A Long-term, Multicenter, Open-label Trial to Evaluate the Safety and Tolerability of Flexible-Dose Brexpiprazole as Maintenance Treatment in Adolescents (13-17 Years Old) With Schizophrenia
Phase: PHASE3
Conditions: Schizophrenia
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

Ots u ka P har mace utical
De vel o p me nt & C o m mercializati o n, I nc.
I n vesti gati o nal Me dici nal Pr o d uct
Bre x pi praz ole ( O P C- 3 4 7 1 2)
R E VI S E D C LI NI C A L P R O T O C O L
A L o n g-ter m, M ultice nter, O pe n-la bel Trial t o E val uate t he Safet y a n d T olera bilit y of 
Fle xi ble- D ose Bre x pi praz ole as Mai nte na nce Treat me nt i n A d olesce nts ( 1 3- 1 7 Years 
Ol d) Wit h Sc hiz o p hre nia
Pr ot oc ol N o. 3 3 1- 1 0- 2 3 6
I N D N o. 1 0 1, 8 7 1
E u dra C T N o. 2 0 1 7- 0 0 1 4 5 9- 3 0
C O N FI D E N TI A L – P R O P RI E T A R Y I N F O R M A TI O N
Cli nical De vel o p me nt P hase:  
3
S p o ns or:
Ots u ka P har mace utical De vel o p me nt & 
C o m mercializati o n, I nc.
2 4 4 0 Researc h B o ule var d
R oc k ville, Mar yla n d  2 0 8 5 0, U nite d States
I m me diatel y Re p orta ble E ve nt 
S y ne os Healt h Safet y a n d 
P har mac o vi gila nce
Iss ue Dates:
Ori gi nal Pr ot oc ol:
0 4 Ma y 2 0 1 7
Date of A me n d me nt 1:
0 1 Dec 2 0 1 7
Date of A me n d me nt 2:
1 3 Se p 2 0 1 8
Date of A me n d me nt 3:
0 3 J u n 2 0 1 9
Date of A me n d me nt 4:
1 6 J u n 2 0 2 0
Date of A me n d me nt 5:
0 4 A u g 2 0 2 1
Versi o n N o.:
6. 0
C CI

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Trial Conduct for COVID-19
All procedures and assessments in this protocol are to be followed to the fullest 
extent possible.  The sponsor, in coordination with the sites, investigators, and 
medical monitor, will continuously monitor and evaluate the benefits and risks to 
subject participation in the clinical trial as it relates to COVID-19.  If any 
protocol-specified activities were not able to be performed, or cannot be performed 
due to COVID-19 considerations, refer to the COVID-19 Addendum for the 
appropriate measures to be followed.  Appropriate measures may include 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.

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Protocol Synopsis 
Name of Sponsor:  Otsuka Pharmaceutical 
Development & Commercialization, Inc.
Name of Investigational Medicinal Product:  
Brexpiprazole (OPC-34712)
Protocol No.:  331-10-236
IND No.:  101,871
EudraCT No.:  
2017-001459-30
Protocol Title:
A Long-term, Multicenter, Open-label Trial to Evaluate the 
Safety and Tolerability of Flexible-Dose Brexpiprazole as 
Maintenance Treatment in Adolescents (13-17 Years Old) 
With Schizophrenia
Clinical Phase/Trial 
Type:
3/Long-term safety and tolerability
Treatment Indication:  Schizophrenia
Objective(s):  
To further characterize the long-term safety and tolerability of 
brexpiprazole in adolescents with schizophrenia
Trial Design:
This is a long-term, multicenter, open-label trial designed to 
examine the long-term safety and tolerability of brexpiprazole 
in adolescent subjects, ages 13 to 17 years, with a Diagnostic 
and Statistical Manual of Mental Disorders - Fifth Edition 
(DSM-5) diagnosis of schizophrenia.  Subjects from 
Trial 331-10-234 who turned 18 years old during that trial are 
also permitted to enroll in this trial.  Enrollment into the trial 
will be drawn from eligible subjects who, in the investigator’s 
judgment, could potentially benefit from monotherapy 
treatment with oral brexpiprazole for schizophrenia and will 
include rollover subjects from the double-blind, phase 3 
efficacy trial, Trial 331-10-234, and may include de novo 
subjects from select sites.  Rollover subjects will be considered 
as those who are able to rollover within ≤ 7 days of the Week 6 
visit of Trial 331-10-234.  Subjects who are only able to 
rollover from Trial 331-10-234 after > 7 days from the Week 6 
visit may be allowed to enter Trial 331-10-236 as de novo 
subjects following approval by the medical monitor.
The trial will be conducted on an outpatient basis.  
Hospitalization for psychosocial reasons (eg, homelessness or 
need for shelter that is unrelated to the subject’s underlying 
psychiatric condition) will be considered outpatient status for 
the purpose of enrollment in Trial 331-10-236.
Subjects remaining in hospital at the Week 6 visit of 
Trial 331-10-234 (for other than psychosocial reasons) will be 
permitted to enroll in Trial 331-10-236 at the Week 6 visit of 

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the double-blind trial if they are planned to be discharged from 
the hospital before the open-label treatment period Week 1 
visit of Trial 331-10-236 and following approval by the 
medical monitor.  De novo subjects hospitalized at the time of 
the Trial 331-10-236 screening visit will be permitted to be 
screened for the trial if they are planned to be discharged from 
the hospital prior to the baseline (Day 1) visit of the open-label 
treatment period and following approval by the medical 
monitor.
The trial will be organized as follows:
Rollover Subjects from Trial 331-10-234
Screening/Baseline:  Subjects will be screened for eligibility at 
the last visit of the double-blind trial (ie, Week 6 visit of 
Trial 331-10-234).  Subjects or their parents/legal guardians 
will sign either via wet signature or electronic signature a 
separate informed consent form (ICF) or assent form for 
participation in Trial 331-10-236 before any procedures 
specific to the open-label trial are performed.  The assessments 
from the last visit of the double-blind trial will serve as the 
baseline measures for Trial 331-10-236 for any assessment 
that is not unique to the open-label trial.  Medical history will 
be updated, if necessary.  Because the blind for all rollover 
subjects will be maintained until the last subject completes 
Trial 331-10-234, rollover subjects will follow a titration 
schedule the first week in the open-label treatment period in 
this trial.
Open-label Treatment:  Eligible subjects from 
Trial 331-10-234 will receive daily treatment with open-label 
brexpiprazole in the open-label treatment period of 
Trial 331-10-236 as described in the Investigational Medicinal 
Product, Dose, Formulation, Mode of Administration section.
De Novo Subjects
Screening:  For de novo subjects who did not participate in 
Trial 331-10-234, the initial diagnosis of schizophrenia for this 
trial (as defined by DSM-5 criteria) should be made and 
documented by an adequately trained clinician (psychiatrist, or 
local medical equivalent who is experienced in treating 
adolescents with schizophrenia), and the diagnosis should then 
be confirmed 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.

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Subjects will enter a pretreatment screening phase that will 
range from a minimum of 3 days to a maximum of 28 days to 
assess eligibility criteria and to washout from prohibited 
concomitant medications, if applicable.  Screening begins on 
the day that the subject or legal guardian/parent signs the ICF, 
and the subject, if not old enough to sign the ICF, completes 
the assent form.  Subjects will be assigned a unique screening 
number for each subject with a signed ICF (and assent form if 
required) prior to enrollment.  If a de novo subject previously 
participated in Trial 331-10-234, they will retain their subject 
identification number from Trial 331-10-234.  Subjects who 
are able to complete the required washout of prohibited 
medications will proceed directly to the baseline (Day 1) visit 
of the open-label treatment period after completion and review 
of screening assessments provided that all eligibility criteria 
are met.  If the washout of prohibited medications prior to the 
baseline (Day 1) visit is not appropriate for subjects, in the 
opinion of the investigator, the subjects will participate in the 
conversion period.
Conversion:  If the washout of prohibited medications prior to 
the baseline (Day 1) of the open-label treatment period is not 
appropriate for subjects, in the opinion of the investigator, the 
subjects will undergo cross-titration to oral brexpiprazole for 
1 to 4 weeks during the conversion period, as described in the 
Investigational Medicinal Product, Dose, Formulation, Mode 
of Administration section.  Visits will occur at the end of each 
week during the conversion period.  The goal of de novo 
subjects during the conversion period is to achieve a 
brexpiprazole monotherapy target starting dose of 1, 2, or 
3 mg daily at any time after Week 1 per the investigator’s 
discretion and to achieve washout of prohibited medications.  
The subject will proceed to the baseline (Day 1) visit of the 
open-label treatment period once the target starting dose has 
been achieved and the required washout of prohibited 
medications has been completed.
Baseline and Open-label Treatment:  After completing 
baseline assessments, eligible subjects will receive daily 
treatment with open-label brexpiprazole in the open-label 
treatment period, as described in the Investigational Medicinal 
Product, Dose, Formulation, Mode of Administration section.
Follow-up:  Subjects will be followed up for safety via 
telephone contact or clinic visit 21 (± 2) days after the last 
dose of IMP.

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Subject Population:
The trial population will include subjects from 
Trial 331-10-234 and de novo subjects between 13 and 
17 years of age, inclusive, at the time of informed 
consent/assent and at the baseline (Day 1) visit of the 
open-label treatment period.  For de novo subjects who did not 
participate in Trial 331-10-234, the initial diagnosis of 
schizophrenia for this trial (as defined by DSM-5 criteria) must 
be made and documented and the diagnosis confirmed by the 
K-SADS-PL, at screening.  Subjects from Trial 331-10-234 
who turned 18 years old during that trial are also permitted to 
enroll in this trial.  Approximately 350 subjects are anticipated 
to be enrolled with the expectation that at least 100 will 
complete a minimum of 1 year of exposure to open-label 
brexpiprazole.
Inclusion/Exclusion 
Criteria:  
Rollover subjects must meet the inclusion criteria at the 
completion of Trial 331-10-234 for entry to Trial 331-10-236.  
Key inclusion criteria for both rollover and de novo subjects 
include the following:

Subjects with a current diagnosis of schizophrenia, as 
defined by DSM-5 criteria and confirmed by the 
K-SADS-PL completed at entry into Trial 331-10-234.  
For de novo subjects who did not participate in 
Trial 331-10-234, the initial diagnosis of schizophrenia for 
this trial (as defined by DSM-5 criteria) must be made and 
documented and the diagnosis confirmed by the 
K-SADS-PL, at screening.

Subjects who, in the investigator’s judgment, require 
treatment with antipsychotic medication(s).
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).

Any neurological disorder, with the exception of Tourette’s 
syndrome.

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
Subjects experiencing acute depressive symptoms within 
the past 30 days prior to screening that, according to the 
investigator’s judgment, require treatment with an 
antidepressant.

Subjects with schizophrenia 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 with a history of failure of clozapine treatment or 
response to clozapine treatment only.
Trial Site(s):  
An estimated 120 sites in North America, Europe, and rest of 
world will enroll subjects.
Investigational 
Medicinal Product(s), 
Dose, Dosage 
regimen, Treatment 
period, Formulation, 
Mode of 
Administration:
Investigational medicinal product (IMP) will be supplied to the 
investigators by the sponsor or designated agent and will 
consist of open-label brexpiprazole 0.50 mg, 1 mg, 2 mg, 3 mg 
and 4 mg tablets in bottles, each containing sufficient tablets 
for the designated visit level.  Brexpiprazole will be 
administered orally as a once-a-day dose without regard to 
meals.
For rollover subjects from Trial 331-10-234, the first dose of 
open-label brexpiprazole will be taken 1 day after the last dose 
of double-blind IMP is taken in Trial 331-10-234 so that 
treatment continues without interruption.  Whenever possible, 
it is anticipated that the last dose of the double-blind, phase 3 
efficacy trial will be taken the day of the Week 6 visit of 
Trial 331-10-234 (ie, the day of the screening/baseline visit for 
the open-label trial).  Subjects should not be dosed with 
double-blind (331-10-234) and open-label (331-10-236) study 
medication on the same day.
Rollover subjects from the double-blind, phase 3 efficacy trial 
will begin dosing with brexpiprazole in the open-label 
Treatment period, starting at 0.5 mg/day, increasing to 
1.0 mg/day on Day 5, and an optional increase to 2 mg/day if 
tolerated on Day 8.  If this dose is well tolerated, but the 
response is inadequate, weekly dose increases can be made in 
1 mg increments up to a maximum dose of 4 mg/day, based on 
the clinical judgment of the investigator.  If the dose of 
brexpiprazole is not well tolerated, the investigator has the 
option to decrease the dose of brexpiprazole in a step-wise 
manner (1 mg decrements) at subsequent scheduled or 

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unscheduled visits according to his/her clinical judgment based 
on the subject’s response to treatment.  Daily dosing for this 
trial includes 1, 2, 3, or 4 mg.
De novo subjects from select sites will proceed to the 
conversion period or the open-label treatment period after 
screening, depending on their current antipsychotic treatment 
regimen.  If the washout of prohibited medications prior to the 
baseline (Day 1) visit of the open-label treatment period is not 
appropriate for subjects, in the opinion of the investigator, the 
subjects will undergo cross-titration to oral brexpiprazole 
during the conversion period.  De novo subjects who enter the 
conversion period of 1 to 4 weeks, will receive brexpiprazole 
in addition to their current antipsychotic(s).  The dose of 
brexpiprazole will be increased as clinically indicated during 
the conversion period.  Simultaneously, the dose of other 
antipsychotic(s) will be decreased and eventually discontinued.  
Once monotherapy with brexpiprazole and the washout of 
prohibited medications is achieved, the subject can begin the 
open-label treatment period of the study.  De novo subjects 
should be outpatient at the baseline (Day 1) visit of the 
open-label treatment period.
De novo subjects will begin brexpiprazole monotherapy 
dosing of either 0.5 mg (no conversion) or 1, 2, or 3 mg (after 
conversion) in the open-label treatment period.  De novo 
subjects who do not require a conversion period will follow 
the same titration schedule as rollover subjects from 
Trial 331-10-234, ie, 0.5 mg/day on Day 1, increasing to 
1 mg/day on Day 5, and an optional increase to 2 mg/day if 
tolerated on Day 8.  If doses are well tolerated, but the 
response is inadequate, weekly dose increases can be made in 
1 mg increments up to a maximum dose of 4 mg/day, based on 
the clinical judgment of the investigator.  Daily dosing for this 
trial includes 1, 2, 3, or 4 mg.
For all subjects, the maximum dose of brexpiprazole to be 
used in this trial is 4 mg/day.  The dose of brexpiprazole may 
be decreased at any time based on the investigator’s judgment 
after the start of the open-label treatment period.  Dose 
decreases will occur in 1 mg decrements, with the frequency of 
the 1 mg decreases based upon tolerability.  Those unable to 
tolerate the minimum daily dose of brexpiprazole (1 mg/day) 
must be withdrawn from the trial.  Rechallenge with higher 
doses of brexpiprazole is permitted following dose decreases, 
if clinically warranted based on the investigator’s judgment.

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If clinically indicated, subjects may be required to return to the 
clinic for unscheduled visits if dose adjustments for 
brexpiprazole are required between scheduled visits.  Dose 
adjustments must ultimately be made based upon the clinical 
judgment of the investigator as it relates to tolerability and 
therapeutic response.
Trial Assessments:
Efficacy:  Positive and Negative Syndrome Scale (PANSS) 
and Children’s Global Assessment Scale (CGAS) , Clinical 
Global Impression - Severity of Illness scale (CGI-S), and 
Clinical Global Impression - Improvement scale (CGI-I).
Safety:  adverse events (AEs) and concomitant medications, 
clinical laboratory tests, urinalysis, vital signs, 12-lead 
electrocardiogram (ECG), physical examination, body weight, 
height, body mass index (BMI), waist circumference, 
extrapyramidal scales (Simpson Angus Scale [SAS], 
Abnormal Involuntary Movement Scale [AIMS], and Barnes 
Akathisia Rating Scale [BARS]), Udvalg for Kliniske 
Undersogelser (UKU), New York Assessment for Adverse 
Cognitive Effects of Neuropsychiatric Treatment 
(NY-AACENT), Tanner Staging Scale for sexual 
development, and suicidality using the Columbia-Suicide 
Severity Rating Scale (C-SSRS).
Screening/Other:  demography, medical history, psychiatric 
history (K-SADS-PL), prior and concomitant medications, 
serum/urine pregnancy test, and urine drug screen.
Criteria for 
Evaluation:
Primary Endpoint:
The primary endpoints of this trial are the frequency and 
severity of AEs, serious treatment-emergent adverse events 
(TEAEs) (clinical and laboratory), and discontinuation from 
trial due to AEs.
Secondary Endpoints
The secondary safety endpoints are as follows:

Mean change from baseline and incidence of clinically 
significant abnormalities in clinical laboratory tests and 
urinalysis results (including fasting blood lipids, 
glucose and insulin, serum prolactin, glycosylated 
hemoglobin [HbA1c] and creatine phosphokinase 
[CPK]), vital signs (supine and standing positions), 
weight, height, body mass index (BMI), waist 
circumference, and ECG parameters

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
Mean change from baseline on the AIMS, Simpson-
Angus Scale (SAS), and Barnes Akathisia Rating Scale 
(BARS)

Analysis of potential suicide events recorded on the 
C-SSRS

Comprehensive psychotropic side effects as assessed 
by UKU side effect rating scale

The frequency of symptom items for the clinician-
administered NY-AACENT

Baseline and postbaseline Tanner Staging Scale data

Time to discontinuation due to AE
The secondary efficacy endpoints are as follows:

Change in the PANSS Total Score and the Positive and 
Negative Subscale Scores

Change in the CGAS Score

CGI-S scale

CGI-I scale
Statistical Methods:
Sample size was not determined by a formal computation to 
achieve a target power.  Sample size was planned to attain at 
least 100 subjects completing 1 year of exposure to open-label 
brexpiprazole.  
Descriptive statistics will be provided for all efficacy and 
safety variables.  Continuous variables will be summarized by 
tabulations of mean, median, range, and standard deviation.  
Tabulations of frequency distributions will be provided for 
categorical variables.  A Kaplan-Meier curve will be plotted 
for the time to discontinuation due to AE variable.
Safety tabulations will include duration on brexpiprazole, the 
frequency of AEs, serious TEAEs, ECGs, vital sign 
abnormalities, weight, BMI, waist circumference changes, 
laboratory abnormalities and therapy discontinuations.  The 
efficacy variables (for subjects with schizophrenia:  PANSS 
Total score, PANSS Positive and Negative Subscales, and 
CGAS) will be summarized by change from baseline over 
time.  Tanner Staging Scale data will be summarized using 
shift tables.  The incidence of suicidality, suicidal behavior and 
suicidal ideation will be summarized from the data recorded on 
the C-SSRS forms, and results will be summarized by visit.  
Other outcomes including PANSS Cognitive Subscale will be 
summarized for their change from baseline by visit.

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No inferential statistical analyses are planned for this 
open-label trial.  All analyses will be exploratory and 
conducted only to report the long-term safety of brexpiprazole 
for all subjects who are administered at least 1 dose of 
brexpiprazole.
Trial Duration:
The duration of this trial from first subject enrolled to last 
subject completed is estimated to be approximately 66 months, 
of which 40 months are allotted for recruitment of subjects.  
Individual participation for rollover subjects who complete the 
trial without early withdrawal will be approximately 
25 months, consisting of a 24-month open-label treatment 
period, and a 21 (± 2)-day follow-up, if applicable.  Individual 
participation for de novo subjects who complete the trial 
without early withdrawal will be approximately 27 months, 
consisting of a screening period of up to 28 days, a conversion 
period of 1 to 4 weeks, a 24-month open-label treatment 
period, and a 21 (± 2)-day follow-up, if applicable. 

Pr ot oc ol 3 3 1- 1 0- 2 3 6
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Tri al C o n d uct f or C O VI D- 1 9....................................................................... 2
Pr ot oc ol S y n o psis........................................................................................... 3
T a ble of C o nte nts ........................................................................................ 1 2
List of I n-te xt T a bles................................................................................... 1 8
List of I n-te xt Fi g ures ................................................................................. 1 9
List of A p pe n dices....................................................................................... 2 0
List of A b bre vi ati o ns a n d Defi niti o ns of Ter ms....................................... 2 1
1 
I ntr o d ucti o n........................................................................................ 2 4
1. 2 
Cli nical Data...................................................................................................... 2 7
1. 2. 1 
P har mac o ki netics/ P har mac o d y na mics ........................................................... 2 7
1. 2. 2 
Sc hiz o p hre nia ................................................................................................. 2 8
1. 2. 3  
Maj or De pressi ve Dis or der............................................................................. 2 9
1. 2. 4  
Ot her I n dicati o ns ............................................................................................ 2 9
1. 3  
K n o w n a n d P ote ntial Ris ks a n d Be nefits.......................................................... 3 0
2 
Tri al R ati o n ale a n d O bjecti ves ......................................................... 3 2
2. 1 
Trial Rati o nale................................................................................................... 3 2
2. 2  
D osi n g Rati o nale............................................................................................... 3 2
2. 3 
Trial O bjecti ves................................................................................................. 3 3
3 
Tri al Desi g n......................................................................................... 3 3
3. 1 
T y pe/ Desi g n of Trial......................................................................................... 3 3
3. 2 
Trial Treat me nts................................................................................................ 3 9
3. 2. 1 
R oll o ver S u bjects fr o m Trial 3 3 1- 1 0- 2 3 4....................................................... 3 9
3. 2. 2  
De N o v o S u bjects........................................................................................... 4 0
3. 2. 2. 1 
C o n versi o n.................................................................................................. 4 0
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O pe n-la bel Treat me nt Peri o d...................................................................... 4 1
3. 3 
Trial P o p ulati o n................................................................................................. 4 2
C C
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3.3.1
Number of Subjects and Description of Population .......................................42
3.3.2
Subject Selection and Numbering ..................................................................43
3.4
Eligibility Criteria .............................................................................................43
3.4.1
Informed Consent ...........................................................................................43
3.4.2
Inclusion Criteria ............................................................................................44
3.4.2.1
Rollover Subjects ........................................................................................44
3.4.2.2
De Novo Subjects........................................................................................45
3.4.3
Exclusion Criteria...........................................................................................46
3.4.3.1
Rollover Subjects ........................................................................................46
3.4.3.2
De Novo Subjects........................................................................................49
3.5
Endpoints...........................................................................................................52
3.5.1
Primary Endpoints ..........................................................................................52
3.5.2
Secondary Endpoints ......................................................................................52
3.5.2.1
Secondary Safety Endpoints .......................................................................52
3.5.2.2
Secondary Efficacy Endpoints....................................................................53
3.6
Measures to Minimize/Avoid Bias....................................................................53
3.7
Trial Procedures ................................................................................................53
3.7.1
Schedule of Assessments................................................................................60
3.7.1.1
Screening and Baseline ...............................................................................60
3.7.1.1.1
Rollover Subjects.....................................................................................60
3.7.1.1.2
De Novo Subjects....................................................................................60
3.7.1.1.2.1
Screening..............................................................................................60
3.7.1.1.2.2
Conversion Period................................................................................63
3.7.1.1.2.3
Baseline (Open-label Treatment Period) .............................................64
3.7.1.2
Open-label Treatment .................................................................................65
3.7.1.2.1
Weeks 1, 2, and 4 ....................................................................................65
3.7.1.2.2
Months 2, 3, and 4...................................................................................66
3.7.1.2.3
Month 6 ...................................................................................................67
3.7.1.2.4
Months 8 and 10......................................................................................68
3.7.1.2.5
Month 12 .................................................................................................68
3.7.1.2.6
Months 15, 18, and 21.............................................................................69
3.7.1.2.7
Months 5, 7, 9, 11, 13, 14, 16, 17, 19, 20, 22, and 23.............................71

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3.7.1.2.8
Month 24/Early Termination (End of Treatment)...................................71
3.7.1.3
Follow-up....................................................................................................72
3.7.2
Efficacy Assessments .....................................................................................72
3.7.2.1
Positive and Negative Syndrome Scale ......................................................72
3.7.2.2
Children’s Global Assessment Scale ..........................................................73
3.7.2.3
Clinical Global Impression - Severity of Illness Scale ...............................73
3.7.2.4
Clinical Global Impression - Improvement Scale.......................................73
3.7.3
Safety Assessments.........................................................................................73
3.7.3.1
Adverse Events ...........................................................................................73
3.7.3.2
Clinical Laboratory Assessments................................................................74
3.7.3.3
Physical Examination and Vital Signs........................................................77
3.7.3.3.1
Physical Examination ..............................................................................77
3.7.3.3.2
Vital Signs ...............................................................................................78
3.7.3.4
Electrocardiogram Assessments .................................................................79
3.7.3.5
Other Safety Assessments...........................................................................79
3.7.3.5.1
Simpson Angus Scale..............................................................................80
3.7.3.5.2
Abnormal Involuntary Movement Scale .................................................80
3.7.3.5.3
Barnes Akathisia Rating Scale ................................................................81
3.7.3.5.4
Udvalg for Kliniske Undersogelser.........................................................81
3.7.3.5.5
New York Assessment for Adverse Cognitive Effects of 
Neuropsychiatric Treatment ....................................................................81
3.7.3.5.6
Tanner Staging Scale...............................................................................82
3.7.3.5.7
Suicidality................................................................................................82
3.7.4
End of Trial.....................................................................................................83
3.7.5
Independent Data Monitoring Committee......................................................83
3.8
Stopping Rules, Withdrawal Criteria, and Procedures......................................83
3.8.1
Entire Trial......................................................................................................83
3.8.2
Individual Site.................................................................................................83
3.8.3
Individual Subject Discontinuation ................................................................84
3.8.3.1
Treatment Interruption ................................................................................84
3.8.3.2
Treatment Discontinuation..........................................................................84
3.8.3.3
Documenting Reasons for Treatment Discontinuation...............................84

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3.8.3.4
Withdrawal of Consent ...............................................................................85
3.8.3.5
Procedures to Encourage Continued Trial Participation.............................86
3.9
Screen Failures ..................................................................................................86
3.10
Definition of Completed Subjects.....................................................................87
3.11
Definition of Subjects Lost to Follow-up..........................................................87
3.12
Subject Compliance...........................................................................................87
3.13
Protocol Deviations...........................................................................................88
4
Restrictions .........................................................................................88
4.1
Prohibited Medications .....................................................................................88
4.2
Other Restrictions..............................................................................................92
4.2.1
Restricted Therapies and Precautions.............................................................92
4.2.2
Non-therapy Precautions and Restrictions......................................................93
4.2.2.1
Precautions..................................................................................................93
4.2.2.2
Restrictions..................................................................................................93
5
Reporting of Adverse Events.............................................................94
5.1
Definitions.........................................................................................................94
5.2
Eliciting and Reporting Adverse Events ...........................................................96
5.3
Immediately Reportable Events ........................................................................97
5.4
Potential Serious Hepatotoxicity.......................................................................97
5.5
Pregnancy..........................................................................................................97
5.6
Procedure for Breaking the Blind......................................................................99
5.7
Follow-up of Adverse Events............................................................................99
5.7.1
Follow-up of Nonserious Adverse Events......................................................99
5.7.2
Follow-up of Serious Adverse Events............................................................99
5.7.3
Follow-up and Reporting of Serious Adverse Events Occurring after 
Last Scheduled Contact ................................................................................100
6
Pharmacokinetic Analysis ...............................................................100
7
Statistical Analysis............................................................................100
7.1
Sample Size.....................................................................................................100
7.2
Datasets for Analysis.......................................................................................100
7.3
Primary and Secondary Endpoint Analyses....................................................101

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7.3.1
Primary Endpoint Analysis...........................................................................101
7.3.2
Secondary Endpoint Analysis.......................................................................101
7.4
Analysis of Demographic and Baseline Characteristics..................................101
7.5
Safety Analysis................................................................................................101
7.5.1
Adverse Events.............................................................................................101
7.5.2
Clinical Laboratory Data ..............................................................................102
7.5.3
Physical Examination and Vital Signs Data.................................................102
7.5.4
Electrocardiogram Data................................................................................102
7.5.5
Other Safety Data .........................................................................................102
7.5.5.1
Special Pediatric Safety Assessments.......................................................102
7.5.5.2
Extrapyramidal Symptoms........................................................................103
7.5.5.3
Suicidality .................................................................................................103
7.5.5.4
Tanner Staging ..........................................................................................103
8
Management of Investigational Medicinal Product......................103
8.1
Packaging and Labeling ..................................................................................103
8.2
Storage.............................................................................................................103
8.3
Accountability .................................................................................................104
8.4
Returns and Destruction..................................................................................104
8.5
Reporting of Product Quality Complaints.......................................................104
8.5.1
Eliciting and Reporting Product Quality Complaints...................................105
8.5.2
Information Required for Reporting Purposes .............................................105
8.5.3
Return Process ..............................................................................................105
8.5.4
Assessment/Evaluation.................................................................................105
9
Records Management ......................................................................106
9.1
Source Documents...........................................................................................106
9.2
Data Collection................................................................................................106
9.3
File Management at the Trial Site...................................................................107
9.4
Records Retention at the Trial Site..................................................................107
10
Quality Control and Quality Assurance.........................................108
10.1
Monitoring.......................................................................................................108
10.2
Auditing...........................................................................................................108

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11
Ethics and Responsibility.................................................................108
12
Confidentiality..................................................................................109
13
Amendment Policy ...........................................................................109
14
Publication Authorship Requirements...........................................110
15
References .........................................................................................111

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List of In-text Tables
Table 3.2.1-1
Dose Adjustments for Brexpiprazole in the Open-label 
Treatment Period (Both Rollover Subjects from 
Trial 331-10-234 and Nonconversion De Novo Subjects) ............40
Table 3.2.2.1-1
Recommendation for Switching from Other Antipsychotics 
to Oral Brexpiprazole Monotherapy..............................................41
Table 3.2.2.2-1
Dose Adjustments for Brexpiprazole in the Open-label 
Treatment Period for De Novo Subjects after Conversion............42
Table 3.4.2.1-1
Inclusion Criteria for Rollover Subjects from 
Trial 331-10-234............................................................................45
Table 3.4.2.2-1
Inclusion Criteria for De Novo Subjects........................................45
Table 3.4.3.1-1
Exclusion Criteria for Rollover Subjects from 
Trial 331-10-234............................................................................47
Table 3.4.3.2-1
Exclusion Criteria for De Novo Subjects.......................................49
Table 3.7-1
Schedule of Assessments - Rollover Subjects from 
Trial 331-10-234............................................................................54
Table 3.7-2
Schedule of Assessments - De Novo Subjects...............................56
Table 3.7.3.2-1
Clinical Laboratory Assessments...................................................75
Table 4.1-1
Washout of Prohibited Medications Required Before the 
Trial - De Novo Subjects ...............................................................89
Table 4.1-2
List of Medications Prohibited During the Trial............................90
Table 4.1-3
Oral Benzodiazepine Rescue Therapy During the Trial................91
Table 4.1-4
Selected CYP2D6 Inhibitors and CYP3A4 Inhibitors and 
Inducers Prohibited During the Trial.............................................91

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List of In-text Figures
Figure 3.1-1
Trial Design Schematic - Rollover Subjects from 
Trial 331-10-234............................................................................37
Figure 3.1-2
Trial Design Schematic - De Novo Subjects .................................38

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List of Appendices
Appendix 1
Criteria for Identifying Vital Signs of Potential 
Clinical Relevance .......................................................................113
Appendix 2
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance .......................................................................114
Appendix 3
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance .......................................................................115
Appendix 4
Handling and Shipment of Bioanalytical Samples ......................116
Appendix 5
Positive and Negative Syndrome Scale (PANSS) .......................117
Appendix 6
Children’s Global Assessment Scale (CGAS).............................121
Appendix 7
Clinical Global Impression - 
Severity of Illness Scale (CGI-S).................................................123
Appendix 8
Clinical Global Impression - Improvement Scale (CGI-I) ..........124
Appendix 9
Simpson Angus Scale (SAS) .......................................................125
Appendix 10
Abnormal Involuntary Movement Scale (AIMS)........................128
Appendix 11
Barnes Akathisia Rating Scale (BARS).......................................129
Appendix 12
Udvalg for Kliniske Undersogelser (UKU).................................131
Appendix 13
New York Assessment for Adverse Cognitive Effects of 
Neuropsychiatric Treatment (NY-AACENT)..............................139
Appendix 14
Tanner Staging.............................................................................142
Appendix 15
Columbia-Suicide Severity Rating Scale (C-SSRS)....................143
Appendix 16
Protocol Amendment(s)/Administrative Change(s) ....................153

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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
ACTH
Adrenocorticotropic hormone
ADHD
Attention-deficit/hyperactivity disorder
ADT
Antidepressant therapy
AE
Adverse event
AIMS
Abnormal Involuntary Movement Scale
ALT
Alanine aminotransferase
APO
Apomorphine
AST
Aspartate aminotransferase
AUC0-24h
Area under the plasma concentration-time curve from time 0 hours to 
time 24 hours
AUCτ
Area under the plasma concentration-time curve to the last 
observable concentration
BARS
Barnes Akathisia Rating Scale
BMI
Body mass index
BP
Blood pressure
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
Maximum concentration 
Cmax,ss
Maximum concentration at steady state
CNS
Central nervous system
CPK
Creatine phosphokinase
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
Cytochrome P450
D2
Dopamine D2
D3
Dopamine D3
DBP
Diastolic blood pressure
DMC
Data Monitoring Committee
DSM-5
Diagnostic and Statistical Manual of Mental Disorders - Fifth 
Edition
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
GAS
Adult Global Assessment Scale
GCP
Good Clinical Practice

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GGT
Gamma glutamyl transferase
GMR
Geometric mean ratio
HbA1c
Glycosylated hemoglobin
HDL
High-density lipoprotein
5-HT
Serotonin type receptor
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
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
MAOI
Monoamine oxidase inhibitors
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MDD
Major depressive disorder
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
PD
Pharmacodynamic
PET
Positron emission tomography
PK
Pharmacokinetic
PQC
Product quality complaint
PTSD
Post-traumatic stress disorder
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

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SAE
Serious adverse event
SAS
Simpson Angus Scale
SBP
Systolic blood pressure
T4
Thyroxine
Tx
Treatment
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
United States 
WBC
White blood cell

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1
Introduction
Schizophrenia is a severely debilitating mental illness that affects approximately 1% of 
the world population.1,2  Hallucinations and delusions are the most striking characteristic 
positive symptoms of schizophrenia; however, more subtle negative symptoms (eg, social 
withdrawal, lack of emotion, energy, and motivation) may also be present.  The first 
antipsychotics developed for the treatment of schizophrenia were dopamine D2 (D2) 
receptor antagonists.  These agents were effective against positive symptoms, but showed 
little efficacy for negative symptoms and were also associated with a high incidence of 
hyperprolactinemia and extrapyramidal symptom (EPS)-related side effects.3  Second 
generation antipsychotics, commonly referred to as “atypical antipsychotics,” act as 
antagonists at serotonin 5-HT2A receptors in addition to the dopamine receptor.  The 
atypical antipsychotics are efficacious and exhibit a reduced tendency to promote EPS 
relative to typical antipsychotics, but they are not devoid of undesirable side effects.  
High incidences of weight gain, related metabolic abnormalities, and hyperprolactinemia 
have been observed with some of these agents.4,5,6
Brexpiprazole (OPC-34712, OPC 331, and Lu AF41156) is a new chemical entity 
discovered by Otsuka that is being co-developed by Otsuka and H. Lundbeck A/S 
(Lundbeck).  While the precise mechanism of action of brexpiprazole in treating 
psychiatric conditions is unknown, the pharmacology of brexpiprazole is believed to be 
mediated by a combination of high binding affinity and functional activities at multiple 
monoaminergic receptors.  It has modulatory activity at the serotonin and dopamine 
systems that combines partial agonist activity at serotonergic 5-HT1A and at 
dopaminergic D2 receptors with antagonist activity at serotonergic 5-HT2A receptors, 
with similar high affinities at all of these receptors (inhibition constant [Ki]:  0.1-0.5 nM).  
Brexpiprazole also shows antagonist activity at noradrenergic α1B/2C with affinity in the 
same sub-nanomolar Ki range (Ki:  0.2-0.6 nM).  The 5-HT1A/D2 receptor partial agonist 
activity in combination with 5-HT2A and α1B/2C receptors antagonism of brexpiprazole 
may correlate with antipsychotic and antidepressant efficacy.
Overall, the broad spectrum of brexpiprazole receptor binding profile shows that it has 
high affinity (Ki < 5 nM) for multiple monoaminergic receptors including serotonin 
5-HT1A, 5-HT2A, 5-HT2B, 5-HT7, dopamine D2, D3, and noradrenergic α1A, α1B, α1D, and 
α2C receptors.  Brexpiprazole acts as a partial agonist at the 5-HT1A, D2, and D3 receptors 

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and as an antagonist at 5-HT2A, 5-HT2B, 5-HT7, α1A, α1B, α1D, and α2C receptors.  Dose 
response occupancy and brain/plasma exposure relationship were determined in vivo or 
ex vivo for D2/D3, 5-HT2A, 5-HT1A, 5-HT6, and 5-HT7 receptors as well as for the 5-HT 
transporter in preclinical studies.  These results are consistent with the relative in vitro 
binding affinities and indicate that brexpiprazole may have efficient activity at several 
targets in the central nervous system at therapeutic plasma exposures.
Brexpiprazole 2 to 4 mg, taken orally once daily, was approved for the treatment of 
schizophrenia and as adjunctive treatment for major depressive disorder (MDD) in adults 
(ages 18 to 65) by the United States (US) Food and Drug Administration (FDA) on 
10 Jul 2015.  This approval for treatment of schizophrenia in adults was based on data 
from 2 completed short-term, fixed-dose, placebo-controlled trials.  In addition, data from 
2 long-term, open-label trials were included in the New Drug Application (NDA).  To 
date, the schizophrenia program for brexpiprazole has primarily targeted adult subjects 
18 to 65 years of age.  In 2015, a dose-escalation pharmacokinetic (PK) trial in 
adolescents with schizophrenia and bipolar disorder (Trial 331-10-233) was initiated and 
results support dosing for the double-blind, placebo-controlled Trial 331-10-234, which 
was conducted to determine the safety and efficacy of brexpiprazole for the treatment of 
adolescents with schizophrenia.  The current trial is an open-label trial using a similar 
dose range of brexipiprazole as maintenance treatment for adolescents with 
schizophrenia.
The onset of schizophrenia symptoms typically peaks in late adolescence and early 
adulthood; however, prodromal symptoms may be present for several years before the 
initial psychotic episode.  In a minority of cases, the initial episode may occur during 
childhood or early adolescence.  Patients who experience this “early-onset schizophrenia” 
exhibit symptoms that tend to be more severe and follow a more chronic course.7  
Whereas adults with schizophrenia typically experience exacerbations of psychotic 
symptoms between periods of relative normalcy, adolescents with schizophrenia may 
never achieve full remission of the initial episode.  The prognosis for early-onset 
schizophrenia tends to be poor; cognitive impairment is greater compared with 
individuals whose onset of schizophrenia occurs later in life.8  In addition, refinement of 
social interaction skills that takes place during the teen years is interrupted, leading to a 
reduced ability for successful function in adulthood.9  Several antipsychotics have been 
investigated for the treatment of adolescent schizophrenia.8  Management of these 

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Brexpiprazole decreased blood pressure (BP) at doses of 3 mg/kg or higher and 
prolonged both QT interval and corrected QT interval (QTc, by Van de Water's formula) 
at 30 mg/kg.  Brexpiprazole inhibited human ether-a-go-go related gene current in 
Chinese hamster ovary cells at concentrations of 10−8 mol/L or higher, with a 50% 
inhibitory concentration of 1.17  10−7 mol/L.  The mechanism for the BP decreasing 
effect of brexpiprazole was suggested to result from a blockade of the α1-adrenoceptor in 
peripheral blood vessels, which is a part of the compound’s pharmacological profile.  
Proarrhythmic risk was also evaluated by examining the effects of brexpiprazole on 
monophasic action potential parameters in halothane-anesthetized dogs.  Brexpiprazole 
did not affect the terminal repolarization period even at an intravenous dose of 3 mg/kg, 
suggesting a low potential for proarrhythmic effects.  In general, the changes in the CNS, 
respiratory, and cardiovascular systems observed with brexpiprazole occurred at doses or 
exposure levels higher than those at which efficacy was confirmed in rats (3 mg/kg), and 
similar changes were shown to occur after administration of risperidone at similar or 
lower doses.
1.2
Clinical Data
Pharmacokinetic and pharmacodynamic (PD) data, as well as data from schizophrenia, 
MDD, and other indications are summarized below.  A complete description of the 
available data from clinical trials can be found in the IB.11 
1.2.1
Pharmacokinetics/Pharmacodynamics
The PK of single and multiple doses of brexpiprazole was studied in healthy subjects and 
in subjects with MDD, attention-deficit/hyperactivity disorder (ADHD), and 
schizophrenia or schizoaffective disorder.  Based on preclinical data and human clinical 
trials, brexpiprazole (OPC-34712) and one metabolite, DM-3411, were identified as the 
major analytes that are present in human plasma.  In vitro, the activity of DM-3411 is 
17 times lower than that of brexpiprazole and thus is considered as an inactive 
metabolite.  Both brexpiprazole and DM-3411 PK were linear following single oral doses 
of brexpiprazole 0.2 to 8 mg to healthy subjects.  The terminal phase elimination half-life 
of brexpiprazole and DM-3411 was 48.3 to 80.8 hours and 48.6 to 77.5 hours, 
respectively.  The median time to maximum (peak) plasma concentration (tmax) occurred 
at approximately 2 to 6 hours postdose for brexpiprazole and at approximately 10 to 
24 hours postdose for DM-3411.  In healthy subjects, administration of single-dose 
brexpiprazole with a high-fat meal did not affect its rate and extent of absorption.

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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 
postdose 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, 

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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:  0.904 and 0.765, 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 AUCs from time 0 to 24 hours (AUC0-24h) (GMR adult/adolescent:  
0.105), and slightly higher dose-normalized maximized concentrations (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.

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1.3
Known and Potential Risks and Benefits
Sites will routinely receive updated versions of the IB on an ongoing basis, and sites 
should refer to that version of the IB as needed. Please refer to the current IB for a 
detailed summary of available nonclinical and clinical safety data.
As of 17 Apr 2016,11 a total of 65 clinical trials were presented in the IB:  53 clinical 
trials have been completed, and 12 are ongoing.  Completed trials include 20 completed 
phase 1 clinical trials in healthy subjects or special populations (ie, hepatic and renal 
impaired subjects) (17 in the US, 2 in Japan, and 1 in Korea); 6 completed phase 1 trials 
in subjects with schizophrenia or schizoaffective disorder, MDD, or ADHD (5 in the US, 
1 in Japan); 1 completed phase 1b trial in adult subjects with stable schizophrenia; 
2 completed phase 2 (1 double-blind and 1 open-label), 2 completed phase 3 (both 
double-blind), and 1 completed phase 3b (open-label) trials in adult subjects with 
schizophrenia; 3 completed phase 2 (2 double-blind and 1 open-label), 4 completed 
phase 3 (3 double-blind and 1 open-label), and 5 completed 3b (all open-label) trials in 
subjects with MDD; and 1 completed phase 2 double-blind trial in subjects with ADHD.  
Ongoing trials include 2 phase 1 trials (1 fixed-dose PET trial in subjects with 
schizophrenia [US] and 1 trial in adolescents with a diagnosis of schizophrenia); 
1 phase 2/3 trial in adult subjects with acute schizophrenia (Japan); 5 phase 3 and 
2 phase 3b trials in subjects with schizophrenia (6 multinational, including the US, and 
1 in Japan); 5 phase 3 and 1 phase 3b trials in subjects with MDD (multinational, 
including the US); 3 phase 3 trials in subjects with agitation associated with dementia of 
the Alzheimer’s type (multinational, including the US); and 1 phase 3 trial in subjects 
with post-traumatic stress disorder (PTSD) (multinational, including the US). 
Combined data from the completed phase 1 clinical trials indicate that the maximum 
tolerated dose (MTD) for healthy subjects was determined to be 6 mg after single-dose 
administration and 2 mg after once-daily, multiple-dose (14 days) administration.  The 
MTD of brexpiprazole in subjects with schizophrenia, MDD, or ADHD has not been 
established.  Data from completed phase 1 clinical trials indicate that brexpiprazole is 
tolerated at multiple oral doses up to 12 mg/day in subjects with schizophrenia or 
schizoaffective disorder; up to 4 mg/day when coadministered with marketed ADT in 
subjects with MDD; up to 3 mg/day in elderly subjects (70 to 85 years of age) with 
MDD; and up to 4 mg/day when coadministered with marketed stimulant therapy in 
subjects with ADHD.  Safety data are available from the 45 completed clinical trials.  
The total number of subjects exposed to either single or multiple doses of brexpiprazole 
is composed of 4488 subjects in trials conducted under US Investigational New Drug 

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(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.

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2
Trial Rationale and Objectives
2.1
Trial Rationale
The onset of schizophrenia symptoms typically peaks in late adolescence and early 
adulthood; however, prodromal symptoms may be present for several years before the 
initial psychotic episode.  In a minority of cases, the initial episode may occur during 
childhood or early adolescence.  Patients who experience this “early-onset schizophrenia” 
exhibit symptoms that are more severe and follow a more chronic course.7  Whereas 
adults with schizophrenia typically experience exacerbations of psychotic symptoms 
between periods of relative normalcy, adolescents with schizophrenia may never achieve 
full remission of the initial episode.  The prognosis for early-onset schizophrenia tends to 
be poor; cognitive impairment is greater compared with individuals whose onset of 
schizophrenia occurs later in life.8  In addition, refinement of social interaction skills that 
takes place during the teen years is interrupted, leading to a reduced ability for successful 
function in adulthood.9  Several antipsychotics have been investigated for the treatment 
of adolescent schizophrenia.8  Management of these subjects presents a particular 
challenge because developing bodies are more sensitive to side effects of antipsychotics, 
particularly with respect to weight gain.10
The current phase 3 trial is part of the brexpiprazole clinical development program that 
has been designed to evaluate the long-term safety and tolerability of brexpiprazole in 
adolescents with schizophrenia.  A 2 year, open-label treatment period is considered to be 
of adequate length to determine long-term safety and tolerability of brexpiprazole.
2.2
Dosing Rationale
Brexpiprazole has been well tolerated at multiple oral doses up to 12 mg/day in adult 
subjects with schizophrenia or schizoaffective disorders.  A dose range of 0.25 to 
6 mg/day was investigated in a phase 2 trial in adults with schizophrenia.  
The safety, tolerability, and PK of brexpiprazole have been studied in healthy adult 
subjects and patients (18 years and older), including those with schizophrenia or 
schizoaffective disorder.  A PK, safety, and tolerability trial in adolescent (13–17 years 
old) subjects with a diagnosis of schizophrenia or other related psychiatric disorders 
(ie, bipolar disorder) was completed (Trial 331-10-233).  Subjects who were deemed 
eligible for 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 

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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 doses of 0.5 mg/day, 1 mg/day, 2 mg/day, 3 mg/day, and 
4 mg/day were 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 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 were deemed necessary in children and 
adolescent and thus a similar efficacious dose range of 1 to 4 mg is proposed for this trial.  
In adult patients brexpiprazole was 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 has been 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 characterize the long-term safety and tolerability of 
brexpiprazole in adolescents with schizophrenia.
3
Trial Design
3.1
Type/Design of Trial
This is a long-term, multicenter, open-label trial designed to examine the long-term safety 
and tolerability of brexpiprazole in adolescent subjects, ages 13 to 17 years at time of 
informed consent/assent and at the baseline (Day 1) visit of the open-label treatment 
period, with a Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition 
(DSM-5) diagnosis of schizophrenia.  Subjects from Trial 331-10-234 who turned 
18 years old during that trial are also permitted to enroll in this trial.  For de novo 
subjects who did not participate in Trial 331-10-234, the initial diagnosis of 
schizophrenia for this trial (as defined by DSM-5 criteria) should be made and 
documented by an adequately trained clinician (psychiatrist, or local medical equivalent 
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then be confirmed 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.  Rollover subjects will be considered as those who 
are able to rollover within ≤ 7 days of the Week 6 visit of Trial 331-10-234.  Subjects 
who are only able to rollover from Trial 331-10-234 after > 7 days from the Week 6 visit 
may be allowed to enter Trial 331-10-236 as de novo subjects following approval by the 
medical monitor.
The trial will be conducted on an outpatient basis.  Hospitalization for psychosocial 
reasons (eg, homelessness or need for shelter that is unrelated to the subject’s underlying 
psychiatric condition) will be considered outpatient status for the purpose of enrollment 
in Trial 331-10-236.
Subjects remaining in hospital at the Week 6 visit of Trial 331-10-234 (for other than 
psychosocial reasons) will be permitted to enroll in Trial 331-10-236 at the Week 6 visit 
of the double-blind trial if they are planned to be discharged from the hospital before the 
open-label treatment period Week 1 visit of Trial 331-10-236 and following approval by 
the medical monitor.  De novo subjects hospitalized at the time of the Trial 331-10-236 
screening visit will be permitted to be screened for the trial if they are planned to be 
discharged from the hospital prior to the baseline (Day 1) visit of the open-label treatment 
period and following approval by the medical monitor.
For rollover subjects, Trial 331-10-236 will consist of a 24-month open-label treatment 
period and a 21 (± 2) day follow-up period.  For de novo subjects, Trial 331-10-236 will 
consist of a 3- to 28-day screening phase, a 1 to 4 weeks conversion phase (if necessary), 
a 24-month open-label treatment phase, and a 21 (± 2) day follow-up period.  Visit 
windows of ± 3 days will be permitted during the trial; however, every effort will be 
made to ensure the individual open-label treatment period does not exceed 24 months.
The decision to enroll into this open-label trial from Trial 331-10-234 will be a joint 
decision between the investigator and subject/parent/guardian or legally acceptable 
representative, as applicable for local laws and will be made without knowledge of the 
subject’s double-blind treatment assignment.  The availability of the open-label trial 
should be discussed with these subjects and an informed consent/assent specific to 
Trial 331-10-236 must be completed for the Trial 331-10-234 rollover subjects before 
any trial-related procedures can take place.  For rollover subjects, the informed consent 
form (ICF) for the open-label trial may be provided to potential candidates or their 
parent/legal guardian or legally acceptable representative, as applicable for local laws, for 
review and discussion toward completion of the double-blind trial, but the form must not 

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be signed until the day of the screening/baseline visit for Trial 331-10-236 (ie, the 
Week 6 visit of Trial 331-10-234).  For de novo subjects, screening begins on the day that 
the subject or their parent/legal guardian or legally acceptable representative, as 
applicable for local laws, signs the ICF.  If any subject should turn 18 years of age (or the 
age of adulthood as specified by local laws or regulations) following entry into 
Trial 331-10-236, the appropriate informed consent must be obtained from the subject.
A schematic of the trial design is provided in Figure 3.1-1 (rollover subjects) and 
Figure 3.1-2 (de novo subjects).
The trial will be organized as follows:
Rollover Subjects from Trial 331-10-234
Screening/Baseline:  Subjects will be assessed for eligibility at the last visit of the 
double-blind trial (ie, Week 6 visit of Trial 331-10-234).  Subjects or their parent/legal 
guardian will complete a separate ICF and subjects will provide assent as required for 
participation in Trial 331-10-236 before any procedures specific to the open-label trial are 
performed.  The assessments from the last visit of the double-blind trial will serve as the 
baseline measures for Trial 331-10-236 for any assessment that is not unique to the 
open-label trial.  Medical history will be updated, if necessary.
Open-label Treatment:  Eligible subjects from Trial 331-10-234 will receive daily 
treatment with open-label brexpiprazole in the open-label treatment period of 
Trial 331-10-236 as described in Section 3.2.1.
Follow-up:  Subjects will be followed up for safety via telephone contact or clinic visit 
21 (± 2) days after the last dose of IMP.
De Novo Subjects
Screening:  Subjects will enter a pretreatment screening phase that will range from a 
minimum of 3 days to a maximum of 28 days to assess eligibility criteria and to wash out 
from prohibited concomitant medications, if applicable.  Screening begins on the day that 
the parent/legal guardian signs the ICF and provides assent (subject) as required, based 
on the local requirements.  Subjects will be assigned a unique screening number for each 
subject with a signed ICF/completed assent prior to enrollment.  If a de novo subject 
previously participated in Trial 331-10-234, they will retain their subject identification 
number from Trial 331-10-234.  Subjects who are able to complete the required washout 
of prohibited medications per Table 4.1-1 will proceed directly to the baseline (Day 1) 
visit of the open-label treatment period after completion and review of screening 

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assessments provided that all eligibility criteria are met (ie, laboratory test results, 
electrocardiograms [ECGs]).  If the washout of prohibited medications per Table 4.1-1 is 
not appropriate for subjects, in the opinion of the investigator, the subjects will 
participate in the conversion period.
Conversion:  If the washout of prohibited medications prior to the baseline (Day 1) visit 
of the open-label treatment period is not appropriate for subjects, in the opinion of the 
investigator, the subjects will undergo cross-titration to oral brexpiprazole for 1 to 
4 weeks, as described in Section 3.2.2.  Visits will occur at the end of each week during 
the conversion period.  The goal of de novo subjects during the conversion period is to 
achieve a brexpiprazole monotherapy target starting dose of 1, 2, or 3 mg daily at any 
time after Week 1 per the investigator’s discretion and to achieve the required washout of 
prohibited medications as per Table 4.1-1.  The subject will proceed to the baseline 
(Day 1) visit of the open-label treatment period once the target starting dose has been 
achieved and the required washout of prohibited medications has been completed.
Baseline and Open-label Treatment:  After completing baseline assessments, eligible 
subjects will receive daily treatment with open-label brexpiprazole in the open-label 
treatment period, as described in Section 3.2.2.
Follow-up:  Subjects will be followed up for safety via telephone contact or clinic visit 
21 (± 2) days after the last dose of IMP.

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3.2
Trial Treatments
All doses of open-label IMP are to be taken orally once daily and can be administered 
without regard to meals.  Every effort should be made to administer the open-label IMP 
at the same time every day.  If the titration schedule needs to be adjusted due to clinical 
or subject-specific need, the site should discuss with the medical monitor. 
3.2.1
Rollover Subjects from Trial 331-10-234 
The first dose of open-label brexpiprazole will be taken 1 day after the last dose of 
double-blind IMP is taken in Trial 331-10-234 so that treatment continues without 
interruption.  Whenever possible, it is anticipated that the last dose of the double-blind, 
phase 3 efficacy trial will be taken the day of the Week 6 visit of Trial 331-10-234 
(ie, the day of the screening/baseline visit for the open-label trial).  Subjects should not be 
dosed with using double-blind (331-10-234) and open-label (331-10-236) study 
medication on the same day.
Rollover subjects from Trial 331-10-234 will begin dosing with brexpiprazole 0.5 mg/day 
on Day 1, increasing to 1 mg/day on Day 5, and an optional increase to 2 mg/day if 
tolerated on Day 8 of the open-label treatment period.  If the 2 mg dose is well tolerated, 
but the response is inadequate, weekly dose increases can be made in 1 mg increments to 
a maximum of 4 mg/day.  Dose changes are allowed based on the clinical judgment of 
the investigator at scheduled or unscheduled visits according to his/her clinical judgment 
based on the subject’s response to treatment.  Daily dosing for this trial includes 1 mg, 
2 mg, 3 mg, or 4 mg.
The dose of brexpiprazole may be decreased at any time based on the investigator’s 
judgment after the start of the open-label treatment period.  Dose decreases will occur in 
1 mg decrements, with the frequency of the 1-mg decreases based upon tolerability.  
Those unable to tolerate the 1 mg daily dose of brexpiprazole must be withdrawn from 
the trial.  The dosing strategy is summarized in Table 3.2.1-1.  Rechallenge with higher 
doses of brexpiprazole (ie, in 1 mg/day increments) is permitted following dose 
decreases, if clinically warranted based on the investigator’s judgment.
If clinically indicated, subjects may return to the clinic for unscheduled visits if dose 
adjustments for brexpiprazole are required between scheduled visits.  Dose adjustments 
must ultimately be made based upon the clinical judgment of the investigator as it relates 
to tolerability and therapeutic response.  

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Table 3.2.1-1
Dose Adjustments for Brexpiprazole in the Open-label 
Treatment Period (Both Rollover Subjects from 
Trial 331-10-234 and Nonconversion De Novo Subjects)
Trial Visit
Dose Options
Dose Changes
Start of the open-label 
treatment period, Days 1–4
0.5 mg/day (starting dose)
Not applicable
Days 5–7
1 mg/day
Not applicable
Days 8–14
1 or 2 mg/day
Maintain same dose or option to 
increase to 2 mg/day if tolerated
Days 15–21
1, 2, or 3 mg/day 
Maintain same dose, or option to 
increase or decrease by 1 mg /day 
(minimum dose 1 mg/day)
Day 22 (Week 3) to Month 24
1, 2, 3, or 4 mg/day 
Maintain same dose, or option to 
increase or decrease dose by 1 mg/day 
(minimum dose 1 mg/day and 
maximum dose 4 mg/day)
3.2.2
De Novo Subjects
 If the washout of prohibited medications per Table 4.1-1 is not appropriate for de novo 
subjects, in the opinion of the investigator, the subjects must enter a conversion period to 
cross-titrate from their current antipsychotic treatment(s) to brexpiprazole monotherapy 
and to washout from prohibited medications.  All other de novo subjects will enter the 
trial at the baseline (Day 1) visit of the open-label treatment period (see Section 3.2.2.2) 
after completion and review of screening assessments, provided that all eligibility criteria 
are met (ie, laboratory test results, ECGs), and will follow the dosing strategy for rollover 
subjects (Table 3.2.1-1).
3.2.2.1
Conversion 
The purpose of the 1- to 4- week conversion period is to cross-titrate de novo subjects 
from current antipsychotic treatment(s) to monotherapy with brexpiprazole 1, 2, or 
3 mg/day and achieve the required washout of prohibited medications per Table 4.1-1 to 
minimize the possibility of rebound (eg, cholinergic or histaminergic) from abrupt 
changes in antipsychotic medication.  The recommended procedure for initiation of oral 
brexpiprazole is an ascending cross-titration scheme.  The recommended procedure as it 
pertains to this protocol is summarized in Table 3.2.2.1-1.12

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Table 3.2.2.1-1
Recommendation for Switching from Other Antipsychotics 
to Oral Brexpiprazole Monotherapy
Conversion Perioda
Trial Visit
Conversion
Baseline
Week 1
Week 2
Week 3
Baseline of 
Open-label 
Txb
Dose of 
brexpiprazole
0.5 mg/day
0.5 or 1 mg/day
1 or 2 mg/day
1, 2, or 
3 mg/day
1, 2, or 
3 mg/day
Dose of other 
antipsychotic(s)
No change
No change
Decrease
Discontinue
Discontinue
Dose of 
aripiprazole
Decrease
Decrease
Discontinue
Discontinue
Discontinue
Tx = treatment.
Note: Washout of required prohibited medications is per Table 4.1-1.
aConversion period will last for 1 to 4 weeks.
bThe baseline (Day 1) visit of the open-label treatment period will coincide with the end of the 
conversion period which is up to 4 weeks in duration
The scheme in Table 3.2.2.1-1 represents the optimal approach for conversion of subjects 
from other antipsychotic(s) to brexpiprazole and is highly recommended for use in this 
trial; however, the investigator may adjust the dose(s) of other antipsychotic(s) during 1- 
to 4-week cross-titration as deemed appropriate for individual subjects.  The dose of 
brexpiprazole can increase up to 3 mg/day during cross-titration, but cannot decrease to 
less than 1 mg/day.  Subjects must achieve a minimum monotherapy dose of 
brexpiprazole 1 mg/day at the end of the conversion period/baseline (Day 1) of the 
open-label treatment period in order to progress to the open-label treatment period.
3.2.2.2
Open-label Treatment Period
Timing of the first dose of brexpiprazole in the open-label treatment period for de novo 
subjects will be as follows:

De novo subjects who participate in the 1- to 4- week conversion period, will 
receive open-label brexpiprazole in the open-label treatment period once all 
prohibited medications are discontinued during the conversion period per 
Table 4.1-1 and once all baseline evaluations are completed.

De novo subjects who are able to complete the required washout of prohibited 
medications per Table 4.1-1 will receive the first dose of open-label brexpiprazole 
in the open-label treatment period as soon as all screening and baseline 
evaluations are completed.
De novo subjects who participated in the conversion period will begin dosing with 
brexpiprazole 1, 2, or 3 mg/day in the open-label treatment period.  If this dose is well 
tolerated, but the response is inadequate, weekly dose increases can be made in 1 mg 

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increments up to a maximum dose of 4 mg/day, based on the clinical judgment of the 
investigator.  
Daily dosing for this trial includes 1, 2, 3, or 4 mg.
The maximum dose of brexpiprazole to be used in this trial is 4 mg daily. The dose of 
brexpiprazole may be decreased at any time based on the investigator’s judgment after 
the start of the open-label treatment period.  Dose decreases will occur in 1 mg 
decrements, with the frequency of the 1 mg decreases based upon tolerability.  Those 
unable to tolerate the minimum 1 mg daily dose of brexpiprazole must be withdrawn 
from the trial.  The dosing strategy is summarized in Table 3.2.2.2-1.  Rechallenge with 
higher doses of brexpiprazole (in 1 mg/day increments) is permitted following dose 
decreases, if clinically warranted based on the investigator’s judgment.  
Dose adjustments must ultimately be made based upon the clinical judgment of the 
investigator as it relates to tolerability and therapeutic response.  
Table 3.2.2.2-1
Dose Adjustments for Brexpiprazole in the Open-label 
Treatment Period for De Novo Subjects after Conversion
Trial Visit
Dose Options
Dose Changes
Start of the open-label 
treatment period, Days 1–7
1, 2, or 3 mg/day
Maintain same dose, or option to increase or 
decrease dose by 1 mg/day
(minimum dose 1 mg/day)
Days 8–14 and Day 15 to 
Month 24
1, 2, 3, or 4 mg/day
Maintain same dose, or option to increase or 
decrease dose by 1 mg/day
(minimum dose 1 mg/day and maximum dose 
4 mg/day)
3.3
Trial Population
3.3.1
Number of Subjects and Description of Population
The trial population will include subjects from Trial 331-10-234 and as needed de novo 
subjects between 13 and 17 years of age, inclusive, at the time of informed consent/assent 
and at baseline (Day 1) visit of the open-label treatment period.  For de novo subjects 
who did not participate in Trial 331-10-234, the initial diagnosis of schizophrenia for this 
trial (as defined by DSM-5 criteria) must be made and documented and the diagnosis 
confirmed by the K-SADS-PL13.  Subjects from Trial 331-10-234 who turned 18 years 
old during that trial are also permitted to enroll in this trial.  Approximately 350 subjects 
are anticipated to be enrolled with the expectation that at least 100 will complete 1 year 
of exposure to open-label brexpiprazole.

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3.3.2
Subject Selection and Numbering
At screening, de novo subjects will be assigned a unique subject identification number 
upon signing the ICF and providing assent based on sequential enrollment in the trial, as 
required.  Subjects from Trial 331-10-234 will retain their subject identification numbers 
from Trial 331-10-234 and are required to sign a new ICF and assent form for this trial, 
as required.  The clinical site will maintain a list identifying all subjects by their subject 
identification number and initials.
3.4
Eligibility Criteria
3.4.1
Informed Consent
Informed consent will be freely obtained from all subjects (or their guardian or legally 
acceptable representative, as applicable for local laws) and documented.  The ICF will be 
approved by the same institutional review board/independent ethics committee (IRB/IEC) 
that approves this protocol.  Subjects who are too young to sign an ICF either via wet 
signature or electronic signature (e-signature) will provide informed assent per local law, 
and the subject must be able to understand that he or she can withdraw from the trial at 
any time and for any reason.
Each ICF will comply with the International Conference on Harmonisation (ICH) Good 
Clinical Practice (GCP) Guideline14 and local regulatory requirements.  The investigator 
will ensure that the sponsor reviews and authorizes any site-specific ICF used in the trial 
before submission to the IRB/IEC.
Investigators may discuss trial availability and the possibility for entry with a potential 
subject without first obtaining consent.  However, informed consent must be obtained and 
documented before initiation of any procedures that are performed solely for the purpose 
of determining eligibility for this trial, including withdrawal from current medication(s).
Potential subjects are free to refuse entry into the trial, or withdraw from the trial at any 
time, without justification, and there will be no consequences to their further care.
At sites where the electronic ICF application is used, prospective trial participants will be 
provided with controlled access to the application by trial site staff.  When the trial site 
staff and the participant agree that the participant has enough information to make an 
informed decision to participate, the participant will electronically sign the ICF or assent 
form in the electronic ICF application and an electronic date and timestamp will be 
applied to the signature.  The subject will be given a printed, signed copy of the ICF and 
assent form.  Any other parties required by the IRB/IEC (trial site staff, witnesses, or 

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legally acceptable representative) are also required to sign electronically and these 
signatures will be stored with the electronic ICF in accordance with the ICH GCP 
Guideline and local regulatory requirements/guidelines.  These signatures cannot be 
altered, removed, or copied.  At sites where the electronic ICF application is not used, 
paper consent and assent forms will be signed after trial site staff and the participant 
agree that the participant has enough information to make an informed decision to 
participate.  Any other parties required to provide signatures will also sign the paper 
forms, and the forms will be stored in accordance with the ICH GCP Guideline and local 
regulatory requirements/guidelines.
Subjects or their parent/legal guardian or legally acceptable representative, as applicable 
for local laws, may be asked to sign additional ICFs if the protocol is amended, and the 
changes to the protocol results in additional information that needs to be provided to the 
subjects, so that they can make a knowledgeable and voluntary decision on trial 
participation.
If any subject should turn 18 years of age (or the age of adulthood as specified by local 
laws or regulations) following entry into Trial 331-10-236, the appropriate informed 
consent must be obtained from the subject.  The subject shall be given a copy of the 
signed ICF and the original shall be kept on file by the investigator.
3.4.2
Inclusion Criteria
3.4.2.1
Rollover Subjects
Subjects are required to meet the inclusion criteria presented in Table 3.4.2.1-1.

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Table 3.4.2.1-1
Inclusion Criteria for Rollover Subjects from 
Trial 331-10-234
1.
Written informed consent/assent obtained from a legally acceptable representative (eg, guardian) 
or subject prior to the initiation of any protocol-required procedures.  In addition, the subject must 
provide informed assent at screening and must be able to understand that he or she can withdraw 
from the trial at any time.  All informed consent/assent procedures must be in accordance with the 
trial site’s IRB/IEC and local regulatory requirements.
2.
Ability, in the opinion of the principal investigator, of the subject and the subject’s legally 
acceptable representative (eg, guardian) or caregiver(s) to understand the nature of the trial and 
follow protocol requirements, including the prescribed dosage regimens, tablet ingestion, and 
discontinuation of prohibited concomitant medications, to read and understand the written word in 
order to complete subject-reported outcomes measures, and to be reliably rated on assessment 
scales.
3.
Male and female subjects 13 to 18 years of age, inclusive, at the time of informed consent/assent 
and at baseline.  Subjects who turned 18 years old during Trial 331-10-234 are permitted in this 
trial.
4.
Subjects who complete Trial 331-10-234 and who, in the opinion of the investigator, could 
potentially benefit from monotherapy treatment with oral brexpiprazole for schizophrenia.  The 
baseline visit for Trial 331-10-236 coincides with the Week 6 visit of Trial 331-10-234.  If the visit 
cannot be done within ≤ 7 days of the Week 6 visit of Trial 331-10-234 then the subject may be 
able to enter Trial 331-10-236 as a de novo subject following approval by the medical monitor.
5.
Outpatient status at the last visit of Trial 331-10-234.  Hospitalization for psychosocial reasons 
(eg, homelessness or need for shelter that is unrelated to the subject’s underlying psychiatric 
condition) will be considered outpatient status for the purpose of enrollment in Trial 331-10-236.  
Subjects remaining in hospital at the Week 6 visit of Trial 331-10-234 (for other than psychosocial 
reasons) will be permitted to enroll in Trial 331-10-236 at the Week 6 visit of the double-blind trial 
if they are planned to be discharged from the hospital before the open-label treatment period 
Week 1 visit of Trial 331-10-236 and following approval by the medical monitor.
3.4.2.2
De Novo Subjects
Subjects are required to meet the inclusion criteria presented in Table 3.4.2.2-1.
Table 3.4.2.2-1
Inclusion Criteria for De Novo Subjects
1.
Written informed consent obtained from a legally acceptable representative (eg, guardian) prior 
to the initiation of any protocol-required procedures.  In addition, the subject must provide 
informed assent at screening and must be able to understand that he or she can withdraw from 
the trial at any time.  All informed consent/assent procedures must be in accordance with the 
trial site’s IRB/IEC and local regulatory requirements.
2.
Ability, in the opinion of the principal investigator, of the subject and the subject’s legally 
acceptable representative (eg, guardian) or caregiver(s) to understand the nature of the trial and 
follow protocol requirements, including the prescribed dosage regimens, tablet ingestion, and 
discontinuation of prohibited concomitant medications, to read and understand the written word 
in order to complete subject-reported outcomes measures, and to be reliably rated on assessment 
scales.
3.
Male and female subjects 13 to 17 years of age, inclusive, at the time of informed consent/assent 
and at the baseline (Day 1) visit of the open-label treatment period. Subjects who turned 
18 years of age since participation in Trial 331-10-234, if applicable, are permitted to enroll in 
this trial.

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Table 3.4.2.2-1
Inclusion Criteria for De Novo Subjects
4.
Subjects with a current primary diagnosis of schizophrenia, as defined by DSM-5 criteria and a 
history of the illness (diagnosis or symptoms) for at least 6 months prior to screening (as per 
subject, family, or healthcare provider, or by previous medical records).  For subjects who did 
not participate in Trial 331-10-234, the initial diagnosis of schizophrenia for this trial (as 
defined by DSM-5 criteria) must be made and documented by an adequately trained clinician 
(psychiatrist, or local medical equivalent who is experienced in treating adolescents with 
schizophrenia), and the diagnosis should then be confirmed utilizing the K-SADS-PL performed 
by an adequately trained rater at the time of entry into Trial 331-10-236.  (Subjects with a 
diagnosis of ADHD and treated with stimulants or other ADHD medications within 28 days are 
prohibited.)
5.
Subjects who, in the investigator’s judgment, require treatment with antipsychotic 
medication(s).
6.
Removed with Amendment 2.
7.
Outpatient status. Hospitalization for psychosocial reasons (eg, homelessness or need for shelter 
that is unrelated to the subject’s underlying psychiatric condition) will be considered outpatient 
status for the purpose of enrollment in Trial 331-10-236.  Subjects hospitalized at the time of the 
Trial 331-10-236 screening visit will be permitted to be screened for the trial if they are planned 
to be discharged from the hospital prior to the baseline (Day 1) visit of the open-label treatment 
period and following approval by the medical monitor.
8.
Subjects willing to discontinue all prohibited psychotropic medications to meet 
protocol-required washouts prior to and during the trial period.
Inclusion Criteria Assessed Prior to Entry into the Conversion Period
9.
Removed with Amendment 4.
10.
Subject is receiving antipsychotic(s) other than clozapine. These subjects must be cross-titrated 
to brexpiprazole monotherapy over 1 to 4 weeks during the conversion period to a minimum 
dose of 1 mg/day as a starting dose in the open-label treatment period (see Section 3.2.2.1).
Inclusion Criteria Assessed Prior to Entry into the Open-label Treatment Period
11.
Adequate washout of prohibited concomitant medications (see Table 4.1-1).
12.
Subject is ready to receive oral brexpiprazole as monotherapy for treatment of schizophrenia.
3.4.3
Exclusion Criteria
3.4.3.1
Rollover Subjects
Subjects will be excluded if they meet any of the exclusion criteria in Table 3.4.3.1-1.  
Some laboratory results may not be available from the last visit at the time of entry into 
the open-label treatment period in this trial.  Investigators will need to contact the 
medical monitor if there are any clinically significant laboratory results to discuss a 
subject’s ability to continue in the trial.

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Table 3.4.3.1-1
Exclusion Criteria for Rollover Subjects from 
Trial 331-10-234
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.
Administrative
3.
Noncompliance, due to subject’s failure to follow study procedures during the course of their 
participation in the double-blind phase 3 trial, Trial 331-10-234 (eg, subjects deemed to be 
noncompliant. with the visit schedule, trial assessments, or treatment regimen in Trial 331-10-
234).  The medical monitor should be contacted if the investigator is unsure of a subject’s 
eligibility.
Target Disease
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 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 “Since Last Visit” version of the C-SSRS.  
Medical History and Concurrent Diseases
6.
Subjects with current hypothyroidism or hyperthyroidism (unless the condition has been 
stabilized with medications for at least the past 90 days).  Eligibility of subjects that have an 
abnormal free T4 result that is considered not clinically significant can be discussed with the 
medical monitor if, in the investigator’s judgment, the subject is a suitable candidate for the 
trial.
7.
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 glucose (non-fasting) < 200 mg/dL.  (If the non-fasting glucose is ≥ 200 mg/dL, 
subjects must be retested in the fasting state.  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.
8.
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.

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Table 3.4.3.1-1
Exclusion Criteria for Rollover Subjects from 
Trial 331-10-234
Physical and Laboratory Results
9.
Subjects with a positive drug screen for cocaine, alcohol, or other drugs of abuse (excluding 
known prescription stimulants and other prescribed medications and cannabis).  Positive results 
for cannabis, barbiturates, or opiates in the drug screen are not exclusionary if in the 
investigator’s documented opinion the subject does not meet DSM-5 criteria for substance use 
disorders and in the investigator’s documented opinion the positive test does not signal a clinical 
condition that would impact the safety of the subject or interpretation of the trial results, and 
participation is agreed to by the medical monitor prior to treatment.
10.
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 result, unless discussed with and approved by the medical monitor.  
(Note:  Free T4 is measured only if result for TSH is abnormal.)
11) QTcF or QTcN  450 msec for males and  470 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 in Appendix 1, Appendix 2, and Appendix 3 to assist investigators in their 
assessments of results that may be potentially medically significant, depending on the subject’s 
medical history and clinical presentation.  Abnormal results for laboratory parameters, ECG, or 
vital signs should be repeated 1 time to ensure reproducibility of the abnormality before 
excluding a subject based on the criteria noted above.  Eligibility should be based on the last 
available measurement during Trial 331-10-234.  The medical monitor should be contacted if 
the investigator is unsure of a subject’s eligibility.
Prohibited Therapies or Medications
11.
Subjects who would be likely to require prohibited concomitant therapy during the trial 
including CYP2D6 or CYP3A4 inhibitors or CYP3A4 inducers or who are anticipated to require 
use of such agents during the trial.
Other
12.
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.
13.
Inability to tolerate oral medication or swallow tablets.
14.
Any subject who, in the opinion of the investigator, should not participate in the trial.
Added with Amendment 2
15.
Subject is known to have medication compliance issues that lead to IM depot medication use.
16.
Subjects who report a true allergic response to aripiprazole or brexpiprazole.
17.
Subjects who are known poor metabolizers of CYP2D6 or CYP3A4.

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ALT = alanine aminotransferase; AST = aspartate aminotransferase; C-SSRS = Columbia-Suicide 
Severity Rating Scale; CPK = creatine phosphokinase; DBP = diastolic blood pressure; 
HbA1c = glycosylated hemoglobin; IDDM = insulin-dependent diabetes mellitus; 
IM = intramuscular; QTcN = QT interval as corrected for heart rate by the FDA Neuropharm 
Division formula; QTcF = QT interval as corrected for heart rate by Fridericia’s formula; 
SBP = systolic blood pressure; T4 = thyroxine; TSH = thyroid-stimulating hormone; WBC = white 
blood cell.
Rollover subjects who do not qualify for the open-label trial at the screening/baseline 
visit may not be rescreened at a later date. If results of clinical laboratory tests from the 
last visit of the prior double-blind trial (ie, the Week 6 visit of Trial 331-10-234) are not 
available to assess eligibility, the assessment for the affected criteria should be based on 
the last available measurement during the double-blind trial.  Results from the last visit of 
the double-blind trial should be reviewed when they become available and action should 
be taken as described in Section 3.7.3.2 if there are any clinically significant and/or 
exclusionary values.
3.4.3.2
De Novo Subjects
Subjects will be excluded if they meet any of the exclusion criteria in Table 3.4.3.2-1.
Table 3.4.3.2-1
Exclusion Criteria for De Novo Subjects
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 current exacerbation of schizophrenia at the 
time of the baseline (Day 1) visit of the open-label treatment period.
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.
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.
9.
Subjects experiencing acute depressive symptoms within the past 30 days prior to screening 
that, according to the investigator’s judgment, require treatment with an antidepressant.

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Table 3.4.3.2-1
Exclusion Criteria for De Novo Subjects
10.
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.
Medical History and Concurrent Diseases
11.
Subjects with hypothyroidism or hyperthyroidism (unless the condition has been stabilized with 
medications for at least the past 90 days).  Eligibility of subjects that have an abnormal free T4 
result that is considered not clinically significant can be discussed with the medical monitor if, 
in the investigator’s judgment, the subject is a suitable candidate for the trial.
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 glucose (non-fasting) < 200 mg/dL.  (If the non-fasting glucose is ≥ 200 mg/dL, 
subjects must be retested in the fasting state.  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 have met DSM-5 criteria for substance use disorder or dependence within the past 
180 days; including alcohol and benzodiazepines, but excluding caffeine and nicotine.
Physical and Laboratory Results
16.
Subjects with a positive drug screen for cocaine, alcohol, or other drugs of abuse (excluding 
known prescription stimulants and other prescribed medications and cannabis).  Positive results 
for cannabis, barbiturates, or opiates in the drug screen are not exclusionary if in the 
investigator’s documented opinion the subject does not meet DSM-5 criteria for substance use 
disorders and in the investigator’s documented opinion the positive test does not signal a clinical 
condition that would impact the safety of the subject or interpretation of the trial results, and 
participation is agreed to by the medical monitor prior to treatment.

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Table 3.4.3.2-1
Exclusion Criteria for De Novo Subjects
17.
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 result, unless discussed with and approved by the medical monitor.  
(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, ECGs, 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
18.
Subjects with a history of failure of clozapine treatment or response to clozapine treatment only.
19.
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.
20.
Subjects who would be likely to require prohibited concomitant therapy during the trial 
including CYP2D6 or CYP3A4 inhibitors or CYP3A4 inducers or who are anticipated to require 
use of such agents during the trial.
Allergies and Adverse Drug Reactions
21.
Subjects with a history of neuroleptic malignant syndrome.
22.
Subjects with a history of true allergic response (ie, not intolerance) to more than one class of 
medications.
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.
Any subject who, in the opinion of the investigator, should not participate in the trial.
Added with Amendment 2
26.
Subject is known to have medication compliance issues that lead to IM depot medication use.
27.
Subjects who report a true allergic response to aripiprazole or brexpiprazole.
28.
Subjects who participated in any clinical trial within the last 30 days prior to screening (not 
applicable to participation in Trial 331-10-234).

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Table 3.4.3.2-1
Exclusion Criteria for De Novo Subjects
29.
Subjects who are known poor metabolizers of CYP2D6 or CYP3A4.
Added with Amendment 4
30.
Subjects on IM depot therapy within 5 × half-lives of the medication prior to the baseline 
(Day 1) visit of the open-label treatment period.
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, de novo subjects excluded for 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.  If a de novo subject previously participated in Trial 331-10-234, they will 
retain their subject identification number from Trial 331-10-234.
Subjects who are discontinued from the trial during the conversion period are not eligible 
to be rescreened.
3.5
Endpoints
3.5.1
Primary Endpoints
The primary endpoints of this trial are the frequency and severity of adverse events 
(AEs), serious TEAEs (clinical and laboratory), and discontinuation from trial due to 
AEs.
3.5.2
Secondary Endpoints
3.5.2.1
Secondary Safety Endpoints
The secondary safety endpoints are as follows:

Mean change from baseline and incidence of clinically significant abnormalities 
in clinical laboratory tests and urinalysis results (including fasting blood lipids, 
glucose and insulin, serum prolactin, glycosylated hemoglobin [HbA1c] and 
creatine phosphokinase [CPK]), vital signs (supine and standing positions), 
weight, height, body mass index (BMI), waist circumference, and ECG 
parameters

Mean change from baseline on the Abnormal Involuntary Movement Scale 
(AIMS), Simpson-Angus Scale (SAS), and Barnes Akathisia Rating Scale 
(BARS)

Analysis of potential suicide events recorded on the Columbia-Suicide Severity 
Rating Scale (C SSRS)

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
Comprehensive psychotropic side effects as assessed by Udvalg for Kliniske 
Undersogelser (UKU) side effect rating scale

The frequency of symptom items for the clinician-administered New York 
Assessment for Adverse Cognitive Effects of Neuropsychiatric Treatment:  
(NY-AACENT)

Baseline and postbaseline Tanner Staging Scale data

Time to discontinuation due to AE
3.5.2.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are as follows:

Change from baseline in the Positive and Negative Syndrome Scale (PANSS) 
Total Score and the Positive and Negative Subscale Scores

Change from baseline in the Children’s Global Assessment Scale (CGAS) Score

Clinical Global Impression Severity (CGI-S) scale

Clinical Global Impression Improvement (CGI-I) scale
3.6
Measures to Minimize/Avoid Bias
Not applicable; this is an open-label trial.
3.7
Trial Procedures
Trial assessment time points are summarized in Table 3.7-1 (rollover subjects from 
Trial 331-10-234) and Table 3.7-2 (de novo subjects).
All visits may occur within ± 3 days of the target visit date.  Follow-up contact may occur 
within ± 2 days of the target date.
For scheduling trial visits, a month will be considered as 31 days (± 3 days).
Although there is a ± 3-day visit window during the open-label treatment period, every 
attempt should be made to track each subject’s monthly visits to ensure that the subject’s 
final Month 24 visit meets the protocol’s intended treatment duration of 2 calendar years.

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Table 3.7-1
Schedule of Assessments - Rollover Subjects from Trial 331-10-234
24-Month Open-label Treatment Period
End of 
Treatment
Follow-up
(clinic 
visit not 
required)b
Assessment
Screening/ 
Baseline
Last visit 
from Trial 
331-10-234/ 
Baseline for 
Trial 
331-10-236
W1, 2, 4
(± 3 
days)
M2, 3, 4 
(monthly)
(± 3 days)
M6
(± 3 
days)
M8, 10 
(every 
2 months)
(± 3 days)
M12
(± 3 
days)
M15, 18, 
21 (every 
3 months
)
(± 3 days)
M5, 7, 9, 
11, 13, 14, 
16, 17, 19, 
20, 22, 23
(± 3 days)a
M24 / ET
(± 3 days)
21 (± 2) 
days after 
last dose 
of IMP
Informed consent, update 
medical history, as needed
X
Prior medications
X
Entrance criteria
X
PANSS 
X
X W4 
only
X
X
X
X
X M18 
only
X
CGI-S and CGI-I
X
X W4 
only
X
X
X
X
X M18 
only
X
CGAS
X
X
X
X
X
X
X
X
SAS, AIMS, & BARS
X
X
X
X
X
X
X
X
C-SSRSc
X
X
X
X
X
X
X
X
UKU and NY-AACENT
X
X
X
X
X
X
X
X
Tanner Staging
X
X
X
X M18 
only
X
Physical examination
X
X
X
X M18 
only
X
Body weight and waist 
circumference
X
X
X
X
X
X
X
X
Height
X
X
X
X M18 
only
X
Vital signs (supine, sitting, 
& standing BP, pulse, and 
body temperature)d
X
X
X
X
X
X
X
X

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Table 3.7-1
Schedule of Assessments - Rollover Subjects from Trial 331-10-234
24-Month Open-label Treatment Period
End of 
Treatment
Follow-up
(clinic 
visit not 
required)b
Assessment
Screening/ 
Baseline
Last visit 
from Trial 
331-10-234/ 
Baseline for 
Trial 
331-10-236
W1, 2, 4
(± 3 
days)
M2, 3, 4 
(monthly)
(± 3 days)
M6
(± 3 
days)
M8, 10 
(every 
2 months)
(± 3 days)
M12
(± 3 
days)
M15, 18, 
21 (every 
3 months
)
(± 3 days)
M5, 7, 9, 
11, 13, 14, 
16, 17, 19, 
20, 22, 23
(± 3 days)a
M24 / ET
(± 3 days)
21 (± 2) 
days after 
last dose 
of IMP
ECG
X
X W4 
only
X
X
X M18 
only
X
Clinical laboratory tests 
(hematology, serum 
chemistry [including 
prolactin, HbA1c and TSH], 
and urinalysis)
X
X W4 
only
X
X
X M18 
only
X
Serum pregnancy test
X
X W4 
only
X
X
X M18 
only
X
Urine pregnancy test
X
Xe
Xe
X
Xe
X
Xe
Urine drug screen
X
X
X
X
X
X
X
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
Dispense investigational 
product
X
X
X
X
X
X
X
BP = blood pressure; ET = early termination; M = month; W = week
aFollow-up contact may not be necessary if a subject who early terminated received the last dose of IMP  > 21 (± 2) days from the ET visit.
bTelephone, Web, or other acceptable means of contact.
c“Since Last Visit” version of the C-SSRS will be completed at each visit.
dVital Signs – refers to pulse and heart rate interchangeably throughout the protocol.
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. 

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Table 3.7-2
Schedule of Assessments - De Novo Subjects
Conversion 
Perioda
24-Month Open-label Treatment Period 
End of 
Trea-
tmentd
Follow-up
(clinic 
visit not 
required)e
Assessment
Screen
Base-
line
W1, 
2, 3
(± 3 
days)
Baseline
(D1)b
W1, 
2, 4
(± 3 
days)
M2, 3, 4 
(monthly) 
(± 3 days)
M6
(± 3 
days)
M8, 10 
(every 
2 months
)
(± 3 days)
M12
(± 3 
days)
M15, 18, 
21 (every 
3 months
)
(± 3 days)
M5, 7, 9, 
11, 13, 14, 
16, 17, 19, 
20, 22, 23
(± 3 
days)c
M24 / 
ET
(± 3 
days)
21 (± 2) 
days after 
last dose 
of IMP
Informed 
consent, 
demography, 
medical history, 
psychiatric 
history
X
K-SADS-PLf
X
Prior 
medications
X
X
Entrance criteria
X
X
PANSS 
X
X
X 
W4 
only
X
X
X
X
X M18 
only
X
CGI-S and 
CGI-I
Xg
Xg
X 
W4 
only
X
X
X
X
X M18 
only
X
CGAS
X
X
X
X
X
X
X
X
X
SAS, AIMS, & 
BARS
X
X
X
X
X
X
X
X
X
C-SSRSh
X
X
X
X
X
X
X
X
X
X
X
UKU and 
NY-AACENT
X
X
X
X
X
X
X
X
X

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Table 3.7-2
Schedule of Assessments - De Novo Subjects
Conversion 
Perioda
24-Month Open-label Treatment Period 
End of 
Trea-
tmentd
Follow-up
(clinic 
visit not 
required)e
Assessment
Screen
Base-
line
W1, 
2, 3
(± 3 
days)
Baseline
(D1)b
W1, 
2, 4
(± 3 
days)
M2, 3, 4 
(monthly) 
(± 3 days)
M6
(± 3 
days)
M8, 10 
(every 
2 months
)
(± 3 days)
M12
(± 3 
days)
M15, 18, 
21 (every 
3 months
)
(± 3 days)
M5, 7, 9, 
11, 13, 14, 
16, 17, 19, 
20, 22, 23
(± 3 
days)c
M24 / 
ET
(± 3 
days)
21 (± 2) 
days after 
last dose 
of IMP
Tanner staging
X
X
X
X M18 
only
X
Physical 
examination
X
X
X
X M18 
only
X
Body weight & 
waist 
circumference
X
X
X
X
X
X
X
X
X
X
Height
X
X
X
X
X M18 
only
X
Vital signs 
(supine, sitting, 
& standing BP, 
pulse, and body 
temperature)i
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X 
W4 
only
X
X
X M18 
only
X

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Table 3.7-2
Schedule of Assessments - De Novo Subjects
Conversion 
Perioda
24-Month Open-label Treatment Period 
End of 
Trea-
tmentd
Follow-up
(clinic 
visit not 
required)e
Assessment
Screen
Base-
line
W1, 
2, 3
(± 3 
days)
Baseline
(D1)b
W1, 
2, 4
(± 3 
days)
M2, 3, 4 
(monthly) 
(± 3 days)
M6
(± 3 
days)
M8, 10 
(every 
2 months
)
(± 3 days)
M12
(± 3 
days)
M15, 18, 
21 (every 
3 months
)
(± 3 days)
M5, 7, 9, 
11, 13, 14, 
16, 17, 19, 
20, 22, 23
(± 3 
days)c
M24 / 
ET
(± 3 
days)
21 (± 2) 
days after 
last dose 
of IMP
Clinical 
laboratory tests 
(hematology, 
serum chemistry 
[including 
prolactin, 
HbA1c and 
TSH], and 
urinalysis)
X
X
X 
W4 
only
X
X
X M18 
only
X
Serum 
pregnancy test
X
X
X 
W4 
only
X
X
X M18 
only
X
Urine pregnancy 
test
X
X
Xj
Xj
X
Xj
X
Xj
Urine drug 
screen
X
X
X
X 
X
X
X
X
X 
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense 
investigational 
product
X
X
X
X
X
X
X
X
X

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aThe conversion period lasts up to 4 weeks with a ± 3 day window for each weekly visit.
bFor subjects that participated in the conversion period, the baseline (Day 1) visit of the open-label treatment period will coincide with the end of the 
conversion period which is up to 4 weeks in duration.
cTelephone, Web, or other acceptable means of contact.
dIf a subject discontinues early before Month 24, either during the conversion period or the open-label treatment period, procedures noted for Month 24 must 
be completed at the ET visit.
eAll subjects (completers as well as premature withdrawals from either the conversion period or open-label treatment period) will be followed up either by 
telephone or other acceptable means of contact. Follow-up contact may not be necessary if a subject who early terminated received the last dose of 
IMP > 21 (± 2) days from the ET visit.
fTo be completed only for de novo subjects who did not formerly participate in Trial 331-10-234.
gCGI-I will not be administered at screening or the baseline (Day 1) visit of the open-label treatment period.
hBaseline/Screening” version of the C-SSRS will be completed at screening and the “Since Last Visit” version will be completed at all other in-clinic visits. 
iVital Signs – refers to pulse and heart rate interchangeably throughout the protocol.
jIf 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.

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3.7.1
Schedule of Assessments
3.7.1.1
Screening and Baseline
3.7.1.1.1
Rollover Subjects
Screening for rollover subjects occurs simultaneously with baseline at the 
end-of-treatment visit (Week 6) of Trial 331-10-234 (see Table 3.7-1).  Rollover subjects 
entering from Trial 331-10-234 or their parent/legal guardian must sign the ICF for the 
open-label trial before any procedures specific to Trial 331-10-236 can be performed.  
Subjects will retain the same subject identification (Subject ID) number assigned in 
Trial 331-10-234.  Screening/baseline values will be derived from the last visit of the 
double-blind phase 3 trial (ie, the Week 6 of Trial 331-10-234) for the following 
assessments:  PANSS, CGI-S, CGI-I, CGAS, SAS, AIMS, BARS, C-SSRS, UKU, 
NY-AACENT, Tanner Staging Scale, physical examination, body weight, height, waist 
circumference, vital signs, ECG, clinical laboratory tests, urine drug screen, serum 
pregnancy test, and urine pregnancy test.  The only additional procedures to be performed 
for rollover subjects at screening/baseline of the open-label trial are as follows:

An assessment of all inclusion and exclusion criteria will be made to determine 
the subject’s eligibility for the trial.

Medical history from Trial 331-10-234 will be retained, but will be updated if 
necessary.

Concomitant medications will be reviewed to assure that the subject is not 
receiving any prohibited medications.

AE recording will begin with the signing of the ICF for Trial 331-10-236.

The IMP will be dispensed to the subject.
3.7.1.1.2
De Novo Subjects
De novo subjects, whether or not they participated in Trial 331-10-234 must attend 
separate screening and baseline visits to allow for completion of eligibility assessments 
and washout of prohibited concomitant medications, if applicable.
3.7.1.1.2.1
Screening
For de novo subjects, the screening period begins after written informed consent and 
assent have been obtained and will take place between Day −28 and Day −1 prior to 
enrollment.  Although the screening period continues up to administration of the first 
dose of IMP, screening procedures should be initiated with a sufficient amount of time 
allotted in order to obtain laboratory results and ECG results from the central reader prior 

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to the first dose.  The sponsor reserves the right to utilize external quality oversight 
methods to ensure the validity of diagnosis, severity of illness, and other factors 
determining appropriateness of subject selection.  After a subject has been told that a 
reliable informant may accompany the subject at all visits, the subject's parent/legal 
guardian has provided informed consent, and the subject has provided assent, a screening 
number will be provided.  If a de novo subject previously participated in 
Trial 331-10-234, they will retain their subject identification number from 
Trial 331-10-234.  Completion of screening activities may require more than 1 visit; 
however, only the initial visit will be registered.  The screening period maximum of 
28 days may be extended following approval by the medical monitor.  Screening 
evaluations will include the following:

Trial personnel will enter subject data into eSource to register all trial visits 
(initial screening visit only).

An assessment of all inclusion and exclusion criteria will be made to determine 
the subject’s eligibility for the trial.

Demographic data will be recorded.

Medical and psychiatric history will be recorded, including the DSM-5 diagnosis 
of schizophrenia that will be made by an adequately trained clinician.

Previous medications taken within 30 days of screening will be recorded.  
Lifetime antipsychotic use will be recorded.  Washout from prohibited 
concomitant medications will begin, if applicable (see Table 4.1-1).

Diagnosis of schizophrenia will be confirmed by the K-SADS-PL, performed by 
an adequately trained rater (to be completed only for de novo subjects who did not 
formerly participate in Trial 331-10-234).

A qualified and certified rater will administer the PANSS. 

A qualified rater will administer the CGI-S. 

A qualified rater will administer the CGAS.

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.

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
The investigator (or qualified designee) will complete Tanner Staging Scale 
assessment.  
Note:  The collection of Tanner Staging Scale 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 exam 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 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.

A physical examination will be performed.

Body weight, height, and waist circumference will be recorded.

Vital sign measurements (including blood pressure, pulse, and body temperature) 
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.  See Table 3.4.3.2-1 for exclusions based on outcome of 
screening vital sign measurements.  Vital signs are to be completed before any 
blood is drawn.

A standard 12-lead ECG will be performed after the subject has been supine and 
at rest for at least 5 minutes.  Subjects with screening QT interval corrected for 
heart rate by Fridericia’s formula (QTcF) or QT interval corrected for heart rate 
by the FDA Neuropharm Division formula (QTcN) ≥ 450 msec for males and 
≥ 470 msec for females per the central reader’s report will be excluded from the 
trial (see Table 3.4.3.2-1 and Section 3.7.3.4).  The ECG is to be completed 
before any blood is drawn.  

Blood samples will be collected for clinical laboratory tests, including 
hematology and serum chemistry (with prolactin, glycosylated hemoglobin 
[HbA1c], and thyroid-stimulating hormone [TSH and free thyroxine [T4]).  Blood 
will be drawn after a minimum 8-hour fast, if at all possible (see Section 3.7.3.2).  
See Table 3.4.3.2-1 for exclusions based on outcome of screening clinical 
laboratory tests.  Vital sign and ECG assessments should be completed before any 
blood samples are collected.

A serum pregnancy test will be performed for all females.  Subjects with a 
positive serum test result will be excluded from the trial.

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
Urine will be collected from all potential subjects for urinalysis and urine 
screen(s) for drugs of abuse.  See Table 3.4.3.2-1 for exclusions based on 
outcome of urine drug screen(s). A urine pregnancy test will be performed for all 
females.

AEs and concomitant medications will be recorded beginning with the signing of 
the ICF.
3.7.1.1.2.2
Conversion Period 
If the washout of prohibited medications prior to the baseline (Day 1) visit of the 
open-label treatment period is not appropriate for any de novo subject, in the opinion of 
the investigator, the subject must undergo cross-titration to oral brexpiprazole for 1 to 
4 weeks during the conversion period, as described in Section 3.2.2.1.  Visits will occur 
at the end of each week during the conversion period.  The goal of de novo subjects 
during the conversion period is to achieve a brexpiprazole monotherapy target starting 
dose of 1, 2, or 3 mg daily at any time after Week 1 per the investigator’s discretion and 
to achieve the required washout of prohibited medications as per Table 4.1-1.  The 
subject will proceed to the baseline (Day 1) visit of the open-label treatment period once 
the target starting dose has been achieved and the required washout of prohibited 
medications has been completed.
All subjects will be assessed weekly at scheduled visits during the conversion period.  
The following evaluations will be performed at the baseline visit of the conversion 
period:

The “Since Last Visit” version of the C-SSRS form will be completed.

AEs and concomitant medications will be recorded.

The IMP will be dispensed to the subject.
The following evaluations will be performed at each visit (ie, Week 1, 2, and 3):

The “Since Last Visit” version of the C-SSRS form will be completed at Weeks 1, 
2, and 3 visit. 

Body weight and waist circumference will be recorded.

Vital sign measurements (including blood pressure, pulse, and body temperature) 
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.

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
Urine will be collected from all potential subjects for urinalysis and urine 
screen(s) for drugs of abuse.  

AEs and concomitant medications will be recorded.

The IMP will be dispensed to the subject.
If a subject discontinues prematurely before the end of the conversion period, all 
procedures for the Month 24/ET visit must be completed at the ET visit.
3.7.1.1.2.3
Baseline (Open-label Treatment Period)
If the subject is found to be eligible for the trial during the screening/conversion period, 
the subject will attend a baseline (Day 1) visit for the open-label treatment period. For 
subjects that participated in the conversion period, the baseline (Day 1) visit of the 
open-label treatment period will coincide with the end of the conversion period which is 
up to 4 weeks in duration. The following procedures will be completed during the 
baseline (Day 1) visit of the open-label treatment period, prior to the subject starting 
open-label IMP:

Inclusion/exclusion criteria will be reviewed.

Prior medications will be reviewed.

A qualified and certified rater will administer the PANSS.

A qualified rater will administer the CGI-S.

A qualified rater will administer the CGAS.

The investigator (or qualified designee) will administer the SAS, AIMS, and 
BARS.

The investigator (or qualified designee) will complete the “Since Last Visit” 
version of the C-SSRS form.

The investigator (or qualified designee) will administer the UKU and 
NY-AACENT.

Body weight, height, and waist circumference will be recorded.

Vital sign measurements (including blood pressure, pulse and body temperature) 
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.

Blood samples will be collected for clinical laboratory tests (hematology and 
serum chemistry [including prolactin, HbA1c, and TSH]) after a minimum 8-hour 
fast.  Vital sign and ECG assessments should be completed before any blood 
samples are collected.

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
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.

Urine will be collected for urinalysis and from all potential subjects for urine 
screen(s) for drugs of abuse.  

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.

AEs and concomitant medications will be recorded.

If the subject remains eligible for the trial after completion of the baseline 
evaluations, trial personnel will use eSource to obtain an IMP assignment.  The 
subject will receive the first dose of IMP from the assigned bottle, and the date 
and time of the first dose will be recorded in eSource.

The IMP will be dispensed to the subject.
3.7.1.2
Open-label Treatment 
All subjects will be assessed at various scheduled clinic visits as described below.  A 
number of visits will be conducted via telephone, the Internet, or other acceptable means 
of contact, and are presented in Section 3.7.1.2.7. 
3.7.1.2.1
Weeks 1, 2, and 4
The following evaluations will be performed at Weeks 1, 2, and 4 visits:

A qualified rater will administer the CGAS.

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, pulse, and body temperature) 
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.

Urine will be collected from all potential subjects for urine screen(s) for drugs of 
abuse.  Urinalysis will be performed at Week 4.

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
A urine pregnancy test will be performed for all females.  The result must be 
negative prior to dosing.  If the urine pregnancy test is positive at Weeks 1 or 2, 
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.

AEs and concomitant medications will be recorded.

A qualified and certified rater will administer the PANSS (Week 4 only).

A qualified rater will administer the CGI-S and CGI-I (Week 4 only).

A standard 12-lead ECG will be performed 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 (Week 4 only). 

Blood samples will be collected for clinical laboratory tests, including 
hematology and serum chemistry (with prolactin, HbA1c, and TSH]).  Blood will 
be drawn after a minimum 8-hour fast, if at all possible (see Section 3.7.3.2).  See 
Table 3.4.3.2-1 for exclusions based on outcome of screening clinical laboratory 
tests (Week 4 only).

A serum pregnancy test will be performed for all females.  Subjects with a 
positive serum test result will be excluded from the trial (Week 4 only).

The IMP will be dispensed to the subject.
3.7.1.2.2
Months 2, 3, and 4
The following evaluations will be performed at the Month 2, 3, and 4 visits:

A qualified and certified rater will administer the PANSS.

A qualified rater will administer the CGI-S and CGI-I.

A qualified rater will administer the CGAS.

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, pulse, and body temperature) 
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.

Urine will be collected from all potential subjects for urine screen(s) for drugs of 
abuse.  

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
A urine pregnancy test will be performed for all females.  The result must be 
negative prior to dosing.  If 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.

AEs and concomitant medications will be recorded.

The IMP will be dispensed to the subject.
3.7.1.2.3
Month 6
The following evaluations will be performed at the Month 6 visit:

A qualified and certified rater will administer the PANSS.

A qualified rater will administer the CGI-S and CGI-I.

A qualified rater will administer the CGAS.

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, height, and waist circumference will be recorded.

Vital sign measurements (including blood pressure, pulse, and body temperature) 
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.

Urine will be collected from all potential subjects for urine screen(s) for drugs of 
abuse.  Urinalysis will be performed.

A urine pregnancy test will be performed for all females.  The result must be 
negative prior to dosing.  Additional urine pregnancy testing may be done at the 
discretion of the investigator.

AEs and concomitant medications will be recorded.

The investigator (or qualified designee) will complete the Tanner Staging Scale 
assessment. 

A physical examination will be performed. 

A standard 12-lead ECG will be performed 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.  

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
Blood samples will be collected for clinical laboratory tests, including 
hematology and serum chemistry (with prolactin, HbA1c, and TSH).  Blood will 
be drawn after a minimum 8-hour fast, if at all possible (see Section 3.7.3.2).  

A serum pregnancy test will be performed for all females.  Subjects with a 
positive serum test result will be discontinued from the trial.

The IMP will be dispensed to the subject.
3.7.1.2.4
Months 8 and 10
The following evaluations will be performed at the Month 8 and 10 visits:

A qualified and certified rater will administer the PANSS.

A qualified rater will administer the CGI-S and CGI-I.

A qualified rater will administer the CGAS.

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, pulse, and body temperature) 
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.

Urine will be collected from all potential subjects for urine screen(s) for drugs of 
abuse.  

A urine pregnancy test will be performed for all females.  The result must be 
negative prior to dosing.  If 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.

AEs and concomitant medications will be recorded.

The IMP will be dispensed to the subject.
3.7.1.2.5
Month 12
The following activities and assessments will occur at Month 12 visit:

A qualified and certified rater will administer the PANSS.

A qualified rater will administer the CGI-S and CGI-I.

A qualified rater will administer the CGAS.

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
The investigator (or qualified designee) will administer the SAS, AIMS, and 
BARS.

The investigator (or qualified designee) will complete the “Since Last Visit” 
C-SSRS form.

The investigator (or qualified designee) will administer the UKU and 
NY-AACENT.

Body weight, height, and waist circumference will be recorded.

The investigator (or qualified designee) will complete Tanner staging assessment.

A physical examination will be performed.

Vital sign measurements (including blood pressure, pulse, and body temperature) 
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.

Urine will be collected from all potential subjects for urinalysis and urine 
screen(s) for drugs of abuse.

Blood samples will be collected for clinical laboratory tests (hematology and 
serum chemistry [including prolactin, HbA1c, and TSH]) after a minimum 8-hour 
fast.  Vital sign and ECG assessments should be completed before any blood 
samples are collected.

A standard 12-lead ECG will be performed 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.

A serum pregnancy test will be performed for all females.  Subjects with a 
positive serum test result will be discontinued from the trial.

A urine pregnancy test will be performed predose for all females.  The result must 
be negative prior to dosing.  Additional urine pregnancy testing may be done at 
the discretion of the investigator.

AEs and concomitant medications will be recorded.

The IMP will be dispensed to the subject.
3.7.1.2.6
Months 15, 18, and 21
The following evaluations will be performed at the Month 15, 18, and 21 visits:

A qualified and certified rater will administer the CGAS.

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.

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
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, pulse, and body temperature) 
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.

Urine will be collected from all potential subjects for urine screen(s) for drugs of 
abuse.  Urinalysis will be performed at Month 18 only.

A urine pregnancy test will be performed for all females.  The result must be 
negative prior to dosing.  If the urine pregnancy test is positive at Months 15 or 
21, 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.

AEs and concomitant medications will be recorded.

A qualified and certified rater will administer the PANSS (Month 18 only).

A qualified rater will administer the CGI-S and CGI-I (Month 18 only).

The investigator (or qualified designee) will complete Tanner Staging Scale 
assessment.  (Month 18 only)

A physical examination will be performed (Month 18 only).

Height will be measured (Month 18 only).

A standard 12-lead ECG will be performed 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 (Month 18 only).  

Blood samples will be collected for clinical laboratory tests, including 
hematology and serum chemistry (with prolactin, HbA1c, and TSH).  Blood will 
be drawn after a minimum 8-hour fast, if at all possible (see Section 3.7.3.2).  See 
Table 3.4.3.2-1 for exclusions based on outcome of screening clinical laboratory 
tests.  Vital sign and ECG assessments should be completed before any blood 
samples are collected (Month 18 only).

A serum pregnancy test will be performed for all females.  Subjects with a 
positive serum test result will be discontinued from the trial (Month 18 only).

The IMP will be dispensed to the subject.

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3.7.1.2.7
Months 5, 7, 9, 11, 13, 14, 16, 17, 19, 20, 22, and 23
Visits for Months 5, 7, 9, 11, 13, 14, 16, 17, 19, 20, 22, and 23, will be conducted via 
telephone, the Internet, or other acceptable means of contact.  The following activities 
and assessments will occur for all subjects:

AEs and concomitant medications will be recorded.
3.7.1.2.8
Month 24/Early Termination (End of Treatment)
The treatment period for the entire trial will conclude at the Month 24 visit.  If a subject 
discontinues early before Month 24, either during the conversion period or the open-label 
treatment period, procedures noted for Month 24 must be completed at the ET visit.  
Attempts should be made to complete all evaluations for the Month 24 visit prior to the 
administration of any new psychotropic medications.  The following activities and 
assessments will occur at Month 24/ET:

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 CGI-S and CGI-I.

A qualified rater will administer the CGAS.

The investigator (or qualified designee) will administer the SAS, AIMS, and 
BARS.

The investigator (or qualified designee) will complete the “Since Last Visit” 
C-SSRS form.

The investigator (or qualified designee) will administer the UKU and 
NY-AACENT.

Body weight, height, and waist circumference will be recorded.

The investigator (or qualified designee) will complete Tanner staging assessment.

A physical examination will be performed.

Vital sign measurements (including blood pressure, pulse, and body temperature) 
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.

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
Blood samples will be collected for clinical laboratory tests (hematology and 
serum chemistry [including adrenocorticotropic hormone (ACTH), cortisol, 
prolactin, HbA1c, and TSH]) after a minimum 8-hour fast.  Vital sign and ECG 
assessments should be completed before any blood samples are collected.

A serum pregnancy test will be performed for all females.

Urine will be collected from all potential subjects for urinalysis and urine 
screen(s) for drugs of abuse.

AEs and concomitant medications will be recorded.
3.7.1.3
Follow-up
All subjects (rollover and de novo completers as well as premature withdrawals from 
either the conversion period or open-label treatment period) will be followed up either by 
telephone or other acceptable means of contact 21 (± 2) days after the last dose of IMP to 
assess any new or ongoing AEs and to record any concomitant medications.  Depending 
upon the type of follow-up required, other evaluations or tests may be conducted or 
performed.
3.7.2
Efficacy Assessments
3.7.2.1
Positive and Negative Syndrome Scale 
The PANSS15 consists of 3 subscales containing a total of 30 symptom constructs.  For 
each symptom construct, severity is rated on a 7-point scale, with a score of 1 indicating 
the absence of symptoms and a score of 7 indicating extremely severe symptoms.  The 
symptom constructs for each subscale are as follows:
1) Positive Subscale (7 positive symptom constructs:  delusions, conceptual 
disorganization, hallucinatory behavior, excitement, grandiosity, 
suspiciousness/persecution, and hostility),
2) Negative Subscale (7 negative symptom constructs:  blunted affect, emotional 
withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in 
abstract thinking, lack of spontaneity and conversation flow, stereotyped 
thinking), and
3) General Psychopathology Subscale (16 symptom constructs:  somatic concern, 
anxiety, guilt feelings, tension, mannerisms and posturing, depression, motor 
retardation, uncooperativeness, unusual thought content, disorientation, poor 
attention, lack of judgment and insight, disturbance of volition, poor impulse 
control, preoccupation, and active social avoidance).
A copy of the PANSS is provided in Appendix 5.

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3.7.2.2
Children’s Global Assessment Scale 
The CGAS is a 100-point rating scale measuring psychological, social and school 
functioning for children aged 6-17.16  It was adapted from the Adult Global Assessment 
Scale (GAS).  The GAS is a rating scale for evaluating the overall functioning of a 
subject during a specified time period on a continuum from psychological or psychiatric 
sickness to health.  The CGAS is a valid and reliable tool for rating a child's general level 
of functioning on a health-illness continuum.  The CGAS was developed by Schaffer and 
colleagues to provide a global measure of severity of disturbance in children and 
adolescent.  Notation in the subject’s trial records should substantiate the ratings.  A copy 
of the CGAS is provided in Appendix 6.
3.7.2.3
Clinical Global Impression - Severity of Illness Scale 
The severity of illness for each subject will be rated using the CGI-S.17  To perform this 
assessment, the rater or investigator will answer the following question:  “Considering 
your total clinical experience with this particular population, how mentally ill is the 
patient at this time?”  Response choices include:  0 = not assessed; 1 = normal, not at all 
ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 
6 = severely ill; and 7 = among the most extremely ill patients.  A sample of the CGI-S is 
provided in Appendix 7.
3.7.2.4
Clinical Global Impression - Improvement Scale 
The efficacy of IMP will be rated for each subject using the CGI-I.17  The rater or 
investigator will rate the subject’s total improvement whether or not it is due entirely to 
drug treatment.  All responses will be compared to the subject’s condition at baseline 
prior to the first dose of double-blind IMP.  Response choices include:  0 = not assessed, 
1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 
5 = minimally worse, 6 = much worse, and 7 = very much worse.  A sample of the CGI-I 
is provided in Appendix 8.
3.7.3
Safety Assessments
3.7.3.1
Adverse Events
Refer to Section 5, Reporting of Adverse Events. 

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3.7.3.2
Clinical Laboratory Assessments
Table 3.7.3.2-1 presents the protocol-required clinical laboratory test for all subjects in 
this trial.  A central laboratory designated by the sponsor will be used for all laboratory 
testing required during the trial.  The central laboratory should be used for all laboratory 
testing whenever possible (including unscheduled and follow-up laboratory tests, if 
needed).  In cases where an immediate result is required for a particular laboratory test, 
the sample should be divided and sent to both a local laboratory and the designated 
central laboratory.  Urine will be collected and blood will be drawn from each subject 
during screening prior to treatment with IMP and then at the scheduled visits designated 
in Table 3.7-1 (rollover subjects from Trial 331-10-234) and Table 3.7-2 (de novo 
subjects).  The results of these tests must be reviewed by the investigator prior to 
initiation of IMP.  Additional urine and blood samples may be collected for further 
evaluation of safety as warranted by the investigator’s judgment.  Subjects must be 
fasting for a minimum of 8 hours prior to blood draws for screening laboratory 
assessments, if at all possible.  If fasting blood samples are not feasible at screening, 
nonfasting blood samples may be obtained initially for determining eligibility for the 
trial.  If a subject is not fasting at a visit, the blood draw should still be performed and the 
status documented as nonfasting on the laboratory requisition sheet.  The central 
laboratory will provide laboratory results to the sponsor electronically.

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Table 3.7.3.2-1
Clinical Laboratory Assessments
Hematology:
Hematocrit
Hemoglobin
MCHC
MCV
Platelets
RBC count
WBC count with differential 
Urinalysis:
Appearance
Color 
Blood
Glucose
Microscopic analysis, WBC/RBC counts per high 
powered field
pH
Protein
Specific gravity
Serum Chemistry:
ALP
ALT
AST
Bilirubin, total 
BUN 
Calcium
Chloride
Cholesterol (total, LDL and HDL)
CPK
Creatinine
GGT
Glucose
LDH
Potassium
Protein, total 
Sodium
Triglycerides
Uric acid
Additional Tests:
Urine or serum pregnancy for all females
TSH, with reflex to free T4 if TSH is abnormal
ACTH
Cortisol
HbA1c
Prolactin
BUN = blood urea nitrogen; GGT = gamma glutamyl transferase; HDL = high-density lipoprotein; 
LDH = lactic dehydrogenase; LDL = low-density lipoprotein; MCHC = mean corpuscular hemoglobin 
concentration; MCV = mean corpuscular volume; RBC = red blood cell; WBC = white blood cell
No more than 16.5 mL of blood will be taken at any given visit designated in Table 3.7-1 
and Table 3.7-2 for the purposes of clinical laboratory assessments, analyses, or 
pregnancy tests.  
A pregnancy test will be conducted in all females prior to trial intervention; results must 
be available prior to the administration of the IMP.  Subjects with a positive serum test 
result at screening will be excluded from the trial.  A urine pregnancy test will be 
conducted per the schedule of assessments (Table 3.7-1 for rollover subjects and 
Table 3.7-2 for de novo subjects).  The urine pregnancy test must be negative prior to 
dosing on Day 1.  The frequency of pregnancy tests may be modified based on local 
regulatory requirements. Additional urine or serum pregnancy testing may be done at the 
discretion of the investigator.

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Any value outside the normal range will be flagged for the attention of the investigator, 
who must indicate whether or not a flagged value is of clinical significance.  If 1 or more 
values are questionable, the test(s) may be repeated.  If the result of any test (or repeat 
test, if done) is indicated as clinically significant in the samples taken during the 
screening period, the subject will NOT be enrolled into the trial without the permission of 
the medical monitor.  In addition, follow-up unscheduled laboratory tests should be 
performed on clinically significant abnormalities.  Unscheduled laboratory tests may be 
repeated at any time at the discretion of the investigator for appropriate medical care.
The following laboratory test results are exclusionary:
1) Platelets ≤ 75000/mm3
2) Hemoglobin ≤ 11 g/dL
3) Neutrophils, absolute ≤ 1000/mm3
4) WBC count ≤ 2800/mm3
5) Aspartate aminotransferase (AST) > 3 × the upper limit of normal (ULN)
6) Alanine aminotransferase (ALT) > 3 × the ULN
7) Creatinine ≥ 2 mg/dL
8) HbA1c ≥ 7.0%
9) CPK > 3 × ULN
10) Abnormal free T4 unless discussed with and approved by medical monitor.  
(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
In addition, subjects should be excluded if they have any other abnormal laboratory test 
result at screening that, in the investigator’s judgment, is medically significant in that it 
would impact the safety of the subject or the interpretation of the trial results.  However, 
any abnormal screening laboratory result(s) considered to be clinically significant should 
be repeated as soon as possible to confirm the finding(s) before excluding the subject 
from the trial.  Appendix 2 is included to assist investigators in their assessments of 
results that may be potentially medically significant, depending on the subject’s medical 
history and clinical presentation.

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3.7.3.3
Physical Examination and Vital Signs
3.7.3.3.1
Physical Examination
The physical examination will consist of measurement of height and a review of the 
following body systems:  head, ears, eyes, nose, and throat; thorax; abdomen; urogenital; 
extremities; neurological; and skin and mucosae.  Height will be measured with a 
stadiometer, measuring stick or tape.  The principal investigator or his/her appointed 
designee is primarily responsible to perform the physical examination.  If the appointed 
designee is to perform the physical examination, he/she must be permitted by local 
regulations and his/her name must be included on the FDA Form 1572.  Whenever 
possible, the same individual should perform all physical examinations.  Any condition 
present at the post-treatment physical examination that was not present at the baseline 
examination should be documented as an AE and followed to a satisfactory conclusion.
A complete physical examination is an integral part of study safety assessments and 
includes a urogenital assessment.  A urogenital assessment should be performed on all 
trial subjects according to local medical standards as applied to other body systems.  For 
the purposes of this trial, at a minimum, a baseline urogenital exam is required which 
could have been performed up to 1 calendar year prior to the date of ICF being signed, or 
can be performed during the screening period.  Additionally, at the Trial 331-10-236 
rollover screen baseline visit, the information will have been collected as part of the 
Trial 331-10-234 Week 6 visit.  The urogenital examination may be performed by the 
subject’s primary care provider or pediatrician as long as the source records are obtained 
and the findings documented.  Post-baseline, medically relevant questions about the 
urogenital body system must be asked of the subject at all protocol-required physical 
exams, with answers documented accordingly in the source.  The extent and scope of any 
part of the physical examination is to be left to the discretion of the investigator as 
deemed appropriate for each subject.
The following procedures will aid in the standardization of waist circumference 
measurements:

The subject should be minimally clothed (ie, lightweight clothing; no heavy 
overgarments).

Waist circumference should be recorded before a subject’s meal and at 
approximately the same time at each visit.

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
Measurement will be accomplished by locating the upper hip bone and the top of 
the right iliac crest and placing a weighted measuring tape in a horizontal plane 
around the abdomen at the level of the crest.  Before reading the tape measure, the 
assessor should assure that the tape is snug, but does not compress the skin, and is 
parallel to the floor.  The measurement is to be made at the end of a normal 
exhalation.18
3.7.3.3.2
Vital Signs
Vital sign measurements will include body weight, body temperature, systolic blood 
pressure (SBP), diastolic blood pressure (DBP), and heart rate.  The following guidelines 
will aid in the standardization of body weight measurements:

The same scale should be used to weigh a given subject each time, if possible.

Scales should be calibrated and reliable; scales should be at zero just prior to each 
subject’s weigh-in session.

A subject should void prior to being weighed and be minimally clothed (ie, no 
shoes or heavy overgarments).

Weight should be recorded before a subject’s meal and at approximately the same 
time at each visit.
Blood pressure and heart rate measurements will be made in the supine, sitting, and 
standing positions after the subject has been in each position for at least 3 minutes.  The 
supine measurements will be performed first, followed by sitting, and finally standing.  
Vital signs scheduled at the same visit as blood samples are to be completed before blood 
is drawn.
Subjects should be excluded if they have any vital sign measurement at screening that, in 
the investigator’s judgment, is medically significant in that it would impact the safety of 
the subject or the interpretation of the trial results.  However, any abnormal screening 
vital sign result(s) considered to be clinically significant may be repeated once to confirm 
the finding(s) before excluding the subject from the trial.  Appendix 1 is included to assist 
investigators in their assessments of results that may be potentially medically significant, 
depending on the subject’s medical history and clinical presentation.

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3.7.3.4
Electrocardiogram Assessments
Twelve-lead ECG recordings will be obtained after the subject has been supine and at rest 
for at least 5 minutes.  Additional 12-lead ECGs may be obtained per the investigator’s 
discretion and should always be obtained in the event of an early termination.  A central 
ECG service will be utilized for reading all ECGs in order to standardize interpretations 
for the safety analysis.  In addition, ECG results will be evaluated at the investigational 
site to monitor safety during the trial.  The principal investigator or qualified designee 
will review each ECG reading, noting whether or not any abnormal results are of clinical 
significance.  The ECGs should be repeated 1 time if a result is considered to be 
clinically significant. 
A screening ECG finding of QTcF or QTcN ≥ 450 msec for males and ≥ 470 msec for 
females based on the results from the central reader is exclusionary (see Table 3.4.3.1-1 
for rollover subjects and Table 3.4.3.2-1for de novo subjects).  In addition, subjects 
should be excluded if they have any other abnormal ECG finding at screening that, in the 
investigator’s judgment, is medically significant in that it would impact the safety of the 
subject or the interpretation of the trial results.  However, any screening ECG with 
abnormal result(s) considered to be clinically significant should be repeated as soon as 
possible to confirm the finding(s) before excluding the subject from the trial.  Appendix 3 
is provided as a guide for determining potentially clinically relevant ECG abnormalities.  
For both rollover subjects from Trial 331-10-234 and de novo subjects, central reader 
results for verification of exclusion criteria at baseline visit will not be available prior to 
dosing; therefore, subjects will be enrolled based on screening ECG results from the 
central reader and baseline ECG results from the trial site.  However, if the baseline ECG 
results from the central reader, when available, indicate a QTcF or QTcN ≥ 450 msec for 
males and ≥ 470 msec for females at baseline, the investigator must contact the medical 
monitor to discuss the subject’s continued participation in the trial.
3.7.3.5
Other Safety Assessments
It is required that a trained and experienced clinician administer the safety assessments, 
including the EPS scales (SAS, AIMS, and BARS), C-SSRS, UKU, NY-AACENT, and 
Tanner Staging Scale assessment.  The number of raters within each trial site should be 
kept to a minimum.  All efforts will be made to ensure that the same clinician administers 
the scales for a given subject.  Notations in the subject’s trial records should substantiate 
the ratings.  Training and materials for rating will be provided by Otsuka or designee.

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3.7.3.5.1
Simpson Angus Scale 
The SAS19 (Appendix 9) consists of a list of 10 symptoms of Parkinsonism (gait, arm 
dropping, shoulder shaking, elbow rigidity, wrist rigidity, head rotation, glabella tap, 
tremor, salivation, and akathisia).  Each item will be rated on a 5-point scale, with a score 
of zero representing absence of symptoms, and a score of 4 representing a severe 
condition.  The SAS Total Score is the sum of the scores for all 10 items.  
Anticholinergics, propranolol, benzodiazepines, and non-benzodiazepine sleep aids are 
not permitted within 12 hours of scale administration (see Section 4).  Investigators are 
encouraged to delay scale administration until 12 hours have elapsed, if at all possible.  
However, if delaying administration of the scale is not feasible, the SAS should still be 
administered and the use of the medication documented, including a notation of the drug 
name, dose, and time of administration on the eSource.
3.7.3.5.2
Abnormal Involuntary Movement Scale 
The AIMS17 assessment (Appendix 10) consists of 10 items describing symptoms of 
dyskinesia.  Facial and oral movements (items 1 through 4), extremity movements (items 
5 and 6), and trunk movements (item 7) will be observed unobtrusively while the subject 
is at rest (eg, in the waiting room), and the investigator will also make global judgments 
on the subject’s dyskinesias (items 8 through 10).  Each item will be rated on a 5-point 
scale, with a score of zero representing absence of symptoms (for item 10, no awareness), 
and a score of 4 indicating a severe condition (for item 10, awareness, severe distress).  
For this scale, the subject is to be sitting on a hard, firm chair.  In addition, the AIMS 
includes two yes/no questions that address the subject’s dental status.  Anticholinergics, 
propranolol, benzodiazepines, and non-benzodiazepine sleep aids are not permitted 
within 12 hours of scale administration (see Section 4).  Investigators are encouraged to 
delay scale administration until 12 hours have elapsed, if at all possible.  However, if 
delaying administration of the scale is not feasible, the AIMS should still be administered 
and the use of the medication documented, including a notation of the drug name, dose, 
and time of administration on the eSource.
The AIMS Movement Rating Score is defined as the sum of items 1 through 7 (ie, items 
1 through 4, facial and oral movements; items 5 and 6, extremity movements; and item 7, 
trunk movements).

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3.7.3.5.3
Barnes Akathisia Rating Scale 
The BARS20 (Appendix 11) consists of 4 items related to akathisia:  objective 
observation of akathisia by the investigator, subjective feelings of restlessness by the 
subject, subjective distress due to akathisia, and global clinical assessment of akathisia.  
The first 3 items will be rated on a 4-point scale, with a score of zero representing 
absence of symptoms and a score of 3 representing a severe condition.  The global 
clinical evaluation will be made on a 6-point scale, with zero representing absence of 
symptoms and a score of 5 representing severe akathisia.  To complete this scale, subjects 
will be observed while they are seated and then standing for a minimum of 2 minutes in 
each position.  Symptoms observed in other situations (eg, while engaged in neutral 
conversation or engaged in activity on the ward) may also be rated.  Subjective 
phenomena are to be elicited by direct questioning.  Anticholinergics, propranolol, 
benzodiazepines, and non-benzodiazepine sleep aids are not permitted within 12 hours of 
scale administration (see Section 4).  Investigators are encouraged to delay scale 
administration until 12 hours have elapsed, if at all possible.  However, if delaying 
administration of the scale is not feasible, the BARS should still be administered and the 
use of the medication documented, including a notation of the drug name, dose, and time 
of administration on the eSource.
The BARS Global Score is defined as the global clinical assessment of akathisia.
3.7.3.5.4
Udvalg for Kliniske Undersogelser 
The UKU scale has been included in this trial to satisfy regulatory authorities.  The UKU 
is used to assess side effects of subjects being treated with antipsychotic drugs and to 
determine whether there is a causal relationship.  A copy of the UKU is provided in 
Appendix 12.
3.7.3.5.5
New York Assessment for Adverse Cognitive Effects of 
Neuropsychiatric Treatment 
The NY-AACENT is not a validated scale.  It has been included in this trial to satisfy 
regulatory authorities.  No validated scale addressing these issues is currently available.
The NY-AACENT is used to detect changes in cognitive function subsequent to 
pharmacological or similar treatments for neurological or psychiatric problems.  It is 
specifically designed to be used in pediatric populations (ages 12-17 years), but can be 
utilized with other age groups as appropriate.  The clinician-administered NY-AACENT 
will be completed per the schedule of assessments (Table 3.7-1 for rollover subjects and 
Table 3.7-2 for de novo subjects).

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The clinician form is attached in Appendix 13.
3.7.3.5.6
Tanner Staging Scale
The 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 by the same trial-affiliated clinician in the most inconspicuous 
manner for the subject as possible.  Tanner Staging could be completed by trial 
psychiatrist, trial-affiliated pediatrician or family practitioner (additionally physician’s 
assistant or nurse-practitioner in the US).  When Tanner Staging is not completed at a 
required visit, it should be performed at the next trial visit.
Tanner Staging will be recorded at the visits specified in Table 3.7-1 for rollover subjects 
and Table 3.7-2 for de novo subjects.  The Tanner Staging Scale assessment consists of 
2 domains (pubic hair and breast development) for girls and 3 domains (pubic hair, penis 
development, and testes development) for boys.  The Tanner Staging Scale assessment as 
a reference for the completing clinician is included in Appendix 14.  A subject who 
reaches Stage 5 (both in pubic hair and genitalia) does not need to continue with Tanner 
Staging.  The clinician will arrive at a single score summarizing the domains (not 
individual domain scores) when evaluating the subject.
Any psychiatrist who will perform the Tanner Staging Scale 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 
examination performed by the same gender as the subject.  Otherwise, trial-affiliated 
personnel of the same gender as the subject (ie, nurse) should be in the same examination 
room as the subject.
3.7.3.5.7
Suicidality
Suicidality will be monitored during the trial using the Columbia-Suicide Severity Rating 
Scale (C-SSRS).  This trial will use the “Baseline/Screening” and “Since Last Visit” 
versions of the scale.  The “Baseline/Screening” version, which assesses the lifetime 
experience of the subject with suicide events and suicidal ideation and the occurrence of 
suicide events or ideation within a specified time period prior to entry into the trial, will 
be completed for all de novo subjects at the screening visit to determine the eligibility 
(prior to the first dose of open-label brexpiprazole).  Any subject with active suicidal 
ideation within the last 30 days, suicidal behaviors within the last year, or who in the 

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clinical judgment of the investigator presents a serious risk of suicide should be excluded 
from the trial (see Table 3.4.3.1-1 for rollover subjects and Table 3.4.3.2-1 for de novo 
subjects).  The “Since Last Visit” C-SSRS form will be completed at all other in-clinic 
visits for all subjects (rollover and de novo).  Copies of the C-SSRS forms are provided 
in Appendix 15.
3.7.4
End of Trial
The end of trial date is defined as the last date of contact or the date of final contact 
attempt from the post-treatment follow-up eSource page for the last subject completing or 
withdrawing from the trial.
3.7.5
Independent Data Monitoring Committee
A data monitoring committee (DMC) will provide oversight for safety monitoring.  The 
details of the DMC structure and its roles and responsibilities will be documented in a 
DMC charter.
3.8
Stopping Rules, Withdrawal Criteria, and Procedures
3.8.1
Entire Trial
If the sponsor terminates or suspends the trial for any reason, prompt notification will be 
given to investigators, IRBs/IECs, and regulatory authorities in accordance with 
regulatory requirements.
3.8.2
Individual Site
Individual trial site participation may be discontinued by the sponsor, the investigator, or 
the IRB/IEC if judged to be necessary for medical, safety, regulatory, ethical or other 
reasons consistent with applicable laws, regulations, and GCP.  A particular trial site may 
be terminated from the trial at the discretion of the investigator, sponsor, or IRB/IEC, 
eg, for non-enrollment of subjects or noncompliance with GCP or with the protocol.  The 
investigator will notify the sponsor promptly if the trial is terminated by the investigator 
or the IRB/IEC at the site.

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3.8.3
Individual Subject Discontinuation
3.8.3.1
Treatment Interruption
All attempts should be made to avoid treatment interruption during the trial.  For subjects 
who have an interruption of treatment, the investigator or designee will contact the 
sponsor at the earliest possible time by telephone.  The sponsor should be notified when 
there is a planned or inadvertent treatment interruption of 4 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 in the eSource and also recorded as a protocol deviation 
(Section 3.13).
3.8.3.2
Treatment Discontinuation
After starting open-label IMP, a subject may stop treatment permanently for a variety of 
reasons.  Treatment discontinuations may be initiated by a subject who is not satisfied 
with treatment or may become medically necessary due to AEs, required treatment with a 
disallowed medication or therapy, or other issues, as determined by the investigator.  
However, each investigator must comprehensively review the circumstances and offer the 
subject options for continued treatment to the degree possible as described in 
Section 3.8.3.5.
If a subject discontinues from the trial prematurely, the reason must be fully evaluated 
and recorded appropriately in source documents and in eSource.  If the subject is being 
withdrawn because of an AE, that AE should be indicated as the reason for withdrawal.  
All subjects have the right to withdraw at any point during treatment without prejudice.  
The investigator can discontinue a subject’s participation in the trial at any time if 
medically necessary.  
3.8.3.3
Documenting Reasons for Treatment Discontinuation
A subject may discontinue IMP for a number of reasons including those listed below:

Reasons related to AE:

Subject decides to discontinue because of annoyance or discomfort due to a 
non-serious AE which is not otherwise determined to be an undue hazard

Continuing IMP places the subject at undue risk as determined by the 
investigator (eg, a safety concern that is possibly, probably, or likely related to 
IMP)

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
Serious TEAE 

Clinical worsening, suicidality, and unusual changes in behavior, and the 
risk of increased suicidality

Death

Reasons unrelated to medical condition (provide detail and review AE history 
with subject)

Withdrawal of informed consent

Lost to follow-up

Pregnancy (see Section 5.5)

Termination of all or part of the trial by the sponsor
If the subject discontinues IMP due to an AE, the investigator, or other trial personnel, 
will make every effort to follow the event until it has resolved or stabilized.
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 or 
parents/legal guardians 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.

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
Contact of alternative person(s) who have been designated in source records as 
being available to discuss the subject’s medical condition, even if only by 
telephone, mail, or e-mail (eg, family, spouse, partner, legal representative, friend, 
neighbor, or physician).

Access to medical information from alternative sources (eg, hospital/clinic 
medical records, referring doctor’s notes, public records, dialysis, transplantation 
or vital registries, social media sources). 
Withdrawal of consent 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 
(see Section 3.8.3.1), which is not equivalent to a complete withdrawal of consent for 
further participation (see Section 3.8.3.2).  A subject may, however, indicate that further 
trial participation is creating a burden on their work or social schedule.  Therefore, the 
investigator should follow the procedures outlined in Section 3.8.3.3 to determine if the 
subject can continue participation in the trial if modifications to his/her treatment 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 brexpiprazole 
treatment.  For the purposes of this trial, treatment begins with the first dose of oral 
brexpiprazole during the conversion period or open-label treatment period.
Subjects who fail to qualify for the trial during screening for a reason other than a 
positive screen for drugs of abuse may be eligible to be rescreened one additional time at 
a later date.  The medical monitor must be contacted before the rescreening of any 
de novo subject.  In the event that a de novo subject is rescreened for trial participation, a 

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new ICF must be signed and a new screening number assigned.  If a de novo subject 
previously participated in Trial 331-10-234, they will retain their subject identification 
number from Trial 331-10-234.
3.10
Definition of Completed Subjects
The treatment period is defined as the time period during which subjects are evaluated for 
primary and secondary objectives of the trial irrespective of whether or not the subject 
actually consumed all doses of the IMP.  Subjects who are evaluated at the last scheduled 
visit during the treatment period will be defined as trial completers.  For purposes of this 
trial, subjects who complete Month 24 will be defined as trial completers.
3.11
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted on or before Month 24 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 (open-label brexpiprazole) to subjects.  
Accountability and compliance verification should be documented in the subject’s trial 
records.  Subjects must be counseled on the importance of taking the IMP as directed at 
all trial visits.  If poor compliance continues (eg, multiple missed doses resulting in less 
than 80% overall compliance), discontinuation of the subject from the trial should be 
considered.

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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 (or designee)  at 
the earliest possible time by telephone.  The investigator and sponsor will come as 
quickly as possible to a joint decision regarding the subject’s continuation in the trial.  
This decision will be documented by the investigator and the sponsor, and reviewed by 
the site monitor.
4
Restrictions
4.1
Prohibited Medications
All subjects must agree to abstain from prohibited medications during the trial.  
Prohibited medications for de novo subjects are listed in Table 4.1-1.  Other therapies 
prohibited prior to enrollment and during the trial are presented in Section 4.2.

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Table 4.1-1
Washout of Prohibited Medications Required Before the 
Trial - De Novo Subjects
Medication
Required Washout Prior to
Open-label Treatment Period
Antipsychotics
Oral aripiprazole
Oral antipsychotics (other than cariprazine and clozapine)
Depot or long-acting injectable antipsychotics
Cariprazine (Vraylar) and clozapine
14 days
7 days
5 × half-lives of the medication
6 months
Antidepressants
Fluoxetine or Symbyax
MAOIs
Citalopram and escitalopram
Venlafaxine and desvenlafaxine
All other antidepressants
28 daysa
14 days
8 days
3 days
14 days
Atomoxetine
Stimulants
28 days with the diagnosis of ADHD; 
minimum 5× half-life for subjects 
without diagnosis of ADHD
Mood stabilizers (ie, lithium or anticonvulsants)
7 days
Varenicline
5 days
Oral benzodiazepines used as rescue therapy during washoutb
Lorazepam, oxazepam, diazepam, or clonazepam
Other benzodiazepines
12 hours before scalesc
14 days
CYP2D6 inhibitors and CYP3A4 inhibitors and inducers 
(see Table 4.1-4)
14 days
MAOIs = monoamine oxidase inhibitors.
aExtension to the screening window is needed for washout, contact the medical director.
bUse of IM benzodiazepines and continual use of oral benzodiazepines are prohibited throughout the 
trial.  However, limited use of specific oral benzodiazepines is permitted during screening to treat 
agitation or insomnia (see Table 4.1-3).
cBenzodiazepines must not be administered within 12 hours prior to scheduled efficacy and safety 
assessments, including EPS scales.  Investigators are encouraged to delay scale administration until 
12 hours have elapsed, if at all possible.  However, if delaying administration of efficacy and safety 
scales is not feasible, the scales should still be administered and the use of benzodiazepine 
documented, including a notation of the drug name, dose, and time of administration on the eSource.
Table 4.1-2 lists all medications prohibited during the trial, including exceptions, where 
appropriate.

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Table 4.1-2
List of Medications Prohibited During the Trial
1.
All psychotropic agents including, but not limited to, the following:
a) Antipsychotics, including IR IM and depot or long-acting injectable formulations
b) Antidepressants (including MAOIs)
c) Symbyax or fluoxetine
d) Mood stabilizers (ie, lithium or anticonvulsants)
e) Benzodiazepines, except specific benzodiazepines when used as rescue therapya
f)
Stimulantsb
g) Other psychotropics (ie, atomoxetine)
2.
Ramelteon and other non-benzodiazepine sleep aids, except for limited use of specific 
medications for the treatment of insomniac
3.
Antihistamines (except for loratadine and cetirizine)
4.
Varenicline
5.
Other nutritional supplements and nonprescription herbal preparations with central nervous 
system effects (eg, St. John’s Wort, omega-3 fatty acids, kava extracts, GABA supplements) 
unless approved in advance by the medical monitor.
6.
CYP2D6 inhibitors and CYP3A4 inhibitors and inducers (see Table 4.1-4)
7.
Investigational agents
GABA = gamma-aminobutyric acid; IR = immediate-release.
aUse of IM benzodiazepines and continual use of oral benzodiazepines are prohibited throughout the 
trial.  However, limited use of specific oral benzodiazepines is allowed for the control of agitation or 
insomnia as shown in Table 4.1-3.
bOnly for de novo subjects: Stimulants with the diagnosis of ADHD and treatment with stimulants 
within 28 days prior to screening; otherwise washout of > 5× half-life for subjects without diagnosis 
of ADHD.
cNon-benzodiazepine sleep aids (ie, zolpidem, zaleplon, zopiclone, and eszopiclone only) are permitted 
for the treatment of insomnia, but not on the same day as administration of a benzodiazepine, 
regardless of indication.  For the non-benzodiazepine sleep aids, sites should only utilize one of the 
listed medications that are approved for this indication in their respective countries and the 
country-specific prescribing information is to be used to determine the maximum allowable daily 
dose for the treatment of insomnia.  Non-benzodiazepine sleep aids must not be administered within 
12 hours prior to scheduled efficacy and safety assessments, including EPS scales.  Investigators are 
encouraged to delay scale administration until 12 hours have elapsed, if at all possible.  However, if 
delaying administration of efficacy and safety scales is not feasible, the scales should still be 
administered and the use of the sleep aid documented, including a notation of the drug name, dose, 
and time of administration on the eSource.
During the course of the trial, oral benzodiazepine rescue medication can be used for 
symptomatic relief based on the investigator’s judgment with the exceptions and 
restrictions outlined in Table 4.1-3.  All concomitant medications should be prescribed 
according to the respective drug labels.  Subjects who are started on therapy should be 
observed closely for clinical worsening, suicidality, and unusual changes in behavior, and 
the risk of increased suicidality must be balanced with the clinical need.  

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Table 4.1-3
Oral Benzodiazepine Rescue Therapy During the Trial
Oral Benzodiazepine
Maximum Allowable Dose (mg/day)
Screening to Month 24 Visit
Lorazepama
3
Oxazepama
45
Diazepama,b
15
Clonazepama,b
1.5
aBenzodiazepines must not be administered within 12 hours prior to scheduled efficacy and safety 
assessments, including EPS scales.  Investigators are encouraged to delay scale administration until 
12 hours have elapsed, if at all possible.  However, if delaying administration of efficacy and safety 
scales is not feasible, the scales should still be administered and the use of benzodiazepine 
documented, including a notation of the drug name, dose, and time of administration on the eSource.
bIn countries or institutions where no short-acting benzodiazepines are commercially available, use of 
oral diazepam or oral clonazepam may be acceptable if prior authorization is obtained from the 
medical monitor.
Table 4.1-4 below provides a select list of CYP2D6 inhibitors and CYP3A4 inhibitors 
and inducers which are prohibited within 14 days of first dose of IMP and for the 
duration of the trial.  Except for episodic use of ibuprofen, acetaminophen/paracetamol, 
naproxen, or equivalent, clinical sites must apprise the medical monitor of the use of all 
over-the-counter medications including supplements and vitamins.  Any medication 
needing to be used in a chronic manner requires discussion with the medical monitor.
Table 4.1-4
Selected CYP2D6 Inhibitors and CYP3A4 Inhibitors and 
Inducers Prohibited During the Trial
Selected CYP2D6 Inhibitors
Celecoxib
Hydroxyzine
Chloroquine
Methadone
Chlorpheniramine
Moclobemide
Clemastine
Paroxetine
Clomipramine
Pyrilamine
Diphenhydramine
Quinidine
Fluoxetine
Terbinafine
Halofantrine
Tripelennamine
Selected CYP3A4 Inhibitors
Amiodarone
Fluvoxamine
Amprenavir
Indinavir
Aprepitant
Itraconazole
Chloramphenicol
Ketoconazole
Cimetidine
Nefazodone
Clarithromycin
Nelfinavir
Clotrimazole (if used orally)
Quinupristin/Dalfopristin 
Delavirdine
Ritonavir
Diltiazem
Saquinavir
Erythromycin
Troleandomycin

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Table 4.1-4
Selected CYP2D6 Inhibitors and CYP3A4 Inhibitors and 
Inducers Prohibited During the Trial
Selected CYP2D6 Inhibitors
Fluconazole
Verapamil
Selected CYP3A4 Inducers
Carbamazepine
Phenytoin
Dexamethasone
Primidone
Efavirenz
Rifampin
Nevirapine
St. John’s Wort
Oxcarbazepine
Troglitazone
Phenobarbital
4.2
Other Restrictions
4.2.1
Restricted Therapies and Precautions
Any history of electroconvulsive therapy is exclusionary.
Use of intramuscular (IM) benzodiazepines is prohibited throughout the trial.  Short-term 
use of specific oral benzodiazepines is allowed during the trial for the control of agitation 
or insomnia as shown in Table 4.1-3.  Short-acting benzodiazepines (ie, lorazepam or 
oxazepam) are to be used whenever possible.  In countries or institutions where no 
short-acting benzodiazepines are commercially available, use of oral diazepam or oral 
clonazepam may be acceptable if prior authorization is obtained from the medical 
monitor.  The investigator should contact the medical monitor to discuss any subject who 
requires frequent use of a benzodiazepine for agitation or insomnia beyond the first 
2 weeks of the trial.
Non-benzodiazepine sleep aids (ie, zolpidem, zaleplon, zopiclone, and eszopiclone only) 
are permitted for the treatment of insomnia, but not on the same day as administration of 
a benzodiazepine, regardless of indication.  For the non-benzodiazepine sleep aids, sites 
should only utilize 1 of the listed medications that are approved for this indication in their 
respective countries and the country-specific prescribing information is to be used to 
determine the maximum allowable daily dose for the treatment of insomnia.
Anticholinergics are permitted for the treatment of EPS up to a maximum of 4 mg/day 
benztropine or its equivalent and propranolol is permitted for akathisia or tremor up to a 
maximum of 60 mg/day.  Subjects receiving a stable dose of propranolol for other 
conditions at entry into Trial 331-10-236 may remain on propranolol.  Trial sites should 
only utilize medications that are approved for these indications in their respective 
countries.

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Benzodiazepines, non-benzodiazepine sleep aids, anticholinergics, and propranolol must 
not be administered within 12 hours prior to scheduled efficacy and safety assessments, 
including EPS scales.  Investigators are encouraged to delay scale administration until 
12 hours have elapsed, if at all possible.  However, if delaying administration of efficacy 
and safety scales is not feasible, the scales should still be administered and the use of the 
medication documented, including a notation of the drug name, dose, and time of 
administration on the eSource.
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 (minor surgery, dental surgery, orthopedic 
surgery, etc) that might require hospitalization or general anesthesia should be deferred 
until after the trial whenever clinically appropriate.
4.2.2.2
Restrictions
With the exception of inpatient group therapy and outpatient group therapy, new-onset 
psychotherapy is prohibited during the trial.  In other words, except for inpatient and 
outpatient group therapies, subjects may 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/baseline and 
commit to maintain their participation during the course of the trial at the current 
frequency or unless permission is obtained from the medical monitor.

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Consumption of grapefruit, grapefruit products, Seville oranges, or Seville orange 
products within 72 hours prior to dosing and during the trial is prohibited.  Subjects will 
be instructed to refrain from drinking alcoholic beverages or using illicit drugs during 
participation in the trial.  The investigator may request a blood or urine drug screen at any 
time during the trial if there is a suspicion of illicit drug use.
5
Reporting of Adverse Events
5.1
Definitions
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  AEs would not include information recorded as medical 
history at Trial 331-10-234 End of Treatment or pre-planned procedures for which the 
underlying condition was known and no worsening occurred.  An adverse reaction is any 
untoward and unintended response to an IMP related to any dose administered.
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE.  For the purpose of 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.
A serious adverse event (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.

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
Other medically significant events that, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above; eg, allergic 
bronchospasm requiring intensive treatment in an emergency room or home, 
blood dyscrasias or convulsions that do not result in hospitalization, or the 
development of drug dependency or drug abuse.
Nonserious adverse events are all AEs that do not meet the criteria for a “serious” AE.
If a subject is experiencing an EPS, the specific EPS must be indicated on the AE page of 
the 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 page of the 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 CRF 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 

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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 on 
the CRF.  The intensity of an adverse experience is defined as follows:
1 = Mild:
Discomfort noticed, but no disruption to daily activity.
2 = Moderate:
Discomfort sufficient to reduce or affect normal daily activity.
3 = Severe:
Inability to work or perform normal daily activity.
IMP Causality:  Assessment of causal relationship of an AE to the use of the IMP is 
defined as follows:
Related:  
There is a reasonable possibility of a temporal and causal 
relationship between the IMP and the AE.
Not Related:  
There is no temporal or causal relationship between the IMP and 
the AE.
5.2
Eliciting and Reporting Adverse Events
The investigator will periodically assess subjects for the occurrence of AEs.  To avoid 
bias in eliciting AEs, subjects should be asked the non-leading question:  “How have you 
felt since your last visit?”  All AEs (serious and nonserious) reported by the subject must 
be recorded on the source documents and CRFs provided by the sponsor.  Adverse event 
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 on the eSource.
Note:  Normal pregnancy is not an AE and should not be recorded on the eSource; 
guidelines outlined in Section 5.5 should be followed for pregnancy reporting.

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In addition, the sponsor must be notified immediately by telephone, fax, or e-mail of any 
IREs according to the procedure outlined below, in Section 5.3.  Special attention should 
be paid to recording hospitalization and concomitant medications.
5.3
Immediately Reportable Events 
The investigator must immediately report after either the investigator or site personnel 
become aware of any SAE, potential serious hepatotoxicity, or confirmed pregnancy, by 
telephone, fax, or e-mail to the sponsor using the contact information on the cover page 
of this protocol.  An IRE form must be completed and sent by e-mail, fax, or overnight 
courier to the sponsor.  (Please note that the IRE form is NOT the AE 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 
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 on the eSource.
5.5
Pregnancy
For females and for men who are sexually active, there must be a documented agreement 
that the subject and 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.

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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 sign an informed consent form stating that the above-
mentioned risk factors and the consequences were discussed with her.
A urine or serum pregnancy test for human chorionic gonadotropin (hCG) will be 
performed at screening on all females.  If a urine test is performed and is positive, the 
investigator will follow up with a confirmatory serum test.
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. 

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Protocol-required procedures for trial discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies).  Other appropriate 
pregnancy follow-up procedures should be considered, if indicated.  In addition, the 
investigator must report to the sponsor, on appropriate Pregnancy Surveillance Form(s), 
follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome.  Infants will be followed for a minimum of 6 months from the date of 
birth.  Local regulatory requirements must be followed for follow-up and reporting on 
pregnancy cases and infants.
5.6
Procedure for Breaking the Blind
Not applicable; this is an open-label trial.
5.7
Follow-up of Adverse Events 
For this trial, information on AEs will be followed for up to 21 (± 2) days after the last 
dose of IMP has been administered.
5.7.1
Follow-up of Nonserious Adverse Events
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE eSource with the current status noted.  All nonserious events that are ongoing at the 
last scheduled contact will be recorded as ongoing on the eSource.  For any AE having 
been identified throughout the trial, during analysis, additional relevant medical history 
information may be requested to further ascertain causality (including, but not limited to, 
information such as risk-related behavior, family history and occupation).
5.7.2
Follow-up of Serious Adverse Events
This trial requires that subjects be actively monitored for SAEs up to 21 (± 2) days after 
the last dose of IMP is administered.
Serious AEs that are identified or ongoing at the last scheduled contact must be 
recorded on the AE CRF page and reported to the sponsor according to the reporting 
procedures outlined in Section 5.3.  This may include unresolved previously reported 
SAEs, or new SAEs.  The investigator will follow SAEs until the events are resolved, 
stabilized, or the subject is lost to follow-up.  Resolution means that the subject has 
returned to the baseline state of health and stabilized means that the investigator does not 
expect any further improvement or worsening of the subject’s condition.  The 
investigator will continue to report any significant follow-up information to the sponsor 
up to the point the event has been resolved.

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5.7.3
Follow-up and Reporting of Serious Adverse Events Occurring 
after Last Scheduled Contact
Any new SAEs reported by the subject to the investigator that occur after the last 
scheduled contact, and are determined by the investigator to be reasonably associated 
with the use of the IMP, should be reported to the sponsor.  This may include SAEs that 
are captured on follow-up telephone contact or at any other time point after the defined 
trial period (ie, up to last scheduled contact).  The investigator should follow SAEs 
identified after the last scheduled contact until the events are resolved, stabilized, or the 
subject is lost to follow-up.  The investigator should continue to report any significant 
follow-up information to the sponsor up to the point the event has been resolved or 
stabilized.
6
Pharmacokinetic Analysis
Pharmacokinetics will not be assessed in this trial.
7
Statistical Analysis
7.1
Sample Size
The sample size is not based on statistical power considerations.  Approximately 
350 subjects are anticipated to be enrolled with the expectation that at least 
100 adolescent subjects with schizophrenia will complete a minimum of 1 year of 
exposure to open-label brexpiprazole.
7.2
Datasets for Analysis
The following analysis samples are defined for this trial:
Enrolled Sample:  All subjects who sign an informed consent form for the trial.
Safety Sample:  All subjects who receive at least 1 dose of brexpiprazole.
Efficacy Sample:  All subjects who receive at least 1 dose of brexpiprazole and have at 
least 1 post baseline efficacy evaluation.

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7.3
Primary and Secondary Endpoint Analyses
7.3.1
Primary Endpoint Analysis
The primary objective of this trial is to evaluate safety and tolerability.  The primary 
endpoints are the frequency and severity of AEs, serious TEAEs (clinical and laboratory), 
and discontinuation from trial due to AEs.  As there is no primary efficacy objective, 
there is no defined efficacy endpoint.
7.3.2
Secondary Endpoint Analysis
Descriptive statistics will be provided for mean change from baseline in PANSS Total 
Score, PANSS Positive and Negative Subscales, and CGAS scores for subjects with 
schizophrenia.  The analysis will be carried out on the Efficacy Sample.  Descriptive 
statistics will be summarized at each trial visit using the observed cases (OC) data set and 
at the last visit using the last observation carried forward (LOCF) data set.
7.4
Analysis of Demographic and Baseline Characteristics
Baseline demographic characteristics including age, race, ethnicity, gender, weight, 
height, and BMI will be summarized by descriptive statistics (frequency, mean, median, 
standard deviation, maximum, minimum, and percentage when applicable).
7.5
Safety Analysis
7.5.1
Adverse Events
All AEs will be coded by system organ class and Medical Dictionary for Regulatory 
Activities (MedDRA [most current version]) preferred term.  The incidence of the 
following events will be summarized for the Safety Sample:

TEAEs

TEAEs by severity

TEAEs potentially causally related to the IMP

TEAEs with an outcome of death

Serious TEAEs

TEAEs leading to discontinuation of the IMP 
In addition, a Kaplan-Meier curve will be plotted for the time to discontinuation due to 
AEs.

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7.5.2
Clinical Laboratory Data
The incidence of potentially clinically significant values for routine laboratory tests and 
of prolactin concentrations above the upper limit of normal will be calculated for the 
Safety Sample.
In addition to the evaluation of potentially clinically significant values, mean change 
from baseline in clinical laboratory values will be calculated.  Results will be summarized 
by visit.
7.5.3
Physical Examination and Vital Signs Data
The incidence of potentially clinically significant vital sign abnormalities will be 
calculated.  Body weight changes will be evaluated by calculating the mean change from 
baseline and by tabulating the incidence of clinically significant changes in body weight, 
defined as ≥ 7% increase or decrease from baseline.  Mean changes in BMI, waist 
circumference and z-scores for height and body weight from baseline will also be 
summarized by visit.  Physical examination findings will be listed by subject.
7.5.4
Electrocardiogram Data
Mean change from baseline and the incidence of clinically significant changes will be 
calculated for ECG parameters for the Safety Sample.
For the analysis of QT and QTc, data from 3 consecutive complexes (representing 
3 consecutive heart beats) will be measured to determine average values.  The following 
QT corrections will be used for reporting purposes in the clinical study report:
1) QTcF is the length of the QT interval corrected for heart rate by the Fridericia 
formula:  QTcF = QT/(RR)0.33
2) QTcN is the length of the QT interval corrected for heart rate by the FDA 
Neuropharm Division formula:  QTcN = QT/(RR)0.37
Results will be summarized by visit.
7.5.5
Other Safety Data
7.5.5.1
Special Pediatric Safety Assessments
Some special pediatric safety assessments will be performed in this trial.  They include 
comprehensive psychotropic side effects as assessed by the UKU side effect rating scale, 
and cognitive adverse effects as assessed by NY-AACENT.

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Descriptive statistics will be provided for the frequency of symptom items recorded in the 
Safety Sample.  In addition, for symptoms recorded in NY-AACENT, a total score at any 
level of present, attribution, severity or impairment may be calculated.  The total score 
and its change from baseline at each visit will be summarized using descriptive statistics 
for the Safety Sample by disease under study.
7.5.5.2
Extrapyramidal Symptoms
Descriptive statistics will be provided for the mean change from baseline to end of period 
in SAS, AIMS, and BARS scores for the Safety Sample.  Results will be summarized by 
visit.
7.5.5.3
Suicidality
The incidence of suicidality, suicidal behavior and suicidal ideation will be calculated 
from the potential suicide events recorded on the C-SSRS.  Results will be summarized 
by visit and presented for all subjects in the Safety Sample.
7.5.5.4
Tanner Staging
Shift tables will be provided for the Tanner Staging scores.
8
Management of Investigational Medicinal Product
For full details on IMP management, please refer to the brexpiprazole IB.11 
8.1
Packaging and Labeling
The IMP will be provided to the investigator(s) by the sponsor or designated agent.  The 
IMP (open-label brexpiprazole) will be supplied in child resistant high density 
polyethylene bottles, containing 18 tablets for 0.5 mg strength and 34 tablets for the 1, 2, 
3, and 4 mg strengths.  Each bottle used in the dosing period will be labeled to clearly 
disclose the subject identification (ID), compound ID, trial number, sponsor’s name and 
address, instructions for use, route of administration, appropriate precautionary 
statements, and other information required by local regulatory authorities.  
8.2
Storage
The IMP will be stored in a securely locked cabinet or enclosure.  Access will be limited 
to investigators and their designees.  Neither investigators nor any designees may provide 
IMP to any subject not participating in this protocol.

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Brexpiprazole 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 received, 
dispensed, administered, and returned.
8.4
Returns and Destruction
Upon completion or termination of the trial, all used IMP containers, unused IMP, and 
partially used IMP must be returned to the sponsor or a designated agent, or destroyed at 
the trial site(s). The IMP may only be destroyed by the trial site(s). 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 with 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)

Bottle defects (eg, under/over-fill, no safety seal)

Vial defects

Product defect (eg, odor, chipped, broken, embossing illegible)

Loss or theft of product

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8.5.1
Eliciting and Reporting Product Quality Complaints
The investigator or designee must record all PQCs identified through any means from the 
receipt of the IMP from the sponsor, or sponsor’s designee, through and including 
reconciliation and up to destruction, including subject dosing.  The investigator or 
designee must notify the sponsor (or sponsor’s designee) by e-mail 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
IMP-PQC@otsuka-us.com.
Identification of a PQC by the subject should be reported to the site investigator, who 
should then follow the reporting mechanism above.
8.5.2
Information Required for Reporting Purposes

Description of complaint

Reporter identification (eg, subject, investigator, site)

Reporter contact information (eg, address, phone 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 compliant sample is available for return.  If 
complaint sample is available for return, return it in the product retrieval package, which 
will be provided by the sponsor.
It must be documented in the site accountability record that a complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation.
8.5.4
Assessment/Evaluation
Assessment and evaluation of PQCs will be handled by the sponsor.

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9
Records Management
9.1
Source Documents
Source documents are defined as the results of original observations and activities of a 
clinical investigation.  Source documents will include but are not limited to progress 
notes, electronic data, screening logs, and recorded data from automated instruments.  All 
source documents pertaining to this trial will be maintained by the investigators and made 
available for direct inspection by authorized persons.
Investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, 
and regulatory inspection(s) by providing direct access to source data/documents by 
authorized persons as defined in the ICF.  In all cases, subject confidentiality must be 
maintained in accordance with local regulatory requirements.
9.2
Data Collection
Source document and source data will be captured electronically in this trial, and will 
meet the same fundamental elements of data quality (eg, attributable, legible, 
contemporaneous, original, and accurate) as paper records.  These data will be collected 
into a system that is fully validated.  Changes to the data will be captured by an automatic 
audit trail.
The trial site will be given a tablet to directly record subject data and clinical 
observations on electronic forms.  Designated trial site staff will not be given access to 
the system until they have been appropriately trained.  Information to be originally 
captured and reviewed electronically shall include details of the subject visit and the 
protocol-required assessments performed as a part of these visits, medical history, AEs, 
and concomitant medications.  Because this trial is using an electronic source record as 
the original point of data capture, there is no additional data entry step for the site for data 
collected directly into the application - rather, the electronic source record directly 
populates the trial database.
Some data may be captured via paper and then entered into the eSource system.  These 
and any other data treated in this manner will be source data verified by the trial clinical 
research associate, and the location of the source data (ie, eSource, paper, or a local 
electronic system) will be documented before the trial start.  Any changes to information 
in paper source documents will be initialed and dated on the day the change is made by a 
trial site staff member authorized to make the change.  Changes will be made by striking 
a single line through erroneous data (so as not to obliterate the original data), and clearly 

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entering the correct data (eg, wrong data right data).  If the reason for the change is not 
apparent, a brief explanation for the change will be written in the source documentation 
by the clinician.
Another exception will be safety laboratory data, where the official source documentation 
will be considered the report issued by the analyzing laboratory.
Remote monitoring of the original electronic source record will take place, however 
on-site monitoring inspections will continue to take place in order to review data entry 
source documentation directly captured on paper and transcribed into the system, to 
ensure protocol adherence, to assess site operational capabilities and to perform other 
monitoring activities that cannot be performed remotely.  
At the end of the trial, the investigator must certify that the data entered into the eSource 
application are complete and accurate.  After database lock, the investigator will receive 
an electronic copy of the subject data. 
9.3
File Management at the Trial Site
The investigator will ensure that the trial site file is maintained in accordance with 
Section 8 of the ICH GCP Guideline E6 and as required by applicable local regulations.  
The investigator/institution will take measures to prevent accidental or premature 
destruction of these documents.
9.4
Records Retention at the Trial Site
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.  
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 

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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 (or designee’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 
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 

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care in protecting subject privacy.  To this end, a subject number and subject 
identification code will be used to identify each subject.
Financial aspects, subject insurance and the publication policy for the trial will be 
documented in the agreement between the sponsor and the investigator.
12
Confidentiality
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission.  Subject confidentiality requirements of the region(s) where the trial 
is conducted will be met.  However, authorized regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy the records, 
consistent with local requirements.  All IMPs, subject bodily fluids, and 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 
timelines.  The sponsor will submit protocol amendments to the applicable regulatory 
agencies within local applicable timelines.

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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.

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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;374:635-645.
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;65:267-272.
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;22:1085-1096.
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;65:57-61.
7
Hollis C. Adult outcomes of child- and adolescent-onset schizophrenia: Diagnostic 
stability and predictive validity.  Am J Psychiatry. 2000;157:1652-1659.
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. Schiz Bull. 2000;26:801-816.
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;49:583-594.
11 Brexpiprazole (OPC-34712) Investigator's Brochure, Otsuka Pharmaceutical 
Development & Commercialization, Inc.  Edition 12, 18 Aug 2016.
12 Correll CU. From receptor pharmacology to improved outcomes:  individualising the 
selection, dosing, and switching of antipsychotics.  Eur Psychiatry. 2010;25(Suppl 
2):S12-21.
13 Kaufman J, Birmaher B, Axelson S, Perepletchkova F,  Brent D, Ryan N. K-SADS-
PL DSM-5. November 2016. Pittsburgh, PA:  University of Pittsburgh, Department 
of Psychiatry; 2016.
14 International Council for Harmonisation (ICH) [homepage on the Internet].  E6:  
Good Clinical Practice:  Consolidated Guideline [finalized 1996 May, corrected 1996 
Jun; cited 2015 May 07].  Available from:  
http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html.

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15 Kay SR, Opler LA, Fiszbein A.  Positive and Negative Syndrome Scale (PANSS) 
Rating Criteria. North Tonawanda, NY: Multi-Health Systems; 1999.
16 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;40:1228-1231.
17 Guy W. ECDEU Assessment Manual for Psychopharmacology.  US Department of 
Health, Education, and Welfare publication (ADM) 76-338.  Rockville, MD:  
National Institute of Mental Health; 1976.
18 The Practical Guide: Identification, evaluation, and treatment of overweight and 
obesity in adults.  Developed by National Institutes of Health National Heart, Lung 
and Blood Institute.  North American Association for the Study of Obesity.  NIH 
Publication Number 00-4084, October 2000.
19 Simpson GM, Angus JW.  A rating scale for extrapyramidal side effects.  Acta 
Psychiatr Scand Suppl. 1970;212(Suppl 44):S11-19.
20 Barnes TR.  A rating scale for drug-induced akathisia. Br J Psychiatry. 
1989;154:672-676.

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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).

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Appendix 2
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
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

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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 ≥ 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.

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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 (eg, Day 
1 predose); 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
None collected for this trial. 
Pharmacogenomics Sample
None collected for this trial. 

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