H os pital: T he Harriet La ne Ha n d b o o k. 
2 1st e diti o n. 2 0 1 5.
1 5
Fl y n n J T, Kael ber D C, Ba ker- S mit h C M, Bl o we y D, Carr oll A E, Da niels S R, et al. 
Cli nical practice g ui deli ne f or scree ni n g a n d ma na ge me nt of hi g h bl o o d press ure i n 
c hil dre n a n d a d olesce nts. Pe diatrics. 2 0 1 7; 1 4 0( 3).
1 6
S o g hier L, P ha m K, R o o ne y S. Refere nce ra n ge val ues f or pe diatric care. T he 
A merica n Aca de m y of Pe diatrics. 2 0 1 4.
1 7
C o va nce. Ce ntral la b orat or y ser vices ma n ual; Pr ot oc ol 3 3 1- 2 0 1- 0 0 1 4 8. Create d 
2 8 Se p 2 0 1 9, re vise d 1 1 Dec 2 0 1 9.
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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.
4 2


S A P 3 3 1- 2 0 1- 0 0 1 4 8
C o nfi de ntial - Pr o prietar y I nf or mati o n
4 3
2 8 Se p 2 0 2 2
1 8
A merica n Dia betes Ass ociati o n. 2. Classificati o n a n d Dia g n osis of Dia betes: 
Sta n dar ds of Me dical Care i n Dia betes- 2 0 1 9. Dia betes Care. 2 0 1 9; 4 2( S u p pl 1): 
S 1 3- S 2 8.
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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.
4 3








S A P 3 3 1- 2 0 1- 0 0 1 4 8
C o nfi de ntial - Pr o prietar y I nf or mati o n
4 7
2 8 Se p 2 0 2 2
A p pe n di x 3  
Criteri a f or I de ntif yi n g E C G Me as ure me nt of P ote nti al 
Cli nic al Rele v a nce
V ari a ble
Criteri o n V al ue a
C h a n ge Rel ati ve t o B aseli ne a
R h yt h m
Si n us tac h ycar dia b
≥ 1 1 0 b p m
i ncrease of ≥ 1 5 b p m
Si n us bra d ycar dia c
≤ 6 0 b p m
decrease of ≥ 1 5 b p m
S u pra ve ntric ular pre mat ure beat
all
n ot prese nt  prese nt
Ve ntric ular pre mat ure beat
all
n ot prese nt  prese nt
S u pra ve ntric ular tac h ycar dia
all
n ot prese nt  prese nt
Ve ntric ular tac h ycar dia
all
n ot prese nt  prese nt
Atrial fi brillati o n
all
n ot prese nt  prese nt
Atrial fl utter
all
n ot prese nt  prese nt
C o n d ucti o n
1° atri o ve ntric ular bl oc k
P R ≥ 2 0 0 msec
i ncrease of ≥ 5 0 msec
2° atri o ve ntric ular bl oc k
all
n ot prese nt  prese nt
3° atri o ve ntric ular bl oc k
all
n ot prese nt  prese nt
Left b u n dle- bra nc h bl oc k
all
n ot prese nt  prese nt
Ri g ht b u n dle- bra nc h bl oc k
all
n ot prese nt  prese nt
Pre-e xcitati o n s y n dr o me
all
n ot prese nt  prese nt
Ot her i ntra ve ntric ular c o n d ucti o n 
bl oc k d
Q R S ≥ 1 2 0 msec
i ncrease of ≥ 2 0 msec
I nf arcti o n
Ac ute or s u bac ute
all
n ot prese nt  prese nt
Ol d
all
n ot prese nt  prese nt
≥ 1 2 wee ks p ost-trial e ntr y
S T/ T M or p h ol o gic al
M y ocar dial Isc he mia
all
n ot prese nt  prese nt
S y m metrical T- wa ve i n versi o n
all
n ot prese nt  prese nt
I ncrease i n Q Tc
Q Tc F ≥ 4 5 0 msec f or 
males, ≥ 4 7 0 msec 
f or fe males
i ncrease of 6 0 msec fr o m 
baseli ne
aT he criteri o n val ue a n d c ha n ge relati ve t o baseli ne re prese nte d i n t his ta ble are i nte n de d t o i de ntif y o n-
treat me nt val ues o utsi de of n or mal c ha n ges a n d t hat c o ul d p ote ntiall y be cli nicall y rele va nt. I n or der 
t o be i de ntifie d as p ote ntiall y cli nicall y rele va nt, t he o n-treat me nt val ue m ust meet t he “ Criteri o n 
Val ue” a n d als o re prese nt a c ha n ge fr o m t he s u bject’s baseli ne val ue of at least t he ma g nit u de s h o w n 
i n t he “ C ha n ge Relati ve t o Baseli ne” c ol u m n. W he n e val uati n g t hese val ues t he e m oti o nal state of t he 
s u bject m ust be ta ke n i nt o c o nsi derati o n (e g, cr yi n g, screa mi n g) a n d d oc u me nte d as a p plica ble.
b N o c urre nt dia g n osis of s u pra ve ntric ular tac h ycar dia, ve ntric ular tac h ycar dia, atrial fi brillati o n, atrial 
fl utter, or ot her r h yt h m a b n or malit y.
cN o c urre nt dia g n osis of atrial fi brillati o n, atrial fl utter, or ot her r h yt h m a b n or malit y.
d N o c urre nt dia g n osis of left b u n dle bra nc h bl oc k or ri g ht b u n dle bra nc h bl oc k.
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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.
4 7


S A P 3 3 1- 2 0 1- 0 0 1 4 8
C o nfi de ntial - Pr o prietar y I nf or mati o n
4 8
2 8 Se p 2 0 2 2
1 4
Pr o p o s e d Li st of S u m m ar y T a bl e s 
C T- 1. 1   S u bject Dis p ositi o n
C T- 1. 2   S u bject Dis p ositi o n b y Ce nter 
C T- 1. 3   S u bject C o m pleti o n Rates b y Wee k ( Ra n d o mize d Sa m ple)
C T- 1. 4. 1   E nr oll me nt b y A ge Gr o u p ( Ra n d o mize d Sa m ple)
C T- 1. 4. 2   E nr oll me nt b y B o d y Wei g ht Gr o u p ( Ra n d o mize d Sa m ple)
C T- 1. 5   S u m mar y of Pr o p orti o n of t he Face-t o- Face a n d Virt ual Visits b y St u d y Wee k ( Ra n d o mize d 
Sa m ple)
C T- 2. 1   Reas o ns f or Disc o nti n uati o n ( Ra n d o mize d Sa m ple)
C T- 2. 2   Reas o ns f or Disc o nti n uati o n d ue t o C O VI D- 1 9 ( Ra n d o mize d Sa m ple)
C T- 3. 1   De m o gra p hic C haracteristics ( Ra n d o mize d Sa m ple)
C T- 3. 2. 1   Me dical Hist or y ( Ra n d o mize d Sa m ple)
C T- 3. 2. 2   Ps yc hiatric Hist or y ( Ra n d o mize d Sa m ple) 
C T- 3. 3   Baseli ne Ps yc hiatric Scale E val uati o n ( Ra n d o mize d Sa m ple)  
C T- 4. 1. 1   C o nc o mita nt Me dicati o ns: Me dicati o ns Ta ke n Pri or t o Start of St u d y T hera p y ( Safet y Sa m ple)
C T- 4. 1. 2   C o nc o mita nt Me dicati o ns: Me dicati o ns Ta ke n D uri n g St u d y T hera p y ( Safet y Sa m ple)
C T- 4. 1. 3   C o nc o mita nt Me dicati o ns: Me dicati o ns Ta ke n P ost St u d y T hera p y ( Safet y Sa m ple)
C T- 5. 1     S u m mar y of Efficac y Res ults at Wee k 8 of t he D o u ble- Bli n d Treat me nt Peri o d ( Efficac y 
Sa m ple)
C T- 5. 2. 1   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C-Irrita bilit y S u bscale Sc ore - M M R M, U N ( Efficac y Sa m ple)
C T- 5. 2. 2   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C-Irrita bilit y S u bscale Sc ore - M M R M, T O E P H E m pirical ( Efficac y Sa m ple)
C T- 5. 2. 3   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C-Irrita bilit y S u bscale Sc ore - M M R M, A R H 1 E m pirical ( Efficac y Sa m ple)
C T- 5. 2. 4   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C-Irrita bilit y S u bscale Sc ore - M M R M, C S H E m pirical ( Efficac y Sa m ple)
C T- 5. 2. 5   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C-Irrita bilit y S u bscale Sc ore - M M R M, D D F M = S A T T E R T H W AI T E ( Efficac y Sa m ple)
C T- 5. 2. 6. 1   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C-Irrita bilit y S u bscale Sc ore - A N C O V A, L O C F ( Efficac y Sa m ple)
C T- 5. 2. 6. 2   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C-Irrita bilit y S u bscale Sc ore - A N C O V A, O C ( Efficac y Sa m ple)
C T- 5. 2. 7. 1   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C-Irrita bilit y S u bscale Sc ore E xcl u di n g Re m ote Assess me nts W hic h S h o ul d Be I n-cli nic 
per Pr ot oc ol - M M R M, U N ( Efficac y Sa m ple)
C T- 5. 2. 7. 2   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C-Irrita bilit y S u bscale Sc ore N o n- C O VI D Data Set - M M R M, U N ( Efficac y Sa m ple)
C T- 5. 2. 7. 3   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C-Irrita bilit y S u bscale Sc ore N o n- C O VI D Sa m ple - M M R M, U N ( Efficac y Sa m ple)
C T- 5. 2. 7. 4   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C-Irrita bilit y S u bscale Sc ore i n S u bjects W h o C o m plete d or Disc o nti n ue d o n or After 
Marc h 1 3, 2 0 2 0 - M M R M, U N ( Efficac y Sa m ple)
C T- 5. 2. 7. 5   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C-Irrita bilit y S u bscale Sc ore i n S u bjects W h o C o m plete d or Disc o nti n ue d Bef ore Marc h 
1 3, 2 0 2 0 - M M R M, U N ( Efficac y Sa m ple)
C T- 5. 3. 1   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n Cli nical Gl o bal I m pressi o n - Se verit y ( C GI- S) Sc ore - M M R M, U N ( Efficac y Sa m ple)
C T- 5. 3. 2   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n Cli nical Gl o bal I m pressi o n - Se verit y ( C GI- S) Sc ore - A N C O V A, L O C F ( Efficac y Sa m ple)
C T- 5. 3. 3   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n Cli nical Gl o bal I m pressi o n - Se verit y ( C GI- S) Sc ore - A N C O V A, O C ( Efficac y Sa m ple)
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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.
4 8


S A P 3 3 1- 2 0 1- 0 0 1 4 8
C o nfi de ntial - Pr o prietar y I nf or mati o n
4 9
2 8 Se p 2 0 2 2
C T- 5. 3. 4. 1   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n Cli nical Gl o bal I m pressi o n - Se verit y ( C GI- S) Sc ore E xcl u di n g Re m ote Assess me nts W hic h 
S h o ul d Be I n-cli nic per Pr ot oc ol - M M R M, U N ( Efficac y Sa m ple)
C T- 5. 3. 4. 2   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n Cli nical Gl o bal I m pressi o n - Se verit y ( C GI- S) Sc ore N o n- C O VI D Data Set - M M R M, U N 
( Efficac y Sa m ple)
C T- 5. 3. 4. 3   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n Cli nical Gl o bal I m pressi o n - Se verit y ( C GI- S) Sc ore N o n- C O VI D Sa m ple - M M R M, U N 
( Efficac y Sa m ple)
C T- 5. 3. 4. 4   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n Cli nical Gl o bal I m pressi o n - Se verit y ( C GI- S) Sc ore i n S u bjects W h o C o m plete d or 
Disc o nti n ue d o n or After Marc h 1 3, 2 0 2 0 - M M R M, U N ( Efficac y Sa m ple)
C T- 5. 3. 4. 5   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n Cli nical Gl o bal I m pressi o n - Se verit y ( C GI- S) Sc ore i n S u bjects W h o C o m plete d or 
Disc o nti n ue d Bef ore Marc h 1 3, 2 0 2 0 - M M R M, U N ( Efficac y Sa m ple)
C T- 5. 4. 1    S u m mar y of Pr o p orti o n of Res p o n ders defi ne d as Ha vi n g at Least 2 5 % Re d ucti o n i n A B C-
Irrita bilit y S u bscale Sc ore a n d at Least 1 P oi nt Re d ucti o n i n C GI- S Sc ore d uri n g t he D o u ble- Bli n d 
Treat me nt Peri o d b y St u d y Wee k - L O C F ( Efficac y Sa m ple) 
C T- 5. 4. 2    S u m mar y of Pr o p orti o n of Res p o n ders defi ne d as Ha vi n g at Least 2 5 % Re d ucti o n i n A B C-
Irrita bilit y S u bscale Sc ore a n d at Least 1 P oi nt Re d ucti o n i n C GI- S Sc ore d uri n g t he D o u ble- Bli n d 
Treat me nt Peri o d b y St u d y Wee k - O C ( Efficac y Sa m ple) 
C T- 5. 5   S u m mar y of Mea n C ha n ge fr o m Baseli ne t o t he E n d p oi nt ( Wee k 8) of t he D o u ble- Bli n d 
Treat me nt Peri o d i n Pe diatric A n xiet y Rati n g Scale ( P A R S) T otal Sc ore - A N C O V A, L O C F ( Efficac y 
Sa m ple) 
C T- 5. 6. 1   S u m mar y of Mea n C ha n ge fr o m Baseli ne t o t he E n d p oi nt ( Wee k 8) of t he D o u ble- Bli n d 
Treat me nt Peri o d i n Pe ds Q L Ge neric C ore Scale A vera ge Sc ore - A N C O V A, L O C F ( Efficac y Sa m ple) 
C T- 5. 6. 2   S u m mar y of Mea n C ha n ge fr o m Baseli ne t o t he E n d p oi nt ( Wee k 8) of t he D o u ble- Bli n d 
Treat me nt Peri o d i n Pe ds Q L Ps yc h os ocial Healt h A vera ge Sc ore - A N C O V A, L O C F ( Efficac y 
Sa m ple) 
C T- 5. 6. 3   S u m mar y of Mea n C ha n ge fr o m Baseli ne t o t he E n d p oi nt ( Wee k 8) of t he D o u ble- Bli n d 
Treat me nt Peri o d i n Pe ds Q L P h ysical Healt h A vera ge Sc ore - A N C O V A, L O C F ( Efficac y Sa m ple) 
C T- 5. 6. 4   S u m mar y of Mea n C ha n ge fr o m Baseli ne t o t he E n d p oi nt ( Wee k 8) of t he D o u ble- Bli n d 
Treat me nt Peri o d i n Pe ds Q L E m oti o nal F u ncti o n A vera ge Sc ore - A N C O V A, L O C F ( Efficac y 
Sa m ple) 
C T- 5. 6. 5   S u m mar y of Mea n C ha n ge fr o m Baseli ne t o t he E n d p oi nt ( Wee k 8) of t he D o u ble- Bli n d 
Treat me nt Peri o d i n Pe ds Q L S ocial F u ncti o n A vera ge Sc ore - A N C O V A, L O C F ( Efficac y Sa m ple) 
C T- 5. 6. 6   S u m mar y of Mea n C ha n ge fr o m Baseli ne t o t he E n d p oi nt ( Wee k 8) of t he D o u ble- Bli n d 
Treat me nt Peri o d i n Pe ds Q L Sc h o ol F u ncti o n A vera ge Sc ore - A N C O V A, L O C F ( Efficac y Sa m ple) 
C T- 5. 6. 7   S u m mar y of Mea n C ha n ge fr o m Baseli ne t o t he E n d p oi nt ( Wee k 8) of t he D o u ble- Bli n d 
Treat me nt Peri o d i n Pe ds Q L Fa mil y I m pact M o d ule A vera ge Sc ore - A N C O V A, L O C F ( Efficac y 
Sa m ple) 
C T- 5. 6. 8   S u m mar y of Mea n C ha n ge fr o m Baseli ne t o t he E n d p oi nt ( Wee k 8) of t he D o u ble- Bli n d 
Treat me nt Peri o d i n Pe ds Q L Pare nt H R Q L A vera ge Sc ore - A N C O V A, L O C F ( Efficac y Sa m ple) 
C T- 5. 6. 9   S u m mar y of Mea n C ha n ge fr o m Baseli ne t o t he E n d p oi nt ( Wee k 8) of t he D o u ble- Bli n d 
Treat me nt Peri o d i n Pe ds Q L Fa mil y F u ncti o ni n g A vera ge Sc ore - A N C O V A, L O C F ( Efficac y 
Sa m ple)
C T- 5. 7. 1   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C- S ocial Wit h dra wal S u bscale Sc ore - M M R M, U N ( Efficac y Sa m ple)
C T- 5. 7. 2   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C- Stere ot y pic Be ha vi or S u bscale Sc ore - M M R M, U N ( Efficac y Sa m ple)
C T- 5. 7. 3   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C- H y peracti vit y/ N o nc o m plia nce S u bscale Sc ore - M M R M, U N ( Efficac y Sa m ple)
C T- 5. 7. 4   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C- I na p pr o priate S peec h S u bscale Sc ore - M M R M, U N ( Efficac y Sa m ple)
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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.
4 9


S A P 3 3 1- 2 0 1- 0 0 1 4 8
C o nfi de ntial - Pr o prietar y I nf or mati o n
5 0
2 8 Se p 2 0 2 2
C T- 5. 8. 1    S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C-Irrita bilit y S u bscale Sc ore - MI, V A N E L T E R E N T E S T ( Efficac y Sa m ple)
C T- 5. 8. 2    S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C-Irrita bilit y S u bscale Sc ore - G E E ( Efficac y Sa m ple)
C T- 5. 8. 3    S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C-Irrita bilit y S u bscale Sc ore - W G E E ( Efficac y Sa m ple)
C T- 5. 9. 1   Se nsiti vit y A nal ysis of M N A R usi n g Patter n Mi xt ure M o del wit h M ulti ple I m p utati o n ( Delta 
Met h o d 1) i n A B C-Irrita bilit y S u bscale Sc ore Ass u me All Dr o p o uts as M N A R ( Efficac y Sa m ple)
C T- 5. 9. 2    Se nsiti vit y A nal ysis of M N A R usi n g Patter n Mi xt ure M o del wit h M ulti ple I m p utati o n ( Delta 
Met h o d 2) i n A B C-Irrita bilit y S u bscale Sc ore Ass u me All Dr o p o uts as M N A R ( Efficac y Sa m ple)
C T- 5. 9. 3    Se nsiti vit y A nal ysis of M N A R usi n g Patter n Mi xt ure M o del wit h M ulti ple I m p utati o n ( Delta 
Met h o d 1) i n A B C-Irrita bilit y S u bscale Sc ore Dr o p o ut d ue t o A E or Lac k of Efficac y ( L O E) or 
Wit h dra wal of C o nse nt as M N A R ( Efficac y Sa m ple)
C T- 5. 9. 4    Se nsiti vit y A nal ysis of M N A R usi n g Patter n Mi xt ure M o del wit h M ulti ple I m p utati o n ( Delta 
Met h o d 2) i n A B C-Irrita bilit y S u bscale Sc ore Dr o p o ut d ue t o A E or Lac k of Efficac y ( L O E) or 
Wit h dra wal of C o nse nt as M N A R ( Efficac y Sa m ple)
C T- 5. 9. 5   Se nsiti vit y A nal ysis of M N A R usi n g Patter n Mi xt ure M o del wit h M ulti ple I m p utati o n ( Delta 
Met h o d 1) i n A B C-Irrita bilit y S u bscale Sc ore Dr o p o uts d ue t o A E or L O E as M N A R ( Efficac y 
Sa m ple)
C T- 5. 9. 6   Se nsiti vit y A nal ysis of M N A R usi n g Patter n Mi xt ure M o del wit h M ulti ple I m p utati o n ( Delta 
Met h o d 2) i n A B C-Irrita bilit y S u bscale Sc ore Dr o p o uts d ue t o A E or L O E as M N A R ( Efficac y 
Sa m ple)
C T- 5. 9. 7   Se nsiti vit y A nal ysis of M N A R usi n g Place b o Base d I m p utati o n i n A B C-Irrita bilit y T otal Sc ore 
( Efficac y Sa m ple)
C T- 5. 9. 8   Se nsiti vit y A nal ysis of M N A R usi n g Patter n Mi xt ure M o del wit h M ulti ple I m p utati o n ( Delta 
Met h o d 1) i n Cli nical Gl o bal I m pressi o n - Se verit y ( C GI- S) Sc ore Ass u me All Dr o p o uts as M N A R 
( Efficac y Sa m ple)
C T- 5. 9. 9   Se nsiti vit y A nal ysis of M N A R usi n g Patter n Mi xt ure M o del wit h M ulti ple I m p utati o n ( Delta 
Met h o d 2) i n Cli nical Gl o bal I m pressi o n - Se verit y ( C GI- S) Sc ore Ass u me All Dr o p o uts as M N A R 
( Efficac y Sa m ple)
C T- 5. 9. 1 0   Se nsiti vit y A nal ysis of M N A R usi n g Patter n Mi xt ure M o del wit h M ulti ple I m p utati o n ( Delta 
Met h o d 1) i n Cli nical Gl o bal I m pressi o n - Se verit y ( C GI- S) Sc ore Dr o p o ut d ue t o A E or Lac k of 
Efficac y ( L O E) or Wit h dra wal of C o nse nt as M N A R ( Efficac y Sa m ple)
C T- 5. 9. 1 1   Se nsiti vit y A nal ysis of M N A R usi n g Patter n Mi xt ure M o del wit h M ulti ple I m p utati o n ( Delta 
Met h o d 2) i n Cli nical Gl o bal I m pressi o n - Se verit y ( C GI- S) Sc ore Dr o p o ut d ue t o A E or Lac k of 
Efficac y ( L O E) or Wit h dra wal of C o nse nt as M N A R ( Efficac y Sa m ple)
C T- 5. 9. 1 2   Se nsiti vit y A nal ysis of M N A R usi n g Patter n Mi xt ure M o del wit h M ulti ple I m p utati o n ( Delta 
Met h o d 1) i n Cli nical Gl o bal I m pressi o n - Se verit y ( C GI- S) Sc ore Dr o p o uts d ue t o A E or L O E as 
M N A R ( Efficac y Sa m ple)
C T- 5. 9. 1 3   Se nsiti vit y A nal ysis of M N A R usi n g Patter n Mi xt ure M o del wit h M ulti ple I m p utati o n ( Delta 
Met h o d 2) i n Cli nical Gl o bal I m pressi o n - Se verit y ( C GI- S) Sc ore Dr o p o uts d ue t o A E or L O E as 
M N A R ( Efficac y Sa m ple)
C T- 5. 9. 1 4   Se nsiti vit y A nal ysis of M N A R usi n g Place b o Base d I m p utati o n i n Cli nical Gl o bal I m pressi o n - 
Se verit y ( C GI- S) Sc ore ( Efficac y Sa m ple)
C T- 5. 9. 1 5 Se nsiti vit y A nal ysis of M N A R Usi n g M o del Base d Met h o ds: S hare d Para meter M o del a n d 
Ra n d o m C oefficie nt Patter n Mi xt ure M o del - O C ( Efficac y Sa m ple)
C T- 6. 1. 1   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C-Irrita bilit y S u bscale Sc ore i n t he S u b gr o u p of Fe males - M M R M ( Efficac y Sa m ple)
C T- 6. 1. 2   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C-Irrita bilit y S u bscale Sc ore i n t he S u b gr o u p of Males - M M R M ( Efficac y Sa m ple)
C T- 6. 2. 1   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C-Irrita bilit y S u bscale Sc ore i n t he S u b gr o u p of W hites - M M R M ( Efficac y Sa m ple)
C T- 6. 2. 2   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C-Irrita bilit y S u bscale Sc ore i n t he S u b gr o u p of All Ot her Races - M M R M ( Efficac y 
Sa m ple)
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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.
5 0


S A P 3 3 1- 2 0 1- 0 0 1 4 8
C o nfi de ntial - Pr o prietar y I nf or mati o n
5 1
2 8 Se p 2 0 2 2
C T- 6. 3. 1   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C-Irrita bilit y S u bscale Sc ore i n S u bjects a ges 5 t o 1 2 - M M R M ( Efficac y Sa m ple) 
C T- 6. 3. 2   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C-Irrita bilit y S u bscale Sc ore i n S u bjects a ges 1 3 t o 1 7 - M M R M ( Efficac y Sa m ple) 
C T- 6. 4. 1   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C-Irrita bilit y S u bscale Sc ore i n S u bjects wit h B o d y Wei g ht < 5 0 k g - M M R M ( Efficac y 
Sa m ple)
C T- 6. 4. 2   S u m mar y of Mea n C ha n ge fr o m Baseli ne d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y 
Wee k i n A B C-Irrita bilit y S u bscale Sc ore i n S u bjects wit h B o d y Wei g ht ≥ 5 0 k g - M M R M ( Efficac y 
Sa m ple) 
C T- 7. 1   E xte nt of E x p os ure t o St u d y Me dicati o n i n t he D o u ble- Bli n d Treat me nt Peri o d ( Safet y Sa m ple)
C T- 7. 2   N u m ber a n d Perce nta ge of S u bjects Ha vi n g Recei ve d St u d y Me dicati o n a n d Mea n a n d Ra n ge of 
A vera ge Dail y D ose i n t he D o u ble- Bli n d Treat me nt Peri o d ( Safet y Sa m ple)
C T- 8. 1   A d verse E ve nts ( All Ca usalities) ( Safet y Sa m ple)
C T- 8. 2. 1   I nci de nce of T E A Es b y S yste m Or ga n Class a n d Me d D R A Preferre d Ter m ( Safet y Sa m ple)
C T- 8. 2. 2   I nci de nce of T E A Es b y S yste m Or ga n Class, Me d D R A Preferre d Ter m a n d Se verit y ( Safet y 
Sa m ple)
C T- 8. 2. 3   I nci de nce of T E A Es wit h Rate bei n g at least 5 % i n Bre x pi praz ole Gr o u p a n d Greater T ha n 
Place b o b y S yste m Or ga n Class a n d Me d D R A Preferre d Ter m ( Safet y Sa m ple)
C T- 8. 2. 4   I nci de nce of T E A Es b y S yste m Or ga n Class a n d Me d D R A Preferre d Ter m, b y Se x ( Safet y 
Sa m ple)
C T- 8. 2. 5   I nci de nce of T E A Es b y S yste m Or ga n Class a n d Me d D R A Preferre d Ter m, b y Race ( Safet y 
Sa m ple)
C T- 8. 2. 6   I nci de nce of T E A Es b y S yste m Or ga n Class a n d Me d D R A Preferre d Ter m, b y A ge Gr o u p 
( Safet y Sa m ple) 
C T- 8. 2. 7   I nci de nce of T E A Es b y S yste m Or ga n Class a n d Me d D R A Preferre d Ter m, b y B o d y Wei g ht 
Gr o u p ( Safet y Sa m ple) 
C T- 8. 2. 8   I nci de nce of N o n- Seri o us T E A E wit h Rate bei n g at Least 5 % i n Bre x pi praz ole Gr o u p a n d 
Greater T ha n Place b o b y S yste m Or ga n Class a n d Me d D R A Preferre d Ter m ( Safet y Sa m ple)
C T- 8. 2. 9   I nci de nce of T E A Es wit h Rate bei n g at Least 2 % i n Bre x pi praz ole Gr o u p a n d Greater T ha n 
Place b o b y S yste m Or ga n Class a n d Me d D R A Preferre d Ter m ( Safet y Sa m ple)
C T- 8. 2. 1 0   Occ urre nce ( N u m ber of E ve nts) of Seri o us T E A Es S yste m Or ga n Class a n d Me d D R A 
Preferre d Ter m ( Safet y Sa m ple)
C T- 8. 2. 1 1   Occ urre nce ( N u m ber of E ve nts) of P ote ntiall y Dr u g- Relate d Seri o us T E A Es b y S yste m Or ga n 
Class a n d Me d D R A Preferre d Ter m ( Safet y Sa m ple)
C T- 8. 2. 1 2   Occ urre nce ( N u m ber of E ve nts) of N o n- Seri o us T E A Es b y S yste m Or ga n Class a n d Me d D R A 
Preferre d Ter m ( Safet y Sa m ple)
C T- 8. 3. 1   I nci de nce of P ote ntiall y Dr u g- Relate d T E A Es b y S yste m Or ga n Class a n d Me d D R A Preferre d 
Ter m ( Safet y Sa m ple)
C T- 8. 3. 2   I nci de nce of P ote ntiall y Dr u g- Relate d T E A Es b y S yste m Or ga n Class, Me d D R A Preferre d 
Ter m a n d Se verit y ( Safet y Sa m ple)
C T- 8. 4   I nci de nce of Deat hs D ue t o T E A Es b y S yste m Or ga n Class a n d Me d D R A Preferre d Ter m ( Safet y 
Sa m ple)
C T- 8. 5. 1   I nci de nce of Seri o us T E A Es b y S yste m Or ga n Class a n d Me d D R A Preferre d Ter m ( Safet y 
Sa m ple)
C T- 8. 5. 2   I nci de nce of Seri o us T E A Es b y S yste m Or ga n Class, Me d D R A Preferre d Ter m a n d Se verit y 
( Safet y Sa m ple)
C T- 8. 6. 1   I nci de nce of T E A Es Res ulti n g i n Disc o nti n uati o n fr o m St u d y Me dicati o n b y S yste m Or ga n 
Class a n d Me d D R A Preferre d Ter m ( Safet y Sa m ple)
C T- 8. 6. 2   I nci de nce of T E A Es Res ulti n g i n Disc o nti n uati o n fr o m St u d y Me dicati o n b y S yste m Or ga n 
Class, Me d D R A Preferre d Ter m a n d Se verit y ( Safet y Sa m ple)
C T- 8. 7   I nci de nce of T E E P S-relate d A Es b y E P S Cate g or y a n d Me d D R A Preferre d Ter m ( Safet y Sa m ple)
C T- 8. 8   I nci de nce of O nset of A kat hisia A d verse E ve nt b y Wee k d uri n g D o u ble- Bli n d Treat me nt Peri o d 
( Safet y Sa m ple)
C T- 8. 9. 1   Listi n g of T E A Es t hat Are Relate d or Pr o ba bl y Relate d t o C O VI D- 1 9 ( Safet y Sa m ple)
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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.
5 1


S A P 3 3 1- 2 0 1- 0 0 1 4 8
C o nfi de ntial - Pr o prietar y I nf or mati o n
5 2
2 8 Se p 2 0 2 2
C T- 8. 9. 2   Listi n g of Seri o us T E A Es or Deat hs t hat Are Relate d or Pr o ba bl y Relate d t o C O VI D- 1 9 ( Safet y 
Sa m ple)
C T- 9. 1   Listi n g of Deat hs ( Safet y Sa m ple)
C T- 9. 2   Listi n g of Seri o us A d verse E ve nts ( Safet y Sa m ple)
C T- 9. 3   Listi n g of Disc o nti n uati o ns d ue t o A d verse E ve nts ( Safet y Sa m ple)
C T- 1 0. 1   Criteria f or La b orat or y Test Val ues wit h P ote ntiall y Cli nical Rele va nce
C T- 1 0. 2. 1   Listi n g of La b orat or y Test Val ues wit h P ote ntiall y Cli nical Rele va nce b y S u bject ( Safet y 
Sa m ple)
C T- 1 0. 2. 2   Listi n g of La b orat or y Test Val ues wit h P ote ntiall y Cli nical Rele va nce b y Test ( Safet y Sa m ple)
C T- 1 0. 2. 3   I nci de nce of La b orat or y Test Val ues wit h P ote ntiall y Cli nical Rele va nce ( Safet y Sa m ple)
C T- 1 0. 3. 1   S u m mar y of C ha n ge fr o m Baseli ne i n Cli nical La b orat or y Test Res ults - Ser u m C he mistr y 
( Safet y Sa m ple)
C T- 1 0. 3. 2   S u m mar y of C ha n ge fr o m Baseli ne i n Cli nical La b orat or y Test Res ults - He mat ol o g y ( Safet y 
Sa m ple)
C T- 1 0. 3. 3   S u m mar y of C ha n ge fr o m Baseli ne i n Cli nical La b orat or y Test Res ults - Uri nal ysis ( Safet y 
Sa m ple)
C T- 1 0. 3. 4   S u m mar y of C ha n ge fr o m Baseli ne i n Cli nical La b orat or y Test Res ults - Pr olacti n, b y Se x 
( Safet y Sa m ple)
C T- 1 0. 3. 5   S u m mar y of C ha n ge fr o m Baseli ne i n Cli nical La b orat or y Test Res ults - Ot her Tests ( Safet y 
Sa m ple)
C T- 1 0. 4. 1   I nci de nce of P ote ntial Seri o us He pat ot o xicit y ( Safet y Sa m ple)
C T- 1 0. 4. 2   Listi n g of P ote ntial Seri o us He pat ot o xicit y ( Safet y Sa m ple)
C T- 1 0. 5. 1   I nci de nce of La b orat or y Test Val ues wit h P ote ntial Cli nical Rele va nce - Ser u m Pr olacti n 
( Safet y Sa m ple)
C T- 1 0. 5. 2   Listi n g of La b orat or y Test Val ues wit h P ote ntial Cli nical Rele va nce - Ser u m Pr olacti n ( Safet y 
Sa m ple)
C T- 1 1. 1   Criteria f or P ote ntiall y Cli nicall y Rele va nt A b n or malities i n Vital Si g ns
C T- 1 1. 2. 1   Listi n g of P ote ntiall y Cli nicall y Rele va nt A b n or malities i n Vital Si g ns ( Safet y Sa m ple)
C T- 1 1. 2. 2   I nci de nce of P ote ntiall y Cli nicall y Rele va nt A b n or malities i n Vital Si g ns ( Safet y Sa m ple)
C T- 1 1. 2. 3   S u m mar y of C ha n ge fr o m Baseli ne i n Vital Si g ns b y St u d y Wee k ( Safet y Sa m ple)
C T- 1 2. 1. 1   Criteria f or P ote ntiall y Cli nicall y Rele va nt A b n or malities i n E C G E val uati o ns
C T- 1 2. 1. 2   E C G Dia g n osis Ma p pi n g f or P ote ntiall y Cli nicall y Rele va nt Electr ocar di o gra m A b n or malities 
( Safet y Sa m ple)
C T- 1 2. 2. 1   Listi n g of P ote ntiall y Cli nicall y Rele va nt A b n or malities i n E C G E val uati o ns ( Safet y Sa m ple)
C T- 1 2. 2. 2   I nci de nce of P ote ntiall y Cli nicall y Rele va nt C ha n ges i n E C G E val uati o ns ( Safet y Sa m ple)
C T- 1 2. 2. 3   S u m mar y of Mea n C ha n ge fr o m Baseli ne i n Electr ocar di o gra m Res ults ( Safet y Sa m ple)
C T- 1 2. 3. 1   Listi n g of Cate g orical C ha n ges i n Q T/ Q Tc ( Safet y Sa m ple)
C T- 1 2. 3. 2   I nci de nce of Cate g orical C ha n ges i n Q T/ Q Tc ( Safet y Sa m ple)
C T- 1 3. 1   S u m mar y of Mea n C ha n ge fr o m Baseli ne t o t he E n d p oi nt ( Wee k 8) of t he D o u ble- Bli n d 
Treat me nt Peri o d i n Si m ps o n- A n g us Scale ( S A S) T otal Sc ore ( Safet y Sa m ple)
C T- 1 3. 2   S u m mar y of Mea n C ha n ge fr o m Baseli ne t o t he E n d p oi nt ( Wee k 8) of t he D o u ble- Bli n d 
Treat me nt Peri o d i n A b n or mal I n v ol u ntar y M o ve me nt Scale ( AI M S) T otal Sc ore a n d Ite m Sc ore o n 
Ite m 8, 9 a n d 1 0 ( Safet y Sa m ple)
C T- 1 3. 3. 1   S u m mar y of Mea n C ha n ge fr o m Baseli ne t o t he E n d p oi nt ( Wee k 8) of t he D o u ble- Bli n d 
Treat me nt Peri o d i n Bar nes A kat hisia Rati n g Scale ( B A R S) Gl o bal Cli nical Assess me nt Sc ore ( Safet y 
Sa m ple)
C T- 1 3. 3. 2   I nci de nce of Bar nes A kat hisia Rati n g Scale ( B A R S) Gl o bal Cli nical Assess me nt of A kat hisia 
D uri n g t he D o u ble- Bli n d Treat me nt Peri o d ( Safet y Sa m ple)
C T- 1 4. 1. 1   C ol u m bia- S uici de Se verit y Rati n g Scale( C- S S R S) d uri n g t he Treat me nt a n d t he F oll o w- u p 
Peri o d, S uici dalit y ( Safet y Sa m ple)
C T- 1 4. 1. 2   C ol u m bia- S uici de Se verit y Rati n g Scale( C- S S R S) d uri n g t he Treat me nt a n d t he F oll o w- u p 
Peri o d, S uici dal I deati o n b y T y pe ( Safet y Sa m ple)
C T- 1 4. 1. 3   C ol u m bia- S uici de Se verit y Rati n g Scale( C- S S R S) d uri n g t he Treat me nt a n d t he F oll o w- u p 
Peri o d, S uici dal Be ha vi or b y T y pe ( Safet y Sa m ple)
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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.
5 2


S A P 3 3 1- 2 0 1- 0 0 1 4 8
C o nfi de ntial - Pr o prietar y I nf or mati o n
5 3
2 8 Se p 2 0 2 2
C T- 1 4. 1. 4   C ol u m bia- S uici de Se verit y Rati n g Scale( C- S S R S) d uri n g t he Treat me nt a n d t he F oll o w- u p 
Peri o d, Treat me nt E mer ge nt S uici dal I deati o n a n d Be ha vi or ( Safet y Sa m ple)  
C T- 1 4. 1. 5   C ol u m bia- S uici de Se verit y Rati n g Scale ( C- S S R S) - Listi n g of Treat me nt E mer ge nt S uici dal 
I deati o n d uri n g t he Treat me nt a n d t he F oll o w- u p Peri o d ( Safet y Sa m ple)
C T- 1 4. 1. 6   C ol u m bia- S uici de Se verit y Rati n g Scale ( C- S S R S) - Listi n g of Treat me nt E mer ge nt S uici dal 
Be ha vi or d uri n g t he Treat me nt a n d t he F oll o w- u p Peri o d ( Safet y Sa m ple)
C T- 1 4. 1. 7   C ol u m bia- S uici de Se verit y Rati n g Scale ( C- S S R S) - Listi n g of Treat me nt E mer ge nt Seri o us 
S uici dal I deati o n d uri n g t he Treat me nt a n d t he F oll o w- u p Peri o d ( Safet y Sa m ple)
C T- 1 4. 1. 8   C ol u m bia- S uici de Se verit y Rati n g Scale ( C- S S R S) - Listi n g of W orse ni n g S uici dal I deati o n 
d uri n g t he Treat me nt a n d t he F oll o w- u p Peri o d ( Safet y Sa m ple)
C T- 1 5. 1. 1   S u m mar y of Mea n C ha n ge fr o m Baseli ne t o t he E n d p oi nt ( Wee k 8) of t he D o u ble- Bli n d 
Treat me nt Peri o d i n B o d y Wei g ht ( U nit: k g) ( Safet y Sa m ple)
C T- 1 5. 1. 2   S u m mar y of Pr o p orti o n of Patie nts wit h P ote ntiall y Cli nicall y Si g nifica nt Wei g ht Gai n or 
Wei g ht L oss d uri n g t he D o u ble- Bli n d Treat me nt Peri o d ( Safet y Sa m ple)
C T- 1 5. 1. 3 I nci de nce of P ote ntiall y Cli nicall y Rele va nt Wei g ht Gai n or L oss b y Baseli ne B MI ( Safet y 
Sa m ple)
C T- 1 5. 2   S u m mar y of Mea n C ha n ge fr o m Baseli ne t o t he E n d p oi nt ( Wee k 8) of t he D o u ble- Bli n d 
Treat me nt Peri o d i n Waist Circ u mfere nce ( U nit: c m) ( Safet y Sa m ple)
C T- 1 5. 3   S u m mar y of Mea n C ha n ge fr o m Baseli ne t o t he E n d p oi nt ( Wee k 8) of t he D o u ble- Bli n d 
Treat me nt Peri o d i n B MI ( U nit: k g/ m 2) ( Safet y Sa m ple)
C T- 1 5. 4. 1   S u m mar y of C ha n ge fr o m Baseli ne i n A ge-a n d- Ge n der- A dj uste d Z-sc ores f or B o d y Wei g ht, 
d uri n g t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y Wee k ( Safet y Sa m ple)
C T- 1 5. 4. 2   S u m mar y of C ha n ge fr o m Baseli ne i n A ge-a n d- Ge n der- A dj uste d Z-sc ores f or Hei g ht d uri n g 
t he D o u ble- Bli n d Treat me nt Peri o d b y St u d y Wee k ( Safet y Sa m ple)
C T- 1 5. 4. 3   S u m mar y of C ha n ge fr o m Baseli ne i n A ge-a n d- Ge n der- A dj uste d Z-sc ores f or B MI d uri n g t he 
D o u ble- Bli n d Treat me nt Peri o d b y St u d y Wee k ( Safet y Sa m ple)
C T- 1 5. 4. 4 I nci de nce of E xcee di n g 0. 5 i n t he c ha n ge fr o m Baseli ne B o d y Wei g ht Z-sc ore f or t he D o u ble-
Bli n d Treat me nt Peri o d ( Safet y Sa m ple)
C T- 1 5. 4. 5  N u m ber a n d Perce nta ge of S u bjects wit h Si g nifica nt C ha n ge i n B MI Z-sc ore f or t he D o u ble-
Bli n d Treat me nt Peri o d ( Safet y Sa m ple)
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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.
5 3


S A P 3 3 1- 2 0 1- 0 0 1 4 8
C o nfi de ntial - Pr o prietar y I nf or mati o n
5 4
2 8 Se p 2 0 2 2
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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.
5 4
C CI


S A P 3 3 1- 2 0 1- 0 0 1 4 8
C o nfi de ntial - Pr o prietar y I nf or mati o n
5 5
2 8 Se p 2 0 2 2
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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.
5 5
C CI


S A P 3 3 1- 2 0 1- 0 0 1 4 8
C o nfi de ntial - Pr o prietar y I nf or mati o n
5 6
2 8 Se p 2 0 2 2
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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.
5 6
C CI


T hi s p a g e i s a m a nif e st ati o n of a n el e ctr o ni c all y c a pt ur e d si g n at ur e
SI G N A T U R E P A G E
D o c u m e nt N a m e: 3 3 1- 2 0 1- 0 0 1 4 8 _ S A P
D o c u m e nt N u m b er: 
D o c u m e nt V er si o n: 4. 0
Si g n e d b y
M e a ni n g of Si g n at ur e
S er v er D at e
( d d- M M M-
y y y y h h: mi n) -
U T C ti m e z o n e
Bi o st ati sti c s A p pr o v al
2 8- S e p- 2 0 2 2
2 1: 2 2: 0 3
Cli ni c al A p pr o v al
2 8- S e p- 2 0 2 2
2 1: 1 3: 5 2
Cli nic al St u d y Re p ort 3 3 1- 2 0 1- 0 0 1 4 8
1 6. 1. 9 D oc u me nt ati o n of St atistic al Met h o ds
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.
5 7
C CI
P P D
P P D