Clinical trial NCT03198078
Conditions: Schizophrenia
Keywords: Brexpiprazole Schizophrenia Adolescent
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Start date: 2017-06-30; Completion date: 2023-04-03
Enrollment: 316 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To determine the safety \& efficacy of brexpiprazole monotherapy in the treatment of adolescents with schizophrenia.

Detailed description:
This is a multicenter, randomized, double-blind, placebo- and active-controlled trial to evaluate the safety and efficacy of brexpiprazole monotherapy compared to placebo in adolescent subjects (ages 13-17) with a DSM-5 diagnosis of schizophrenia.

Arms: arm 1: Participants were administered with brexpiprazole oral tablets, daily, dose titrated up to 0.5 mg by Day 4, 1 mg by Day 7, 2 mg by Day 14, then between 2-4 mg after Day 21 up to Week 6 with a 1 mg increase or decrease, based on the Investigator's decision. arm 2: Participants were administered with aripiprazole oral tablets, daily, dose titrated up to 2 mg by Day 4, 5 mg by Day 7, 10 mg by Day 14, then 10, 15 or 20 mg after Day 21 up to Week 6 with a 5 mg increase or decrease, based on the Investigator's decision. arm 3: Participants were administered with brexpiprazole or aripiprazole matching placebo oral tablets, daily up to Week 6.
Interventions: intervention 1: Brexpiprazole (OPC-34712) intervention 2: Aripiprazole intervention 3: Placebo
Intervention descriptions: intervention 1: Once-daily, tablets intervention 2: Once-daily, tablets intervention 3: Once-daily, tablets

Protocol documents:
Prot_000.pdf: 
7DEOHRI&RQWHQWV
Table of Contents.............................................................................................................
1
Study 331-10-234 Protocol Amendment 03; 05 Jul 2022................................................
2
&OLQLFDO6WXG\5HSRUW
3URWRFRODQG3URWRFRO$PHQGPHQWV
8QWLOWKHLQIRUPDWLRQKHUHLQLVUHOHDVHGE\2WVXNDWRWKHSXEOLFGRPDLQWKHFRQWHQWVRIWKLVGRFXPHQWDUH2WVXND
FRQILGHQWLDOLQIRUPDWLRQDQGVKRXOGQRWEHGXSOLFDWHGRUUHGLVWULEXWHGZLWKRXWSULRUZULWWHQFRQVHQWRI2WVXND

CCI


Otsuka Pharmaceutical
Development & Commercialization, Inc.
Investigational Medicinal Product
Brexpiprazole (OPC-34712)
REVISED CLINICAL PROTOCOL
A Multicenter, Randomized, Double-blind, Placebo- and Active-controlled Trial to 
Evaluate the Efficacy of Brexpiprazole Monotherapy for the Treatment in Adolescents 
(13-17 years old) With Schizophrenia
Protocol No. 331-10-234
IND No. 101,871
EudraCT No. 2017-001447-12
CONFIDENTIAL – PROPRIETARY INFORMATION
Clinical Development Phase:
3
Sponsor:
Otsuka Pharmaceutical Development & 
Commercialization, Inc.
2440 Research Boulevard
Rockville, Maryland 20850, United States
Immediately Reportable Event 
Syneos Health Safety and 
Pharmacovigilance
Issue Date:
10 Mar 2017
Date of Amendment 1
24 Aug 2018
Administrative Change 1
31 May 2019
Date of Amendment 2
16 Jun 2020
Date of Amendment 3
05 Jul 2022
Version No.:
5.0
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
2


Protocol 331-10-234
Confidential - Proprietary Information
2
Version 5.0, 05 Jul 2022 
Trial Conduct for COVID-19
All procedures and assessments in this protocol are to be followed to the fullest 
extent possible.  The sponsor, in coordination with the sites, investigators, and 
medical monitor, will continuously monitor and evaluate the benefits and risks to 
subject participation in the clinical trial as it relates to COVID-19.  If any 
protocol-specified activities were not able to be performed, or cannot be performed, 
due to COVID-19 considerations, refer to the COVID-19 Addendum for the 
appropriate measures to be followed.  Appropriate measures may include but not 
limited to replacing in-person visits with virtual visits as deemed necessary by the 
investigator to ensure subject safety and maintain protocol requirements.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
3


Protocol 331-10-234
Confidential - Proprietary Information
3
Version 5.0, 05 Jul 2022 
Protocol Synopsis 
Name of Sponsor:  Otsuka Pharmaceutical 
Development & Commercialization, Inc.
Name of Investigational Medicinal Product:  
Brexpiprazole (OPC-34712)
Protocol No.:  331-10-234
IND No.:  101,871
EudraCT No.:  2017-001447-12
Protocol Title:
A Multicenter, Randomized, Double-blind, Placebo- and 
Active-controlled Trial to Evaluate the Efficacy of 
Brexpiprazole Monotherapy for the Treatment in Adolescents 
(13-17 years old) With Schizophrenia
Clinical Phase/Trial 
Type:
3/Therapeutic confirmatory
Treatment Indication: Schizophrenia
Objective(s): 
To evaluate the short-term efficacy and safety of brexpiprazole 
monotherapy in the treatment of adolescents with 
schizophrenia
Trial Design:
This is a multicenter, randomized, double-blind, placebo- and 
active-controlled trial designed to assess the effect of 
brexpiprazole compared to placebo in adolescent subjects, ages 
13 to 17 years, with a Diagnostic and Statistical Manual of 
Mental Disorders - Fifth Edition (DSM-5) diagnosis of 
schizophrenia.  The initial diagnosis of schizophrenia should 
be made by an adequately trained clinician (psychiatrist or 
local medical equivalent who is experienced in treating 
adolescents with schizophrenia).  The diagnosis should then be 
confirmed by utilizing the Kiddie Schedule for Affective 
Disorders and Schizophrenia-Present and Lifetime version 
(K-SADS-PL), performed by an adequately trained rater at the 
time of screening.  The trial is planned to be conducted on an 
outpatient basis.
This trial has a 6-week double-blind treatment period.
After a minimum 3-day washout period, subjects who continue 
to meet all entrance criteria (including Positive and Negative 
Syndrome Scale [PANSS] Total Score ≥ 80) at the baseline 
visit (Day 1) will be randomized 1:1:1 to 1 of 3 double-blind 
treatment arms:
•
brexpiprazole
•
aripiprazole 
•
Placebo
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
4


Protocol 331-10-234
Confidential - Proprietary Information
4
Version 5.0, 05 Jul 2022 
Brexpiprazole will be titrated to a minimum dose of 2 mg in 
8 days and aripiprazole will be titrated to a minimum dose of 
10 mg, the therapeutic dose as per the United States (US) 
package insert.  Subjects who are unable to tolerate the 
minimum dose will be discontinued.  At the end of the titration 
period, investigators will be able to adjust the dose of 
double-blind investigational medicinal product (IMP) not to 
exceed brexpiprazole 4 mg/day or aripiprazole 20 mg 
depending upon treatment arm.  Following the first dose 
increase, if the dose adjustment is not well tolerated, the dose 
may be reduced back to the minimum dose allowed by 
protocol (ie, brexpiprazole 2 mg and aripiprazole 10 mg).  
Subjects not able to tolerate the decreased dose will be 
discontinued from the trial.
Mandatory evaluations will take place at Day 1 (baseline), 
Day 4 (telephone call), and Weeks 1, 2, 3, 4, 5, and 6.  
However, at the discretion of the treating physician, more 
frequent evaluations are permitted.
Eligible subjects who complete the 6-week double-blind 
efficacy phase may have the option to enroll into an open-label 
safety trial of brexpiprazole (Protocol 331-10-236).
All subjects who do not enroll in the open-label rollover trial 
(Protocol 331-10-236) will be assessed by a telephone 
assessment 21 (± 2) days after the last dose of IMP to assess 
adverse events (AEs).
Subject Population:
The trial population will include male and female subjects 
between 13 and 17 years of age, inclusive, at the time of 
informed consent/assent and at baseline (Day 1) who continue 
to have a confirmed DSM-5 diagnosis of schizophrenia and a 
PANSS Total Score ≥ 80 at screening and at baseline (Day 1).  
Approximately 645 subjects are anticipated to be screened 
with the expectation that 315 subjects will be randomized.
Inclusion/Exclusion 
Criteria: 
Subjects must meet the inclusion criteria at both screening and 
baseline.  Key inclusion criteria include the following:
•
Subjects ages 13-17 inclusive at time of consent/assent and 
at baseline (Day 1) with a current primary diagnosis of 
schizophrenia, as defined by DSM-5 criteria and confirmed 
by the K-SADS-PL, and a history of the illness (diagnosis 
or symptoms) for at least 6 months prior to screening.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
5


Protocol 331-10-234
Confidential - Proprietary Information
5
Version 5.0, 05 Jul 2022 
•
PANSS Total Score of ≥ 80.
Key exclusion criteria include the following:
•
Subjects with a DSM-5 diagnosis other than schizophrenia 
that has been the primary focus of treatment within 
3 months of screening.
•
Subjects with a clinical presentation or history that is 
consistent with delirium, dementia, amnesia, or other 
cognitive disorders; subjects with psychotic symptoms that 
are better accounted for by another general medical 
condition(s) or direct effect of a substance (eg, medication, 
illicit drug use).
•
Subjects who have been hospitalized > 21 days for a 
current exacerbation of schizophrenia at the time of the 
baseline visit.
•
Subjects who are considered treatment resistant to 
antipsychotic medication, including aripiprazole or 
brexpiprazole, at an adequate dose and duration as 
confirmed by medical history, investigator judgment, or 
subject report.  Subjects with a history of relapse due to 
lack of medication compliance or drug abuse can be 
considered based on investigator judgment.
•
Subjects who have a significant risk of committing violent 
acts, serious self-harm, or attempting suicide based on 
history (eg, suicide attempt in the past 1 year) or routine 
psychiatric status examination, or those who are homicidal 
or are considered to be a high risk to others, or who have 
an answer of “yes” on Questions 4 or 5 (current or over the 
past 1 month) on the suicidal ideation section of the 
baseline screening version of the Columbia-Suicide 
Severity Rating Scale (C-SSRS).
•
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 
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
6


Protocol 331-10-234
Confidential - Proprietary Information
6
Version 5.0, 05 Jul 2022 
infarction or ischemic heart disease, arrhythmia, congestive 
heart failure, or cancer); subjects with a comorbid serious 
systemic illness that requires pharmacotherapy; subjects 
with any history of electroconvulsive therapy.
•
Subjects who test positive for drugs of abuse at screening.  
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 
Advisor prior to randomization. 
Trial Sites: 
An estimated 120 sites in North America, Europe, and the rest 
of the world (ROW) will enroll subjects.
Investigational 
Medicinal Product(s), 
Dose, Dosage 
regimen, Treatment 
period, Formulation, 
Mode of 
Administration:
Brexpiprazole, aripiprazole, and placebo oral tablets will be 
supplied to the investigators by the sponsor or designated 
agent as child-resistant blister cards each containing sufficient 
tablets for the window visit.  When accessed by the site, an 
interactive web response system will assign a specific blister 
card to be dispensed to a subject.
For the 6-week double-blind treatment period, subjects will be 
randomized 1:1:1 to 1 of 3 double-blind treatment arms:
•
2–4 mg brexpiprazole daily
•
10–20 mg aripiprazole daily (subjects will start at 2 mg and 
titrate per label for adolescents diagnosed with 
schizophrenia)
•
Placebo
For all subjects, the number of tablets taken during the titration 
period will be identical to ensure the double-blind nature of the 
trial.  Titration with brexpiprazole will start at 0.5 mg/day, 
increase to 1 mg/day, and increase again to 2 mg/day, which is 
the minimum dose.  Titration with aripiprazole will start at 
2 mg/day, increase to 5 mg/day, and increase again to 
10 mg/day, which is the minimum dose.  At the end of the 
titration period, investigators may either keep the subject at a 
maintenance dose or up-titrate by 1 mg (brexpiprazole) or 
5 mg (aripiprazole) to a maximum dose of 4 mg/day 
(brexpiprazole) or 20 mg/day (aripiprazole).
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
7




Protocol 331-10-234
Confidential - Proprietary Information
8
Version 5.0, 05 Jul 2022 
•
Change in the Clinical Global Impression Severity (CGI-S) 
scale
•
Clinical Global Impression Improvement (CGI-I) scale
Safety will be assessed by the following:
•
The frequency and severity of AEs, serious AEs (clinical 
and laboratory), and discontinuation from the trial due to 
AEs
•
Weight, height, body mass index, and waist circumference
•
Analysis of potential suicide events recorded on the 
C-SSRS
•
Clinical laboratory tests and urinalysis results (including 
serum prolactin), vital signs, and ECG parameters
•
Changes on the SAS, AIMS, and BARS
•
Comprehensive psychotropic side effects as assessed by 
the UKU side effect rating scale
•
Cognitive adverse effects as assessed by the NY-AACENT
Statistical Methods:
Based on the results of the aripiprazole trial conducted in 
adolescent subjects with schizophrenia (Protocol 31-03-239), 
aripiprazole 30 mg and 10 mg had a reduction in PANSS 
Total Score of 7.40 and 5.46, respectively, compared to 
placebo.  The standard deviation (SD) at Week 6 was 19.  
Assuming that brexpiprazole 2–4 mg has comparable 
treatment effects to aripiprazole 30 mg, as well as the same 
SD, a sample size of 105 subjects per arm will provide at least 
80% power at a nominal 2-sided alpha level of 0.05 to detect a 
−7.4 point reduction in PANSS Total score change from 
baseline to Week 6 for brexpiprazole vs placebo assuming an 
SD = 19. With 1:1:1 allocation ratio, the overall sample size of 
this trial is planned to be 315 subjects.
The primary efficacy variable in this trial is the change from 
baseline to Week 6 in PANSS Total Score.  The primary 
statistical comparison of interest is brexpiprazole 2–4 mg vs. 
placebo.  With the assumption of missing at random (MAR), a 
mixed model repeated measures (MMRM) analysis with fixed 
effect factors of treatment, trial site, visit, treatment visit 
interaction, and fixed effect covariates baseline and baseline 
visit interaction will be applied to the change from baseline 
from Week 1 to Week 6 based on all available data (observed 
case dataset).  The data will be modeled using an unstructured 
variance covariance matrix for the within subject variation.  A 
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
9


Protocol 331-10-234
Confidential - Proprietary Information
9
Version 5.0, 05 Jul 2022 
statistical test of the least squares (LS) mean differences at 
Week 6 of the MMRM analysis will serve as the analysis of 
the primary endpoint.
In case there is a convergence problem with the MMRM 
model with the unstructured variance covariance matrix, the 
following structures other than unstructured will be used in 
order of 1) heterogeneous toeplitz, 2) heterogeneous 
autoregressive of order 1, and 3) heterogeneous compound 
symmetry, and the first (co)variance structure converging to 
the best fit will be used as the primary analysis.  If a structured 
covariance has to be used, the “sandwich” estimator of the 
standard error of the fixed effects parameters will be used in 
order to deal with possible model misspecification of the 
covariance matrix.  
In order to explore the robustness of the primary analysis 
based on the MAR assumption, sensitivity analysis of the 
primary efficacy endpoint under a “missing not at random” 
assumption will be conducted, using a pattern-mixture model.
Trial Duration:
Individual participation for subjects who complete the trial 
without early withdrawal will be approximately 13 weeks, 
consisting of a screening period of up to 28 days, a 6-week 
double-blind treatment period, and a 21 (± 2)-day follow-up, if 
applicable.  Subjects may have the option to enter an 
open-label rollover trial after completion of treatment.  Only 
subjects who do not participate in the open-label trial will be 
followed up via telephone contact 21 (± 2) days after the last 
dose of IMP.  
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
10


















Protocol 331-10-234
Confidential - Proprietary Information
18
Version 5.0, 05 Jul 2022 
List of Abbreviations and Definitions of Terms
Abbreviation
Definition
ADHD
Attention-deficit/hyperactivity disorder
ADT
Antidepressant therapy
AE
Adverse event
AIMS
Abnormal Involuntary Movement Scale
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
APO
Apomorphine
AST
Aspartate aminotransferase
AUC0-24h
Area under the concentration-time curve from time zero to 24 hours
AUCτ
Area under the plasma concentration-time curve to the last 
observable concentration
BARS
Barnes Akathisia Rating Scale
BUN
Blood urea nitrogen
CGAS
Children’s Global Assessment Scale
CGI-I
Clinical Global Impression - Improvement scale
CGI-S
Clinical Global Impression - Severity of Illness scale
CL/F
Apparent clearance of drug from plasma after extravascular 
administration
Cmax,ss
Maximum concentration at steady state
CMH
Cochran-Mantel-Haenszel
CNS
Central nervous system
CPK
Creatine phosphokinase
CRO
Clinical Research Organization
CIOMS
Council for International Organizations of Medical Science
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
Cytochrome P450
D2
Dopamine D2
D3
Dopamine D3
DBP
Diastolic blood pressure
DMC
Data monitoring committee
DNA
Deoxyribonucleic acid
DSM-5
Diagnostic and Statistical Manual of Mental Disorders - Fifth 
Edition
e-signature
Electronic signature
ECG
Electrocardiogram
EPS
Extrapyramidal symptom
ET
Early termination
EudraCT
European Clinical Trial Data Base
FDA
(United States) Food and Drug Administration
GABA
Gamma-aminobutyric acid
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
19


Protocol 331-10-234
Confidential - Proprietary Information
19
Version 5.0, 05 Jul 2022 
GAS
Adult Global Assessment Scale
GCP
Good Clinical Practice
GGT
Gamma glutamyl transferase
GMR
Geometric mean ratio
HbA1c
Glycosylated hemoglobin
HDL
High-density lipoprotein
5-HT1A
Serotonin type 1A receptor
5-HT2A
Serotonin type 2A receptor
IAF
Informed assent form
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
ID
Identification
IDDM
Insulin-dependent diabetes mellitus
IEC
Independent ethics committee
IM
Intramuscular
IMP
Investigational medicinal product
IND
Investigational New Drug
IRB
Institutional review board
IRE
Immediately reportable event
IR
Immediate-release
ITT
Intent-to-treat
IWRS
Interactive web response system
K-SADS-PL
Kiddie Schedule for Affective Disorders and Schizophrenia-Present 
and Lifetime version
Ki
Inhibition constant
LDH
Lactic dehydrogenase
LDL
Low-density lipoprotein
LOCF
Last observation carried forward
LS
Least squares
MAOIs
Monoamine oxidase inhibitors
MAR
Missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MDD
Major depressive disorder
MI
Multiple imputation
MMRM
Mixed model repeated measures
MNAR
Missing not at random
MTD
Maximum tolerated dose
NDA
New Drug Application
NY-AACENT
New York Assessment for Adverse Cognitive Effects of 
Neuropsychiatric Treatment 
OC
Observed case
OPC
Otsuka Pharmaceutical Co.
PANSS
Positive and Negative Syndrome Scale
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
20


Protocol 331-10-234
Confidential - Proprietary Information
20
Version 5.0, 05 Jul 2022 
PD
Pharmacodynamic
PET
Positron emission tomography
PGx
Pharmacogenomic
PK
Pharmacokinetic
PQC
Product quality complaint
P-Q-LES-Q
Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire
PTSD
Post-traumatic stress disorder
QD
Once daily
QTc
Corrected QT interval
QTcF
QT interval as corrected for heart rate by Fridericia’s formula
QTcN
QT interval corrected for heart rate by the FDA Neuropharm 
Division formula
RBC
Red blood cell
ROW
Rest of world
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SAS
Simpson Angus Scale
SBP
Systolic blood pressure
SD
Standard deviation
T4
Thyroxine
TEAE
Treatment-emergent adverse event
tmax
Time to maximum (peak) plasma concentration
TSH
Thyroid-stimulating hormone
UKU
Udvalg for Kliniske Undersogelser
ULN
Upper limit of normal
US or USA
United States or United States of America
WBC
White blood cell
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
21






Protocol 331-10-234
Confidential - Proprietary Information
23
Version 5.0, 05 Jul 2022 
1.1.1
Efficacy Pharmacology
Brexpiprazole functions as a partial agonist at the D2 receptor.  In in vitro assay systems 
based on forskolin-induced cyclic adenosine monophosphate accumulation and calcium 
mobilization in human dopamine D2L receptor-expressing cells, its intrinsic activity at the 
D2 receptor was slightly lower than that of aripiprazole, another D2 receptor partial 
agonist.  Brexpiprazole inhibited apomorphine (APO)-induced hyperlocomotion, 
APO-induced stereotyped behavior, and conditioned avoidance response in rats, which 
are predictive animal models for antipsychotic-like efficacy.  The inhibitory effects of 
brexpiprazole were more potent than those of aripiprazole.  Moreover, in contrast to the 
D2 receptor antagonist risperidone, brexpiprazole did not increase plasma prolactin levels 
in reserpine-treated rats, thus demonstrating a D2 receptor partial agonistic profile in vivo.  
Despite its lower intrinsic activity at the D2 receptor, the in vivo catalepsy liability of 
brexpiprazole, an index of EPS, was similar to that of aripiprazole, but still lower than 
that of the typical antipsychotic haloperidol.  Furthermore, brexpiprazole showed high 
binding affinity for the 5-HT2A receptor and dose-dependently inhibited 
(±)-2,5-dimethoxy-4-iodoamphetamine-induced head twitch response in rats, indicating 
that the compound has 5-HT2A receptor antagonistic activity; the effect of brexpiprazole 
was more potent than that of aripiprazole.  In addition, brexpiprazole exhibited high 
binding affinities for the D3 and 5-HT1A receptors, acting as a partial agonist at these 
receptors.
1.1.2
Safety Pharmacology
In safety pharmacology studies in rats at an oral dose of 30 mg/kg or higher, 
brexpiprazole induced pharmacologically mediated clinical signs considered to be due to 
depression of the central nervous system (CNS) and dose-dependent decreases in body 
temperature.  When orally administered at up to 30 mg/kg in conscious male beagle dogs, 
brexpiprazole showed no effect on respiratory parameters or heart rate at any dose tested.  
Brexpiprazole decreased blood pressure at doses of 3 mg/kg or higher and prolonged both 
&OLQLFDO6WXG\5HSRUW
3URWRFRODQG3URWRFRO$PHQGPHQWV
8QWLOWKHLQIRUPDWLRQKHUHLQLVUHOHDVHGE\2WVXNDWRWKHSXEOLFGRPDLQWKHFRQWHQWVRIWKLVGRFXPHQWDUH2WVXND
FRQILGHQWLDOLQIRUPDWLRQDQGVKRXOGQRWEHGXSOLFDWHGRUUHGLVWULEXWHGZLWKRXWSULRUZULWWHQFRQVHQWRI2WVXND

CCI




Protocol 331-10-234
Confidential - Proprietary Information
25
Version 5.0, 05 Jul 2022 
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 95.4 and 89.3 hours, respectively; median tmax 
was 3.0 and 8.0 hours, respectively.
In drug interaction trials in healthy subjects, brexpiprazole was shown to be metabolized 
by cytochrome P450 (CYP) 3A4 and CYP2D6 isozymes and was not an inhibitor of 
CYP3A4, CYP2B6, CYP2D6, or P-glycoprotein.  Co-administration of potent CYP3A4 
or CYP2D6 inhibitors with brexpiprazole resulted in about a 2-fold higher exposure and 
about a 1.5-fold increase in the terminal elimination half-life of brexpiprazole.
In a single-dose trial in healthy subjects, approximately 46.0% and 24.6% of 
administered radioactivity following an oral dose of 14C-brexpiprazole was excreted in 
feces and urine, respectively.  In this same trial, brexpiprazole did not preferentially bind 
to red blood cells.  Brexpiprazole showed high protein binding in human serum 
( 99.8%) in vitro.
The binding of brexpiprazole to dopamine receptors was assessed using positron 
emission tomography (PET).  The mean D2/D3 receptor occupancies at 4 and 24 hours 
post dose after 0.25, 0.5, 1, 2, 4, 5, and 6 mg single-dose administration of brexpiprazole 
to healthy subjects were 11.4% to 17.4%, 36.5% to 46.3%, 45.6% to 60.2%, 52.7% to 
68.6%, 67.9% to 79.5%, 71.9% to 88.2%, and 69.5% to 92.6%, respectively 
(Trial 331-07-202).  Based on the single-dose D2/D3 receptor occupancy data and 
steady-state PK/PD modeling, it was predicted that the D2/D3 receptor occupancy after 
multiple daily dose administration of 1 to 2 mg and higher doses of brexpiprazole will 
result in at least 80% to 90% D2/D3 receptor occupancy.
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 FDA on 10 Jul 2015.  Trial 331-10-233 
was a phase 1, multicenter, open-label dose-escalation trial to assess the safety, 
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
26


Protocol 331-10-234
Confidential - Proprietary Information
26
Version 5.0, 05 Jul 2022 
tolerability, and PK of oral brexpiprazole in adolescents with schizophrenia or other 
related psychiatric disorders.
In that trial, overall systemic exposure was measured by dose-normalized maximum 
concentration at steady state (Cmax,ss) and area under the plasma concentration-time curve 
to the last observable concentration (AUCτ), and was slightly higher (geometric mean 
ratio [GMR] adult/adolescent:  0.765 and0.904, respectively), and apparent clearance of 
drug from plasma after extravascular administration (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 area under the concentration-time curve from time zero to 24 hours 
(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 3 completed placebo-controlled trials (Trials 331-10-227, 331-10-228, and 
331-13-214) and a long-term, open-label safety trial (Trial 331-10-238).  The recently 
completed Trial 331-12-282 was a multicenter, randomized, double-blind, placebo and 
active comparator (Seroquel XR) controlled trial designed to assess the safety and 
efficacy of brexpiprazole (flexible dose) as adjunctive therapy to an assigned open-label 
antidepressant therapy (ADT) in depressed subjects.  The trial was a continuous 18-week 
double-blind treatment period with a 30 (+ 2)-day follow up or entry into an optional 
open-label rollover trial.
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-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.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
27




Protocol 331-10-234
Confidential - Proprietary Information
28
Version 5.0, 05 Jul 2022 
(IND) applications and 143 subjects (collectively) in non-US IND trials conducted in 
Japan and Korea.
Overall, 3101/4488 subjects (69.1%) who received brexpiprazole either alone or 
coadministered with another marketed medication reported at least 1 treatment-emergent 
adverse event (TEAE).  The most frequently reported TEAEs (incidence ≥ 5% of the total 
brexpiprazole group and more than total placebo) in all subjects who received 
brexpiprazole were headache (10.8%), increased weight (9.0%), insomnia (8.1%), 
akathisia (7.5%), dizziness (6.6%), somnolence (5.4%), and nausea (5.3%).  The majority 
of TEAEs reported in the 45 completed brexpiprazole trials were mild or moderate in 
severity.
A total of 26 deaths have been reported in the brexpiprazole clinical development plan:  
25 deaths in the US IND trials and 1 death in the non-US IND trials.  Eight deaths 
occurred in schizophrenia trials, 10 deaths in MDD trials, and 8 deaths in the agitation 
associated with dementia of the Alzheimer’s type trials.  Three deaths occurred in 
completed trials, and the remaining 23 deaths occurred in ongoing trials.  Of the 
26 deaths, 15 occurred in female subjects.  Serious TEAEs have been reported for 
94 subjects who received brexpiprazole in the 45 completed trials, including 91 subjects 
in completed trials conducted under the US INDs and 3 subjects in completed non-US 
IND trials.  Serious TEAEs had been reported for 442 subjects in ongoing trials of 
brexpiprazole.
A total of 312/4488 subjects (7.0%) who received brexpiprazole (either alone or 
coadministered with another medication) and 71/1378 subjects (5.2%) who received 
placebo (either alone or coadministered with another medication) discontinued from 
investigational medicinal product (IMP) due to TEAEs in completed brexpiprazole trials 
conducted under the US INDs (22 phase 1 trials, 1 phase 1b trial, 6 phase 2 trials, 
12 completed phase 3 trials, and 6 phase 3b trials).  A total of 2 subjects discontinued 
from IMP due to TEAEs in completed non-US IND trials, and 110 subjects discontinued 
from IMP due to TEAEs in the 2 ongoing non-US IND trials.  Brexpiprazole is indicated 
in adult patients for use as an adjunctive therapy to antidepressants for the treatment of 
MDD and treatment of schizophrenia.  The recommended dose ranges are as follows:  
2 to 4 mg/day for the treatment of schizophrenia in adults and 2 to 3 mg/day in adult 
subjects with MDD.  The following dose ranges of brexpiprazole were selected for 
evaluation in additional phase 2/3, phase 3, and phase 3b clinical trials (by indication):  
0.5 to 2 mg/day in adult subjects with agitation associated with dementia of the 
Alzheimer’s type and 1 to 3 mg/day in adult subjects with PTSD.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
29




Protocol 331-10-234
Confidential - Proprietary Information
30
Version 5.0, 05 Jul 2022 
Trial 331-10-233 were assigned to a dosing cohort and entered a Dose Titration Phase 
during which they received a starting dose of brexpiprazole (0.5 mg or 1 mg) for 2 to 
10 days based on their assigned titration schedule.  Following the Dose Titration Phase, 
subjects entered the Fixed Dose Phase and were administered the assigned dose (0.5 mg 
to 4 mg) for that cohort for 14 days. For the final Cohort a Dose Titration of 1 mg on 
Days 1 and 2; 2 mg on Days 3 and 4; 2.5 mg on Days 5 and 6; 3 mg on Days 7 and 8; and 
3.5 mg on Days 9 and 10, followed by 4 mg daily for 14 days was followed.  
Brexpiprazole at doses of 0.5 mg/day, 1 mg/day, 2 mg/day, 3 mg/day, and 4 mg/day was 
generally safe and well tolerated in adolescent subjects with schizophrenia, bipolar 
disorder, or other related psychiatric disorders.  Overall, systemic exposure and apparent 
clearance did not appear to be significantly different between adolescent and adult 
subjects while high variability due to limited number of evaluable subjects contributed to 
small differences between the PK evaluable and PK populations.
Based on results of pivotal safety and efficacy in adult patients with schizophrenia, a dose 
range of 2 to 4 mg is shown to be efficacious (Rexulti Label).  Based on the safety and 
PK data in Trial 331-10-233, no dose adjustment is deemed necessary in children and 
adolescents and thus a similar efficacious dose range of 2 to 4 mg is proposed for this 
trial.  In adult patients, brexpiprazole is initiated as 1 mg for 3 days followed by 2 mg for 
3 days, and a similar dose initiation is proposed in adolescent patients as a similar dose 
initiation scheme was evaluated in the final cohort of Trial 331-10-233 with no safety or 
tolerability concerns.  
2.3
Trial Objectives
The objective of the trial is to evaluate the short-term efficacy and safety of brexpiprazole 
monotherapy in the treatment of adolescents with schizophrenia.
3
Trial Design
3.1
Type/Design of Trial
This is a multicenter, randomized, double-blind, placebo- and active-controlled trial 
designed to assess the effect of brexpiprazole compared to placebo in adolescent subjects, 
ages 13 to 17 years at the time of informed consent/assent and at baseline (Day 1), with a 
Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) 
diagnosis of schizophrenia.  The initial diagnosis of schizophrenia should be made by an 
adequately trained clinician (psychiatrist or local medical equivalent who is experienced 
in treating adolescents with schizophrenia).  The diagnosis should then be confirmed by 
utilizing the Kiddie Schedule for Affective Disorders and Schizophrenia-Present and 
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
31








Protocol 331-10-234
Confidential - Proprietary Information
34
Version 5.0, 05 Jul 2022
Table 3.2-1
Dosing Schedule During the Treatment Period
Trial 
Day/Week
Brexpiprazole 
2–4 mg/day
Aripiprazole 
10–20 mg/day
Placebo
Days 1-4
0.5 mg
2 mg
placebo tablets QD
Days 5-7
1 mg
5 mg
placebo tablets QD
Days 8-14
2 mg
10 mg 
placebo tablets QD
Days 15–21
2–3 mg with 
option to 
maintain 2 mg or 
increasea to 3 mg
10 mg or 15 mg with 
option to maintain 10 mg 
or increasea to 15 mg
placebo tablets QD
Day 22+
(Weeks 4-6b)
2, 3, or 4 mg with 
option to remain 
at the same dose, 
or increase or 
decrease dose by 
1 mg
10, 15, or 20 mg with 
option to remain at the 
same dose, or increase or 
decrease dose by 5 mg
placebo tablets QD
QD = once daily.
aDose increases are allowed only at weekly intervals.  Dose decreases are allowed at any time for 
tolerability as long as the minimum required dose is maintained.
bBeginning at Day 22, the dose may be increased or decreased if needed for tolerability or efficacy.  
Subjects who cannot tolerate the minimum dose of 2 mg brexpiprazole or 10 mg aripiprazole will be 
discontinued from the trial.
All doses of double-blind IMP are to be taken orally once daily and can be administered 
without regard to meals.
3.3
Trial Population
3.3.1
Number of Subjects and Description of Population
The trial population will include male and female subjects between 13 and 17 years of 
age, inclusive, at the time of informed consent/assent and at baseline (Day 1) who 
continue to have a confirmed DSM-5 diagnosis of schizophrenia and a PANSS Total 
Score ≥ 80 at screening and at baseline (Day 1).  Approximately 645 subjects are 
anticipated to be screened with the expectation that 315 subjects will be randomized.
3.3.2
Subject Selection and Numbering
At screening, subjects will be assigned a unique subject identification number upon 
signing the informed consent form (ICF) based on sequential enrollment in the trial.  
Subjects will be assigned a unique subject number upon enrollment, prior to dosing on 
Day 1.  The clinical site will maintain a list identifying all subjects by their subject 
identification number and initials.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
35






Protocol 331-10-234
Confidential - Proprietary Information
37
Version 5.0, 05 Jul 2022
Table 3.4.3-1
Exclusion Criteria
Sex and Reproductive Status
1.
Sexually active males or females who do not agree to practice 2 different methods of birth 
control or remain abstinent during the trial and for 30 days after the last dose of IMP.  If 
employing birth control, 2 of the following precautions must be used:  vasectomy, tubal ligation, 
vaginal diaphragm, intrauterine device, birth control pill, birth control implant, birth control 
patch, birth control depot injection, condom with spermicide, or sponge with spermicide.
2.
Females who are breast-feeding or who have a positive pregnancy test result prior to receiving 
IMP.
Target Disease
3.
Subjects with a DSM-5 diagnosis other than schizophrenia that has been the primary focus of 
treatment within 3 months of screening.
4.
Subjects with a clinical presentation or history that is consistent with delirium, dementia, 
amnesia, or other cognitive disorders; subjects with psychotic symptoms that are better 
accounted for by another general medical condition(s) or direct effect of a substance (eg, 
medication, illicit drug use).
5.
Subjects who have been hospitalized > 21 days for a current exacerbation of schizophrenia at the 
time of the baseline visit.
6.
Subjects with known intellectual disability defined as an intelligence quotient less than 70; or, 
either clinical evidence or known social or school history indicative of intellectual disability.
7.
Any neurological disorder, with the exception of Tourette’s Syndrome.
8.
The subject is considered treatment resistant to antipsychotic medication, including aripiprazole 
or brexpiprazole, at an adequate dose and duration as confirmed by medical history, investigator 
judgment, or subject report.  Subjects with a history of relapse due to lack of medication 
compliance or drug abuse can be considered based on investigator judgment.
9.
Subjects who have a significant risk of committing violent acts, serious self-harm, or suicide 
based on history (eg, suicide attempt in the past 1 year) or routine psychiatric status 
examination, or those who are homicidal or are considered to be a high risk to others, or who 
have an answer of “yes” on Questions 4 or 5 (current or over the past 1 month) on the suicidal 
ideation section of the baseline screening version of the C-SSRS.
10.
Subject is known to have medication compliance issues that lead to IM depot medication use.
Medical History and Concurrent Diseases
11.
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 Advisor prior to randomization.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
38


Protocol 331-10-234
Confidential - Proprietary Information
38
Version 5.0, 05 Jul 2022
Table 3.4.3-1
Exclusion Criteria
12.
Subjects with IDDM are excluded.  Subjects with non-IDDM may be eligible for the trial if their 
condition is stable as determined by satisfying ALL of the following criteria:
•
HbA1c < 7.0%,
•
Screening fasting glucose must be ≤ 125 mg/dL or non-fasting glucose < 200 mg/dL.  If the 
non-fasting glucose is ≥ 200 mg/dL, subjects must be retested in the fasting state.  At retest, 
fasting glucose must be ≤ 125 mg/dL
•
Subject has been maintained on a stable regimen of oral antidiabetic medication(s) for at 
least 28 days prior to screening or diabetes has been well-controlled by diet for at least 
28 days prior to screening,
•
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.
13.
Subjects with uncontrolled hypertension (DBP > 95 mmHg) or symptomatic hypotension, or 
orthostatic hypotension which is defined as a decrease of ≥ 30 mmHg in SBP or a decrease of 
≥ 20 mmHg in DBP after at least 3 minutes standing compared to the previous supine blood 
pressure, OR development of symptoms.
14.
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.
15.
Subjects who test positive for drugs of abuse 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 Advisor prior to randomization.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
39


Protocol 331-10-234
Confidential - Proprietary Information
39
Version 5.0, 05 Jul 2022
Table 3.4.3-1
Exclusion Criteria
Physical and Laboratory Results
16.
The following laboratory test and ECG results are exclusionary:
1) Platelets ≤ 75000/mm3
2) Hemoglobin ≤ 11 g/dL
3) Neutrophils, absolute ≤ 1000/mm3
4) WBC count ≤ 2800/mm3
5) AST > 3 × upper limit of normal
6) ALT > 3 × upper limit of normal
7) Creatinine  2 mg/dL
8) HbA1c ≥ 7.0%
9) CPK > 3 × upper limit of normal
10) Abnormal free T4, unless discussed with and approved by the Medical Advisor.  (Note:  Free 
T4 is measured only if result for TSH is abnormal.)
11) QTcF or QTcN  450 msec for males and  470 msec for females
NOTE: In addition, subjects should be excluded if they have any other abnormal laboratory 
tests, vital sign results, or ECG findings which in the investigator’s judgment is medically 
significant and would impact the safety of the subject or the interpretation of the trial results.  
Criteria are provided to assist investigators in their assessments of results that may be potentially 
medically relevant, depending on the subject’s medical history and clinical presentation.  
Abnormal results for laboratory parameters or vital signs should be repeated 1 time to ensure 
reproducibility of the abnormality before excluding a subject based on the criteria noted above.  
Based on the QTcF or QTcN corrections reported by the central service, a subject will be 
excluded if either of the corrections equal or exceeds 450 msec for males and 470 msec for 
female for 2 or more of the 3 time points of the ECGs conducted.  If only 1 ECG time point has 
a corrected QTc of equal to or greater than 450 msec for males or 470 msec for females for 
either correction factor and it is not reproduced at either of the other 2 time points, the subject 
meets the inclusion criteria.
Prohibited Therapies or Medications
17.
Subjects who, according to the investigator’s judgment, will not be able to comply with the 
washout of psychotropic medications as defined by the protocol.
18.
Subjects who would be likely to require prohibited concomitant therapy during the trial, 
including subjects receiving CYP2D6 or CYP3A4 inhibitors or CYP3A4 inducers at screening 
or who are anticipated to require use of such agents during the trial.
19.
Subjects on IM depot therapy within 5 × half-life of the medication prior to screening.
Allergies and Adverse Drug Reactions
20.
Subjects with a history of neuroleptic malignant syndrome.
21.
Subjects with a history of true allergic response (ie, not intolerance) to more than one class of 
medications.
22.
Subjects who report a true allergic response to aripiprazole or brexpiprazole.
Other
23.
Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) or involuntarily 
hospitalized for treatment of either a psychiatric or physical (eg, infectious disease) illness must 
not be enrolled into this trial.
24.
Inability to tolerate oral medication or swallow tablets.
25.
Subjects who participated in any clinical trial within the last 30 days prior to screening.
26.
Any subject who, in the opinion of the investigator, should not participate in the trial.
27.
Subjects who are known poor metabolizers of CYP2D6 or CYP3A4.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
40


Protocol 331-10-234
Confidential - Proprietary Information
40
Version 5.0, 05 Jul 2022
ALT = alanine aminotransferase; AST = aspartate aminotransferase; C-SSRS = Columbia-Suicide 
Severity Rating Scale; CPK = creatine phosphokinase; CYP = cytochrome P450; DBP = diastolic 
blood pressure; ECG = electrocardiogram; HbA1c = glycosylated hemoglobin; IDDM = insulin-
dependent diabetes mellitus; IM = intramuscular; QTcF = QT interval as corrected for heart rate by 
Fridericia’s formula; QTcN = QT intervalcorrected for heart rate by the FDA Neuropharm Division 
formula; SBP = systolic blood pressure; T4 = thyroxine; TSH = thyroid-stimulating hormone; 
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 and assent must be signed and a new screening number 
assigned. 
3.5
Endpoints
3.5.1
Primary Endpoint
The primary endpoint is as follows:
•
Change from baseline to Week 6 in PANSS Total Score
The estimand of the primary efficacy endpoint is described in Section 7.4.
3.5.2
Secondary Endpoints
3.5.2.1
Secondary Efficacy Endpoints
The secondary efficacy endpoints are as follows:
•
Change in the PANSS Positive and Negative Subscale Scores
•
Percentage of subjects achieving response.  Response is defined as at least 30% 
improvement from baseline in PANSS Total Score or CGI score of 1 or 2.
•
Percentage of subjects achieving remission.  Remission is defined as a score of ≤ 3 on 
each of the following specific PANSS items: delusions (P1), unusual thought content 
(G9), hallucinatory behavior (P3), conceptual disorganization (P2). 
mannerisms/posturing (G5), blunted affect (N1), passive/apathetic social withdrawal 
(N4), and lack of spontaneity and conversation flow (N6).
•
Change in the Children’s Global Assessment Scale (CGAS) Score
•
Change in the Clinical Global Impression Severity (CGI-S) scale
•
Clinical Global Impression Improvement (CGI-I) scale
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
41


Protocol 331-10-234
Confidential - Proprietary Information
41
Version 5.0, 05 Jul 2022
3.5.2.2
Secondary Safety Endpoints
Safety will be assessed by the following:
•
The frequency and severity of AEs, serious AEs (clinical and laboratory), and 
discontinuation from the trial due to AEs
•
Weight, height, body mass index, and waist circumference
•
Analysis of potential suicide events recorded on the Columbia-Suicide Severity 
Rating Scale (C-SSRS)
•
Clinical laboratory tests and urinalysis results (including serum prolactin), vital signs, 
physical examinations, and electrocardiogram (ECG) parameters
•
Changes on the Simpson Angus Scale (SAS), Abnormal Involuntary Movement Scale 
(AIMS), and Barnes Akathisia Rating Scale (BARS)
•
Comprehensive psychotropic side effects as assessed by the Udvalg for Kliniske 
Undersogelser (UKU) side effect rating scale
•
Cognitive adverse effects as assessed by the New York Assessment for Adverse 
Cognitive Effects of Neuropsychiatric Treatment (NY-AACENT)
3.6
Measures to Minimize/Avoid Bias
Subjects will be randomly assigned through an IWRS to receive brexpiprazole, 
aripiprazole, or placebo.  The randomized treatments will be administered in a 
double-blind fashion.  Treatment assignments will be based on a computer-generated 
randomization code provided by the Otsuka Pharmaceutical Development & 
Commercialization, Inc. Biometrics Department.
Sponsor personnel, including those involved in monitoring, data management, and data 
analysis, will not have access to the treatment code during the trial.  Access to the 
treatment codes will be restricted to personnel charged with generating and maintaining 
randomization files, packaging IMP, operating the IWRS, and reporting serious adverse 
events (SAEs) to regulatory agencies.
&OLQLFDO6WXG\5HSRUW
3URWRFRODQG3URWRFRO$PHQGPHQWV
8QWLOWKHLQIRUPDWLRQKHUHLQLVUHOHDVHGE\2WVXNDWRWKHSXEOLFGRPDLQWKHFRQWHQWVRIWKLVGRFXPHQWDUH2WVXND
FRQILGHQWLDOLQIRUPDWLRQDQGVKRXOGQRWEHGXSOLFDWHGRUUHGLVWULEXWHGZLWKRXWSULRUZULWWHQFRQVHQWRI2WVXND

CCI




Protocol 331-10-234
Confidential - Proprietary Information
43
Version 5.0, 05 Jul 2022
Table 3.7-1
Schedule of Assessments 
6-Week Double-blind Treatment Period
Follow-up 
Visit
Assessment
Screening
Day 1
Day 4a
(± 1 
day)
Week 1
(± 2 
days)
Week 2
(± 2 
days)
Week 3
(± 2 
days)
Week 4
(± 2 
days)
Week 
5
(± 2 
days)
Week 6/ET
(± 2 days)
21 (± 2) 
days after 
last dose 
of IMP
Informed consent, demography, 
medical history, psychiatric history
X
Entrance criteria
X
X
Prior medications
X
X
K-SADS-PL
X
PANSS
X
X
X
X
X
X
X
X
CGAS
X
X
X
X
X
X
X
X
CGI-S
X
X
X
X
X
X
X
CGI-I
X
X
X
X
X
X
P-Q-LES-Q
X
X
C-SSRS
X
X
X
X
X
X
X
SAS, AIMS, BARS
X
X
X
X
X
X
X
X
UKU
X
X
X
X
X
X
X
X
NY-AACENT
X
X
X
X
X
X
X
X
Tanner Stagingb
X
X
Physical examination
X
X
Body weight and waist 
circumference
X
X
X
X
X
X
X
X
Height
X
X
Dispense Investigational Product
X
X
X
X
X
X
Clinical laboratory tests 
(hematology, serum chemistry 
[including blinded prolactin], and 
urinalysis)
X
X
X
X
HbA1c and TSH
X
X
X
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
44


Protocol 331-10-234
Confidential - Proprietary Information
44
Version 5.0, 05 Jul 2022
Table 3.7-1
Schedule of Assessments 
6-Week Double-blind Treatment Period
Follow-up 
Visit
Assessment
Screening
Day 1
Day 4a
(± 1 
day)
Week 1
(± 2 
days)
Week 2
(± 2 
days)
Week 3
(± 2 
days)
Week 4
(± 2 
days)
Week 
5
(± 2 
days)
Week 6/ET
(± 2 days)
21 (± 2) 
days after 
last dose 
of IMP
Vital signs (supine, sitting, and 
standing blood pressure, body 
temperature and pulse)c
X
X
X
X
X
X
X
X
ECG
X
Xd
Xd
Serum pregnancy test
X
X
X
X
Urine pregnancy teste
X
X
X
Urine drug screen
Xf
Xf
Xf
Pharmacokinetic samples
Xg
Xg
Xg
Pharmacogenomic sample
X
Adverse events
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
ET = early termination.
aThe Day 4 assessments will be conducted via telephone contact.
bThe collection of Tanner Staging data is required for this trial, and every attempt should be made to collect this information. Tanner Staging must be 
completed together with the physical examination in the most inconspicuous manner as possible for the subject. Tanner Staging could be completed by trial 
psychiatrist, trial affiliated pediatrician, nurse-practitioner, or nurse (in case of countries or states where nurses are qualified to perform a complete physical 
examination).  When Tanner Staging is not completed at a required visit, it should be collected at the next trial visit. A subject who reaches Stage 5 (both in 
pubic hair and genitalia) does not need to continue with Tanner Staging. Any psychiatrist who will perform the Tanner Staging evaluation will be trained 
and required to demonstrate inter-rater reliability before receiving certification to conduct the evaluation. A family practitioner or pediatrician who are 
investigators are considered trained and do not need to go through formal inter-rater reliability. Sites should make attempts to have examiners of both 
gender types. Attempts should be made to have the examination performed by the same gender as the subject. Otherwise, a trial-affiliated personnel of the 
same gender (ie, nurse) as the subject should be in the same examination room as the subject.
cVital Signs – refers to pulse and heart rate interchangeably throughout the protocol.
dAn ECG will be obtained predose on Day 1 and postdose on Week 6.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
45


Protocol 331-10-234
Confidential - Proprietary Information
45
Version 5.0, 05 Jul 2022
eIf the urine pregnancy test is positive, the result should be confirmed with a serum pregnancy test if a serum pregnancy test is not being performed during 
that visit.  Additional urine pregnancy testing may be done at the discretion of the investigator.
fA urine drug screen, including a urine alcohol test, is required at the designated times, but either or both can be conducted at any time during the phase at the 
discretion of the investigator.
gA plasma PK sample will be obtained 1–6 hours postdose on Day 1, Week 4, and Week 6. The time of the IMP dose will be recorded.  At the Week 4 and 6 
visits, the time of the last 3 doses of IMP will also be recorded.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
46






Protocol 331-10-234
Confidential - Proprietary Information
48
Version 5.0, 05 Jul 2022
3.7.1.2
Baseline/Day 1 (Randomization)
If the subject is found to be eligible for the trial during the screening period, the subject 
will attend a baseline visit during which the following procedures will be completed prior 
to randomization:
•
Inclusion/exclusion criteria will be verified.  Review of inclusion/exclusion criteria at 
the baseline visit will be based on assessments performed during screening.
•
Prior medications will be reviewed.
•
A qualified and certified rater will administer the PANSS.
•
A qualified rater will administer the CGAS.
•
A qualified and certified rater will administer the CGI-S.
•
The P-Q-LES-Q assessment will be completed by the subject.
•
The investigator (or qualified designee) will complete the “Baseline/Screening” 
C-SSRS form.
•
The investigator (or qualified designee) will administer the SAS, AIMS, and BARS.
•
The investigator (or qualified designee) will administer the UKU and NY-AACENT.
•
Body weight and waist circumference will be recorded.
•
Vital sign measurements (including blood pressure, body temperature, and pulse) 
will be recorded.  Blood pressure and pulse are to be measured in the following 
order:  supine, sitting, and standing after the subject has been in each position at 
least 3 minutes.  Vital signs are to be completed before any blood is drawn.
•
A standard 12-lead ECG will be performed predose after the subject has been supine 
and at rest for at least 5 minutes.  The ECG is to be completed before any blood is 
drawn. 
•
Blood samples will be collected for clinical laboratory tests (hematology and serum 
chemistry [including blinded prolactin, HbA1c, and TSH]) after a minimum 8-hour 
fast, if fasting is possible.  Vital sign and ECG assessments should be completed 
before any blood samples are collected.
•
A urine pregnancy test will be performed predose for all females.  The result must be 
negative prior to dosing.
•
A serum pregnancy test will be collected for all females.
•
Blood will be drawn for a plasma PK sample, which will be obtained 1–6 hours 
postdose, and the sampling time will be recorded.
•
A pharmacogenomics (PGx) sample will be collected to determine the CYP2D6 
metabolizer status.
•
AEs and concomitant medications will be recorded.
•
If the subject remains eligible for the trial after completion of the baseline 
evaluations, trial personnel will capture trial data within the eSource and randomize 
the subject to obtain an IMP assignment.  The subject will receive the first dose of 
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
49


Protocol 331-10-234
Confidential - Proprietary Information
49
Version 5.0, 05 Jul 2022
IMP from the assigned double-blind titration card and the date and time of the first 
dose will be recorded in eSource.
3.7.1.3
Day 4
All subjects will be contacted by telephone on Day 4 to record AEs and concomitant 
medications.
3.7.1.4
Weeks 1, 2, 3, 4, and 5
All subjects will be assessed weekly at scheduled visits during double-blind treatment in 
the acute treatment phase.  The following evaluations will be performed at each visit 
(ie, Weeks 1, 2, 3, 4, and 5):
•
A qualified rater will administer the PANSS.
•
A qualified rater will administer the CGAS.
•
A qualified rater will administer the CGI-I.
•
A qualified rater will administer the CGI-S.
•
The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form.
•
The investigator (or qualified designee) will administer the SAS, AIMS, and BARS.
•
The investigator (or qualified designee) will administer the UKU and NY-AACENT.
•
Body weight and waist circumference will be recorded.
•
Vital sign measurements (including blood pressure, body temperature, and pulse) 
will be recorded.  Blood pressure and pulse are to be measured in the following 
order:  supine, sitting, and standing after the subject has been in each position at 
least 3 minutes.  Vital signs are to be completed before any blood is drawn, if 
applicable at the specific visit.
•
Drug accountability.
•
AEs and concomitant medications will be recorded.
•
The IMP will be dispensed to the subject.
The following additional evaluations will be performed at Week 4 only:
•
Blood samples will be collected for clinical laboratory tests (hematology and serum 
chemistry [including blinded prolactin]) after a minimum 8-hour fast, if fasting is 
possible.  Vital sign assessments should be completed before any blood samples are 
collected.
•
Urine will be collected from all potential subjects for urinalysis and urine screen(s) 
for drugs of abuse.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
50


Protocol 331-10-234
Confidential - Proprietary Information
50
Version 5.0, 05 Jul 2022
•
A plasma PK sample will be obtained within 1-6 hours postdose when possible.  The 
time of each PK sample as well as the time of the last 3 doses of IMP will be 
recorded.
•
A serum pregnancy test will be performed for all females.
3.7.1.5
Week 6 (End of Treatment)
The treatment period will conclude at the Week 6 visit.  Subjects will take the last dose of 
IMP either prior to the Week 6 visit on the same calendar day or during the Week 6 visit 
whenever possible, depending on the time of day when the subject typically takes the 
IMP relative to the scheduled time for the visit.  The following activities and assessments 
will occur at Week 6/end of treatment:
•
Trial personnel will register completion or discontinuation from the trial in eSource.
•
A qualified and certified rater will administer the PANSS.
•
A qualified rater will administer the CGAS.
•
A qualified and certified rater will administer the CGI-S.
•
A qualified and certified rater will administer the CGI-I.
•
The P-Q-LES-Q assessment will be completed by the subject.
•
The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form.
•
The investigator (or qualified designee) will administer the SAS, AIMS, and BARS.
•
The investigator (or qualified designee) will administer the UKU and NY-AACENT.
•
The investigator (or qualified designee) will complete Tanner Staging assessment.
•
A physical examination will be performed.
•
Body weight, height, and waist circumference will be recorded.
•
Vital sign measurements (including blood pressure, body temperature, and pulse) 
will be recorded.  Blood pressure and pulse are to be measured in the following 
order:  supine, sitting, and standing after the subject has been in each position at 
least 3 minutes.  Vital signs are to be completed before any blood is drawn.
•
A standard 12-lead ECG will be performed postdose after the subject has been supine 
and at rest for at least 5 minutes.  The ECG is to be completed before any blood is 
drawn.
•
Blood samples will be collected for clinical laboratory tests (hematology and serum 
chemistry [including blinded prolactin, HbA1c, and TSH]) after a minimum 8-hour 
fast, if fasting is possible.  Vital sign and ECG assessments should be completed 
before any blood samples are collected.
•
A urine pregnancy test will be performed predose for all females.
•
A serum pregnancy test will be performed for all females.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
51
























Protocol 331-10-234
Confidential - Proprietary Information
62
Version 5.0, 05 Jul 2022
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 
sponsor at the earliest possible time by telephone.  The sponsor should be notified when 
there is a planned or inadvertent treatment interruption of 2 days or more in a 7-day 
period.  The investigator and sponsor will come as quickly as possible to a joint decision 
regarding the subject’s continuation in the trial.  This decision will be documented by the 
investigator and the sponsor and reviewed by the site monitor.  The treatment interruption 
will be recorded via 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
Subjects meeting any of the following criteria must discontinue IMP and be withdrawn 
from the trial:
a) occurrence of any AE, intercurrent illness or abnormality in a laboratory assessment 
which, in the opinion of the investigator, warrants the subject’s permanent withdrawal 
from the trial;
b) treatment with a prohibited concomitant medication other than the use of appropriate 
medications for the treatment of AEs under direction of the investigator;
c) subject noncompliance, defined as refusal or inability to adhere to the trial schedule 
or procedures (see Section 3.12);
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
63


Protocol 331-10-234
Confidential - Proprietary Information
63
Version 5.0, 05 Jul 2022
d) at the request of the subject, investigator, sponsor or designee, or regulatory authority;
e) subject becomes pregnant (see Section 5.5);
f)
subject cannot tolerate the assigned dose of IMP;
g) subject is lost to follow-up;
h) death;
i)
subject withdraws informed consent; or
j)
termination of all or part of the trial by the sponsor.
The investigator will notify the sponsor promptly when a subject is withdrawn.  Subjects 
withdrawn prior to Week 6 must complete the Week 6 evaluations at the time of 
withdrawal.  In addition, all subjects who withdraw prematurely from the trial will be 
assessed by a telephone assessment 21 (± 2) days after the last dose of IMP for evaluation 
of safety.  Withdrawn subjects will not be replaced.
3.8.3.4
Withdrawal of Consent
All subjects have the right to withdraw their consent from further participation in the trial 
at any time without prejudice.  Subjects’ parents or legal guardians can also withdraw 
their consent to allow subjects to continue participation in the trial.  Subjects cannot 
withdraw consent for use of data already collected as part of the trial, but only for future 
participation.  The investigator can also discontinue a subject’s participation in the trial at 
any time if medically necessary.  Unless the subject provides their written withdrawal of 
consent or there is other written documentation by the investigator confirming the 
subject’s verbal intent to completely withdraw from the trial, subjects should be followed 
for all protocol-specified evaluations and assessments, if possible.
Complete withdrawal of consent requires a subject’s refusal of ALL of the following 
methods of follow up:
•
Participation in all follow-up procedures specified in the protocol (whether in-clinic, 
by telephone, or by an in-home visit).
•
Participation in a subset of protocol specified follow-up procedures (by a frequency 
schedule and method, as agreed by subject and staff).
•
Contact of the subject by trial personnel, even if only by telephone, to assess current 
medical condition, and obtain necessary medical or laboratory reports relevant to the 
trial’s objectives.
•
Contact of alternative person(s) who have been designated in source records as being 
available to discuss the subject’s medical condition, even if only by telephone, mail, 
or e-mail (eg, family, spouse, partner, legal representative, friend, neighbor, or 
physician).
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
64


Protocol 331-10-234
Confidential - Proprietary Information
64
Version 5.0, 05 Jul 2022
•
Access to medical information from alternative sources (eg, hospital/clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, social media sources). 
Withdrawal of consent is a critical trial event and therefore should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent.  
The reasons for a subject’s intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial.  
A subject may initially express their desire to interrupt or discontinue IMP 
administration, which is not equivalent to a complete withdrawal of consent for further 
participation (see Section 3.8.3.1 and Section 3.8.3.2).  A subject may, however, indicate 
that further trial participation is creating a burden on their work or social schedule.  
Therefore, the investigator should follow the procedures outlined in Section 3.8.3.3 to 
determine if the subject can continue participation in the trial if modifications to his/her 
treatment or schedule of assessments can be accommodated.  Only subjects who 
withdraw their permission for all of the above degrees of follow up are considered to 
have completely withdrawn their consent to participate in the trial.
3.8.3.5
Procedures to Encourage Continued Trial Participation
In all cases of impending IMP discontinuation or consent withdrawal, investigators will 
be given instructions to meet and discuss with the subject their options of continuing in 
the trial, preferably on therapy.  The investigator should ensure understanding and 
documentation of the reasons for the subject’s desire to withdraw consent.  
3.9
Screen Failures
A screen failure subject is one from whom informed consent is obtained and is 
documented in writing (ie, subject signs an ICF), but who is not started on treatment, 
whether through randomization or open assignment.  For the purposes of this trial, 
treatment begins with the first dose of double-blind IMP at the baseline visit.  If a subject 
fails to qualify for the trial during screening for a reason other than a positive screen for 
drugs of abuse, he/she is permitted to be rescreened at a later date.  In the event that a 
screen failure is rescreened for trial participation after the 28-day screening period 
expires, a new ICF must be signed and a new screening number assigned.
3.10
Definition of Completed Subjects
The treatment period is defined as the time period during which subjects are evaluated for 
primary or secondary objectives of the trial irrespective of whether or not the subject 
actually consumed all doses of IMP.  Subjects who are evaluated at the last scheduled 
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
65


Protocol 331-10-234
Confidential - Proprietary Information
65
Version 5.0, 05 Jul 2022
visit during the treatment period will be defined as trial completers.  For purposes of this 
trial, subjects who complete the Week 6 visit will be defined as trial completers.  Protocol 
specified post-treatment follow-up contacts will not qualify as the “last scheduled visit.”  
Subjects who are not completers are defined as those who “discontinued the trial.”
3.11
Definition of Subjects Lost to Follow-Up
Subjects who cannot be contacted on or before the Week 6 visit during the treatment 
period, who do not have a known reason for discontinuation (eg, withdrew consent or 
AE), and for whom a survival status at the end of the trial cannot be determined will be 
classified as “lost to follow-up” as the reason for discontinuation.  Survival status can be 
determined from a variety of sources, either by obtaining acceptable documentation for 
death (ie, death certificate, medical records, public records, statement by a family 
member or primary care physician) or acceptable documentation for life (ie, direct 
contact with the subject, medical records, successful telephone contact with the subject, 
statement by a family member or primary care physician, or public records).
The site will make 3 documented attempts to contact the subject by telephone and in the 
event the site is unable to reach the subject by telephone, the site will attempt to contact 
the subject via certified mail or an alternative similar method, where appropriate, before 
assigning a “lost to follow-up” status.
3.12
Subject Compliance 
Responsible trial personnel will dispense the IMP (ie, brexpiprazole, aripiprazole, and 
placebo) to subjects.  Accountability and compliance verification should be documented 
in the subject’s trial records.  Subjects must be counseled on the importance of taking the 
IMP as directed at all trial visits.  If poor compliance continues after counseling (eg, 
multiple missed doses resulting in less than 80% overall compliance), discontinuation of 
the subject from the trial should be considered.
3.13
Protocol Deviations
This trial is intended to be conducted as described in this protocol.  In the event of a 
significant deviation from the protocol due to an emergency, accident, or mistake (eg, 
violation of informed consent process, IMP dispensing or subject dosing error, treatment 
assignment error, subject enrolled in violation of eligibility criteria or concomitant 
medication criteria), the investigator or designee will contact the sponsor at the earliest 
possible time by telephone.  The investigator and sponsor will come as quickly as 
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
66












Protocol 331-10-234
Confidential - Proprietary Information
71
Version 5.0, 05 Jul 2022
medication documented, including a notation of the drug name, dose, and time of 
administration in eSource.
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.
4.2.2
Non-therapy Precautions and Restrictions
4.2.2.1
Precautions
Subjects should not undergo any elective medical procedure without prior consultation 
with the investigator.  An elective procedure (eg. minor surgery, dental surgery, 
orthopedic surgery) that might require hospitalization or general anesthesia should be 
deferred until after the trial whenever clinically appropriate.
4.2.2.2
Restrictions
With the exception of inpatient group therapy, new-onset psychotherapy is prohibited 
during the trial.  In other words, except for inpatient group therapy, subjects may only 
receive psychotherapy (eg, individual, group, marriage, or family therapy) if they have 
been participating in the therapy regularly (ie, weekly) for at least 6 weeks (42 days) prior 
to screening and commit to maintain their participation during the course of the trial at 
the current frequency or unless permission is obtained from the medical monitor.
Consumption of grapefruit, grapefruit products, Seville oranges, or Seville orange 
products within 72 hours prior to dosing and during the trial is prohibited.  Subjects will 
be instructed to refrain from drinking alcoholic beverages or using illicit drugs during 
participation in the trial.  The investigator may request a blood or urine drug screen at any 
time during the trial if there is a suspicion of illicit drug use.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
72


Protocol 331-10-234
Confidential - Proprietary Information
72
Version 5.0, 05 Jul 2022
5
Reporting of Adverse Events
5.1
Definitions
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  AEs would not include information recorded as medical 
history at screening for preplanned procedures for which the underlying condition was 
known and no worsening occurred.  An adverse reaction is any untoward and unintended 
response to an IMP related to any dose administered.
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE.  For the purpose of IND safety reporting, “reasonable possibility” 
means there is evidence to suggest a causal relationship between the IMP and the AE.  
Suspected adverse reaction implies a lesser degree of certainty about causality.
An SAE includes any event that results in any of the following outcomes:
•
Death
•
Life-threatening; ie, the subject was, in the opinion of the investigator, at immediate 
risk of death from the event as it occurred.  It does not include an event that, had it 
occurred in a more severe form, might have caused death.
•
Persistent or significant incapacity/disability or substantial disruption of the ability to 
conduct normal life functions.
•
Requires inpatient hospitalization or prolongs hospitalization.
•
Hospitalization itself should not be reported as an SAE; whenever possible the 
reason for the hospitalization should be reported.
•
Hospitalizations or prolonged hospitalizations for social admissions (ie, those 
required for reasons of convenience or other 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 an SAE.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
73


Protocol 331-10-234
Confidential - Proprietary Information
73
Version 5.0, 05 Jul 2022
If a subject is experiencing an EPS, the specific EPS must be indicated on the AE screen 
in eSource.  Examples of AEs that are considered EPS include, but are not limited to:  
generalized rigidity, hyperkinesia, bradykinesia, akinesia, dystonia, hypertonia, akathisia, 
tremor, flexed posture, involuntary muscle contractions, athetosis, and chorea.  If a 
subject is experiencing 2 or more of these symptoms, whether or not treatment with an 
anticholinergic is required, this is considered as extrapyramidal syndrome and must be 
entered as “extrapyramidal syndrome” on the AE screen in eSource instead of the 
individual symptoms.  Permitted treatments for EPS are described in Section 4.2.1.
Immediately Reportable Event (IRE):
•
Any SAE.
•
Any AE related to occupational exposure.
•
Potential serious hepatotoxicity cases (any increase of AST or ALT ≥ 3 times the 
upper normal limit or screening value with an increase in total bilirubin ≥ 2 times 
the upper normal limit or screening value) 
•
Pregnancies are also defined as IREs.  Although normal pregnancy is not an AE, 
it will mandate IMP discontinuation and must be reported on an IRE form to the 
sponsor.  Pregnancy will only be documented on the AE screen in 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 
considered medically relevant by the investigator (subject is symptomatic, requiring 
corrective treatment or further evaluation), or if the laboratory value leads to 
discontinuation, or fulfills a seriousness criterion, this is considered an AE. 
Severity:  Adverse events will be graded on a 3-point scale and reported as indicated in 
eSource.  The intensity of an adverse experience is defined as follows:
1 = Mild:
Discomfort noticed, but no disruption to daily activity.
2 = Moderate:
Discomfort sufficient to reduce or affect normal daily activity.
3 = Severe:
Inability to work or perform normal daily activity.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
74


Protocol 331-10-234
Confidential - Proprietary Information
74
Version 5.0, 05 Jul 2022
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 in eSource provided by the sponsor.  The AE 
collection is to begin after a subject has signed the ICF.  
Use medical terminology in AE reporting.  Adverse events should be reported as a single 
unifying diagnosis whenever possible or, in the absence of a unifying diagnosis, as 
individual signs or symptoms.  Exacerbation or disease progression should be reported as 
an AE only if there are unusual or severe clinical features that were not present, or 
experienced earlier, or not expected based on the course of the condition.  A reported AE 
that undergoes a change in severity, seriousness, or toxicity should be reported as a new 
AE in eSource.
Note:  Normal pregnancy is not an AE and should not be recorded as one in eSource; 
guidelines outlined in Section 5.5 should be followed for pregnancy reporting.
In addition, the sponsor must be notified immediately by telephone, fax, or e-mail of any 
IREs according to the procedure outlined below, in Section 5.3.  Special attention should 
be paid to recording hospitalization and concomitant medications.
5.3
Immediately Reportable Events 
The investigator must immediately report after either the investigator or site personnel 
become aware of any SAE, 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 screen in 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 
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
75


Protocol 331-10-234
Confidential - Proprietary Information
75
Version 5.0, 05 Jul 2022
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 AST or ALT that is ≥ 3 times the ULN, a 
total bilirubin level should also be evaluated.  If the total bilirubin is ≥ 2 times the ULN, 
complete an IRE form with all values listed and also report as an AE in eSource.
5.5
Pregnancy
For females and for men who are sexually active, there must be a documented agreement 
that the subject or their partner will take effective measures (ie, double-barrier method) to 
prevent pregnancy during the course of the trial and for 30 days after the last dose of 
IMP.  Unless the subject is sterile (ie, females who have had a bilateral oophorectomy or 
hysterectomy or who have been postmenopausal for at least 12 consecutive months; or 
men who have had a bilateral orchidectomy) or remains abstinent, 2 of the following 
precautions must be used:  vasectomy, tubal ligation, vaginal diaphragm, intrauterine 
device, birth control pills, birth control depot injection, birth control implant, birth control 
patch, condom with spermicide, or sponge with spermicide.  Any single method of birth 
control, including vasectomy and tubal ligation, may fail, leading to pregnancy.  The 
contraceptive method will be documented at each trial visit.
Before enrolling females in this clinical trial, investigators must review the below 
guidelines about trial participation with all females.  The topics should generally include:
•
General information
•
Informed consent form
•
Pregnancy prevention information
•
Drug interactions with hormonal contraceptives
•
Contraceptives in current use
•
Guidelines for the follow up of a reported pregnancy
Before trial enrollment, females must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy.  The subject must provide assent or e-sign the electronic ICF stating that the 
above-mentioned risk factors and the consequences were discussed with her. 
A urine or serum pregnancy test for human chorionic gonadotropin will be performed at 
screening on all female subjects.  At any time during the trial if a urine test is performed 
and is positive, the investigator will follow up with a confirmatory serum test.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
76


Protocol 331-10-234
Confidential - Proprietary Information
76
Version 5.0, 05 Jul 2022
During the trial, all females 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), 
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.  Local regulatory requirements must be followed for follow up and reporting on 
pregnancy cases or infants.
5.6
Procedure for Breaking the Blind
The investigator is encouraged to contact the sponsor/Clinical Research Organization 
(CRO) medical advisor to discuss their rationale for unblinding.  However, to prevent 
delays to the investigator or medical personnel responding to a potentially emergent 
situation, unblinding of IMP will not be dependent upon the investigator receiving 
approval from the sponsor/CRO medical advisor (ie, the investigator will be able to 
obtain the code break information independent of the sponsor/CRO medical advisor).  
The investigator must contact the sponsor/CRO medical advisor by telephone or e-mail 
with an explanation of the need for opening the treatment assignment code within 
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
77


Protocol 331-10-234
Confidential - Proprietary Information
77
Version 5.0, 05 Jul 2022
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 
Post-trial follow-up is not required for eligible subjects who enter the optional open-label 
trial.
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 screen in eSource with the current status noted.  For this trial, information on AEs 
will be followed for up to 21 (± 2) days after the last dose of IMP has been administered.  
All nonserious events that are ongoing at the last scheduled contact will be recorded as 
ongoing in eSource.  For any AE having been identified throughout the trial, during 
analysis, additional relevant medical history information may be requested 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 and as described below in Section 5.7.3.
Serious adverse events that are identified or ongoing at the last scheduled contact must 
be recorded on the AE screen in eSource and reported to the sponsor according to the 
reporting procedures outlined in Section 5.3.  This may include unresolved previously 
reported SAEs, or new SAEs.  The investigator will follow SAEs until the events are 
resolved, stabilized, or the subject is lost to follow-up.  Resolution means that the subject 
has returned to the baseline state of health and stabilized means that the investigator does 
not expect any further improvement or worsening of the subject’s condition.  The 
investigator will continue to report any significant follow-up information to the sponsor 
up to the point the event has been resolved.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
78




Protocol 331-10-234
Confidential - Proprietary Information
79
Version 5.0, 05 Jul 2022
The core dataset for all efficacy analyses is based on the intent-to-treat (ITT) population, 
which is defined in the Efficacy Sample above.  The observed case (OC) dataset will be 
used in the primary analysis of efficacy endpoints.  As described below, in order to 
handle missing data and restrictions imposed by different types of analyses (eg, change 
from baseline analysis), datasets derived from the ITT population will be used for the 
efficacy analyses.
7.3
Handling of Missing Data
The PANSS scale is utilized as the primary efficacy assessment in this trial.  The PANSS 
Total Score is the sum of the rating scores for 7 positive scale items, 7 negative scale 
items, and 16 general psychopathology scale items from the PANSS panel in eSource.  If 
fewer than 24 of the 30 items are recorded, the PANSS Total Score is not evaluable.  If 
24 to 29 of the 30 items are recorded, the PANSS Total Score is equal to the mean of the 
recorded items multiplied by 30 and then rounded to the first decimal place.
In general, missing data will be handled by analysis of mixed model repeated measures 
(MMRM) methodology based on all data from protocol-specified visits in the ITT 
population under the assumption of missing at random (MAR), which is a reasonable 
assumption in longitudinal clinical trials with psychiatric drugs.  However, the possibility 
of “missing not at random” (MNAR) data can never be ruled out.  As sensitivity analyses, 
multiple imputation (MI) will be used to explore data missing mechanisms of MNAR and 
investigate the response profile of dropout reasons.  Details of these exploratory analyses 
will be provided in the Statistical Analysis Plan (SAP).
The OC dataset will consist of actual observations recorded at each visit during 
double-blind treatment and no missing data will be imputed.  An MMRM will be 
performed on the OC dataset.
In order to assess sensitivity of results due to missing data, a last observation carried 
forward (LOCF) analysis will be performed as a sensitivity analysis.  In contrast to the 
OC dataset, the LOCF dataset will include data recorded at a scheduled visit, ie, all OC 
data, or, if no observation is recorded at that visit, data carried forward from the 
previously scheduled visit.  Baseline data will not be carried forward to impute missing 
values for the LOCF dataset.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
80


Protocol 331-10-234
Confidential - Proprietary Information
80
Version 5.0, 05 Jul 2022
7.4
Primary and Secondary Endpoint Analyses
7.4.1
Primary Endpoint Analysis
The primary efficacy variable in this trial is the change from baseline to Week 6 in 
PANSS Total Score.
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 adolescents with schizophrenia.  The estimand, or target 
of estimation, following this hypothetical strategy is the treatment effect seen, assuming 
that 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 had their treatment effect masked had the subjects taken other 
treatment after withdrawal.  This would mean 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 schizophrenia 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: Adolescent subjects 13 to 17 years of age with schizophrenia who 
met the protocol-defined inclusion/exclusion criteria and were qualified for the 
Efficacy Sample
•
Endpoint: Change from Baseline to Week 6 in the PANSS Total Score
•
Intercurrent Events: Refers to premature treatment discontinuation (ie, early dropout) 
prior to Week 6 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 as a combination of the responses of on 
treatment completers at Week 6 and the imputation of the endpoint to Week 6 following 
the trend in each treatment group, using the MMRM method to impute missing data for 
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
81


Protocol 331-10-234
Confidential - Proprietary Information
81
Version 5.0, 05 Jul 2022
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 
treatment period. Analyses with missing values imputed by MI under MNAR and other 
methods will be performed as sensitivity analyses.
The primary statistical comparison of interest is brexpiprazole 2–4 mg versus placebo.  
With the assumption of MAR, an MMRM analysis with fixed-effect factors of treatment, 
trial site, visit, treatment by visit interaction, and fixed effect covariates of baseline and 
baseline by visit interaction will be applied to the change from baseline from Week 1 to 
Week 6 in PANSS Total Score based on all available data (OC dataset).  The data will be 
modeled using an unstructured variance covariance matrix for the within subject 
variation.  A statistical test of the least squares (LS) mean differences at Week 6 of the 
MMRM analysis will serve as the analysis of the primary endpoint.  The Efficacy Sample 
will be used in the analysis of the primary endpoint.  The comparison will be tested at a 
significance level of 0.05 (2-side).
In case there is a convergence problem with the MMRM model with the unstructured 
variance covariance matrix, the following structures other than unstructured will be used 
in order of 1) heterogeneous toeplitz, 2) heterogeneous autoregressive of order 1, and 
3) heterogeneous compound symmetry, and the first (co)variance structure converging to 
the best fit will be used as the primary analysis.  If a structured covariance has to be used, 
the “sandwich” estimator of the standard error of the fixed effects parameters will be used 
in order to deal with possible model misspecification of the covariance matrix.  
In order to explore the robustness of the primary analysis based on the MAR assumption, 
sensitivity analysis of the primary efficacy endpoint under the MNAR assumption will be 
conducted, using a pattern-mixture model. 
Additional details, including pooling of small trial sites are provided in the SAP. 
7.4.2
Secondary Endpoint Analysis
For all continuous secondary endpoints (CGI-S, CGI-I, CGAS, PANSS Positive Subscale 
score, and PANSS Negative Subscale score), an MMRM analysis with factors of 
treatment, trial site, visit, treatment by visit interaction, and baseline and baseline by visit 
interaction as covariates with an unstructured variance covariance structure to the visits 
will be applied to these endpoints based on all available data (OC dataset).  The CGI-I 
score at endpoint will be analyzed at the last visit using the Cochran-Mantel-Haenszel 
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
82


Protocol 331-10-234
Confidential - Proprietary Information
82
Version 5.0, 05 Jul 2022
(CMH) row mean scores differ test controlling for trial site.  The CMH general 
association test controlling for trial site will be applied to the analysis of percentage of 
subjects achieving response and remission by week on LOCF data, for the Efficacy 
Sample.  Response is defined as reduction of ≥ 30% from baseline in PANSS Total Score 
or CGI-I score of 1 or 2.  Remission is defined as a score of ≤ 3 on each of the following 
specific PANSS items: delusions (P1), unusual thought content (G9), hallucinatory 
behavior (P3), conceptual disorganization (P2), mannerisms/posturing (G5), blunted 
affect (N1), passive/apathetic social withdrawal (N4), and lack of spontaneity and 
conversation flow (N6). 
7.4.3
Exploratory Endpoint Analysis
The change in the P-Q-LES-Q total score (ie, 14 items) will be summarized using an 
MMRM analysis with factors of treatment, trial site, visit, treatment by visit interaction, 
and baseline and baseline by visit interaction as covariates, with an unstructured variance 
covariance structure.  All available data (OC dataset) will be applied in the model.  
Additionally, change from baseline in the overall score of P-Q-LES-Q will be 
summarized using the CMH row mean scores differ test controlling for trial site.
Hospitalization data will be summarized by 2 categories:  hospitalization due to 
worsening schizophrenia and hospitalizations due to other causes.
Additional details for exploratory endpoint analysis are provided in the SAP.
7.4.4
Interim Analysis
No formal unblinded interim analysis is planned for this trial.
7.5
Analysis of Demographic and Baseline Characteristics
Demographic characteristics, disease severity, and psychiatric and medical history at 
(predose) baseline will be summarized by descriptive statistics, eg, proportion, mean, 
median, SD, and minimum and maximum values.  These summary statistics will be 
reviewed to identify any potential lack of balance between the treatment groups in the 
Randomized Sample.
7.6
Safety Analysis
Standard safety variables to be analyzed include AEs, clinical laboratory tests, vital signs, 
ECGs, body weight, waist circumference, and body mass index.  In addition, data from 
the following safety scales will be evaluated:  SAS, AIMS, BARS, and C-SSRS.  The 
safety analysis will be conducted based on the Safety Sample which is defined in 
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
83


Protocol 331-10-234
Confidential - Proprietary Information
83
Version 5.0, 05 Jul 2022
Section 7.2.  In general, baseline of a safety variable is defined as the last observation of 
the variable before taking the first dose of IMP, unless specified otherwise.  Details of the 
safety analysis will be provided in the SAP.
7.6.1
Adverse Events
All AEs will be coded by system organ class and the Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term.  The incidence of the following events will be 
summarized by treatment group:
•
TEAEs
•
TEAEs by severity
•
TEAEs potentially causally related to the IMP
•
TEAEs with an outcome of death
•
Serious TEAEs
•
TEAEs leading to discontinuations of the IMP
The above summaries will also be prepared for TEAEs potentially causally related to the 
IMP.
7.6.2
Clinical Laboratory Data
Summary statistics for changes from baseline in the routine clinical laboratory 
measurements, prolactin concentrations, HbA1c, and TSH will be provided.  In addition, 
potentially clinically relevant results in laboratory tests identified using prospectively 
defined criteria, such as liver function tests for cases of potential serious hepatotoxicity, 
will be summarized.
7.6.3
Physical Examination, Waist Circumference, and Vital Signs Data
By-patient listings will be provided for physical examination data.  Summary statistics 
for changes from baseline in vital signs, body weight, waist circumference, and BMI will 
be provided.  Potentially clinically relevant results in vital signs and body weight will 
also be summarized.  In addition, z-scores for height, body weight, and BMI from 
baseline will also be summarized by visit.  Additional details will be provided in the 
SAP.
7.6.4
Electrocardiogram Data
Mean change from baseline and the incidence of clinically significant changes will be 
calculated for ECG parameters.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
84




Protocol 331-10-234
Confidential - Proprietary Information
85
Version 5.0, 05 Jul 2022
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.
Brexpiprazole, aripiprazole, and placebo tablets 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.
8.3
Accountability
The investigator or designee must maintain an inventory record of IMP (brexpiprazole, 
aripiprazole, and placebo) received, dispensed, administered, and returned.
8.4
Returns and Destruction
Upon completion or termination of the trial, all used IMP containers, unused IMP, and 
partially-used IMP must be returned to the sponsor or designee agent, or destroyed at the 
trial sites.  The IMP may only be destroyed by the trial sites if approved by the sponsor 
and if the IMP destruction meets all local regulations.
All IMP returned to the sponsor must be accompanied by the appropriate documentation 
and be clearly identified by protocol number and trial site number on the outermost 
shipping container.  Returned supplies should be in the original containers (eg, subject 
kits).  The assigned trial monitor will facilitate the return or destruction of used IMP 
containers, unused IMP, and partially used IMP.
8.5
Reporting of Product Quality Complaints
A product quality complaint (PQC) is any written, electronic, or verbal communication 
by a healthcare professional, consumer, subject, medical representative, Competent 
Authority, regulatory agency, partner, affiliate or other third party that alleges 
deficiencies or dissatisfaction related to identity, quality, labeling, packaging, reliability, 
safety, durability, tampering, counterfeiting, theft, effectiveness or performance of a drug 
product or medical device after it is released for distribution.  Examples include, but are 
not limited to, communications involving:
•
Failure/malfunction of a product to meet any of its specifications
•
Incorrect or missing labeling
•
Packaging issues (eg, damaged, dirty, crushed, missing product)
•
Blister defects (eg, missing, empty blisters)
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
86


Protocol 331-10-234
Confidential - Proprietary Information
86
Version 5.0, 05 Jul 2022
•
Bottle defects (eg, under/over-fill, no safety seal)
•
Vial defects
•
Product defect (eg, odor, chipped, broken, embossing illegible)
•
Loss or theft of product
8.5.1
Eliciting and Reporting Product Quality Complaints
The investigator or designee must record all PQCs identified through any means from the 
receipt of the IMP from the sponsor, or sponsor’s designee, through and including 
reconciliation and up to destruction, including subject dosing.  The investigator or 
designee must notify the sponsor (or sponsor’s designee) by e-mail or telephone within 
24 hours of becoming aware of the PQC according to the procedure outlined below.
•
Online – Send information required for reporting purposes (listed below) to 
OAPIEQCProductComplaints@Otsuka-us.com.
•
Telephone - Rocky Mountain Call Center at 1-800-438-6055.
Identification of a PQC by the subject should be reported to the site investigator, who 
should then follow one of the reporting mechanisms above.
8.5.2
Information Required for Reporting Purposes
•
Description of complaint
•
Reporter identification (eg, subject, investigator, site, etc.)
•
Reporter contact information (eg, address, telephone number, e-mail address)
•
ID of material (product/compound name, coding)
•
Clinical protocol reference (number 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.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
87


Protocol 331-10-234
Confidential - Proprietary Information
87
Version 5.0, 05 Jul 2022
8.5.4
Assessment/Evaluation
Assessment and evaluation of PQCs will be handled by the sponsor.
9
Records Management
9.1
Source Documents
Source documents are defined as the results of original observations and activities of a 
clinical investigation.  Source documents will include but are not limited to progress 
notes, electronic data, screening logs, and recorded data from automated instruments.  All 
source documents pertaining to this trial will be maintained by the investigators and made 
available for direct inspection by authorized persons.
Investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, 
and regulatory inspection(s) by providing direct access to source data/documents by 
authorized persons as defined in the ICF.  In all cases, subject confidentiality must be 
maintained in accordance with local regulatory requirements.
9.2
Data Collection
Source document and source data will be captured electronically in this trial and will 
meet the same fundamental elements of data quality (eg, attributable, legible, 
contemporaneous, original, and accurate) as paper records.  These data will be collected 
into a system that is fully validated.  Changes to the data will be captured by an automatic 
audit trail.
The trial site will be given a tablet to directly record subject data and clinical 
observations on electronic forms.  Designated trial site staff will not be given access to 
the system until they have been appropriately trained.  Information to be originally 
captured and reviewed electronically shall include details of the subject visit and the 
protocol-required assessments performed as a part of these visits, medical history, AEs, 
and concomitant medications.  Because this trial is using an electronic source record as 
the original point of data capture, there is no additional data entry step for the site for data 
collected directly into the application - rather, the electronic source record directly 
populates the trial database.
Some data may be captured via paper and then entered into the eSource.  These and any 
other data treated in this manner will be source data verified by the trial clinical research 
associate, and the location of the source data (ie, eSource, paper, or a local electronic 
system) will be documented before the trial start.  Any changes to information in paper 
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
88


Protocol 331-10-234
Confidential - Proprietary Information
88
Version 5.0, 05 Jul 2022
source documents will be initialed and dated on the day the change is made by a trial site 
staff member authorized to make the change.  Changes will be made by striking a single 
line through erroneous data (so as not to obliterate the original data), and clearly entering 
the correct data (eg, wrong data right data).  If the reason for the change is not apparent, a 
brief explanation for the change will be written in the source documentation by the 
clinician.
Another exception will be safety laboratory data, where the official source documentation 
will be considered the report issued by the analyzing laboratory.
Remote monitoring of the original electronic source record will take place, however 
on-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.  Per regulatory guidelines, sites must retain any 
documents that are uploaded to eSource.
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.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
89


Protocol 331-10-234
Confidential - Proprietary Information
89
Version 5.0, 05 Jul 2022
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 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.
11
Ethics and Responsibility
This trial must be conducted in compliance with the protocol, FDA regulations, ICH GCP 
Guideline (E6), international ethical principles derived from the Declaration of Helsinki 
and Council for International Organizations of Medical Science (CIOMS) guidelines, and 
applicable local laws and regulations.  Each trial site will seek approval/favorable opinion 
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
90


Protocol 331-10-234
Confidential - Proprietary Information
90
Version 5.0, 05 Jul 2022
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 using screens in eSource, 
the investigator, subinvestigator, 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, 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 and subsequent approval/favorable opinion by the IRB/IEC.  Any 
permanent change to the protocol, whether an overall change or a change for specific trial 
site(s), must be handled as a protocol amendment.  Any amendment will be written by the 
sponsor.  Each amendment will be submitted to the IRB/IEC, as required by local 
regulations.  Except for “administrative” or “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 
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
91


Protocol 331-10-234
Confidential - Proprietary Information
91
Version 5.0, 05 Jul 2022
timelines.  The sponsor will submit protocol amendments to the applicable regulatory 
agencies within local applicable timelines.
When the IRB/IEC, investigators, or the sponsor conclude that the protocol amendment 
substantially alters the trial design or increases the potential risk to the subject, the 
currently approved written ICF will require similar modification.  In such cases, after 
approval/favorable opinion of the new ICF by the IRB/IEC, repeat written informed 
consent will be obtained from subjects enrolled in the trial before expecting continued 
participation and before the amendment-specified changes in the trial are implemented.
14
Publication Authorship Requirements
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 
criteria (http://www.icmje.org/recommendations).  According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met:
1. Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND
2. Drafting the work or revising it critically for important intellectual content; AND
3. Final approval of the version to be published; AND
4. Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors.
Investigators or other trial participants who do not qualify for authorship may be 
acknowledged in publications resulting from the trial.  By agreeing to participate in the 
trial, investigators or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
92


Protocol 331-10-234
Confidential - Proprietary Information
92
Version 5.0, 05 Jul 2022
15
References
1
Messias E, Chen CY, Eaton WW. Epidemiology of schizophrenia: Review of 
findings and myths. Psychiatr Clin North Am. 2007;30(3):323-338.
2
McGrath J, Saha S, Chant D, Welham J. Schizophrenia: a concise overview of 
incidence, prevalence, and mortality. Epidemiol Rev. 2008;30:67-76.
3
van Os J, Kapur S. Schizophrenia. Lancet. 2009;374(9690):635-645.
4
American Diabetes Association, American Psychiatric Association, American 
Association of Clinical Endocrinologists, North American Association for the Study 
of Obesity. Consensus Development Conference on Antipsychotic Drugs and Obesity 
and Diabetes. J Clin Psychiatry. 2004;65(2):267-272.
5
David SR, Taylor CC, Kinon BJ, Breier A. The effects of olanzapine, risperidone, 
and haloperidol on plasma prolactin levels in patients with schizophrenia. Clin Ther. 
2000;22(9):1085-1096.
6
Volavka J, Czobor P, Cooper TB, Sheitman B, Lindenmayer JP, Citrome L, et al. 
Prolactin levels in schizophrenia and schizoaffective disorder patients treated with 
clozapine, olanzapine, risperidone, or haloperidol. J Clin Psychiatry. 2004;65(1):57-
61.
7
Hollis C. Adult outcomes of child- and adolescent-onset schizophrenia: Diagnostic 
stability and predictive validity. Am J Psychiatry. 2000;157(10):1652-1659.
8
Sikich L. Efficacy of atypical antipsychotics in early-onset schizophrenia and other 
psychotic disorders. J Clin Psychiatry. 2008;69(Suppl 4):21-25.
9
Lay B, Blanz B, Hartmann M, Schmidt MH. The psychosocial outcome of 
adolescent-onset schizophrenia: A 12-year followup. Schizophr Bull. 2000;26(4):801-
816.
10 Findling RL, Johnson JL, McClellan J, Frazier JA, Vitiello B, Hamer RM, et al. 
Double-blind maintenance safety and effectiveness findings from the treatment of 
early-onset schizophrenia spectrum (TEOSS) study. J Am Acad Child Adolesc 
Psychiatry. 2010;49(6):583-594.
11 Otsuka Pharmaceutical Co, Ltd., Otsuka Pharmaceutical Development & 
Commercialization, Inc., H. Lundbeck A/S. REXULTI® (brexpiprazole) 
Investigator's Brochure, Edition 12. Otsuka Report, issued 18 Aug 2016.
12 Brexpiprazole (OPC-34712) Investigator's Brochure, Otsuka Pharmaceutical 
Development & Commercialization, Inc. Version No. 9, 09 Sep 2013.
13 International Conference for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. Guideline For Good Clinical 
Practice: E6(R1). Geneva, Switzerland: International Conference on Harmonisation; 
1996.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
93


Protocol 331-10-234
Confidential - Proprietary Information
93
Version 5.0, 05 Jul 2022
14 Kay SR, Fiszbein A, Opler LA. Positive and Negative Syndrome Scale (PANSS) 
Technical Manual. North Tonawanda, NY: Multi-Health Systems; 2006.
15 Shaffer D, Gould MS, Brasic J, Ambrosini P, Fisher P, Bird H, et al. A children's 
global assessment scale (CGAS). Arch Gen Psychiatry. 1983;40(11):1228-1231.
16 Guy W. ECDEU Assessment Manual for Psychopharmacology. US Department of 
Health, Education, and Welfare publication (ADM) 76-338. Rockville, MD: National 
Institute of Mental Health; 1976.
17 The Practical Guide: Identification, evaluation, and treatment of overweight and 
obesity in adults. Developed by National Institutes of Health National Heart, Lung 
and Blood Institute. North American Association for the Study of Obesity. NIH 
Publication Number 00-4084, October 2000.
18 Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta 
Psychiatr Scand Suppl. 1970;212(Suppl 44):S11-19.
19 Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672-
676.
20 Kaufman J, Birmaher B, Brent D, Rao U, Ryan N. Kiddie-Sads-Present and Lifetime 
Version (K-SADS-PL). Version 1.0 of Oct 1996 ed. Pittsburgh, PA:  Department of 
Psychiatry, University of Pittsburgh School of Medicine; 1996.
21 US Food and Drug Administration. Clinicaltrial.gov register. Efficacy and Safety of 
Cariprazine in the Treatment of Adolescent Participants (13 to 17 Years of Age) With 
Schizophrenia. Available at: https://www.clinicaltrials.gov/ct2/show/NCT03817502. 
Assessed on 08 March 2022.
22 European Medicines Agency/59804/2021. Committee for Medicinal Products for 
Human Use (CHMP). Latuda Assessment Report. 23 July 2020. Procedure No. 
EMEA/H/C/002713/II/0029.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
94


Protocol 331-10-234
Confidential - Proprietary Information
94
Version 5.0, 05 Jul 2022
Appendix 1
Criteria for Identifying Vital Signs of Potential 
Clinical Relevance
Variable
Criterion Valuea
Change Relative to Baselinea
Heart Rateb
> 120 bpm
< 50 bpm
≥ 15 bpm increase
≥ 15 bpm decrease
Systolic Blood Pressureb
> 180 mmHg
< 90 mmHg
≥ 20 mmHg increase
≥ 20 mmHg decrease
Diastolic Blood Pressureb
> 105 mmHg
< 50 mmHg
≥ 15 mmHg increase
≥ 15 mmHg decrease
Orthostatic Hypotension
≥ 20 mmHg decrease in systolic blood 
pressure and a ≥ 25 bpm increase in 
heart rate from supine to 
sitting/standing
Not Applicable
(baseline status not considered)
Weight
-
≥ 7% increase
≥ 7% decrease
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column.
bAs defined in “Supplementary Suggestions for Preparing an Integrated Summary of Safety Information 
in an Original NDA Submission and for Organizing Information in Periodic Safety Updates,” FDA 
Division of Neuropharmacological Drug Products draft (2/27/87).
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
95


Protocol 331-10-234
Confidential - Proprietary Information
95
Version 5.0, 05 Jul 2022
Appendix 2
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance
Laboratory Tests
Criteria
Chemistry
AST (SGOT)
≥ 3 x ULN
ALT (SGPT)
≥ 3 × ULN
Alkaline phosphatase
≥ 3 × ULN
LDH
≥ 3 × ULN
BUN
≥ 30 mg/dL
Creatinine
≥ 2.0 mg/dL
Uric Acid
Men
≥ 10.5 mg/dL
Women
≥ 8.5 mg/dL
Bilirubin (total)
≥ 2.0 mg/dL
CPK
≥ 3 × ULN
Prolactin
> ULN
Hematology
Hematocrit
Men
≤ 37 % and decrease of  3 percentage points from Baseline
Women
≤ 32 % and decrease of  3 percentage points from Baseline
Hemoglobin
Men
≤ 11.5 g/dL
Women
≤ 9.5 g/dL
White blood count
≤ 2,800/ mm3 or ≥ 16,000/ mm3
Eosinophils
≥ 10%
Neutrophils
≤ 15%
Absolute neutrophil count
≤ 1,000/ mm3
Platelet count
≤ 75,000/ mm3 or ≥ 700,000/ mm3
Urinalysis
Protein
Increase of ≥ 2 units
Glucose
Increase of ≥ 2 units
Casts
Increase of ≥ 2 units
Additional Criteria
Chloride
≤ 90 mEq/L or ≥ 118 mEq/L
Potassium
≤ 2.5 mEq/L or ≥ 6.5 mEq/L
Sodium
≤ 126 mEq/L or ≥ 156 mEq/L
Calcium
≤ 8.2 mg/dL or ≥ 12 mg/dL
Glucose
Fasting
≥ 100 mg/dL 
Non-Fasting
≥ 200 mg/dL
Total Cholesterol, Fasting
≥ 240 mg/dL 
LDL Cholesterol, Fasting
≥ 160 mg/dL 
HDL Cholesterol, Fasting
Men
< 40 mg/dL
Women
< 50 mg/dL
Triglycerides, Fasting
≥ 150 mg/dL
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
96


Protocol 331-10-234
Confidential - Proprietary Information
96
Version 5.0, 05 Jul 2022
Appendix 3
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance
Variable
Criterion Valuea
Change Relative to Baselinea
Rate
Tachycardia
≥ 120 bpm
increase of ≥ 15 bpm
Bradycardia
≤ 50 bpm
decrease of ≥ 15 bpm
Rhythm
Sinus tachycardiab
≥ 120 bpm
increase of ≥ 15 bpm
Sinus bradycardiac
≤ 50 bpm
decrease of ≥ 15 bpm
Supraventricular premature beat
all
not present  present
Ventricular premature beat
all
not present  present
Supraventricular tachycardia
all
not present  present
Ventricular tachycardia
all
not present  present
Atrial fibrillation
all
not present  present
Atrial flutter
all
not present  present
Conduction
1° atrioventricular block
PR ≥ 200 msec
increase of ≥ 50 msec
2° atrioventricular block
all
not present  present
3° atrioventricular block
all
not present  present
Left bundle-branch block
all
not present  present
Right bundle-branch block
all
not present  present
Pre-excitation syndrome
all
not present  present
Other intraventricular conduction 
blockd
QRS ≥ 120 msec
increase of ≥ 20 msec
Infarction
Acute or subacute
all
not present  present
Old
all
not present  present
≥ 12 weeks post-trial entry
ST/T Morphological
Myocardial Ischemia
all
not present  present
Symmetrical T-wave inversion
all
not present  present
Increase in QTc
QTcF or QTcN 
≥ 450 msec for males, 
≥ 470 msec for females
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column.
bNo current diagnosis of supraventricular tachycardia, ventricular tachycardia, atrial fibrillation, atrial 
flutter, or other rhythm abnormality.
cNo current diagnosis of atrial fibrillation, atrial flutter, or other rhythm abnormality.
dNo current diagnosis of left bundle branch block or right bundle branch block.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
97


Protocol 331-10-234
Confidential - Proprietary Information
97
Version 5.0, 05 Jul 2022
Appendix 4
Handling and Shipment of Bioanalytical Samples
Handling of Specimens
Labels should be secured to each storage tube.  Labels should contain the following 
information:  Protocol number; subject number; time point of sample collection; and 
aliquot/matrix (eg, Plasma Aliquot 1 or Plasma Aliquot 2).  All tubes must be labeled 
such that the protocol number, date of collections, and protocol time can be verified.  It is 
important to note the exact time of the blood collection in eSource, not the scheduled 
time for the drawing.
Pharmacokinetic Plasma Samples
Collect PK blood samples using 4-mL draw green-top Vacutainer evacuated collection 
tubes containing sodium heparin.  After obtaining the blood sample, mix the collection 
tube thoroughly by slowly inverting it several times before placing it in an ice/water bath.  
Within 45 minutes of collection, process collection tubes in a refrigerated centrifuge set 
at approximately 2000 x G for 15 minutes at approximately 5C ± 3°C.  Transfer 
duplicate plasma aliquots of approximately equal volume, using standard laboratory 
technique, into 2 appropriately labeled storage tubes.  Within 90 minutes of collection, 
store both plasma aliquot samples in a freezer set to maintain a temperature 
−70C ± 10°C.  Specimens must be neatly packed and restrained in an insulated container 
appropriate for dry ice, and organized by subject where possible.  Completely fill the 
insulated container and avoid air spaces that allow evaporation of the dry ice.  Samples 
must be shipped via an overnight carrier, Monday through Thursday, to the central 
laboratory.  Shipments should not be made on Fridays, Saturdays, or any day prior to a 
holiday.  Plasma Aliquot 1 samples should be shipped preferably on the day of collection 
or else within 1 week of sample collection.  Plasma Aliquot 2 specimens should be 
shipped to the central laboratory using the same procedure, once confirmation is received 
that the Plasma Aliquot 1 specimen was received. 
Pharmacogenomics Sample
Blood samples for pharmacogenomic analysis will be collected into one 6-mL K2EDTA 
Vacutainer tube.  Each tube should be gently inverted 10 times to ensure proper mixing 
with the anticoagulant.  Samples should be refrigerated in an upright position at 4C for 
at least one day (no longer than 4 days).  The samples should then be stored at -20C or 
below prior to shipment.  If refrigerating is not possible, samples may be frozen directly 
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
98


Protocol 331-10-234
Confidential - Proprietary Information
98
Version 5.0, 05 Jul 2022
from ambient.  Samples must be shipped to the central laboratory via an overnight carrier, 
Monday through Thursday, preferably on the day of collection or else within 1 week of 
sample collection.  Shipments should not be made on Fridays, Saturdays, or any day prior 
to a holiday. 
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
99


Protocol 331-10-234
Confidential - Proprietary Information
99
Version 5.0, 05 Jul 2022
Appendix 5
Positive and Negative Syndrome Scale (PANSS)
This scale consists of symptom constructs, each to be rated on a 7-point scale of severity.
For each symptom, please mark the rating which best describes the patient’s present 
condition (from 1 = absent to 7 = extreme).
1=absent 
2=minimal 
3=mild 
4=moderate 
5=moderate severe
6=severe
7=extreme
POSITIVE SCALE (P)
1.
DELUSIONS
Beliefs that are unfounded, unrealistic, and idiosyncratic.
Basis for Rating: thought content expressed during the interview and its 
influence on social relations, and behavior, as reported by primary care workers 
or family.
2.
CONCEPTUAL 
DISORGANIZATION
There is a disorganized thinking process characterized by goal-directed 
sequencing disruption (eg circumstantiality, tangentiality, loose associations, non-
sequiturs, gross illogicality, or thought block).
Basis for Rating: cognitive verbal processes observed during the interview.
3.
HALLUCINATORY 
BEHAVIOR
Verbal report or behavior indicate perceptions that are not generated by external 
stimuli.  These occurrences may be auditory, visual, olfactory, or somatic.  
Basis for Rating: Verbal report and physical manifestations during the interview 
as well as behavior reports by primary care workers or family.
4.
EXCITEMENT
Hyperactivity is reflected in accelerated motor behavior, heightened responsivity 
to stimuli, hypervigilance, or excessive mood lability.
Basis for Rating: behavioral manifestations during the interview, as well as 
behavior reports by primary care workers or family.
5.
GRANDIOSITY
There exists an exaggerated self-opinion and unrealistic convictions of 
superiority, including delusions of extraordinary abilities, wealth, knowledge, 
fame, power, and moral righteousness.
Basis for Rating: thought content expressed in the interview and its influence on 
behavior as reported by primary care workers or family.
6.
SUSPICIOUSNESS/ 
PERSECUTION
Unrealistic or exaggerated ideas of persecution are shown, as reflected in 
guardedness, a distrustful attitude, suspicious hypervigilance, or frank delusions 
that others mean harm.
Basis for Rating: thought content expressed in the interview and its influence on 
behavior as reported by primary care workers or family.  
7.
HOSTILITY
There are verbal and nonverbal expressions of anger and resentment, including 
sarcasm, passive-aggressive behavior, verbal abuse, and assaultiveness.  
Basis for Rating: interpersonal behavior observed during the interview and 
reports by primary care workers or family.  
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
100


Protocol 331-10-234
Confidential - Proprietary Information
100
Version 5.0, 05 Jul 2022
NEGATIVE SCALE (N)
1.
BLUNTED AFFECT
There is diminished emotional responsiveness characterized by a reduction in 
facial expression, modulation of feelings, and communicative gestures.  
Basis for Rating: observation of the patient’s affective tone and emotional
responsiveness during the interview.  
2.
EMOTIONAL 
WITHDRAWAL
There is a lack of interest in, involvement with, and affective commitment to life’s 
events.  
Basis for Rating: reports of functioning from primary care workers or family, and 
interpersonal behavior observations during the interview.  
3.
POOR RAPPORT
There is a lack of interpersonal empathy, a lack of openness in conversation, and 
also a minimal sense of closeness, interest or involvement with the interviewer.  
Poor rapport is evidenced by interpersonal distancing and reduced verbal and 
nonverbal communication.  
Basis for Rating: interpersonal behavior during the interview.  
4.
PASSIVE/APATHETIC 
AND SOCIAL 
WITHDRAWAL
Diminished interest and initiative in social interactions due to passivity, apathy, 
anergy, or avolition leading to reduced interpersonal involvements and neglect of 
daily living activities.
Basis for Rating: social behavior reports from primary care workers or family.  
5.
DIFFICULTY IN 
ABSTRACT 
THINKING
The patient shows impairment using the abstract-symbolic thinking mode, as 
demonstrated by difficulty with classification, forming generalizations, and 
moving beyond concrete or egocentric thinking in problem-solving tasks.
Basis for Rating: responses to questions on similarities and proverb interpretation, 
and use of concrete vs. abstract mode during the interview.  
6.
LACK OF 
SPONTANEITY AND 
FLOW OF 
CONVERSATION
There is a reduction in the normal flow of communication associated with apathy, 
avolition, defensiveness, or cognitive deficit.  This disruption in normal flow is 
manifested by diminished fluidity and productivity of the verbal interactional 
process.
Basis for Rating: cognitive-verbal processes observed during the interview.  
7.
STEREOTYPED 
THINKING
There is decreased fluidity, spontaneity, and flexibility of thinking, as evidenced in 
rigid, repetitious, or barren thought content.
Basis for Rating: cognitive-verbal processes observed during the interview.  
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
101


Protocol 331-10-234
Confidential - Proprietary Information
101
Version 5.0, 05 Jul 2022
GENERAL PSYCHOPATHOLOGY SCALE (G)
1.  
SOMATIC CONCERN 
There are physical complaints or beliefs about bodily illness or malfunctions.  
This patient’s concerns may range from a vague sense of ill being to clear-cut 
delusions of catastrophic physical disease.
Basis for Rating: thought content expressed in the interview.  
2.  
ANXIETY 
There are subjective experiences of nervousness, worry, apprehension, or 
restlessness, ranging from excessive concern about the present or future to 
feelings of panic.  
Basis for Rating: verbal report during the interview and corresponding 
physical manifestations.  
3.  
GUILT FEELINGS 
The patient exhibits a sense of remorse or self-blame for real or imagined 
misdeeds in the past.
Basis for Rating: verbal reports of guilt feelings during the interview and the 
influence of these feelings on the patient’s attitudes and thoughts.
4.  
TENSION 
There are overt physical manifestation of fear, anxiety, and agitation, such as 
stiffness, tremor, profuse sweating, and restlessness.
Basis for Rating: verbal report attesting to anxiety and, thereupon, the severity 
of physical manifestations of tension observed during the interview.
5.
MANNERISM AND 
POSTURING 
Unnatural movements or posture are shown as characterized by an awkward, 
stilted, disorganized, or bizarre appearance.
Basis for Rating: observation of physical manifestations during the interview 
as well as reports from primary care workers or family.
6.  
DEPRESSION 
There are feelings of sadness, discouragement, helplessness, and pessimism.  
Basis for Rating: verbal report of depressed mood during the interview and its 
observed influence on the patient’s attitude and behavior as reported from 
primary care workers or family.  
7.
MOTOR 
RETARDATION
There is a reduction in motor activity reflected by the slowing or lessening of 
movements and speech, diminished responsiveness to stimuli, and reduced 
body tone.  
Basis for Rating: manifestations during the interview as well as reports from 
primary care workers or family.  
8.
UNCOOPERATIVENESS
There is an active refusal to comply with the will of significant others, 
including the interviewer, hospital staff, or family, perhaps associated with 
distrust, defensiveness, stubbornness, negativism, rejection of authority, 
hostility, or belligerence.  
Basis for Rating: interpersonal behavior observed during the interview as well 
as reports from care workers or family.  
9.
UNUSUAL THOUGHT 
CONTENT
Thinking is characterized by strange, fantastic, or bizarre ideas, ranging from 
those that are remote or atypical to those that are distorted, illogical, and 
patently absurd.  
Basis for Rating: thought content expressed during the interview.  
10.
DISORIENTATION
There is a lack of awareness of one’s relationship to one’s surroundings, 
including persons, places, and time that may be due to confusion or withdrawal.  
Basis for Rating: responses to interview questions on orientation.  
11.
POOR ATTENTION
Poor focused alertness is manifested by poor concentration, distractibility from 
internal and external stimuli, and difficulty in harnessing, sustaining, or shifting 
focus to new stimuli.  
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
102


Protocol 331-10-234
Confidential - Proprietary Information
102
Version 5.0, 05 Jul 2022
Basis for Rating: manifestations during the interview.  
12.
LACK OF JUDGMENT 
AND INSIGHT
There is an impaired awareness or understanding of one’s own psychiatric 
condition and life situation.  This impairment is evidenced by the patient’s 
inability to recognize past or present psychiatric illness or symptoms, denial of 
his or her need for psychiatric hospitalization or treatment, decisions 
characterized by poor anticipation of the consequences, and unrealistic 
short-term and long-range planning.  
Basis for Rating: thought content expressed during the interview.  
13.
DISTURBANCE OF 
VOLITION
There is disturbance in the willful initiation, sustenance, and control of one’s 
thoughts, behavior, movements, and speech.  
Basis for Rating: thought content and behavior manifested during the 
interview.  
14.
POOR IMPULSE 
CONTROL
There is disordered regulation and control when acting on inner urges, resulting 
in sudden, unmodulated, arbitrary, or misdirected discharge of tension and 
emotions without concern about the consequences.  
Basis for Rating: the patient’s behavior during the interview and reports from 
primary care workers or family.  
15.
PREOCCUPATION 
There is absorption with internally generated thoughts and feelings or with 
autistic experiences to the detriment of reality orientation and adaptive 
behavior.  
Basis for Rating: interpersonal behavior observed during the interview.  
16.
ACTIVE SOCIAL 
AVOIDANCE 
There is diminished social involvement associated with unwarranted fear, 
hostility, or distrust.  
Basis for Rating: social functioning reports from primary care workers or 
family.  
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
103


Protocol 331-10-234
Confidential - Proprietary Information
103
Version 5.0, 05 Jul 2022
Appendix 6
Children’s Global Assessment Scale (CGAS)
The C-GAS is a 100-point rating scale measuring psychological, social, and school 
functioning for children aged 6-17.  It was adapted from the Adult Global Assessment 
Scale and is a valid and reliable tool for rating a child’s general level of functioning on a 
health-illness continuum. 
100-91
Superior functioning in all areas (at home, at school and with peers), involved in a range or 
activities and has many interests (e.g., has hobbies or participates in extracurricular activities 
or belongs to an organized group such as Scouts, etc.). Likable, confident, “everyday” 
worries never get out of hand. Doing well in school, no symptoms
90-81 
Good functioning in all areas. Secure in family, school and with peers. There may be 
transient difficulties and “everyday” worries that occasionally get out of hand (e.g. mild 
anxiety associated with an important exam, occasional “blow ups” with siblings, parents or 
peers).
80-71 
No more than slight impairment in functioning at home, at school, or with peers. Some 
disturbance of behavior or emotional distress may be present in response to life stresses (e.g., 
parental separations, deaths, births of a sib) but these are brief and interference with 
functioning is transient. Such children are only minimally disturbing to others who are not 
considered deviant by those who know them.
70-61 
Some difficulty in a single area, but generally functioning pretty well, (e.g., sporadic or 
isolated antisocial acts, such as occasionally playing hooky or petty theft; consistent minor 
difficulties with school work, mood changes of brief duration; fears and anxieties which do 
not lead to gross avoidance behavior; self doubts). Has some meaningful interpersonal 
relationships. Most people who do not know the child well would not consider him/her 
deviant but those who do know him/her well might express concern.
60-51 
Variable functioning with sporadic difficulties or symptoms in several but not all social 
areas. Disturbance would be apparent to those who encounter the child in a dysfunctional 
setting or time but not those who see the child in other settings.
50-41 
Moderate degree of interference in functioning in most social areas or severe 
impairment of functioning in one area, such as might result from, for example, suicidal 
preoccupations and ruminations, school refusal and other forms of anxiety, obsessive rituals, 
major conversion symptoms, frequent anxiety attacks, frequent episodes of aggressive or 
other antisocial behavior with some preservation of meaningful social relationships.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
104


Protocol 331-10-234
Confidential - Proprietary Information
104
Version 5.0, 05 Jul 2022
40-31 
Major impairment in functioning in several areas and unable to function in one of these 
areas, i.e., disturbed at home, at school, with peers, or in the society at large, e.g., persistent 
aggression without clear instigation; markedly withdrawn and isolated behavior due to either 
mood or thought disturbance, suicidal attempts with clear lethal intent. Such children are 
likely to require special schooling or hospitalization or withdrawal from school (but this is 
not a sufficient criterion for inclusion in this category).
30-21 
Unable to function in almost all areas, e.g., stays at home, in ward or in bed all day without 
taking part in social activities OR severe impairment in reality testing OR serious impairment 
in communication (e.g., sometimes incoherent or inappropriate).
20-11 
Needs considerable supervision to prevent hurting other or self, e.g., frequently violent, 
repeated suicide attempts OR to maintain personal hygiene OR gross impairment in all forms 
of communication, e.g., severe abnormalities in verbal and gestural communication, marked 
social aloofness, stupor, etc.
10-1
Needs constant supervision (24-hour care) due to severely aggressive or self-destructive 
behavior or gross impairment in reality testing, communication, cognition, affect, or personal 
hygiene.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
105


Protocol 331-10-234
Confidential - Proprietary Information
105
Version 5.0, 05 Jul 2022
Appendix 7
Clinical Global Impression - Severity of Illness Scale (CGI-S)
Considering your total clinical experience with this particular population, how mentally 
ill is the patient at this time?
0 = Not assessed
4 = Moderately ill
1 = Normal, not at all ill
5 = Markedly ill
2 = Borderline mentally ill
6 = Severely ill
3 = Mildly ill
7 = Among the most extremely ill patients
Guy, W. ed. ECDEU Assessment Manual for Psychopharmacology. US Dept of HEW, Publication No. 
(Adm):  76-338, 1976.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
106


Protocol 331-10-234
Confidential - Proprietary Information
106
Version 5.0, 05 Jul 2022
Appendix 8
Clinical Global Impression - Improvement scale (CGI-I)
Rate total improvement whether or not in your judgment it is due entirely to drug 
treatment.  Compared to his/her condition at baseline, how much has patient changed?
0 = Not assessed
4 = No change
1 = Very much improved
5 = Minimally worse
2 = Much improved
6 = Much worse
3 = Minimally improved
7 = Very much worse
Guy, W. ed. ECDEU Assessment Manual for Psychopharmacology. US Dept of HEW, Publication No. 
(Adm): 76-338, 1976.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
107


Protocol 331-10-234
Confidential - Proprietary Information
107
Version 5.0, 05 Jul 2022
Appendix 9
Pediatric Quality of Life Enjoyment and Satisfaction 
Questionnaire (P-Q-LES-Q)
INSTRUCTIONS:  This survey asks for your views about your general health, 
well-being, and feelings about your life.  Please answer EVERY question by circling the 
number for your response.  If you are not sure about how to answer a question, please 
give the best answer you can.  Remember, there are no right or wrong answers.
Very 
Poor
Poor
Fair
Good
Very 
Good
Over the past week, how have 
things been with...
 
 
 
 
 
1. Your health?
1
2
3
4
5
2. Your mood or feelings?
1
2
3
4
5
3. School or learning?
1
2
3
4
5
4. Helping out at home?
1
2
3
4
5
5. Getting along with friends?
1
2
3
4
5
6. Getting along with your family?
1
2
3
4
5
7. Play or free time?
1
2
3
4
5
8. Getting things done?
1
2
3
4
5
9. Your love or affection?
1
2
3
4
5
10. Getting or buying things?
1
2
3
4
5
11. The place where you live?
1
2
3
4
5
12. Paying attention?
1
2
3
4
5
13. Your energy level?
1
2
3
4
5
14. Feelings about yourself?
1
2
3
4
5
15. Overall, how has your life 
been?
1
2
3
4
5
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
108


Protocol 331-10-234
Confidential - Proprietary Information
108
Version 5.0, 05 Jul 2022
Appendix 10
Simpson Angus Scale (SAS)
Circle the appropriate score for each item:
1.
GAIT
The patient is examined as he walks into the examining room; his gait, the swing of arms, his 
general posture; all form the basis for an overall score for this item.  This is rated as follows:
0
Normal
1
Mild diminution in swing while the patient is walking 
2
Obvious diminution in swing suggesting shoulder rigidity
3
Stiff gait with little or no arm swing noticeable
4
Rigid gait with arms slightly pronated; or stooped-shuffling gait with propulsion and 
retropulsion.
2.
ARM DROPPING
The patient and the examiner both raise their arms to shoulder height and let them fall to their 
sides, in a normal subject a stout slap is heard as the arms hit the sides.  In the patient with 
extreme Parkinson’s syndrome, the arms fall very slowly.
0
Normal, free fall with loud slap and rebound
1
Fall slowed slightly with less audible contact and little rebound
2
Fall slowed, no rebound
3
Marked slowing, no slap at all
4
Arms fall as though against resistance; as though through glue
3.
SHOULDER SHAKING
The subject’s arms are bent at a right angle at the elbow and taken one at a time by the examiner 
who grabs one hand and also clasps the other around the patient’s elbow.  The subject’s upper 
arm is pushed to and fro and the humerus is externally rotated.  The degree of resistance from 
normal to extreme rigidity is scored as follows:
0
Normal
1
Slight stiffness and resistance
2
Moderate stiffness and resistance
3
Marked rigidity with difficulty in passive movement
4
Extreme stiffness and rigidity with almost a frozen joint
4.
ELBOW RIGIDITY
The elbow joints are separately bent at right angles and passively extended and flexed, with the 
subject’s biceps observed and simultaneously palpated.  The resistance to the procedure is rated.  
(The presence of cogwheel rigidity is noted separately.)
0
Normal
1
Slight stiffness and resistance
2
Moderate stiffness and resistance
3
Marked rigidity with difficulty in passive movement
4
Extreme stiffness and rigidity with almost a frozen joint
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
109


Protocol 331-10-234
Confidential - Proprietary Information
109
Version 5.0, 05 Jul 2022
5.
WRIST RIGIDITY
The wrist is held in one hand and then the fingers held by the examiner’s other hand with the 
wrist moved to extension, and both ulnar and radial deviation.  The resistance to this procedure is 
rated:
0
Normal
1
Slight stiffness and resistance
2
Moderate stiffness and resistance
3
Marked rigidity with difficulty in passive movement
4
Extreme stiffness and rigidity with almost a frozen joint
6.
HEAD ROTATION
The patient sits or stands and is told that you are going to move his head from side to side, that it 
will not hurt and that he should try and relax.  (Questions about pain in the cervical area or 
difficulty in moving his head should be obtained to avoid causing any pain.)  Clasp the patient’s 
head between the two hands with fingers on back of the neck.  Gently rotate the head in a circular 
motion 3 times and evaluate the muscular resistance to the movement.
0
Loose, no resistance
1
Slight resistance to movement although the time to rotate may be normal
2
Resistance is apparent and time of rotation is slowed
3
Resistance is obvious and rotation is slowed
4
Head appears stiff and rotation is difficult to carry out
7.
GLABELLA TAP
Subject is told to open his eyes and not to blink.  The glabella region is tapped at a steady, rapid 
speed.  The number of times patient blinks in succession is noted:
0
0-5 blinks
1
6-10 blinks
2
11-15 blinks
3
16-20 blinks
4
21 and more blinks
8.
TREMOR
Patient is observed walking into examining room and then is examined for this item:
0
Normal
1
Mild finger tremor, obvious to sight and touch
2
Tremor of hand or arm occurring spasmodically
3
Persistent tremor of one or more limbs
4
Whole body tremor
9.
SALIVATION
Patient is observed while talking and then asked to open his mouth and elevate his tongue.  The 
following ratings are given:
0
Normal
1
Excess salivation so that pooling takes place if the mouth is open and the tongue raised
2
Excess salivation is present and might occasionally result in difficulty in speaking
3
Speaking with difficulty because of excess salivation
4
Frank drooling
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
110


Protocol 331-10-234
Confidential - Proprietary Information
110
Version 5.0, 05 Jul 2022
10.
AKATHISIA
Patient is observed for restlessness.  If restlessness is noted, ask: “Do you feel restless or jittery 
inside; is it difficult to sit still?”  Subjective response is not necessary for scoring but patient 
report can help make the assessment.
0
No restlessness reported or observed
1
Mild restlessness observed
2
Moderate restlessness observed
3
Restlessness is frequently observed
4
Restlessness persistently observed
Adapted and used with permission by:  Simpson GN, Angus JW. A rating scale for extrapyramidal side 
effects. Acta Psychiatrica Scandinavica. 1970;45(suppl 212):11-9.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
111


Protocol 331-10-234
Confidential - Proprietary Information
111
Version 5.0, 05 Jul 2022
Appendix 11
Abnormal Involuntary Movement Scale (AIMS)
Movement ratings: rate highest severity observed. Rate 
movements that occur upon activation one less than those 
observed spontaneously.
Code for items 1-7:
0 = None
1 = Minimal, may be extreme normal
2 = Mild
3 = Moderate
4 = Severe
(Circle One)
1.
MUSCLES OF FACIAL EXPRESSION e.g. 
movements of forehead, eyebrows, periorbital 
area, cheeks; include frowning, blinking, smiling, 
grimacing
0
1
2
3
4
2.
LIPS AND PERIORAL AREA e.g. puckering, 
pouting, smacking.
0
1
2
3
4
3.
JAW e.g. biting, clenching, chewing, mouth 
opening, lateral movement.
0
1
2
3
4
FACIAL AND
ORAL
MOVEMENTS:
4.
TONGUE Rate only increase in movement both 
in and out of mouth, not inability to sustain 
movement.
0
1
2
3
4
5.
UPPER (ARMS, WRISTS, HANDS, 
FINGERS) include choreic movements (i.e. 
rapid, objectively purposeless, irregular, 
spontaneous), athetoid movements (i.e. slow, 
irregular, complex, serpentine). Do not include 
tremor (i.e. repetitive, regular, rhythmic).
0
1
2
3
4
EXTREMITY 
MOVEMENTS:
6.
LOWER (LEGS, KNEES, ANKLES, TOES) 
e.g. lateral knee movement, foot tapping, heel 
dropping, foot squirming, inversion and eversion 
of foot
0
1
2
3
4
TRUNK 
MOVEMENTS:
7.
NECK, SHOULDERS, HIPS e.g. rocking, 
twisting, squirming, pelvic gyrations
0
1
2
3
4
None, normal
0
Minimal
1
Mild
2
Moderate
3
8.
Severity of abnormal movements
Severe
4
None, normal
0
Minimal
1
Mild
2
Moderate
3
9.
Incapacitation due to abnormal movements
Severe
4
No awareness
0
Aware, no distress
1
Aware, mild distress
2
Aware, moderate distress
3
GLOBAL 
JUDGMENTS:
10. Patient’s awareness of abnormal movements
Rate only subject’s report.
Aware, severe distress
4
No
0
11. Any current problems with teeth or dentures?
Yes
1
No
0
DENTAL
STATUS:
12. Does patient usually wear dentures?
Yes
1
Guy W. ECDEU Assessment Manual for Psychopharmacology. US Department of Health, Education, and 
Welfare publication (ADM) 76-338. Rockville, MD: National Institute of Mental Health; 1976.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
112


Protocol 331-10-234
Confidential - Proprietary Information
112
Version 5.0, 05 Jul 2022
Appendix 12
Barnes Akathisia Rating Scale (BARS)
Instructions
Patient should be observed while they are seated, and then standing while engaged in 
neutral conversation (for a minimum of two minutes in each position).  Symptoms 
observed in other situations, for example while engaged in activity on the ward, may also 
be rated.  Subsequently, the subjective phenomena should be elicited by direct 
questioning.
Objective
0
Normal, occasional fidgety movements of the limbs
1
Presence of characteristic restless movements: shuffling or tramping movements 
of the legs/feet, or swinging one leg while sitting, or rocking from foot to foot or 
“walking on the spot” when standing, but movements present for less than half the 
time observed
2
Observed phenomena, as described in (1) above, which are present for at least 
half the observation period
3
Patient is constantly engaged in characteristic restless movements, or has the 
inability to remain seated or standing without walking or pacing, during the time 
observed
Subjective
Awareness of restlessness
0
Absence of inner restlessness
1
Non-specific sense of inner restlessness
2
The patient is aware of an inability to keep the legs still, or a desire to move the 
legs, or complains of inner restlessness aggravated specifically by being required 
to stand still
3
Awareness of intense compulsion to move most of the time or reports strong 
desire to walk or pace most of the time
Distress related to restlessness
0
No distress
1
Mild
2
Moderate
3
Severe
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
113


Protocol 331-10-234
Confidential - Proprietary Information
113
Version 5.0, 05 Jul 2022
Global clinical assessment of akathisia
0
Absent. No evidence of awareness of restlessness. Observation of characteristic 
movements of akathisia in the absence of a subjective report of inner restlessness 
or compulsive desire to move the legs should be classified as pseudoakathisia
1
Questionable. Non-specific inner tension and fidgety movements
2
Mild akathisia. Awareness of restlessness in the legs or inner restlessness worse 
when required to stand still. Fidgety movements present, but characteristic restless 
movements of akathisia not necessarily observed. Condition causes little or no 
distress
3
Moderate akathisia. Awareness of restlessness as described for mild akathisia 
above, combined with characteristic restless movements such as rocking from 
foot to foot when standing. Patient finds the condition distressing
4
Marked akathisia. Subjective experience of restlessness includes a compulsive 
desire to walk or pace. However, the patient is able to remain seated for at least 
five minutes. The condition is obviously distressing
5
Severe akathisia. The patient reports a strong compulsion to pace up and down 
most of the time. Unable to sit or lie down for more than a few minutes. Constant 
restlessness which is associated with intense distress and insomnia
Reproduced from:  Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672-6.
© 1989 The Royal College of Psychiatrists.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
114


Protocol 331-10-234
Confidential - Proprietary Information
114
Version 5.0, 05 Jul 2022
Appendix 13
Udvalg for Kliniske Undersogelser (UKU)
The UKU is used to assess side effects of subjects being treated with antipsychotic drugs 
and to determine whether there is a causal relationship.  Assessment of the individual 
symptoms is best accomplished by a semi structured interview with the subject during 
which the scale is gone through point by point as well as obtaining information from case 
records and clinical observation.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
115


Protocol 331-10-234
Confidential - Proprietary Information
115
Version 5.0, 05 Jul 2022
THE UKU SIDE EFFECTS RATING SCALE FOR THE
REGISTRATION OF UNWANTED EFFECTS OF PSYCHOTROPICS
MANUAL ENGLISH VERSION, October 1986
(UKU)
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
116


Protocol 331-10-234
Confidential - Proprietary Information
116
Version 5.0, 05 Jul 2022
Patient Information
Day
Mth.
Year
Hour
Min
Patient
Date
Time
Personal Notes
Psychic
Not 
Ass.
Degree last 3 days (see 
manual) 
Causal 
relationship 
Category 
of side 
effects 
Symptom 
9
0
1
2
3
Imp
Pos
Prb
1.1
Concentration Dificulties 
1.2
Asthenia/Lasitude/lncreased 
Fatiguability 
1.3
Slepines/Sedation 
1.4
Failing Memory 
1.5
Depresion 
1.6
Tension/lner Unrest 
1.7
Increased Duration of Sleep 
1.8
Reduced Duration of Sleep  
1.9
Increased Dream Activity 
1.10
Emotional Indifference 
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
117


Protocol 331-10-234
Confidential - Proprietary Information
117
Version 5.0, 05 Jul 2022
Neurologic
Not 
Ass.
Degree last 3 days (see 
manual) 
Causal 
relationship 
Category 
of side 
effects 
Symptom 
9
0
1
2
3
Imp
Pos
Prb
2.1
Dystonia
2.2
Rigidity
2.3
Hypokinesia/Akinesia
2.4
Hyperkinesia logic
2.5
Tremor
2.6
Akathisia
2.7
Epileptic Seizures
2.8
Paraesthesias
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
118


Protocol 331-10-234
Confidential - Proprietary Information
118
Version 5.0, 05 Jul 2022
Autonomic
Not 
Ass.
Degree last 3 days (see 
manual) 
Causal 
relationship 
Category 
of side 
effects 
Symptom 
9
0
1
2
3
Imp
Pos
Prb
3.1
Acomodation Disturbances
3.2
Increased Salivation
3.3
Reduced Salivation
3.4
Nausea/Vomiting
3.5
Diarhoea
3.6
Constipation
3.7
Micturition Disturbances
3.8
Polyuria/Polydipsia
3.9
Orthostatic Dizines
3.10
Palpitations/Tachycardia
3.1
Increased Tendency to 
Sweating
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
119


Protocol 331-10-234
Confidential - Proprietary Information
119
Version 5.0, 05 Jul 2022
Other
Not 
Ass.
Degree last 3 days (see 
manual) 
Causal 
relationship 
Category 
of side 
effects 
Symptom 
9
0
1
2
3
Imp
Pos
Prb
4.1
Rash
4.1a
- Morbiliform
4.1b
- Petechial
4.1c
- Urticarial
4.1d
- Psoriatic
4.1e
- Canot be clasified
4.2
Pruritus
4.3
Photosensitivity
4.4
Increased Pigmentation
4.5
Weight Gain
4.6
Weight Los
4.7
Menorhagia
4.8
Amenorhoea
4.9
Galactorhoea
4.10
Gynaecomastia
4.1
Increased Sexual Desire
4.12
Diminished Sexual Desire
4.13
Erectile Dysfunction
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
120


Protocol 331-10-234
Confidential - Proprietary Information
120
Version 5.0, 05 Jul 2022
Other-continued
Not 
Ass.
Degree last 3 days (see 
manual) 
Causal 
relationship 
Category 
of side 
effects 
Symptom 
9
0
1
2
3
Imp
Pos
Prb
4.14
Ejaculatory Dysfunction
4.15
Orgastic Dysfunction
4.16
Dry Vagina
4.17
Headache
4.17a
- Tension headache
4.17b
- Migraine
4.17c
- 0ther forms
4.18
Physical Dependence
4.19
Psychic Dependence
Assessed by
Global assessment of the interference by existing side effects with the 
patient’s daily performance:
Patient
Doctor
0
No side efects
1
Mild side efects that do not interfere with the patient’s performance
2
Side efects that interfere moderately with the patient’s performance
3
Side efects that interfere markedly with the patient’s performance
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
121


Protocol 331-10-234
Confidential - Proprietary Information
121
Version 5.0, 05 Jul 2022
Consequence 
0
No action
1
More frequent asesment of the patient, but no reduction of dose, or ocasional drug 
treatment of side efects
2
Reduction of dose or continuous drug, treatment of side efects
3
Discontinuation of drug or change to another preparation
 
Day
Mth.
Year
Hour
Min
Date
Time
Signature
 
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
122




Protocol 331-10-234
Confidential - Proprietary Information
123
Version 5.0, 05 Jul 2022
Clinician Form: Please complete each section below: 
1.
Working memory: Trouble remembering things that people (parents, teachers, friends) 
have just said?
 Present 
during past 
week
 Not 
present in 
past week
 Evident 
During Visit
 Not Evident 
During Visit
 Not drug related 
 Due to study 
drug 
 Other drug
 Drug/drug 
interaction
 Not applicable
 Mild
 Moderate
 Severe
 Extreme
 Not 
applicable
 Functional/ 
Role 
Impairment
 No 
Functional/ Role 
Impairment
 Not applicable
2.
Attention/Vigilance: Trouble paying attention in class, home, or while playing games, 
watching TV, browsing the internet or using computers?
 Present 
during past 
week
 Not 
present in 
past week
 Evident 
During Visit
 Not Evident 
During Visit
 Not drug related 
 Due to study 
drug 
 Other drug
 Drug/drug 
interaction
 Not applicable
 Mild
 Moderate
 Severe
 Extreme
 Not 
applicable
 Functional/ 
Role 
Impairment
 No 
Functional/ Role 
Impairment
 Not applicable
3.
Verbal Learning/Memory: Difficulty remembering or learning words to things (book, 
songs, TV shows)? Trouble coming up with words in conversation?
 Present 
during past 
week
 Not 
present in 
past week
 Evident 
During Visit
 Not Evident 
During Visit
 Not drug related 
 Due to study 
drug 
 Other drug
 Drug/drug 
interaction
 Not applicable
 Mild
 Moderate
 Severe
 Extreme
 Not 
applicable
 Functional/ 
Role 
Impairment
 No 
Functional/ Role 
Impairment
 Not applicable
4.
Visual Learning/Memory: Patient has difficulty recalling how things look, such as shapes 
and colors?
 Present 
during past 
week
 Not 
present in 
past week
 Evident 
During Visit
 Not Evident 
During Visit
 Not drug related 
 Due to study 
drug 
 Other drug
 Drug/drug 
interaction
 Not applicable
 Mild
 Moderate
 Severe
 Extreme
 Not 
applicable
 Functional/ 
Role 
Impairment
 No 
Functional/ Role 
Impairment
 Not applicable
5.
Reasoning & Problem Solving: Trouble doing classwork or homework, solving math 
problems, doing puzzles?
 Present 
during past 
week
 Not 
present in 
past week
 Evident 
During Visit
 Not Evident 
During Visit
 Not drug related 
 Due to study 
drug 
 Other drug
 Drug/drug 
interaction
 Not applicable
 Mild
 Moderate
 Severe
 Extreme
 Not 
applicable
 Functional/ 
Role 
Impairment
 No 
Functional/ Role 
Impairment
 Not applicable
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
124


Protocol 331-10-234
Confidential - Proprietary Information
124
Version 5.0, 05 Jul 2022
6.
Speed of Processing: Feeling “slowed down”, does it take you longer than usual to do 
things?
 Present 
during past 
week
 Not 
present in 
past week
 Evident 
During Visit
 Not Evident 
During Visit
 Not drug related 
 Due to study 
drug 
 Other drug
 Drug/drug 
interaction
 Not applicable
 Mild
 Moderate
 Severe
 Extreme
 Not 
applicable
 Functional/ 
Role 
Impairment
 No 
Functional/ Role 
Impairment
 Not applicable
7.
Social Cognition: Trouble understanding what other people intend, participating in social 
situations, or interacting with others?
 Present 
during past 
week
 Not 
present in 
past week
 Evident 
During Visit
 Not Evident 
During Visit
 Not drug related 
 Due to study 
drug 
 Other drug
 Drug/drug 
interaction
 Not applicable
 Mild
 Moderate
 Severe
 Extreme
 Not 
applicable
 Functional/ 
Role 
Impairment
 No 
Functional/ Role 
Impairment
 Not applicable
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
125


Protocol 331-10-234
Confidential - Proprietary Information
125
Version 5.0, 05 Jul 2022
Appendix 15
Columbia-Suicide Severity Rating Scale (C-SSRS)
COLUMBIA-SUICIDE SEVERITY
RATING SCALE
(C-SSRS)
Baseline/Screening Version
Version 1/14/09
 Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; 
Fisher, P.; Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J. 
Disclaimer:
This scale is intended to be used by individuals who have received training in its administration. 
The questions contained in the Columbia-Suicide Severity Rating Scale are suggested probes. 
Ultimately, the determination of the presence of suicidal ideation or behavior depends on the 
judgment of the individual administering the scale.
Definitions of behavioral suicidal events in this scale are based on those used in The 
Columbia Suicide History Form, developed by John Mann, MD and Maria Oquendo, 
MD, Conte Center for the Neuroscience of Mental Disorders (CCNMD), New York State 
Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., Halberstam 
B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. 
In M.B. First [Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.)
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 
1051 Riverside Drive, New York, New York, 10032; inquiries and training requirements contact 
posnerk@childpsych.columbia.edu 
 2008 The Research Foundation for Mental Hygiene, Inc.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
126


Protocol 331-10-234
Confidential - Proprietary Information
126
Version 5.0, 05 Jul 2022
SUICIDAL IDEATION
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. 
If the answer to question 2 is “yes”, ask questions 3, 4 and 5.  If the answer to 
question 1 or 2 is “yes”, complete “Intensity of Ideation” section below.
Lifetime: 
Time He/She 
Felt Most 
Suicidal
Past 1 
month
1.  Wish to be Dead 
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep 
and not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up? 
If yes, describe:
Yes       No
□    □
Yes       No
□    □
2.  Non-Specific Active Suicidal Thoughts
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought 
about killing myself”) without thoughts of ways to kill oneself/associated methods, intent, or 
plan during the assessment period. 
Have you actually had any thoughts of killing yourself?
If yes, describe:
Yes      No
□    □
Yes      No
□    □
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to 
Act
Subject endorses thoughts of suicide and has thought of at least one method during the 
assessment period. This is different than a specific plan with time, place or method details 
worked out (e.g.  thought of method to kill self but not a specific plan).  Includes person who 
would say, “I thought about taking an overdose but I never made a specific plan as to when, 
where or how I would actually do it…..and I would never go through with it.” 
Have you been thinking about how you might do this?
If yes, describe:
Yes      No
□    □
Yes      No
□    □
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such 
thoughts, as opposed to “I have the thoughts but I definitely will not do anything about them.”
Have you had these thoughts and had some intention of acting on them?
If yes, describe:
Yes       No
□    □
Yes       No
□    □
5.  Active Suicidal Ideation with Specific Plan and Intent
Thoughts of killing oneself with details of plan fully or partially worked out and subject has 
some intent to carry it out.
Have you started to work out or worked out the details of how to kill yourself? Do you intend 
to carry out this plan?
   
If yes, describe:
Yes      No
□    □
Yes      No
□    □
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
127


Protocol 331-10-234
Confidential - Proprietary Information
127
Version 5.0, 05 Jul 2022
INTENSITY OF IDEATION
The following features should be rated with respect to the most severe type of ideation 
(i.e.,1-5 from above, with 1 being the least severe and 5 being the most severe ). Ask 
about time he/she was feeling the most suicidal. 
Lifetime -           Most Severe Ideation: ________
_______________________
Type # (1-5)
Description of  Ideation
Past 6 Months - Most Severe Ideation:  ________
________________________
Type # (1-5)
Description of  Ideation
Lifetime: 
Time He/She 
Felt Most 
Suicidal
Past 1 
month
Frequency
How many times have you had these thoughts? 
(1) Less than once a week   (2) Once a week  (3)  2-5 times in week   (4) Daily or almost 
daily   (5) Many times each day
____
____
Duration
When you have the thoughts, how long do they last?
(1) Fleeting - few seconds or minutes            (4) 4-8 hours/most of day
(2) Less than 1 hour/some of the time            (5) More than 8 hours/persistent or continuous
(3) 1-4 hours/a lot of time
____
____
Controllability
Could/can you stop thinking about killing yourself or wanting to die if you want 
to?
(1) Easily able to control thoughts                   (4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty  (5) Unable to control thoughts
(3) Can control thoughts with some difficulty (0) Does not attempt to control thoughts
____
____
Deterrents
Are there things - anyone or anything (e.g., family, religion, pain of death) - 
that stopped you from wanting to die or acting on thoughts of committing 
suicide?
(1) Deterrents definitely stopped you from       (4) Deterrents most likely did not stop you 
attempting suicide   
(2) Deterrents probably stopped you                 (5) Deterrents definitely did not stop you 
(3) Uncertain that deterrents stopped you         (0) Does not apply
____
____
Reasons for Ideation
What sort of reasons did you have for thinking about wanting to die or killing 
yourself?  Was it to end the pain or stop the way you were feeling (in other 
words you couldn’t go on living with this pain or how you were feeling) or was 
it to get attention, revenge or a reaction from others? Or both?
(1) Completely to get attention, revenge or (4) Mostly to end or stop the pain (you 
a reaction from others
couldn’t go on living with the pain or
(2) Mostly to get attention, revenge or a 
how you were feeling).
reaction from others.
(5) Completely to end or stop the pain (you
(3) Equally to get attention, revenge or a 
couldn’t go on living with the pain or  how
reaction from others and to end/stop
you were feeling).
the pain.
(0) Does not apply
____
____
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
128


Protocol 331-10-234
Confidential - Proprietary Information
128
Version 5.0, 05 Jul 2022
SUICIDAL BEHAVIOR
(Check all that apply, so long as these are separate events; must ask about all types)
Lifetime 
Past 1 
year
Actual Attempt: 
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior 
was in part thought of as method to kill oneself. Intent does not have to be 100%.  If there is any 
intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There 
does not have to be any injury or harm, just the potential for injury or harm. If person pulls 
trigger while gun is in mouth but gun is broken so no injury results, this is considered an attempt.  
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the 
behavior or circumstances. For example, a highly lethal act that is clearly not an accident so no other 
intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a high floor/story). 
Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be 
inferred. 
Have you made a suicide attempt?
Have you done anything to harm yourself?
Have you done anything dangerous where you could have died?
What did you do?
Did you______ as a way to end your life? 
Did you want to die (even a little) when you_____? 
Were you trying to end your life when you _____?
Or did you think it was possible you could have died from_____?
Or did you do it purely for other reasons / without ANY intention of killing yourself 
(like to relieve stress, feel better, get sympathy, or get something else to happen)?  
(Self-Injurious Behavior without suicidal intent)
If yes, describe:
Has subject engaged in Non-Suicidal Self-Injurious Behavior?
Yes      No
□   □
Total # of
Attempts
Yes    No
□   □
Yes      No
□   □
Total # of
Attempts
Yes    No
□   □
Interrupted Attempt:  
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious 
act (if not for that, actual attempt would have occurred).
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this 
becomes an attempt rather than an interrupted attempt. Shooting: Person has gun pointed toward self, 
gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the 
trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and 
taken down from ledge. Hanging: Person has noose around neck but has not yet started to hang - is 
stopped from doing so.
Has there been a time when you started to do something to end your life but 
someone or something stopped you before you actually did anything?
If yes, describe:
Yes      No
□   □
Total # of 
interrupted
Yes      No
□   □
Total # of 
interrupted
Aborted Attempt:  
When person begins to take steps toward making a suicide attempt, but stops themselves before they 
actually have engaged in any self-destructive behavior. Examples are similar to interrupted attempts, 
except that the individual stops him/herself, instead of being stopped by something else.
Has there been a time when you started to do something to try to end your life but 
you stopped yourself before you actually did anything?
If yes, describe:
Yes      No
□   □
Total # of
aborted
______
Yes      No
□   □
Total # of
aborted
______
Preparatory Acts or Behavior:
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a 
verbalization or thought, such as assembling a specific method (e.g., buying pills, purchasing a gun) or 
preparing for one’s death by suicide (e.g., giving things away, writing a suicide note). 
Have you taken any steps towards making a suicide attempt or preparing to kill 
yourself (such as collecting pills, getting a gun, giving valuables away or writing a 
suicide note)?
If yes, describe:
Yes      No
□   □
Yes      No
□   □
Suicidal Behavior:
Suicidal behavior was present during the assessment period?
Yes      No
□   □
Yes      No
□   □
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
129


Protocol 331-10-234
Confidential - Proprietary Information
129
Version 5.0, 05 Jul 2022
Answer for Actual Attempts Only
Most Recent 
Attempt Date:
Most Lethal 
Attempt Date:
Initial/
First Attempt 
Date:
Actual Lethality/Medical Damage:  
0.  No physical damage or very minor physical damage (e.g., surface scratches).
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild 
bleeding; sprains).
2.  Moderate physical damage; medical attention needed (e.g., conscious but 
sleepy, somewhat responsive; second-degree burns; bleeding of major 
vessel).
3.  Moderately severe physical damage; medical hospitalization and likely 
intensive care required (e.g., comatose with reflexes intact; third-degree 
burns less than 20% of body; extensive blood loss but can recover; major 
fractures).
4.  Severe physical damage; medical hospitalization with intensive care required 
(e.g., comatose without reflexes; third-degree burns over 20% of body; 
extensive blood loss with unstable vital signs; major damage to a vital area).
5.  Death
Enter Code
_________
Enter Code
_________
Enter Code
_________
Potential Lethality: Only Answer if Actual Lethality=0
Likely lethality of actual attempt if no medical damage (the following examples, 
while having no actual medical damage, had potential for very serious lethality: 
put gun in mouth and pulled the trigger but gun fails to fire so no medical 
damage; laying on train tracks with oncoming train but pulled away before run 
over).
0 = Behavior not likely to result in injury
1 = Behavior likely to result in injury but not likely to cause death
2 = Behavior likely to result in death despite available medical care 
Enter Code
_________
Enter Code
_________
Enter Code
_________
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
130


Protocol 331-10-234
Confidential - Proprietary Information
130
Version 5.0, 05 Jul 2022
COLUMBIA-SUICIDE SEVERITY
RATING SCALE
(C-SSRS)
Since Last Visit
Version 1/14/09
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; 
Fisher, P.; Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J. 
Disclaimer:
This scale is intended to be used by individuals who have received training in its administration. 
The questions contained in the Columbia-Suicide Severity Rating Scale are suggested probes. 
Ultimately, the determination of the presence of suicidal ideation or behavior depends on the 
judgment of the individual administering the scale.
Definitions of behavioral suicidal events in this scale are based on those used in The 
Columbia Suicide History Form, developed by John Mann, MD and Maria Oquendo, 
MD, Conte Center for the Neuroscience of Mental Disorders (CCNMD), New York State 
Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., Halberstam 
B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. 
In M.B. First [Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.)
 For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 
1051 Riverside Drive, New York, New York, 10032; inquiries and training requirements contact 
posnerk@childpsych.columbia.edu 
 2008 The Research Foundation for Mental Hygiene, Inc.
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
131


Protocol 331-10-234
Confidential - Proprietary Information
131
Version 5.0, 05 Jul 2022
SUICIDAL IDEATION
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the 
answer to question 2 is “yes”, ask questions 3, 4 and 5.  If the answer to question 1 or 2 is 
“yes”, complete “Intensity of Ideation” section below.
Since Last 
Visit
1.  Wish to be Dead 
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up? 
If yes, describe:
Yes       No
 □    □
2.  Non-Specific Active Suicidal Thoughts
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing 
myself”) without thoughts of ways to kill oneself/associated methods, intent, or plan during the assessment period. 
Have you actually had any thoughts of killing yourself?
If yes, describe:
 Yes      No
 □    □
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is 
different than a specific plan with time, place or method details worked out (e.g.,  thought of method to kill self 
but not a specific plan).  Includes person who would say, “I thought about taking an overdose but I never made a 
specific plan as to when, where or how I would actually do it…..and I would never go through with it.” 
Have you been thinking about how you might do this?
If yes, describe:
 Yes      No
 □    □
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as 
opposed to “I have the thoughts but I definitely will not do anything about them.”
Have you had these thoughts and had some intention of acting on them? 
If yes, describe:
Yes       No
 □    □
5.  Active Suicidal Ideation with Specific Plan and Intent
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it 
out.
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this 
plan?
   
If yes, describe:
 Yes      No
 □    □
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
132


Protocol 331-10-234
Confidential - Proprietary Information
132
Version 5.0, 05 Jul 2022
INTENSITY OF IDEATION
The following features should be rated with respect to the most severe type of ideation (i.e.,1-5 from 
above, with 1 being the least severe and 5 being the most severe ).
                                            
Most Severe Ideation:             _____              _________________________________________
                                              
                                                                                                           Type # (1-5)                                Description of  Ideation
Most 
Severe
Frequency
How many times have you had these thoughts? 
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    
(5) Many times each day
____
Duration
When you have the thoughts, how long do they last?
(1) Fleeting - few seconds or minutes                                    (4) 4-8 hours/most of day
(2) Less than 1 hour/some of the time                                    (5) More than 8 hours/persistent or continuous
(3) 1-4 hours/a lot of time
____
Controllability
Could/can you stop thinking about killing yourself or wanting to die if you want to?
(1) Easily able to control thoughts                                          (4) Can control thoughts with a lot of difficulty
(2) Can control thoughts with little difficulty                         (5) Unable to control thoughts
(3) Can control thoughts with some difficulty                        (0) Does not attempt to control thoughts
____
Deterrents
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you 
from wanting to die or acting on thoughts of committing suicide?
(1) Deterrents definitely stopped you from attempting suicide      (4) Deterrents most likely did not stop you 
(2) Deterrents probably stopped you                                               (5) Deterrents definitely did not stop you 
(3) Uncertain that deterrents stopped you                                       (0) Does not apply
____
Reasons for Ideation
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was 
it to end the pain or stop the way you were feeling (in other words you couldn’t go on living 
with this pain or how you were feeling) or was it to get attention, revenge or a reaction from 
others? Or both?
(1) Completely to get attention, revenge or a reaction from others.
(4) Mostly to end or stop the pain (you 
(2) Mostly to get attention, revenge or a reaction from others.
couldn’t go on living with the pain or 
(3) Equally to get attention, revenge or a reaction from others
how you were feeling).
     and to end/stop the pain.
(5) Completely to end or stop the pain
(you couldn’t go on living with the
pain or how you were feeling).
(0) Does not apply
                                                                      
____
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
133


Protocol 331-10-234
Confidential - Proprietary Information
133
Version 5.0, 05 Jul 2022
SUICIDAL BEHAVIOR
(Check all that apply, so long as these are separate events; must ask about all types)
Since Last 
Visit
Actual Attempt: 
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part 
thought of as method to kill oneself. Intent does not have to be 100%.  If there is any intent/desire to die associated 
with the act, then it can be considered an actual suicide attempt. There does not have to be any injury or 
harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no 
injury results, this is considered an attempt.  
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or 
circumstances. For example, a highly lethal act that is clearly not an accident so no other intent but suicide can be 
inferred (e.g., gunshot to head, jumping from window of a high floor/story). Also, if someone denies intent to die, 
but they thought that what they did could be lethal, intent may be inferred. 
Have you made a suicide attempt?
Have you done anything to harm yourself?
Have you done anything dangerous where you could have died?
What did you do?
Did you______ as a way to end your life? 
Did you want to die (even a little) when you_____? 
Were you trying to end your life when you _____?
Or did you think it was possible you could have died from_____?
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to 
relieve stress, feel better, get sympathy, or get something else to happen)?  (Self-Injurious Behavior 
without suicidal intent)
If yes, describe:
Has subject engaged in Non-Suicidal Self-Injurious Behavior?
Yes      No
□   □
Total # of
Attempts
______
Yes     No
□   □
Interrupted Attempt:  
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not 
for that, actual attempt would have occurred).
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an 
attempt rather than an interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken away by 
someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, even if the gun fails to fire, 
it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has 
noose around neck but has not yet started to hang - is stopped from doing so.
Has there been a time when you started to do something to end your life but someone or 
something stopped you before you actually did anything?
If yes, describe:
Yes      No
□   □
Total # of 
interrupted
______
Aborted Attempt:  
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have 
engaged in any self-destructive behavior. Examples are similar to interrupted attempts, except that the individual 
stops him/herself, instead of being stopped by something else.
Has there been a time when you started to do something to try to end your life but you 
stopped yourself before you actually did anything?
If yes, describe:
Yes      No
□   □
Total # of
aborted
_____
Preparatory Acts or Behavior:
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a 
verbalization or thought, such as assembling a specific method (e.g., buying pills, purchasing a gun) or preparing 
for one’s death by suicide (e.g., giving things away, writing a suicide note). 
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such 
as collecting pills, getting a gun, giving valuables away or writing a suicide note)?
If yes, describe:
Yes      No
□   □
Suicidal Behavior:
Suicidal behavior was present during the assessment period?
Yes      No
□   □
Completed Suicide:
   Yes    No
□   □
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
134


Protocol 331-10-234
Confidential - Proprietary Information
134
Version 5.0, 05 Jul 2022
Answer for Actual Attempts Only
Most Lethal 
Attempt 
Date:
Actual Lethality/Medical Damage:  
0.  No physical damage or very minor physical damage (e.g., surface scratches).
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains).
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-
degree burns; bleeding of major vessel).
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose 
with reflexes intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major 
fractures).
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; 
third-degree burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital 
area).
5.  Death
Enter Code
________
Potential Lethality: Only Answer if Actual Lethality=0
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical 
damage, had potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no 
medical damage; laying on train tracks with oncoming train but pulled away before run over).
0 = Behavior not likely to result in injury
1 = Behavior likely to result in injury but not likely to cause death
2 = Behavior likely to result in death despite available medical care 
Enter Code
________
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
135


Protocol 331-10-234
Confidential - Proprietary Information
135
Version 5.0, 05 Jul 2022
Appendix 16
Tanner Scale
Classification of Sex Maturity Stages in Girls
Stage
Pubic Hair
Breasts
1
Preadolescent
Preadolescent
2
Sparse, lightly pigmented, 
straight, medial border of labia
Breast and papilla elevated as 
small mound; areolar diameter 
increased
3
Darker, beginning to curl, 
increased amount
Breast and areola enlarged, no 
contour separation
4
Coarse, curly, abundant but 
amount less than adult
Areola and papilla form 
secondary mound
5
Adult feminine triangle, spread 
to medial surface of thighs
Mature; nipple projects, areola 
part of the general breast contour
Classification of Sex Maturity Stages in Boys
Stage
Pubic Hair
Penis
Testes
1
None
Preadolescent
Preadolescent
2
Scanty, long, slightly 
pigmented
Slight enlargement
Enlarged scrotum, pink 
texture altered
3
Darker, starts to curl, 
small amount
Longer
Larger
4
Resembles adult type 
but less in quantity; 
coarse, curly
Larger; glans and 
breadth increase in size
Larger, scrotum dark
5
Adult distribution, 
spread to medial 
surface of thighs
Adult size
Adult Size
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
136


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


Protocol 331-10-234
Confidential - Proprietary Information
14
Version 2.0, 29 May 2019 
Agreement
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator's Brochure) and agree that it contains all the ethical, legal and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor's (or designee's) Clinical Trial Agreement.
I will provide copies of the protocol to all physicians, nurses, and other professional personnel to 
whom I delegate trial responsibilities. I will discuss the protocol with them to ensure that they are 
sufficiently informed regarding the investigational new drug, OPC-34712, the concurrent 
medications, the efficacy and safety parameters and the conduct of the trial in general. I am 
aware that this protocol must be approved by the Institutional Review Board (IRB) or receive a 
favorable opinion by the Independent Ethics Committee (IEC) responsible for such matters in the 
clinical trial facility where OPC-34712 will be tested prior to commencement of this trial. I agree to 
adhere strictly to the attached protocol (unless amended in the manner set forth in the sponsor's 
Clinical Trial Agreement, at which time I agree to adhere strictly to the protocol as amended).
I understand that this IRB- or IEC-approved protocol will be submitted to the appropriate 
regulatory authority/ies by the sponsor. I agree that clinical data entered on case report forms by 
me and my staff will be utilized by the sponsor in various ways, such as for submission to 
governmental regulatory authorities or in combination with clinical data gathered from other 
research sites, whenever applicable. I agree to allow sponsor and designee monitors and 
auditors full access to all medical records at the research facility for subjects screened or enrolled 
in the trial.
I agree to await IRB/IEC approval before implementation of any substantial amendments to this 
protocol. If, however, there is an immediate hazard to subjects, I will implement the amendment 
immediately, and provide the information to the IRB/IEC within the required local applicable 
timelines. Administrative changes to the protocol will be transmitted to the IRB/IEC for 
informational purposes only, if required by local regulations.
I agree to provide all subjects with informed consent forms, as required by the applicable 
regulations and by ICH guidelines. I agree to report to the sponsor any adverse experiences in 
accordance with the terms of the sponsor's Clinical Trial Agreement and the relevant regional 
regulation(s) and guideline(s). I further agree to provide all required information regarding 
financial certification or disclosure to the sponsor for all investigators and sub-investigators in 
accordance with the terms of the relevant regional regulation(s). I understand that participation in 
the protocol involves a commitment to publish the data from this trial in a cooperative publication 
before publication of efficacy and safety results on an individual basis may occur, and I consent to 
be acknowledged in any such cooperative publications that result.
____________________________
_____________________________
___________
Principal Investigator Print Name
Signature
Date
Clinical Study Report 331-10-234
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
196


7KLVSDJHLVDPDQLIHVWDWLRQRIDQHOHFWURQLFDOO\FDSWXUHGVLJQDWXUH
6,*1$785(3$*(
'RFXPHQW1DPHB&RXQWU\6SHFLILF3URWRFRO$PHQGPHQWB+XQJDU\
'RFXPHQW1XPEHU
6LJQHGE\
0HDQLQJRI6LJQDWXUH
6HUYHU'DWH
GG000
\\\\KKPLQ
87&WLPH]RQH
&OLQLFDO$SSURYDO
-XQ

%LRVWDWLVWLFV$SSURYDO
-XQ

&OLQLFDO6WXG\5HSRUW
3URWRFRODQG3URWRFRO$PHQGPHQWV
8QWLOWKHLQIRUPDWLRQKHUHLQLVUHOHDVHGE\2WVXNDWRWKHSXEOLFGRPDLQWKHFRQWHQWVRIWKLVGRFXPHQWDUH2WVXND
FRQILGHQWLDOLQIRUPDWLRQDQGVKRXOGQRWEHGXSOLFDWHGRUUHGLVWULEXWHGZLWKRXWSULRUZULWWHQFRQVHQWRI2WVXND

CCI
PPD
PPD

SAP_001.pdf: 
Table of Contents
Table of Contents.............................................................................................................
1
Statistical Analysis Plan - 14 Mar 2023...........................................................................
2
Statistical Analysis Plan Addendum - 21 Aug 2023........................................................
57
Clinical Study Report 331-10-234
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
1


Otsuka Pharmaceutical Development & Comercialization, Inc.
Investigational New Drug
Brexpiprazole (OPC-34712)
Protocol 331-10-234
IND No. 101,871
EudraCT No. 2017-001447-12
A Multicenter, Randomized, Double-blind, Placebo- and
Active-controlled Trial to Evaluate the Efficacy of Brexpiprazole Monotherapy for the 
Treatment in Adolescents (13-17 years old) With Schizophrenia
Statistical Analysis Plan
Version: 2.0
Date: 14 Mar 2023
Protocol Date: 05 Jul 2022
Confidential
May not be used, divulged, published, or otherwise disclosed without the prior written 
consent of Otsuka Pharmaceutical Development & Commercialization, Inc. 
Clinical Study Report 331-10-234
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
2














SAP 331-10-234
Confidential - Proprietary Information
8
14 Mar 2023
List of Abreviations and Definition of Terms
Abreviation
Definition
AE
Adverse event
AIM
Abnormal involuntary movement
AIMS
Abnormal Involuntary Movement Scale
ALT
Alanine transaminase
ANCOVA
Analysis of covariance
AST
Aspartate transaminase
BARS
Barnes Akathisia Rating Scale
BMI
Body mass index
CDC
Center for Disease Control and Prevention
CGAS
Children’s Global Assessment Scale
CGI-I
Clinical Global Impression Improvement
CGI-S
Clinical Global Impression Severity
CL
Total body clearance of drug from plasma following intravascular 
administration
CMH
Cochran-Mantel-Haenszel
CRF
Case report form
C-SSRS
Columbia-Suicide Severity Rating Scale
ECG
Electrocardiogram
EPS
Extrapyramidal symptoms
ET
Early Termination
EudraCT
European Clinical Trial Data Base
FDA
Food and Drug Administration
FU
Follow-up
ICF
Informed consent form
IMP
Investigational medicinal product(s)
IND
Investigative new drug
IWRS
Interactive web response system
kg
Kilogram
L
Liter
LOCF
Last observation carried forward
LS
Least squares
MAR
Missing at random
MCMC
Monte Carlo Markov Chain
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
MI
Multiple Imputation
MMRM
Mixed model repeated measures
NY-AACENT
New York Assessment for Adverse Cognitive Effects of 
Neuropsychiatric Treatment
OC
Observed case
PANSS
Positive and Negative Syndrome Scale
PMM
Pattern Mixture Models
QD
Dosing once per day
Clinical Study Report 331-10-234
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
9


SAP 331-10-234
Confidential - Proprietary Information
9
14 Mar 2023
RR
Relative risk
s
Second
SAP
Statistical analysis plan
SAS
Simpson Angus Scale
SD
Standard deviation
TEAEs
Treatment-emergent AEs
UKU
Udvalg for Kliniske Undersogelser
ULN
Upper limit of normal
US
United States
Clinical Study Report 331-10-234
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
10


SAP 331-10-234
Confidential - Proprietary Information
10
14 Mar 2023
1
Introduction
This statistical analysis plan (SAP) documents the statistical methodology and data 
analysis algorithms and conventions to be applied for statistical analysis and reporting of 
efficacy and safety data of trial 331-10-234. All amendments to the protocol are taken 
into consideration in developing this SAP.
2
Trial Objectives
The objective of the trial is to evaluate the short-term efficacy and safety of brexpiprazole 
monotherapy in the treatment of adolescents with schizophrenia.
3
Trial Design
3.1
Type/Design of Trial
This is a multicenter, randomized, double-blind, placebo- and active-controlled trial 
designed to assess the effect of brexpiprazole compared to placebo in adolescent subjects, 
ages 13 to 17 years at the time of informed consent/assent and at baseline (Day 1), with a 
Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) 
diagnosis of schizophrenia and by utilizing the Kiddie Schedule for Affective Disorders 
and Schizophrenia-Present and Lifetime version (K-SADS-PL). The trial is planned to be 
conducted on an outpatient basis. Any hospitalization needed for prospective subjects, 
such as hospitalization needed to allow subjects to change medications in preparation for 
this trial requires discussion with the Medical Advisor.
This trial has a 6-week treatment double-blind period.
After a minimum 3-day washout period, subjects who continue to meet all entrance 
criteria (including Positive and Negative Syndrome Scale [PANSS] Total Score ≥ 80) at 
the baseline visit (Day 1) will be randomized 1:1:1 to 1 of 3 double-blind treatment arms: 
•
Brexpiprazole 2 - 4 mg daily flexible dose
•
Aripiprazole 10 - 20 mg daily flexible dose
•
Placebo
Subjects will be randomly assigned through an interactive web response system (IWRS). 
Treatment assignments will be based on a computer-generated randomization code 
provided by the Otsuka Pharmaceutical Development & Commercialization, Inc. 
Biometrics Department
Clinical Study Report 331-10-234
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
11














SAP 331-10-234
Confidential - Proprietary Information
17
14 Mar 2023
Rationale for estimand: hypothetical estimand justifiable to evaluate the pharmacological 
effect, had 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 had their treatment effect masked had the subjects taken other 
treatment after withdrawal. This would mean 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 assessed only once at the Early Termination (ET) Visit. Every 
effort will be made to complete all of the ET evaluations prior to administering any 
additional medications for the treatment of schizophrenia 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.
For the primary efficacy analysis, the estimator will be the Mixed Model Repeated 
Measurements (MMRM) estimate for treatment difference at Week 6, based on all 
observed case (OC) data until discontinuation from the trial. Under the MAR assumption, 
MMRM provides an unbiased estimate of treatment effect for the treatment period. 
Analyses with missing values imputed by MI under MNAR and other methods will be 
performed as sensitivity analyses.
Of note, the population attribute is slightly different in this SAP compared to the Protocol 
(dated 05 Jul 2022). Adjustment has been made based on FDA feedback to better reflect 
the target population expected to use the product.
6.2
Secondary Outcome Variables
6.2.1
Secondary Eficacy Endpoints
The secondary efficacy endpoints are as follows:
•
Change in the PANSS Positive and Negative Subscale Scores
•
Percentage of subjects achieving response. Response is defined as at least 30% 
improvement from baseline in PANSS Total Score or CGI score of 1 or 2.
•
Percentage of subjects achieving remission. Remission is defined as a score of ≤ 3 on 
each of the following specific PANSS items: delusions (P1), unusual thought content 
(G9), hallucinatory behavior (P3), conceptual disorganization (P2). 
mannerisms/posturing (G5), blunted affect (N1), passive/apathetic social withdrawal 
(N4), and lack of spontaneity and conversation flow (N6).
•
Change in the Children’s Global Assessment Scale (CGAS) Score
•
Change in the Clinical Global Impression Severity (CGI-S) scale
•
Clinical Global Impression Improvement (CGI-I) scale
Clinical Study Report 331-10-234
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
18


SAP 331-10-234
Confidential - Proprietary Information
18
14 Mar 2023
6.2.2
Secondary Safety Endpoints
Safety will be assessed by the following secondary endpoints:
•
The frequency and severity of AEs, serious AEs (clinical and laboratory), and 
discontinuation from the trial due to AEs
•
Weight, height, body mass index, and waist circumference
•
Analysis of potential suicide events recorded on the Columbia-Suicide Severity 
Rating Scale (C-SSRS)
•
Clinical laboratory tests and urinalysis results (including serum prolactin), vital signs, 
physical examinations, and electrocardiogram (ECG) parameters
•
Changes on the Simpson Angus Scale (SAS), Abnormal Involuntary Movement Scale 
(AIMS), and Barnes Akathisia Rating Scale (BARS)
•
Comprehensive psychotropic side effects as assessed by the Udvalg for Kliniske 
Undersogelser (UKU) side effect rating scale
•
Cognitive adverse effects as assessed by the New York Assessment for Adverse 
Cognitive Effects of Neuropsychiatric Treatment (NY-AACENT)
7
Disposition and Demographic Analysis
7.1
Subject Disposition
Subject disposition (such as “Enrolled”, “Treated”, “Discontinued”, “Completed”, etc.) 
will be summarized on the Enrolled Sample. Study completion rate and reasons for 
discontinuation will also be summarized. 
For purposes of this trial, subjects who completed the end-of-trial visit (ie, the Week 6 
visit) will be defined as trial completers.
Disposition will be summarized by treatment group and by subgroup of sex, race, region 
and age category (< 15, ≥ 15 years).
Reasons for discontinuation will be summarized for the randomized sample by treatment 
group and by subgroup of sex, race, age category (< 15, ≥ 15 years) and region (US, 
Europe [continent], Mexico).
&OLQLFDO6WXG\5HSRUW
'RFXPHQWDWLRQRI6WDWLVWLFDO0HWKRGV
8QWLOWKHLQIRUPDWLRQKHUHLQLVUHOHDVHGE\2WVXNDWRWKHSXEOLFGRPDLQWKHFRQWHQWVRIWKLVGRFXPHQWDUH2WVXND
FRQILGHQWLDOLQIRUPDWLRQDQGVKRXOGQRWEHGXSOLFDWHGRUUHGLVWULEXWHGZLWKRXWSULRUZULWWHQFRQVHQWRI2WVXND

CCI


SAP 331-10-234
Confidential - Proprietary Information
19
14 Mar 2023
7.2
Demographic and Baseline Characteristics
Baseline measurements of efficacy and safety variables are defined as their last 
measurements prior to the first dose of IMP.
Baseline demographic characteristics include age, sex, race, ethnicity, height, weight, 
waist circumference, and body mass index (BMI). For the Randomized Sample, 
demographic characteristics will be summarized by treatment group. 
Mean, median, SD, minimum and maximum values will be used to describe continuous 
variables such as age. Frequency distributions will be tabulated for categorical variables 
such as race and age category (< 15, ≥ 15 years).
Demographics will be summarized by treatment group and by subgroup of sex, race, age 
category (< 15, ≥ 15 years) and region (US, Europe [continent], Mexico).
7.3
Baseline Disease Evaluation
A summary of medical and psychiatric history will be presented for the Randomized 
Sample (by treatment group and overall). Prior antipsychotic medication will be 
summarized in frequency. Medical history will also be summarized by using frequency 
distribution of subjects across the medical histories.
Baseline values in the following parameters related to psychiatric evaluation will be 
summarized on the Randomized Sample by using descriptive statistics: PANSS total 
score, PANSS Positive subscale score, PANSS Negative subscale score, CGI-S score, 
CGAS score 
Baseline characteristics will be summarized by treatment group and by subgroup of sex, 
race age category (< 15, ≥ 15 years) and region.
7.4
Treatment Compliance
Treatment compliance will be reported, by treatment group, in the Safety Sample, by 
percentage of subjects taking at least 70%, 80%, and 90% of medications based on IMP 
Accountability panel of the Case Report Form.
7.5
Prior and Concomitant Medications
Number and proportion of subjects taking concomitant medications prior to IMP, during 
the double-blind treatment period, and after IMP are tabulated by drug classification 
using the World Health Organization drug dictionary.
&OLQLFDO6WXG\5HSRUW
'RFXPHQWDWLRQRI6WDWLVWLFDO0HWKRGV
8QWLOWKHLQIRUPDWLRQKHUHLQLVUHOHDVHGE\2WVXNDWRWKHSXEOLFGRPDLQWKHFRQWHQWVRIWKLVGRFXPHQWDUH2WVXND
FRQILGHQWLDOLQIRUPDWLRQDQGVKRXOGQRWEHGXSOLFDWHGRUUHGLVWULEXWHGZLWKRXWSULRUZULWWHQFRQVHQWRI2WVXND

CCI


SAP 331-10-234
Confidential - Proprietary Information
20
14 Mar 2023
7.6
Protocol Deviations
Protocol deviations data will be summarized by type of deviations by trial site and 
treatment group for the Randomized Sample. In addition, a subjects listing will be 
provided describing the deviations for each subject.
8
Eficacy Analysis
8.1
Primary Eficacy Endpoint
The primary efficacy endpoint is the change from baseline to Week 6 in PANSS Total 
Score. The primary statistical comparison of interest is brexpiprazole 2 - 4 mg versus 
placebo based on all available data (OC dataset). All randomized subjects who have both 
baseline and post-baseline PANSS total score will be included in the primary efficacy 
analysis. 
8.1.1
Primary Eficacy Analysis 
The primary statistical comparison of interest is brexpiprazole 2 - 4 mg versus placebo. 
With the assumption of MAR, an MMRM analysis with fixed-effect factors of treatment, 
trial site, visit, treatment by visit interaction, and fixed effect covariates of baseline and 
baseline by visit interaction will be applied to the change from baseline from Week 1 to 
Week 6 in PANSS Total Score based on all available data (OC dataset). The data will be 
modeled using an unstructured variance covariance matrix for the within subject 
variation. A statistical test of the least squares (LS) mean differences at Week 6 of the 
MMRM analysis will serve as the analysis of the primary endpoint. The Kenward-Roger 
approximation will be used to estimate denominator degree of freedom and adjust 
standard errors.
The contrast (ie, difference in least-square means between brexpiprazole and placebo) at 
the Week 6 visit will be estimated from the interaction term of treatment by visit week 
and will serve as the primary treatment comparison. The point estimate and the 95% 
confidence interval estimate of the contrast at the Week 6 visit will be reported. 
Significance test will be based on the contrast estimate at the Week 6 visit by using a 
two-sided 0.05 level.
In case there is a convergence problem with the MMRM model with the unstructured 
variance covariance matrix, the following structures other than unstructured will be used 
in order of 1) heterogeneous toeplitz, 2) heterogeneous autoregressive of order 1, and 
3) heterogeneous compound symmetry, and the first (co)variance structure converging to 
the best fit will be used as the primary analysis. If a structured covariance has to be used, 
Clinical Study Report 331-10-234
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
21










SAP 331-10-234
Confidential - Proprietary Information
25
14 Mar 2023
8.1.5
Ukraine-Rusia Conflict Related Sensitivity Analyses
The Ukraine-Russia conflict started on 24 Feb 2022. This trial enrolled many subjects 
from Ukraine and Russia. However, the number of subjects from Russia and Ukraine 
starting treatment in the 9 weeks before the start of the conflict is very limited (N = 6), 
most completed the treatment and had PANSS assessment. No subject from these 
countries started treatment after 22 Feb 2022. Therefore, no specific sensitivity analyses 
will be performed.
8.2
Secondary Eficacy Analysis
The following are the secondary efficacy variables in this trial:
1) Change in the PANSS Positive and Negative Subscale Scores
2) Percentage of subjects achieving response. Response is defined as at least 30% 
improvement from baseline in PANSS Total Score or CGI score of 1 or 2.
3) Percentage of subjects achieving remission. Remission is defined as a score of ≤ 3 
on each of the following specific PANSS items: delusions (P1), unusual thought 
content (G9), hallucinatory behavior (P3), conceptual disorganization (P2). 
mannerisms/posturing (G5), blunted affect (N1), passive/apathetic social 
withdrawal (N4), and lack of spontaneity and conversation flow (N6).
4) Change in the Children’s Global Assessment Scale (CGAS) Score
5) Change in the Clinical Global Impression Severity (CGI-S) scale
6) Clinical Global Impression Improvement (CGI-I) scale
For continuous secondary endpoints (change in CGI-S, change in CGAS, PANSS 
Positive Subscale score, and PANSS Negative Subscale score), an MMRM analysis with 
factors of treatment, trial site, visit, treatment by visit interaction, and baseline and 
baseline by visit interaction as covariates with an unstructured variance covariance 
structure will be applied based on all available data (OC dataset) from the Efficacy 
Sample. ANCOVA with baseline value as covariate and treatment as main effects will 
also be performed on the OC dataset. Data will be presented by week.
The CGI-I score will be evaluated by the Cochran-Mantel-Haenszel row mean score 
differ test  controlling for trial site in last-observation-carried-forward (LOCF) and 
Observed Cases (OC) analyses. Descriptive statistics and differences between arms with 
95% confidence intervals will also be presented. 
Response and remission endpoints will be evaluated by the CMH General Association 
Test controlling for trial site, by week, in OC and LOCF analyses, for the Efficacy 
Sample.
Clinical Study Report 331-10-234
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
26




SAP 331-10-234
Confidential - Proprietary Information
27
14 Mar 2023
9
Safety Analyses
Safety will be assessed by the following secondary endpoints:
•
The frequency and severity of AEs, serious AEs (clinical and laboratory), and 
discontinuation from the trial due to AEs
•
Weight, height, body mass index, and waist circumference
•
Analysis of potential suicide events recorded on the Columbia-Suicide Severity 
Rating Scale (C-SSRS)
•
Clinical laboratory tests and urinalysis results (including serum prolactin), vital signs, 
physical examinations, and electrocardiogram (ECG) parameters
•
Changes on the Simpson Angus Scale (SAS), Abnormal Involuntary Movement Scale 
(AIMS), and Barnes Akathisia Rating Scale (BARS)
•
Comprehensive psychotropic side effects as assessed by the Udvalg for Kliniske 
Undersogelser (UKU) side effect rating scale
•
Cognitive adverse effects as assessed by the New York Assessment for Adverse 
Cognitive Effects of Neuropsychiatric Treatment (NY-AACENT)
Safety analysis will be conducted based on the Safety Sample, which is defined in 
Section 5. In general, baseline of a safety variable is defined as the last observation of the 
variable before taking the first dose of IMP, unless specified otherwise.
Concomitant medication analyses are described under Section 7.5.
&OLQLFDO6WXG\5HSRUW
'RFXPHQWDWLRQRI6WDWLVWLFDO0HWKRGV
8QWLOWKHLQIRUPDWLRQKHUHLQLVUHOHDVHGE\2WVXNDWRWKHSXEOLFGRPDLQWKHFRQWHQWVRIWKLVGRFXPHQWDUH2WVXND
FRQILGHQWLDOLQIRUPDWLRQDQGVKRXOGQRWEHGXSOLFDWHGRUUHGLVWULEXWHGZLWKRXWSULRUZULWWHQFRQVHQWRI2WVXND

CCI


SAP 331-10-234
Confidential - Proprietary Information
28
14 Mar 2023
9.1
Extent of Exposure
The start date of double-blind IMP with brexpiprazole, aripiprazole or placebo will be the 
first day of double-blind dosing. The number and percentage of subjects who receive 
double-blind IMP will be presented by week and by treatment group. Each dosing week 
will be based on the actual week; ie, Day 1 to 7 in Week 1, Day 8 to 14 in Week 2, etc. 
This summary will be performed on the Safety Sample.
The number and percentage of completers will be presented by week and by treatment 
group.
The mean daily dosage will be summarized by week and treatment group using 
descriptive statistics. The mean daily dosage per subject per week will be determined for 
each week of the trial. This will be calculated by dividing the sum of individual total 
doses by the number of days in the week interval. The summary will contain for each 
treatment group the number of subjects receiving double-blind IMP, and the mean and 
range of the mean daily dose for each week.
Extent of exposure will also be summarized by sex, race (White and All Other races), age 
category (< 15, ≥ 15 years) and region (US, Europe [continent], Mexico).
9.2
Adverse Events 
All AEs will be coded by system organ class and Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term. The incidence of the following events will be 
summarized by treatment group:
1)  Treatment-emergent AEs (TEAEs),
2)  TEAEs by severity
3)  TEAEs potentially causally related to the IMP,
4)  TEAEs potentially causally related to the IMP by severity,
5)  TEAEs with an outcome of death,
6)  Serious TEAEs,
7)  TEAEs leading to discontinuations of the IMP.
Treatment-emergent AE is defined as an AE that started after trial drug treatment, or if 
the event was continuing from baseline and was serious, trial drug related, or resulted in 
death, discontinuation, interruption or reduction of trial therapy.
Incidence of TEAEs will also be summarized by sex, race (White and All Other races), 
age category (< 15, ≥ 15 years) and region (US European [continent], Mexico).
Clinical Study Report 331-10-234
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
29
















SAP 331-10-234
Confidential - Proprietary Information
36
14 Mar 2023
within a specified time period prior to entry into the trial, will be completed for all 
subjects at screening to determine eligibility. Any subject with active suicidal ideation 
within the last 6 months, suicidal behaviors within the last 2 years, or who in the clinical 
judgment of the investigator presents a serious risk of suicide should be excluded from 
the trial. The “Since Last Visit” C-SSRS form will also be completed at all visits after 
screening.
10.12
Tanner scale
The scale defines physical measurements of development based on external primary and 
secondary sex characteristics, such as the size of the breasts, genitals, testicular volume 
and development of pubic hair. Boys and girls are rated on a 5-point scale.
11
Pharmacokinetic Analyses
Pharmacokinetic data will be analyzed separately.
12
Pharmacodynamic Analyses
There is no pharmacodynamic analyses in this trial.
13
Pharmacogenomic Analyses
Pharmacogenomic data will be analyzed separately.
14
Interim Analysis
No unblinded interim analysis is planned for this trial.
15 Changes in the Planned Analyses
None. 
16 Revision History
Table 16-1
Document History
Version
Key Changes
Version 2.0, 14 Mar 2023
•
Added 
and 
describing the SAS 
programs for multiple imputation delta method and placebo 
based imputations
•
Section 3.4: corrected typo for target day on week 5
•
Section 8.1.2: indicated that in case of convergence problems 
ANCOVA will be used and refer to the appendix for 
programming details
•
Section 8.1.3.1: corrected the region categories to “(US, Europe 
[continent], Mexico)”
&OLQLFDO6WXG\5HSRUW
'RFXPHQWDWLRQRI6WDWLVWLFDO0HWKRGV
8QWLOWKHLQIRUPDWLRQKHUHLQLVUHOHDVHGE\2WVXNDWRWKHSXEOLFGRPDLQWKHFRQWHQWVRIWKLVGRFXPHQWDUH2WVXND
FRQILGHQWLDOLQIRUPDWLRQDQGVKRXOGQRWEHGXSOLFDWHGRUUHGLVWULEXWHGZLWKRXWSULRUZULWWHQFRQVHQWRI2WVXND

CCI
CCI




SAP 331-10-234
Confidential - Proprietary Information
38
14 Mar 2023
Apendix 1
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance
Laboratory Tests
Criteria
Chemistry
AST (SGOT)
 3 x upper limit of normal (ULN)
ALT (SGPT)
 3 x ULN
Alkaline phosphatase
 3 x ULN
LDH
 3 x ULN
BUN
 30 mg/dL
Creatinine
 2.0 mg/dL
Uric Acid
Men
 10.5 mg/dL
Women
 8.5 mg/dL
Bilirubin (total)
 2.0 mg/dL
CPK
 3 x ULN
Prolactin
> ULN
Hematology
Hematocrit
Men
 37 % and decrease of  3 percentage points from Baseline
Women
 32 % and decrease of  3 percentage points from Baseline
Hemoglobin
Men
 11.5 g/dL
Women
 9.5 g/dL
White blood count
 2,800/ mm3 or  16,000/ mm3
Eosinophils
 10%
Neutrophils
 15%
Absolute neutrophil count
 1,000/ mm3
Platelet count
 75,000/ mm3 or  700,000/ mm3
Urinalysis
Protein
Increase of  2 units
Glucose
Increase of  2 units
Casts
Increase of  2 units
Aditional Criteria
Chloride
 90 mEq/L or  118 mEq/L
Potassium
 2.5 mEq/L or  6.5 mEq/L
Sodium
 126 mEq/L or  156 mEq/L
Calcium
 8.2 mg/dL or  12 mg/dL
Glucose
Fasting
 100 mg/dL 
Non-Fasting
 200 mg/dL
Total Cholesterol, Fasting
 240 mg/dL 
LDL Cholesterol, Fasting
 160 mg/dL 
HDL Cholesterol, Fasting
Men
< 40 mg/dL
Women
< 50 mg/dL
Triglycerides, Fasting
 150 mg/dL
Clinical Study Report 331-10-234
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
39


SAP 331-10-234
Confidential - Proprietary Information
39
14 Mar 2023
Apendix 2
Criteria for Identifying Vital Signs of Potential Clinical 
Relevance
Variable
Criterion Value
a
Change Relative to Baseline
a
Heart Rateb
> 120 bpm
< 50 bpm
 15 bpm increase
 15 bpm decrease
Systolic Blood Pressureb
> 180 mmHg
< 90 mmHg
 20 mmHg increase
 20 mmHg decrease
Diastolic Blood Pressureb
> 105 mmHg
< 50 mmHg
 15 mmHg increase
 15 mmHg decrease
Orthostatic Hypotension
 20 mmHg decrease in systolic blood 
pressure and a  25 bpm increase in 
heart rate from supine to 
sitting/standing
Not Applicable
(baseline status not considered)
Weight
-
 7% increase
 7% decrease
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column.
bAs defined in “Supplementary Suggestions for Preparing an Integrated Summary of Safety Information 
in an Original NDA Submission and for Organizing Information in Periodic Safety Updates,” FDA 
Division of Neuropharmacological Drug Products draft (2/27/87).
Clinical Study Report 331-10-234
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
40


SAP 331-10-234
Confidential - Proprietary Information
40
14 Mar 2023
Apendix 3
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance
Variable
Criterion Value
a
Change Relative to Baseline
a
Rate
Tachycardia
 120 bpm
increase of   15 bpm
Bradycardia
 50 bpm
decrease of  15 bpm
Rhythm
Sinus tachycardiab
 120 bpm
increase of  15 bpm
Sinus bradycardiac
 50 bpm
decrease of  15 bpm
Supraventricular premature beat
all
not present  present
Ventricular premature beat
all
not present  present
Supraventricular tachycardia
all
not present  present
Ventricular tachycardia
all
not present  present
Atrial fibrillation
all
not present  present
Atrial flutter
all
not present  present
Conduction
1 atrioventricular block
PR  200 msec
increase of   50 msec
2 atrioventricular block
all
not present  present
3 atrioventricular block
all
not present  present
Left bundle-branch block
all
not present  present
Right bundle-branch block
all
not present  present
Pre-excitation syndrome
all
not present  present
Other intraventricular conduction blockd
QRS  120 msec
increase of  20 msec
Infarction
Acute or subacute
all
not present  present
Old
all
not present  present
 12 weeks post study entry
ST/T Morphological
Myocardial Ischemia
all
not present  present
Symmetrical T-wave inversion
all
not present  present
Increase in QTc
QTcF or QTcN
≥ 450 msec for males,
≥ 470 msec for
female
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column.
bNo current diagnosis of supraventricular tachycardia, ventricular tachycardia, atrial fibrillation, atrial 
flutter, or other rhythm abnormality.
cNo current diagnosis of atrial fibrillation, atrial flutter, or other rhythm abnormality.
dNo current diagnosis of left bundle branch block or right bundle branch block.
Clinical Study Report 331-10-234
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
41


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


CCI


7KLVSDJHLVDPDQLIHVWDWLRQRIDQHOHFWURQLFDOO\FDSWXUHGVLJQDWXUH
6,*1$785(3$*(
'RFXPHQW1DPH6$3
'RFXPHQW1XPEHU
6LJQHGE\
0HDQLQJRI6LJQDWXUH
6HUYHU'DWH
GG000
\\\\KKPLQ
87&WLPH]RQH
&OLQLFDO$SSURYDO
0DU

%LRVWDWLVWLFV$SSURYDO
0DU

&OLQLFDO6WXG\5HSRUW
'RFXPHQWDWLRQRI6WDWLVWLFDO0HWKRGV
8QWLOWKHLQIRUPDWLRQKHUHLQLVUHOHDVHGE\2WVXNDWRWKHSXEOLFGRPDLQWKHFRQWHQWVRIWKLVGRFXPHQWDUH2WVXND
FRQILGHQWLDOLQIRUPDWLRQDQGVKRXOGQRWEHGXSOLFDWHGRUUHGLVWULEXWHGZLWKRXWSULRUZULWWHQFRQVHQWRI2WVXND

CCI
PPD
PPD


Confidential - Proprietary Information
1
Version Date: 21 Aug 2023
Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigational New Drug
Brexpiprazole (OPC-34712)
Protocol 331-10-234
IND No. 101,871
EudraCT No. 2017-001447-12
A Multicenter, Randomized, Double-blind, Placebo- and
Active-controlled Trial to Evaluate the Efficacy of Brexpiprazole Monotherapy for the 
Treatment in Adolescents (13-17 years old) With Schizophrenia
Statistical Analysis Plan Addendum to v2.0
Version: Final
Date: 21 Aug 2023
Protocol Date: 05 Jul 2022
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Otsuka Pharmaceutical Development & Commercialization, Inc.
Clinical Study Report 331-10-234
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
57




Statistical Analysis Plan Addendum 331-10-234
Confidential - Proprietary Information
3
Version Date: 21 Aug 2023
List of Abbreviations and Definitions of Terms
Abbreviation
Definition
FDA
Food & Drug Administration
MedDRA
Medical Dictionary for Regulatory Activities
PANSS
Positive and Negative Syndrome Scale
SAP
Statistical analysis plan
TEAE
Treatment emergent adverse event
Clinical Study Report 331-10-234
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
59




Statistical Analysis Plan Addendum 331-10-234
Confidential - Proprietary Information
5
Version Date: 21 Aug 2023
3
References
1
US Food and Drug Administration. Diversity Plans to Improve Enrollment of 
Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials 
Guidance for Industry. Draft Guidance, April 2022. Available from: 
https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/diversity-plans-improve-enrollment-participants-underrepresented-racial-
and-ethnic-populations
Clinical Study Report 331-10-234
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
61


7KLVSDJHLVDPDQLIHVWDWLRQRIDQHOHFWURQLFDOO\FDSWXUHGVLJQDWXUH
6,*1$785(3$*(
'RFXPHQW1DPH3B6$3Y$GGHQGXP
'RFXPHQW1XPEHU
6LJQHGE\
0HDQLQJRI6LJQDWXUH
6HUYHU'DWH
GG000
\\\\KKPLQ
87&WLPH]RQH
&OLQLFDO$SSURYDO
$XJ

%LRVWDWLVWLFV$SSURYDO
$XJ

&OLQLFDO6WXG\5HSRUW
'RFXPHQWDWLRQRI6WDWLVWLFDO0HWKRGV
8QWLOWKHLQIRUPDWLRQKHUHLQLVUHOHDVHGE\2WVXNDWRWKHSXEOLFGRPDLQWKHFRQWHQWVRIWKLVGRFXPHQWDUH2WVXND
FRQILGHQWLDOLQIRUPDWLRQDQGVKRXOGQRWEHGXSOLFDWHGRUUHGLVWULEXWHGZLWKRXWSULRUZULWWHQFRQVHQWRI2WVXND

CCI
PPD
PPD